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Hereditary Neuropathies  


... neuropathy, hereditary motor neuropathy, and hereditary sensory and autonomic neuropathy. The most common type is Charcot-Marie- ... Certain types of hereditary neuropathies can affect the autonomic nerves, resulting in impaired sweating, postural hypotension, or ...


Detection of hereditary motor sensory neuropathy type I in childhood.  

PubMed Central

Clinical signs and slowed motor nerve conduction velocities were found in 17 of 36 children under 10 years of age who had one parent with hereditary motor sensory neuropathy type I (HMSN I). Four children had slowed conduction velocities at one year or less. Clinical signs were subtle and included pes planus, distal foot wasting, weakness of ankle eversion and dorsiflexion and areflexia. HMSN I can be detected reliably in children, even before one year of age.

Feasby, T E; Hahn, A F; Bolton, C F; Brown, W F; Koopman, W J



A case of hereditary sensory autonomic neuropathy type IV  

PubMed Central

Hereditary sensory autonomic neuropathy type IV (HSAN -IV), also known as congenital insensitivity to pain with anhidrosis, is a very rare condition that presents in infancy with anhidrosis, absence of pain sensation and self -mutilation. Developmental delay and mental retardation are usually present. Ultrastructural study of the peripheral nerves demonstrates loss of the unmyelinated and small myelinated fibers. We here report a 8 year -old boy with HSAN IV with typical clinical features where the diagnosis was supported by nerve biopsy findings. However, our case was unusual since mental development was normal.

Prashanth, G. P.; Kamate, Mahesh



Focal posterior interosseous neuropathy in the presence of hereditary motor and sensory neuropathy, type I.  


A 30-year-old male with hereditary motor and sensory neuropathy, type I (HMSN I), presented with asymmetric weakness of finger extension and radial deviation with left wrist extension, previously felt to be a manifestation of the peripheral neuropathy. Nerve conduction studies confirmed HMSN I; however, needle EMG revealed marked, ongoing axonal loss in muscles innervated by the left posterior interosseous nerve (PIN) only. At surgery there was focal fusiform swelling in the PIN at exit from the supinator muscle, compatible with localized hypertrophic neuropathy, which has not been reported before in HMSN I. A concomitant focal mononeuropathy should be considered in cases of hereditary neuropathy with marked asymmetry of weakness. PMID:8618563

Carter, G T; Kilmer, D D; Szabo, R M; McDonald, C M



Autosomal recessive forms of hereditary motor and sensory neuropathy.  

PubMed Central

Six families are described with hereditary motor and sensory neuropathy (HMSN) of probable autosomal recessive inheritance. Four of these were classified as HMSN type I and two as type II. The consanguinity rate in this series was high, suggesting that these recessive genes are rare. In comparison with the dominantly inherited forms of these disorders, the mean age of onset was significantly earlier for the type II cases but did not differ for the type I patients. Motor nerve conduction velocity was significantly less for the type I cases but did not differ for the type II form. The recessive type I cases tended to show a greater incidence of weakness, ataxia, tendon areflexia and scoliosis than in the dominant form. The importance of differentiating such cases from Friedreich's ataxia is emphasised. Images

Harding, A E; Thomas, P K



Foot deformities in children with hereditary motor and sensory neuropathy.  


The authors reviewed 104 feet from 52 consecutive children with hereditary motor and sensory neuropathy (HMSN) seen for the first time in clinics in two pediatric institutions between 1996 and 2003. Sixty-nine feet had a cavovarus deformity, 23 feet had a planovalgus deformity, and 12 feet had no significant deformity. All cases with deformity had bilateral involvement, and of those with deformity, only 45% had symmetric involvement. In HMSN I, III, IV, V, and X-linked HMSN, cavovarus was the most common deformity. However, in HMSN II, 55% of feet had a planovalgus deformity, 36% had a cavovarus deformity, and 9% had no deformity. In all, 43 feet underwent surgery of some type. Surgery, and in particularly combined bony and soft tissue procedures, was performed much more frequently on feet with cavovarus than planovalgus deformities. Soft tissue surgery alone was performed at an earlier age than combined bony and soft tissue surgery. PMID:15718910

Wines, Andrew P; Chen, Darren; Lynch, B; Stephens, Michael M


Genes for Hereditary Sensory and Autonomic Neuropathies: A Genotype-Phenotype Correlation  

ERIC Educational Resources Information Center

|Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant ("SPTLC1"…

Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent



Cardiac arrest after anesthetic management in a patient with hereditary sensory autonomic neuropathy type IV.  


Hereditary sensory autonomic neuropathy type IV is a rare disorder with an autosomal recessive transmission and characterized by self-mutilation due to a lack in pain and heat sensation. Recurrent hyperpyrexia and anhydrosis are seen in patients as a result of a lack of sweat gland innervation. Self-mutilation and insensitivity to pain result in orthopedic complications and patients undergone recurrent surgical interventions with anesthesia. However, these patients are prone to perioperative complications such as hyperthermia, hypothermia, and cardiac complications like bradycardia and hypotension. We report a 5-year-old boy with hereditary sensory autonomic neuropathy type IV, developing hyperpyrexia and cardiac arrest after anesthesia. PMID:21655028

Ergül, Yakup; Ekici, Bari?; Keskin, Sabiha



Cardiac arrest after anesthetic management in a patient with hereditary sensory autonomic neuropathy type IV  

PubMed Central

Hereditary sensory autonomic neuropathy type IV is a rare disorder with an autosomal recessive transmission and characterized by self-mutilation due to a lack in pain and heat sensation. Recurrent hyperpyrexia and anhydrosis are seen in patients as a result of a lack of sweat gland innervation. Self-mutilation and insensitivity to pain result in orthopedic complications and patients undergone recurrent surgical interventions with anesthesia. However, these patients are prone to perioperative complications such as hyperthermia, hypothermia, and cardiac complications like bradycardia and hypotension. We report a 5-year-old boy with hereditary sensory autonomic neuropathy type IV, developing hyperpyrexia and cardiac arrest after anesthesia.

Ergul, Yakup; Ekici, Baris; Keskin, Sabiha



Hereditary motor and sensory neuropathy Lom type in an Italian Gypsy family  

Microsoft Academic Search

We describe a form of hereditary motor and sensory neuropathy (HMSN) affecting four siblings in an Italian family of Gypsy ethnic origin with both clinical and pathological findings very reminiscent of the HMSN Lom type (HMSNL), recently described in a group of Bulgarian Gypsies. Genetic analysis demonstrated linkage to chromosome 8q24 and conserved haplotypes in the HMSNL region, thus confirming

L Merlini; M Villanova; P Sabatelli; A Trogu; A Malandrini; P Yanakiev; N. M Maraldi; L Kalaydjieva



Genetics Home Reference: Hereditary sensory and autonomic neuropathy type II  


... that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, ... the sensations of pain, temperature, and touch (sensory neurons). The mutations involved in HSAN2A result in an ...


Genetics Home Reference: Hereditary sensory and autonomic neuropathy type IE  


... HSAN IE is characterized by impaired function of nerve cells called sensory neurons, which transmit information about sensations ... not well understood, the enzyme may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of ...


Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings  

Microsoft Academic Search

Summary A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town where the initial cases were found. It was subsequently identified in other gypsy communities. The disorder, which is of autosomal recessive inheritance, was mapped to chromosome 8q24. It begins consistently in the first decade of life with gait

Luba Kalaydjieva; Amelia Nikolova; Ivo Turnev; Julia Petrova; Anna Hristova; Boryana Ishpekova; Iva Petkova; Alexander Shmarov; Stella Stancheva; L. Middleton; Luciano Merlini; A. Trogu; J. R. Muddle; R. H. M. King; P. K. Thomas



Autosomal recessive hereditary motor and sensory neuropathy with mental retardation, optic atrophy and pyramidal signs.  

PubMed Central

A syndrome is described, consisting of severe neurogenic distal wasting, generalised muscle weakness, absent ankle reflexes, pyramidal signs, mental retardation, optic atrophy and retinal colloid bodies. A sural nerve biopsy from one case showed loss of nerve fibres suggesting the diagnosis of hereditary motor and sensory neuropathy. Progression of the disorder was very slow, all patients still being able to walk more than 20 years after the onset. The persons affected with this syndrome were two brothers and their female cousin from a large Gujerati pedigree where consanguinity was high. Autosomal recessive inheritance is therefore suggested. Images

MacDermot, K D; Walker, R W



Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation  

PubMed Central

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype–phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis.

Rotthier, Annelies; Baets, Jonathan; Vriendt, Els De; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter



Central motor conduction in a family with hereditary motor and sensory neuropathy with pyramidal signs (HMSN V)  

Microsoft Academic Search

Two generations of a family affected by hereditary motor and sensory neuropathy with pyramidal signs (HMSN V) were clinically and electrophysiologically examined. Apart from electroneurographic studies, the central motor conduction (CMC) to arm and leg muscles was assessed using magnetic transcranial motor cortex stimulation. Abnormal CMC was confined to the clinically affected members, with the exception of an unaffected subject

A Schnider; C W Hess; S Koppi



Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: A randomized clinical trial  

Microsoft Academic Search

A randomized clinical trial on the effects of strength training was performed in myotonic dystrophy (MyD) patients and patients with hereditary motor and sensory neuropathy (HMSN). Training and most measurement tools involved the proximal lower extremity muscles. The participants trained 3 times a week for 24 weeks with weights adapted to their force. Strength was evaluated by isokinetically measured knee

Eline Lindeman; Pieter Leffers; Frank Spaans; Jan Drukker; Jos Reulen; Maria Kerckhoffs; Albere Köke



Ultralate cerebral potentials in a patient with hereditary motor and sensory neuropathy type I indicate preserved C-fibre function  

Microsoft Academic Search

Late and ultralate cerebral potentials in response to cutaneous heat (CO2 laser pulses) and electrical nerve stimuli were studied in a patient with hereditary motor and sensory neuropathy type I who showed severe impairment of myelinated nerve fibre function. Cerebral potentials in response to electrical stimuli were absent (tibial nerve) or small (median nerve). With the laser pulses applied to

J Lankers; A Frieling; K Kunze; B Bromm



A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.  


A boy with recurrent pyrexial episodes from early life sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons, the pattern of type V hereditary sensory and autonomic neuropathy (HSAN V). DNA analysis showed that he was homozygous for a mutation in the NTRK1/high-affinity nerve growth factor (TrkA) gene, his parents being heterozygous. Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic. PMID:11310631

Houlden, H; King, R H; Hashemi-Nejad, A; Wood, N W; Mathias, C J; Reilly, M; Thomas, P K



Pulmonary function in patients with hereditary motor and sensory neuropathy: a comparison of patients with and without spinal deformity.  


We assessed pulmonary function in hereditary motor and sensory neuropathy. Fourteen neuropathy patients without spinal deformity (group 1), 14 with spinal deformity (group 2), and 16 individuals with idiopathic spinal deformity (group 3) matched to group 2 for age, height and Cobb angle, were included. Hereditary motor and sensory neuropathy severity was measured with Charcot-Marie-Tooth Neuropathy Score. All participants exhibited mild decrease in maximal inspiratory pressure at the mouth. One-way analysis of variance yielded significant main effects for lung volumes - slow vital capacity, forced expiratory volume in 1s, and total lung capacity (p's<.01), attributable to greater volumes in group 1 compared to groups with spinal deformity - and transfer factor for carbon monoxide (p=.013), reflecting differences between groups 1 vs. 2. Slow vital capacity and total lung capacity correlated with maximal inspiratory pressure at the mouth in group 2, whereas slow vital capacity correlated with muscle work in group 3 (p's<.05). Decreased lung volume may be due to impaired respiratory muscle strength in hereditary motor and sensory neuropathy with spinal deformity and due to spinal deformity in idiopathic patients. PMID:22727686

Horacek, Ondrej; Chlumsky, Jan; Mazanec, Radim; Kolar, Pavel; Andel, Ross; Kobesova, Alena



Epidemiology of hereditary sensory and autonomic neuropathy type IV and V in Japan.  


Hereditary sensory and autonomic neuropathy (HASN) refers to a group of rare congenital disorders characterized by loss of pain sensation and other sensory or autonomic abnormalities. Among them, a relatively large proportion of patients with HSAN type IV, which is accompanied by anhidrosis and intellectual disability, are reported from Israel and Japan. HSAN type V, with normal sweating and mental development, is rarely reported in Japan. In 2009, we founded a research group for congenital insensitivity to pain and performed the first epidemiological survey of HSAN types IV and V in Japan. Questionnaires were sent to a total of 3,488 certified training institutions of five nationwide medical societies comprising pediatricians, neurologists, orthopedic surgeons, and dentists. Answers were obtained from 1,610 institutions, and 192 HSAN patients (152 with type IV and 28 with type V) were reported from 105 institutions. After excluding duplicated patients, we identified a total of 62 current, 36 past, and five deceased patients for HSAN-IV, and a total of 14 current, 13 past, and 0 deceased patients for HSAN-V. Using these figures, we estimated that the number of Japanese patients with HSAN types IV and V as 130-210 and 30-60 patients, respectively. We identified no gender differences, and patients with a family history of the disorder were limited to affected siblings in both conditions. Most patients with HSAN-IV were 5-40 years of age, whereas half of the patients with HSAN-V were 40 years or older. PMID:23495212

Haga, Nobuhiko; Kubota, Masaya; Miwa, Zenzo



[Hereditary sensory and autonomic neuropathy type IV: a report on two cases].  


Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The absence of urticarial reaction to intradermal injection of histamine is a sign of great diagnostic value, but this is common to all types of HSAN. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. Malignant hyperthermia and sepsis are major causes of mortality. We relate the first observations of two Tunisian children with genetically confirmed HSAN IV. Our goal is to review the clinical aspects of this mysterious neuropathy and to emphasize the peculiarities of its management. These two patients are brothers from 1st-degree consanguineous parents (cousins) with no particular medical history. The 1st patient, the family's 1st child, presented in the 1st h of life with hypotonia and persistent fever, which was refractory to antipyretics. At the age of 8 months, the patient presented recurrent febrile seizures and developed significant self-mutilations of the fingers and tongue. He died 3 months later in a context of multivisceral failure from sepsis and malignant hyperthermia. The 2nd patient, currently aged 4 years, was born after a normal sister. He consulted in the neonatal period for a high fever. The diagnosis of HSAN IV was rapidly suspected and genetically confirmed. In fact, this patient is homozygous for the NTRK1 gene, whereas his sister and both parents are heterozygous. Special predispositions have been taken to improve the course of the disease such as air conditioning to control hyperthermia, a dental tray to reduce the injuries resulting from self-mutilation, regular moistening of the eyes to avoid corneal drying, and chlorpromazine to control hyperactivity and reduce injuries. The good progression with all these predispositions and others underlines the importance of appropriate multidisciplinary management and close monitoring of patients suffering from HSAN IV, especially during the first 3 years of life. Indeed, mortality, behavioral disorders, and mental retardation significantly decrease after this age. New curative treatments are expected in the next decade. PMID:21397470

Achouri, E; Gribaa, M; Bouguila, J; Haddad, S; Souayeh, N; Saad, A; Essoussi, A S



Central motor conduction in a family with hereditary motor and sensory neuropathy with pyramidal signs (HMSN V).  

PubMed Central

Two generations of a family affected by hereditary motor and sensory neuropathy with pyramidal signs (HMSN V) were clinically and electrophysiologically examined. Apart from electroneurographic studies, the central motor conduction (CMC) to arm and leg muscles was assessed using magnetic transcranial motor cortex stimulation. Abnormal CMC was confined to the clinically affected members, with the exception of an unaffected subject who had a diminished but normal latency response in a leg. The typical pattern was a significant diminution of the compound muscle action potential from the tibialis anterior and a moderately prolonged cortico-muscular conduction time (CoMCT) to this muscle.

Schnider, A; Hess, C W; Koppi, S



Central motor conduction in a family with hereditary motor and sensory neuropathy with pyramidal signs (HMSN V).  


Two generations of a family affected by hereditary motor and sensory neuropathy with pyramidal signs (HMSN V) were clinically and electrophysiologically examined. Apart from electroneurographic studies, the central motor conduction (CMC) to arm and leg muscles was assessed using magnetic transcranial motor cortex stimulation. Abnormal CMC was confined to the clinically affected members, with the exception of an unaffected subject who had a diminished but normal latency response in a leg. The typical pattern was a significant diminution of the compound muscle action potential from the tibialis anterior and a moderately prolonged cortico-muscular conduction time (CoMCT) to this muscle. PMID:1652623

Schnider, A; Hess, C W; Koppi, S



Growth Hormone Replacement in an Adult with Mild Growth Hormone Deficiency and Hereditary Motor and Sensory Neuropathy: Growth Hormone Restores Independent Mobility  

Microsoft Academic Search

We present the case of an adult patient with growth hormone (GH) insufficiency and hereditary motor and sensory neuropathy type 1. Stopping GH replacement at the attainment of final height was associated with a marked reduction in power and mobility, resulting in the patient becoming wheelchair bound. GH replacement was assessed in a double-blind placebo-controlled trial. During the GH replacement

Catherine A. Lissett; Andrew A. Toogood; Mohammed Didi; Stephen M. Shalet



KIF1A, an Axonal Transporter of Synaptic Vesicles, Is Mutated in Hereditary Sensory and Autonomic Neuropathy Type 2  

PubMed Central

Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.

Riviere, Jean-Baptiste; Ramalingam, Siriram; Lavastre, Valerie; Shekarabi, Masoud; Holbert, Sebastien; Lafontaine, Julie; Srour, Myriam; Merner, Nancy; Rochefort, Daniel; Hince, Pascale; Gaudet, Rebecca; Mes-Masson, Anne-Marie; Baets, Jonathan; Houlden, Henry; Brais, Bernard; Nicholson, Garth A.; Van Esch, Hilde; Nafissi, Shahriar; De Jonghe, Peter; Reilly, Mary M.; Timmerman, Vincent; Dion, Patrick A.; Rouleau, Guy A.



KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.  


Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system. PMID:21820098

Rivière, Jean-Baptiste; Ramalingam, Siriram; Lavastre, Valérie; Shekarabi, Masoud; Holbert, Sébastien; Lafontaine, Julie; Srour, Myriam; Merner, Nancy; Rochefort, Daniel; Hince, Pascale; Gaudet, Rébecca; Mes-Masson, Anne-Marie; Baets, Jonathan; Houlden, Henry; Brais, Bernard; Nicholson, Garth A; Van Esch, Hilde; Nafissi, Shahriar; De Jonghe, Peter; Reilly, Mary M; Timmerman, Vincent; Dion, Patrick A; Rouleau, Guy A



Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type I).  

PubMed Central

The segregation patterns of DNA markers from the pericentromeric regions of chromosomes 1 and 17 were studied in seven pedigrees segregating an autosomal dominant gene for Charcot-Marie-Tooth neuropathy type I (CMT I; hereditary motor and sensory neuropathy I). A multilocus analysis with four markers (pMCR-3, pMUC10, FY, and pMLAJ1) spanning the pericentromeric region of chromosome 1 excluded the CMT I gene from this region in six pedigrees but gave some evidence for linkage to the region of Duffy in one pedigree. Linkage of the CMT I gene to markers in the pericentromeric region of chromosome 17 (markers pA10-41, pEW301, p3.6, and pTH17.19) was established; however, in these seven pedigrees homogeneity analysis with chromosome 17 markers detected significant genetic heterogeneity. This analysis suggested that three of the seven pedigrees are not linked to this same region. Overall, two of the seven CMT I pedigrees were not linked to markers tested from chromosomes 1 or 17. These results confirm genetic heterogeneity in CMT I and implicate the existence of a third autosomal locus, in addition to a locus on chromosome 17, and a probable locus on chromosome 1. This evidence of etiological heterogeneity, supported by statistical tests, will have to be taken into consideration when fine-structure genetic maps of the regions around CMT I are constructed.

Chance, P F; Bird, T D; O'Connell, P; Lipe, H; Lalouel, J M; Leppert, M



Diagnosis of hereditary neuropathies in adult patients  

Microsoft Academic Search

.   This paper reviews the clinical diagnostic approach to hereditary neuropathies in adults by analysing: elements that point\\u000a to a neuropathy of inherited origin, different modalities of presentation, laboratory and instrumental diagnostic tests, including\\u000a molecular tests, symptoms and signs of involvement of other organs. Different phenotypes may be identified according to: disease\\u000a course; involvement of motor, sensory, autonomic fibres; site

Davide Pareyson



The TRK-Fused Gene Is Mutated in Hereditary Motor and Sensory Neuropathy with Proximal Dominant Involvement  

PubMed Central

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C>T (p.Pro285Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration.

Ishiura, Hiroyuki; Sako, Wataru; Yoshida, Mari; Kawarai, Toshitaka; Tanabe, Osamu; Goto, Jun; Takahashi, Yuji; Date, Hidetoshi; Mitsui, Jun; Ahsan, Budrul; Ichikawa, Yaeko; Iwata, Atsushi; Yoshino, Hiide; Izumi, Yuishin; Fujita, Koji; Maeda, Kouji; Goto, Satoshi; Koizumi, Hidetaka; Morigaki, Ryoma; Ikemura, Masako; Yamauchi, Naoko; Murayama, Shigeo; Nicholson, Garth A.; Ito, Hidefumi; Sobue, Gen; Nakagawa, Masanori; Kaji, Ryuji; Tsuji, Shoji



Degeneration of anterior horn cell in neuronal type of Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type II): A Golgi study  

Microsoft Academic Search

A morphological study using the Golgi impregnation method was carried out on the anterior horn cells at cervical (C), thoracic (Th), and lumbar (L) levels of the spinal cord in a patient with neuronal type of Charcot-Maire-Tooth disease (hereditary motor and sensory neuropathy type II) and an age-matched control. The present study demonstrated an uneven cell body surface, loss of

Seiitsu Ono; Kazuyuki Hara; Hiroshi Sasaki; Isamu Sugano; Koichi Nagao



Recurrent fatal necrotizing fasciitis due to Streptococcus pyogenes in a child with hereditary sensory and automic neuropathy type IV.  


Although necrotizing fasciitis (NF) is a rapidly progressive infection, recurrent NF is very rare. Herein we report a rare case of recurrent NF due to Streptococcus pyogenes. A 12-year-old female with hereditary sensory and autonomic neuropathy (HSAN) type IV presented with fever and swelling on her left knee. NF was diagnosed and she was treated successfully. Two years later she was readmitted with NF of the right knee and limb. Despite treatment, progressive tissue necrosis developed and proximal femur amputation was performed. Eight months following the second attack she was readmitted with NF of her left knee and her entire leg. Despite a wide surgical debridement and antibiotic treatment, the clinical status of the patient failed to improve and she subsequently died. Although many conditions have been reported to be predisposing factors for NF, this is the first report of an association between HSAN type IV and recurrent NF due to S. pyogenes. We recommend antibiotic prophylaxis for patients with NF due to S. pyogenes, especially for those with predisposing factors. PMID:21519130

Kuzdan, Canan; Soysal, Ahmet; Altinkanat, Gül?en; Aksu, Burak; Söyletir, Güner; Bakir, Mustafa



Identification of a Novel Gene (HSN2) Causing Hereditary Sensory and Autonomic Neuropathy Type II through the Study of Canadian Genetic Isolates  

PubMed Central

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed “HSN2,” consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.

Lafreniere, Ronald G.; MacDonald, Marcia L. E.; Dube, Marie-Pierre; MacFarlane, Julie; O'Driscoll, Mary; Brais, Bernard; Meilleur, Sebastien; Brinkman, Ryan R.; Dadivas, Owen; Pape, Terry; Platon, Christele; Radomski, Chris; Risler, Jenni; Thompson, Jay; Guerra-Escobio, Ana-Maria; Davar, Gudarz; Breakefield, Xandra O.; Pimstone, Simon N.; Green, Roger; Pryse-Phillips, William; Goldberg, Y. Paul; Younghusband, H. Banfield; Hayden, Michael R.; Sherrington, Robin; Rouleau, Guy A.; Samuels, Mark E.



Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1.  


Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% L-serine–enriched diet reduced dSL levels. L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% L-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, L-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder. PMID:22045570

Garofalo, Kevin; Penno, Anke; Schmidt, Brian P; Lee, Ho-Joon; Frosch, Matthew P; von Eckardstein, Arnold; Brown, Robert H; Hornemann, Thorsten; Eichler, Florian S



Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients.  


The axonal type of Charcot?Marie?Tooth (CMT) disorders is genetically heterogeneous, therefore the causal mutation is unlikely to be observed, even in clinically well characterized patients. Mitofusin?2 (MFN2) gene mutations are the most frequent cause of axonal CMT disorders in a number of populations. There are two phenotypes; early onset, which is severe and late onset, which is a milder phenotype. A cohort of 139 unrelated Czech patients with axonal neuropathy was selected for sequencing and multiplex ligation-dependent probe amplification analysis (MLPA) testing of the MFN2 gene. A total of 11 MFN2 mutations were detected, with eight pathogenic mutations and three potentially rare benign polymorphisms. MLPA testing in 64 unrelated patients did not detect any exon duplication or deletion. The frequency of the pathogenic mutations detected in Czech hereditary motor and sensory neuropathy type II (HMSN II) patients was 7.2%. Early onset was more frequent among pathogenic mutation cases. Therefore we propose to examine the MFN2 gene mainly in patients with early and severe axonal CMT. PMID:24126688

Brožková, Dana Safka; Posádka, Jan; Laššuthová, Petra; Mazanec, Radim; Haberlová, Jana; Sišková, Dana; Sakmaryová, Iva; Neupauerová, Jana; Seeman, Pavel



Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.  


Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range. PMID:22978647

Sevilla, T; Martínez-Rubio, D; Márquez, C; Paradas, C; Colomer, J; Jaijo, T; Millán, J M; Palau, F; Espinós, C



Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity.  


Hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) is an adult-onset peripheral neurodegenerative disorder which has been reported only in the Okinawa Islands, Japan. The disease locus of "Okinawa-type" HMSN-P has been previously mapped to 3q13.1, with all affected individuals sharing an identical haplotype around the locus, suggesting that the undiscovered causative mutation in HMSN-P originated from a single founder. We have newly found two large families from the western part of Japan within which multiple members developed symptoms similar to those exhibited by HMSN-P patients from Okinawa, with no record of affinal connection between the islands. Using these pedigrees with "Kansai-type" HMSN-P, we carried out a linkage study utilizing eight microsatellite markers and identified a candidate region on 3q13.1 cosegregating with the disease (maximum two-point LOD score of 8.44 at theta=0.0) overlapping with the Okinawa-type HMSN-P locus. However, the disease haplotype shared among all affected members in these families was different from that in the Okinawa kindred, suggesting allelic heterogeneity. Such allelic variation should aid in the identification of the disease-causative gene. Moreover, the allelic heterogeneity of HMSN-P in the Japanese population suggests that HMSN-P may be more common across other ethnic groups, but classified into other disease categories. PMID:17906970

Maeda, Kouji; Kaji, Ryuji; Yasuno, Katsuhito; Jambaldorj, Jamiyansuren; Nodera, Hiroyuki; Takashima, Hiroshi; Nakagawa, Masanori; Makino, Satoshi; Tamiya, Gen



Hereditary motor and sensory neuropathy (HMSN) type X1 in an Argentinean family reveals independent GJB1/Cx32 mutations at the identical nucleotide position.  


X-linked Charcot-Marie-Tooth disease (CMT Type X1, OMIM: 302800) represents a frequent cause of hereditary peripheral motor and sensory neuropathies and is associated with mutations in GJB1 encoding the gap junction beta 1 protein connexin 32 (Cx32). Studying an Argentinean family of Italian origin with seven affected males in three generations exhibiting clinical signs of CMT, eight obligate female carriers were identified genealogically. DNA sequencing of exon 2 and adjacent regions of the GJB1 gene in two symptomatic males whose respective maternal grandfathers, both affected, were brothers, revealed mutations in GJB1/Cx32. Surprisingly, each of the two affected patients had a different mutation in hemizygous state at the same nucleotide position: c.383C>T (p.S128L) and c.383C>A (p.S128X). In both cases, the identified mutation was present in heterozygous state in the corresponding maternal genomic DNA. Furthermore, X-chromosomal microsatellite analysis showed identical marker alleles in both patients. Together with the genealogical information, these molecular data imply that a primarily mutated allele mutated for a second time. In conclusion, two different mutations at the same nucleotide position in this Argentinean family represent a finding with a very low probability of occurrence. PMID:23384994

Gerding, Wanda Maria; Koetting, Judith; Rey, Lucía Paola; Bibas Bonet, Hilda; Abdala, Mirta Esther; Mazzeo, Anna; Mostacciuolo, Maria Luisa; Arning, Larissa; Carrero-Valenzuela, Roque



Structural and Functional Measures of Inner Retinal Integrity Following Visual Acuity Improvement in a Patient with Hereditary Motor and Sensory Neuropathy Type VI  

PubMed Central

Purpose To report measures of inner retinal integrity following improvement in visual acuity and visual fields in a patient with hereditary motor and sensory neuropathy type VI (HMSN VI). Case Report The patient is a Caucasian male with HMSN VI (type 2A Charcot-Marie-Tooth disease and associated optic atrophy) and a c.1090C?T (p.R364W) mutation in the mitofusin 2 (MFN2) gene. The patient’s best-corrected visual acuity improved from 20/200 (OD) and 20/400 (OS) at the initial visit to 20/25 in each eye when tested seven years later. The visual field defects in both eyes that were present at the initial visit were absent at the follow-up visit. The structural integrity of the inner retina was assessed by an evaluation of retinal nerve fiber layer thickness (RNFLT) using optical coherence tomography (OCT), and the functional integrity was assessed by the amplitude of the photopic negative response (PhNR) of the electroretinogram (ERG). At the follow-up visit, the patient’s RNFLT was less than the 5th percentile for control subjects in the superior and inferior quadrants OD and in one sector of the temporal quadrant OS, but was within normal limits elsewhere. The PhNR amplitude of each eye was below the lower limit of the normal range. Conclusion The abnormally low PhNR amplitudes and abnormally thin RNFL in certain quadrants of the retina following improvement of visual acuity and visual fields to near-normal values illustrates the potential usefulness of assessing the structure and function of the inner retina in HMSN VI patients.

Gowrisankaran, Sowjanya; Anastasakis, Anastasios; Fishman, Gerald A.; Alexander, Kenneth R.



Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4 ) gene  

Microsoft Academic Search

A spontaneous autosomal recessive mutation was identified in the Sprague-Dawley rat strain with an early onset sensory neuropathy.The main clinical features of the mutation (mutilated foot, mf ), detectable shortly after birth, include ataxia, insensitivity to pain and foot ulceration.The pathological features include a severe reduction in the number of sensory ganglia and fibres.This mutant is therefore an excellent model

Ming-Jen Lee; Dennis A. Stephenson; Michael J. Groves; Mary G. Sweeney; Mary B. Davis; Shu-Fang An; Henry Houlden; Mustafa A. M. Salih; Vincent Timmerman; Peter de Jonghe; Michaela Auer-Grumbach; Francesco Scaravilli; Nicholas W. Wood; Mary M. Reilly



[Diagnosis of the peripheral hereditary neuropathies and its molecular genetics].  


Peripheral neuropathies include a wide range of pathological disorders characterized by damage of peripheral nerves. Among them, peripheral hereditary neuropathies are a group of frequent illnesses and early evolution. They have been named hereditary motor and sensory neuropathy (HMSN) or peripheral hereditary neuropathies type Charcot-Marie-Tooth (CMT). The most frequent types are CMT1, CMT2 and CMTX. Approximately 70% of the cases correspond to subtype CMT1A, associated with tandem duplication of a 1.5 Mb DNA fragment on chromosome 17p11.2-p12 that codifies the peripheral myelin protein PMP22. So far, there five different types of CMT (1,2,3,4,X) with approximately 32 subtypes, associated with more than 30 genes. Have been reported genetic heterogeneity and expression variability of the illness makes it necessary to carry on diagnostic strategies that integrate clinical study for determining genetic clinical history, family history, complete physical exploration, muscular strength, physical deformities, reflexes and sensitivity, and molecular studies allow detection of different types of mutations and help establish a correct diagnosis and an adequate genetic counseling. PMID:18979992

Hernández-Zamora, Edgar; Arenas-Sordo, María de la Luz


Sensory and motor neuropathy in a Border Collie.  


A 5-month-old female Border Collie was evaluated because of progressive hind limb ataxia. The predominant clinical findings suggested a sensory neuropathy. Sensory nerve conduction velocity was absent in the tibial, common peroneal, and radial nerves and was decreased in the ulnar nerve; motor nerve conduction velocity was decreased in the tibial, common peroneal, and ulnar nerves. Histologic examination of nerve biopsy specimens revealed considerable nerve fiber depletion; some tissue sections had myelin ovoids, foamy macrophages, and axonal degeneration in remaining fibers. Marked depletion of most myelinated fibers within the peroneal nerve (a mixed sensory and motor nerve) supported the electrodiagnostic findings indicative of sensorimotor neuropathy. Progressive deterioration in motor function occurred over the following 19 months until the dog was euthanatized. A hereditary link was not established, but a littermate was similarly affected. The hereditary characteristic of this disease requires further investigation. PMID:16266014

Harkin, Kenneth R; Cash, Walter C; Shelton, G Diane



[Hereditary neuropathy with pressure hypersensitivity or tomaculous neuropathy].  


Hereditary neuropathy liability to pressure palsies is characterized by recurring accesses of painless paralysis at the level of various nerves likely to be compressed. This affection remains underdiagnosed because of its usually benign course, sometimes without any symptom. The diagnosis is supported by clinical and electrophysiological data associated with, in the majority of patients, a deletion of one of the alleles coding for protein PMP 22 on the level of the locus 17p11.2. PMID:12481468

Tinant, F; Zeevaert, B; Benkirane, H; Laurent, L; Wang, F



Sensory neuropathy in two Border collie puppies.  


A peripheral sensory neuropathy was diagnosed in two Border collie puppies. Neurological, electrophysiological and histopathological examinations suggested a purely sensory neuropathy with mainly distal involvement. Urinary incontinence was observed in one of the puppies and histological examination of the vagus nerve revealed degenerative changes. An inherited disorder was suspected. PMID:15971901

Vermeersch, K; Van Ham, L; Braund, K G; Bhatti, S; Tshamala, M; Chiers, K; Schrauwen, E



Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy  

PubMed Central

Objective: To study the role of mechanical, infectious, and inflammatory factors inducing neuropathic attacks in hereditary brachial plexus neuropathy (HBPN), an autosomal dominant disorder characterised by attacks of pain and weakness, atrophy, and sensory alterations of the shoulder girdle and upper limb muscles. Methods: Four patients from separate kindreds with HBPN were evaluated. Upper extremity nerve biopsies were obtained during attacks from a person of each kindred. In situ hybridisation for common viruses in nerve tissue and genetic testing for a hereditary tendency to pressure palsies (HNPP; tomaculous neuropathy) were undertaken. Two patients treated with intravenous methyl prednisolone had serial clinical and electrophysiological examinations. One patient was followed prospectively through pregnancy and during the development of a stereotypic attack after elective caesarean delivery. Results: Upper extremity nerve biopsies in two patients showed prominent perivascular inflammatory infiltrates with vessel wall disruption. Nerve in situ hybridisation for viruses was negative. There were no tomaculous nerve changes. In two patients intravenous methyl prednisolone ameliorated symptoms (largely pain), but with tapering of steroid dose, signs and symptoms worsened. Elective caesarean delivery did not prevent a typical postpartum attack. Conclusions: Inflammation, probably immune, appears pathogenic for some if not all attacks of HBPN. Immune modulation may be useful in preventing or reducing the neuropathic attacks, although controlled trials are needed to establish efficacy, as correction of the mutant gene is still not possible. The genes involved in immune regulation may be candidates for causing HBPN disorders.

Klein, C; Dyck, P; Friedenberg, S; Burns, T; Windebank, A; Dyck, P



Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.  


In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. PMID:22285450

Timmerman, Vincent; Clowes, Virginia E; Reid, Evan



Deficiency of thiosulphate sulphurtransferase (rhodanese) in Leber's hereditary optic neuropathy.  

PubMed Central

Leber's hereditary optic neuropathy is a rare cause of progressive visual failure. Its cause is unknown, but one hypothesis is that patients have a defect in the detoxication of cyanide. One of the enzymes used in this detoxication is thiosulphate sulphurtransferase (rhodanese). The activity of this enzyme was measured in the rectal mucosa of a group of subjects with Leber's hereditary optic neuropathy, and it was found to be considerably reduced compared with that in a group of controls (p less than 0.001). This finding supports the hypothesis of an inborn error of cyanide detoxication in this condition.

Poole, C J; Kind, P R



Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy  

PubMed Central

Leber’s hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber’s hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber’s hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100?nM of 17?-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber’s hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17?-oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17?-oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor ? localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber’s hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules.

Giordano, Carla; Montopoli, Monica; Perli, Elena; Orlandi, Maurizia; Fantin, Marianna; Ross-Cisneros, Fred N.; Caparrotta, Laura; Martinuzzi, Andrea; Ragazzi, Eugenio; Ghelli, Anna; Sadun, Alfredo A.; d'Amati, Giulia



Leber's hereditary optic neuropathy mutations in ethambutol-induced optic neuropathy.  


Primary mitochondrial DNA (mtDNA) mutation at the nt 11778 site in Leber's hereditary optic neuropathy (LHON) has been reported to be present in patients with ethambutol-induced optic neuropathy. To study further this association between LHON and ethambutol-induced optic neuropathy, we tested ethambutol-induced optic neuropathy patients for the presence of the mtDNA mutations at nucleotides (nt)-11778, nt-14484, nt-3460, nt-15257, nt-9438, nt-9804, nt-13730, and nt-14459 in 24, 15, 8, 6, 5, 5, 5, and 5 patients respectively. However, none of the ethambutol-induced optic neuropathy patients was found to exhibit any pathogenic LHON mtDNA mutation. In conclusion, we found no evidence of any association between ethambutol-induced optic neuropathy and the LHON mutations. PMID:12527998

Hwang, Jeong-Min; Kim, Jiyeon; Park, Sung Sup



A review of primary hereditary optic neuropathies.  


The primary inherited optic neuropathies are a heterogeneous group of disorders that result in loss of retinal ganglion cells, leading to the clinical appearance of optic atrophy. They affect between 1:10,000 to 1:50,000 people. The main clinical features are a reduction in visual acuity, colour vision abnormalities, centro-caecal visual field defects and pallor of the optic nerve head. Electrophysiological testing shows a normal flash electroretinogram, absent or delayed pattern visually evoked potentials suggestive of a conduction deficit and N95 waveform reduction on the pattern electroretinogram, consistent with a primary ganglion cell pathology. The primary inherited optic neuropathies may be sporadic or familial. The mode of inheritance may be autosomal dominant, autosomal recessive, X-linked recessive or mitochondrial. Within each of these groups, the phenotypic characteristics vary in such features as the mode and age of onset, the severity of the visual loss, the colour deficit and the overall prognosis. A number of different genes (most as yet unidentified) in both nuclear and mitochondrial genomes, underlie these disorders. The elucidation of the role of the encoded proteins will improve our understanding of basic mechanisms of ganglion cell development, physiology and metabolism and further our understanding of the pathophysiology of optic nerve disease. It will also improve diagnosis, counselling and management of patients, and eventually lead to the development of new therapeutic modalities. PMID:12889662

Votruba, M; Aijaz, S; Moore, A T



Genetic evaluation of inherited motor/sensory neuropathy.  


Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), chromosome 16 (CMT1C) and chromosome 10 (CMT1D). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-p12. In rare patients it may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (Po or MPZ) gene. Mutations in the SIMPLE gene cause CMT1C, and CMT1D is the result of mutations in the early response 2 (ERG2 or Krox-20) gene. An X-linked form of CMT1 (CMT1X) maps to Xq13 and is associated with mutations in the connexin32 (Cx32) gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy that maps to chromosome 1p35-p36 (CMT2A), chromosome 3q13-q22 (CMT2B), chromosome 7p14 (CMT2D), chromosome 8p21 (CMT2E), chromosome 1q22-q23 (CMT2F) or chromosome 3q13 (CMT2G). Two X-linked forms of CMT2 have been reported (CMT2XA and CMT2XB), but the genes remain unidentified. An area that has recently expanded is the identification of autosomal recessive forms of CMT type 1 and 2. Of the eight recessive forms of CMT1 that have been identified to date, only two have been fully characterized at the molecular level (CMT1 AR B 1 and CMT1 AR D). Point mutations were found in the myotubularin-related protein-2 (MTM2) gene for CMT1 AR B1. CMT1 AR D is the result of point mutations in the N-myc downstream-regulated gene 1 (NDRG1). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene, PO gene, EGR2 gene or the PRX gene (for the recessive form). It shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-p12 that results in reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes that originate from unequal crossover during germ cell meiosis. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q and 11q. PMID:16106622

Chance, Phillip F



[Clinical and molecular genetic analysis of hereditary optic neuropathies].  


DNA samples of 50 patients with optic neuropathy (ON) associated with congenital cataract were studied to find 3 major mt-DNA mutations (m.11778G>A, m.3460G>A, m.14484T>C), mutations in "hot" regions of OPA 1 gene (exons 8, 14, 15, 16, 18, 27, 28) and in the entire coding sequence of OPA3 gene for molecular genetic confirmation of diagnosis of hereditary Leber and autosomal dominant ON. Primary mutations of mtDNA responsible for hereditary Leber ON were found in 16 patients (32%). Pathogenic mutations of OPAl gene (c.869G>A and c. 2850delT) were identified in 2 patients (4%), these mutations were not found in the literature. OPA3 gene mutations were not revealed. PMID:23808173

Avetisov, S É; Sheremet, N L; Vorob'eva, O K; Eliseeva, É G; Chukhrova, A L; Loginova, A N; Khanakova, N A; Poliakov, A V


Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy  

NASA Astrophysics Data System (ADS)

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.



Late-onset Leber hereditary optic neuropathy mimicking Susac's syndrome.  


Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by bilateral painless optic atrophy and blindness. It usually occurs in young men in association with three major mutations in the mitochondrial genome (mtDNA). We report a patient with a history of alcohol abuse who developed at age 63 years visual impairment, sensorineural hearing loss, and memory dysfunction, suggestive of Susac's syndrome. The patient carried the heteroplasmic mt. 11778G>A mutation on the T2e mtDNA haplogroup. It remains unclear if chronic alcohol abuse combined with the mitochondrial genetic background prompted an aged-related neurodegeneration or deferred the onset of the LHON disease. PMID:20632027

Zoccolella, Stefano; Petruzzella, Vittoria; Prascina, Francesco; Artuso, Lucia; Pacillo, Francesca; Dell'Aglio, Rosa; Avolio, Carlo; Delle Noci, Nicola; Attimonelli, Marcella; Specchio, Luigi Maria



Mutations for Leber hereditary optic neuropathy in patients with alcohol and tobacco optic neuropathy  

PubMed Central

Purpose There are many similarities in the clinical presentation of Leber hereditary optic neuropathy (LHON) and in patients who have optic neuropathy and a history of heavy tobacco and alcohol consumption. The main objective of this study is to investigate the frequency of primary and secondary mitochondrial DNA (mtDNA) mutations for LHON in patients diagnosed as having alcohol and tobacco optic neuropathy (ATON). Methods Twenty-six patients who had a history of heavy alcohol and tobacco consumption and who developed bilateral optic neuropathy were tested for primary mutations (G11778A, T14484C, and G3460A) by restriction analysis, and 14 secondary mutations in the genes mitochondrially encoded NADH dehydrogenase 1 (MT-ND1), mitochondrially encoded NADH dehydrogenase 4 (MT-ND4), mitochondrially encoded NADH dehydrogenase 4L (MT-ND4L), mitochondrially encoded NADH dehydrogenase 5 (MT-ND5), mitochondrially encoded NADH dehydrogenase 6 (MT-ND6), and mitochondrially encoded cytochrome B (MT-CYB) by direct sequencing. Results Four (15.4%) of 26 patients tested positive for LHON primary mutations, two for the G11778A mutation, and two for the T14484C mutation. No patient tested positive for any of the 14 secondary mutations. Familial recurrence was present in four patients, and only three of these patients have presented the LHON mutation. Conclusions The diagnosis of LHON should be considered in all patients diagnosed as having optic neuropathy, particularly those with familial recurrence of vision loss.

Amaral-Fernandes, Marcela Scabello; Marcondes, Ana Maria; Miranda, Paulo Mauricio do Amor Divino; Maciel-Guerra, Andrea Trevas



Hereditary Neuropathy with Liability to Pressure Palsies: Case Report and Discussion  

Microsoft Academic Search

Hereditary neuropathy with liability to pressure palsies (HNPP) is an uncommon diagnosis that should be considered in patients\\u000a with multiple compressive neuropathies. We present the case of a woman who presented with bilateral hand numbness and weakness.\\u000a Electrodiagnostic testing revealed bilateral carpal tunnel syndrome, bilateral ulnar neuropathy at the elbow, left peroneal\\u000a neuropathy at the fibular head, and a primarily

Marc J. Grossman; Joseph Feinberg; Edward F. DiCarlo; Sherri B. Birchansky; Scott W. Wolfe



Assessment of sensory neuropathy in patients with diabetic foot problems.  


Our aim of this study was to compare the accuracy of three different modalities for testing sensory neuropathy in diabetic patients with and without diabetic foot problems. The three devices used included the pin-prick testing using the Neurotip® (PPT), the Semmes-Weinstein 5.07/10 g monofilament testing (SWMT), and the rapid-current perception threshold (R-CPT) measurements using the Neurometer® testing. Our study population consisted of 54 patients (108 feet) with diabetic foot problems treated at the National University Hospital in Singapore by our multi-disciplinary diabetic foot care team. Our results showed no difference in sensory neuropathy detected by PPT and 5.07/10 g SWMT in both the pathological and normal foot. In the pathological foot, there was significant increase in sensory neuropathy detected by the Neurometer® device at both the big toe and ankle sites as compared to PPT and 5.07/10 g SWMT. In the normal foot, there was a significant increase in sensory neuropathy detected by the Neurometer® device at the big toe site only as compared to PPT and 5.07/10 g SWMT. Finally, the Neurometer® measurements detected a statistically higher proportion of feet with sensory neuropathy as compared to detection by the PPT or 5.07/10 g SWMT. PMID:22396819

Nather, Aziz; Keng Lin, Wong; Aziz, Zameer; Hj Ong, Christine; Mc Feng, Bernard; B Lin, Clarabelle



Leber hereditary optic neuropathy, progressive visual loss, and multiple-sclerosis-like symptoms  

Microsoft Academic Search

PURPOSE: To report a case of Leber hereditary optic neuropathy with multiple-sclerosis-like symptoms.METHODS: Observational case report. A 34-year-old man was found to have Leber hereditary optic neuropathy and a mutation at position 11778 of the mitochondrial genome. The progression of vision loss and onset of weakness in the right leg warranted neuroimaging.RESULTS: Magnetic resonance imaging documented multiple lesions in the

Mai Tran; Ravi Bhargava; Ian M MacDonald



Diagnosis and new treatments in genetic neuropathies  

Microsoft Academic Search

The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot–Marie–Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis

M M Reilly; M E Shy



Tactile stimulation and mechanoreceptors in sensory neuropathies  

Microsoft Academic Search

Meissner corpuscles are supposed to play a primary role in generating tactile responses. To verity this hypothesis, we combined electrophysiological and morphological methods. In a group of twelve patients affected by congenital or acquired neuropathies, electrical and tactile evoked potentials were near-nerve recorded along the median nerve. The density of Meissner corpuslces was calculated in the fingertip, exactly in the

M. Nolano; V. Provitera; F. Lullo; A. M. Saltalamacchia; C. Crisci; B. Lanzillo; L. Santoro



Leber’s hereditary optic neuropathy and vitamin B12 deficiency  

Microsoft Academic Search

Background  Leber’s hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA (mtDNA). It is also believed that several epigenetic factors have an influence on the development of LHON.Methods  A case series was observed.Results  Three patients who developed bilateral optic neuropathy are presented. All patients had a primary LHON mutation in their mtDNA, but also a subnormal

Jan Willem R. Pott; Kwok H. Wong



Pes cavus and hereditary neuropathies: when a relationship should be suspected  

PubMed Central

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a “spy sign,” discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

Piazza, S.; Ricci, G.; Caldarazzo Ienco, E.; Carlesi, C.; Volpi, L.; Siciliano, G.



Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy  

PubMed Central

Objective: To identify a new genetic cause of distal hereditary motor neuropathy (dHMN), which is also known as a variant of Charcot-Marie-Tooth disease (CMT), in a Chinese family. Methods: We investigated a Chinese family with dHMN clinically, electrophysiologically, and genetically. We screened for the mutations of 28 CMT or related pathogenic genes using an originally designed microarray resequencing DNA chip. Results: Investigation of the family history revealed an autosomal dominant transmission pattern. The clinical features of the family included mild weakness and wasting of the distal muscles of the lower limb and foot deformity, without clinical sensory involvement. Electrophysiologic studies revealed motor neuropathy. MRI of the lower limbs showed accentuated fatty infiltration of the gastrocnemius and vastus lateralis muscles. All 4 affected family members had a heterozygous missense mutation c.2677G>A (p.D893N) of alanyl-tRNA synthetase (AARS), which was not found in the 4 unaffected members and control subjects. Conclusion: An AARS mutation caused dHMN in a Chinese family. AARS mutations result in not only a CMT phenotype but also a dHMN phenotype.

Zhao, Z.; Hashiguchi, A.; Sakiyama, Y.; Okamoto, Y.; Tokunaga, S.; Zhu, L.; Shen, H.; Takashima, H.



Two cases of elderly-onset hereditary neuropathy with liability to pressure palsy manifesting bilateral peroneal nerve palsies.  


Hereditary neuropathy with liability to pressure palsy (HNPP) is characterized by recurrent focal neuropathies, which usually become symptomatic in the second or third decade of life. However, clinical phenotypic heterogeneity among patients with HNPP has recently been reported. Certain patients show polyneuropathy-type diffuse nerve injuries, whereas others remain asymptomatic at older ages. We present two cases of elderly-onset bilateral peroneal nerve palsies with diffuse muscle weakness in the lower limbs and glove-and-stocking type sensory disturbance. Both patients were diagnosed with HNPP by genetic analyses that detected deletions of chromosome 17p11.2 in peripheral myelin protein 22 genes. Their clinical courses suggested that the Japanese sitting style termed 'seiza', a way of sitting on the floor with the lower legs crossed under the thighs, was a precipitating factor for the bilateral peroneal nerve palsies. PMID:23185166

Kawaguchi, Norihiko; Suzuki, Naoki; Tateyama, Maki; Takai, Yoshiki; Misu, Tatsuro; Nakashima, Ichiro; Itoyama, Yasuto; Aoki, Masashi



Antiretroviral Therapy-Associated Acute Motor and Sensory Axonal Neuropathy  

PubMed Central

Guillain-Barré syndrome (GBS) has been reported in HIV-infected patients in association with the immune reconstitution syndrome whose symptoms can be mimicked by highly active antiretroviral therapy (HAART)-mediated mitochondrial toxicity. We report a case of a 17-year-old, HIV-infected patient on HAART with a normal CD4 count and undetectable viral load, presenting with acute lower extremity weakness associated with lactatemia. Electromyography/nerve conduction studies revealed absent sensory potentials and decreased compound muscle action potentials, consistent with a diagnosis of acute motor and sensory axonal neuropathy. Lactatemia resolved following cessation of HAART; however, neurological deficits minimally improved over several months in spite of immune modulatory therapy. This case highlights the potential association between HAART, mitochondrial toxicity and acute axonal neuropathies in HIV-infected patients, distinct from the immune reconstitution syndrome.

Capers, Kimberly N.; Turnacioglu, Sinan; Leshner, Robert T.; Crawford, John R.



Strategies for Managing Chemotherapy-Induced Sensory Neuropathy  

Microsoft Academic Search

Chemotherapy-induced sensory neuropathy occurs in most patients undergoing treatment with oxaliplatin for colorectal cancer.\\u000a Although the acute form of neurotoxicity is transient, the chronic form, which is correlated with the cumulative dose of oxaliplatin\\u000a administered over time, may be long lasting in a subset of patients and may have a significant impact on function and quality\\u000a of life. Because treatment

Joleen Hubbard; Axel Grothey



Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.  


Leber's hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B?=?0.002; P<0.05) and lack of recovery of visual acuity (B?=?0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons. PMID:23209682

Rizzo, Giovanni; Tozer, Kevin R; Tonon, Caterina; Manners, David; Testa, Claudia; Malucelli, Emil; Valentino, Maria Lucia; La Morgia, Chiara; Barboni, Piero; Randhawa, Ruvdeep S; Ross-Cisneros, Fred N; Sadun, Alfredo A; Carelli, Valerio; Lodi, Raffaele



Secondary Post-Geniculate Involvement in Leber's Hereditary Optic Neuropathy  

PubMed Central

Leber’s hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B?=?0.002; P<0.05) and lack of recovery of visual acuity (B?=?0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.

Rizzo, Giovanni; Tozer, Kevin R.; Tonon, Caterina; Manners, David; Testa, Claudia; Malucelli, Emil; Valentino, Maria Lucia; La Morgia, Chiara; Barboni, Piero; Randhawa, Ruvdeep S.; Ross-Cisneros, Fred N.; Sadun, Alfredo A.; Carelli, Valerio; Lodi, Raffaele



Plasmapheresis in the Treatment of Ataxic Sensory Neuropathy Associated with Sjögren’s Syndrome  

Microsoft Academic Search

Sjögren’s syndrome (SS) is an important but poorly recognized cause of peripheral neuropathy. Several forms of peripheral nerve dysfunction occur, including trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy and pure sensory neuronopathy. The pathological findings vary and the definite treatment is not known. Here we present 4 cases of acute ataxic sensory polyneuropathy with SS, and the experience of

Wei-Hung Chen; Jiann-Horng Yeh; Hou-Chang Chiu



Axonal sensory motor neuropathy in copper-deficient Wilson's disease.  


Copper deficiency may cause myeloneuropathy or progressive limb weakness. By contrast, Wilson's disease (WD) is characterized by progressive copper accumulation with hepatic and neurological impairment and requires life-long treatment with zinc and/or chelator agents. We report a WD patient who developed axonal sensory motor neuropathy in the context of copper deficiency due to his treatment with zinc and chelators. Exhaustive testing for other etiologies was negative. After treatment adjustment, only mild clinical improvement was noted during long-term follow-up. Muscle Nerve 40: 294-296, 2009. PMID:19609919

Foubert-Samier, Alexandra; Kazadi, Annabelle; Rouanet, Marie; Vital, Anne; Lagueny, Alain; Tison, François; Meissner, Wassilios



Chronic progressive sensory ataxic neuropathy associated with limited systemic sclerosis.  


We report the case of a 33-year-old woman with limited systemic sclerosis and chronic progressive sensory ataxic neuropathy. Sural nerve biopsy showed loss of myelinated fibers mostly those of large diameter, axonal degeneration and infiltration of macrophages, but no signs of vasculitis. Physical examination, laboratory testing, neurophysiological and neuroradiological examinations suggested that the dorsal root was primarily affected in this patient. Cytokine analysis by multiplex bead array assay revealed that IL-1beta and GM-CSF were increased both in serum and CSF. Although her symptoms did not respond to corticosteroid therapy, intravenous immunoglobulin (IVIg) therapy resulted in marked improvement. IVIg could be effective in case of immune-mediated reversible neuronal dysfunction associated with collagen disease without vasculitis. PMID:16336975

Nobuhara, Yasuyuki; Saito, Mineki; Goto, Rina; Yoshidome, Yoshihito; Kawamura, Miwako; Kasai, Takefumi; Higashimoto, Ikkou; Eiraku, Nobutaka; Umehara, Fujio; Osame, Mitsuhiro; Arimura, Kimiyoshi



Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy  

PubMed Central

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits.

Rocca, Maria A.; Valsasina, Paola; Pagani, Elisabetta; Bianchi-Marzoli, Stefania; Milesi, Jacopo; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo



Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy  

Microsoft Academic Search

Heat shock protein 27 (HSP27) belongs to a family of small heat shock proteins that play significant roles in the cellular stress response and are also involved in the control of protein–protein interactions as chaperons. Mutation in HSP27 has been identified as the cause of axonal Charcot–Marie–Tooth disease (CMT) and distal hereditary motor neuropathy (HMN). Heat shock protein 22 (HSP22)

Kazuki Kijima; Chikahiko Numakura; Tomohide Goto; Takao Takahashi; Tesshu Otagiri; Kazuo Umetsu; Kiyoshi Hayasaka



A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya  

Microsoft Academic Search

A 4-year-search for spinal muscular atrophies (hereditary motor neuropathies, HMN) in Benghazi, Libya, yielded a total of 24 patients, among whom 18 were index cases. This group comprised 6 acute infantile, 12 chronic childhood, and 3 each with adult-onset proximal, and distal forms of the disorder. Distal HMN constituted 12.5% of the total cases. The crude average annual incidence of

K. Radhakrishnan; A. K. Thacker; J. C. Maloo



Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy  

Microsoft Academic Search

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic

Maria A. Rocca; Paola Valsasina; Elisabetta Pagani; Stefania Bianchi-Marzoli; Jacopo Milesi; Andrea Falini; Giancarlo Comi; Massimo Filippi; Yi Wang



Topiramate and visual loss in a patient carrying a Leber hereditary optic neuropathy mutation.  


We describe a 43-year-old patient who experienced visual loss 4 years after beginning antiepileptic therapy with topiramate. Ophthalmological and neurological examinations led to a preliminary diagnosis of bilateral toxic optic neuritis. Mitochondrial genome sequence analysis detected a Leber hereditary optic neuropathy 11778G>A mutation. The possibility that topiramate might favor a conversion disease, alerts physicians to seek a history of blindness in patients undergoing chronic antiepileptic therapy. PMID:21898092

Rinalduzzi, Steno; Cipriani, Anna Maria; Accornero, Neri



Hereditary motor and sensory neuropathy type I and type II  

Microsoft Academic Search

In an attempt to clearly identify the different HMSN subgroups, we prospectively evaluated 128 subjects (46 index cases, 39 affected and 43 unaffected relatives) on clinical, genetic and electrophysiological grounds. The diagnosis of HMNS I or II was made in 77 patients. Differential diagnosis between type I and II patients was impossible on clinical grounds alone, but nerve conduction study

A. Sghirlanzoni; D. Pareyson; V. Scaioli; R. Marazzi; L. Pacini



Genetics Home Reference: Hereditary sensory neuropathy type 1  


... in sphingolipids disrupts the formation of myelin, causing nerve cells to become less efficient and eventually die. When ... accumulation of toxic byproducts can also lead to nerve cell death. This gradual destruction of nerve cells results ...


Genetics Home Reference: Hereditary sensory and autonomic neuropathy type V  


... symptoms of the condition. Where can I find information about diagnosis or management of HSAN5? These resources address the diagnosis or ... of small myelinated fibers You might also find information on the diagnosis or management of HSAN5 in Educational resources and Patient support . ...


Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER  

PubMed Central

HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy (CART) and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. CHARTER is a U.S. based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ?1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G (odds ratio [95% confidence interval] = 0.27 [0.11-0.65]; p = 0.004) and T489C (odds ratio [95% confidence interval] = 0.41 [0.21-0.80]; p = 0.009). These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups are associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups (odds ratio [95% confidence interval] = 0.29 [0.12-0.71]; p = 0.007 and odds ratio [95% confidence interval] = 0.42 [0.18-1.0]; p = 0.05, respectively). In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.

Holzinger, Emily R.; Hulgan, Todd; Ellis, Ronald J.; Samuels, David C.; Ritchie, Marylyn D.; Haas, David W.; Kallianpur, Asha R.; Bloss, Cinnamon S.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; Marra, Christina M.; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Simpson, David M.; Franklin, Donald R.; Rosario, Debralee; Selph, Doug; Letendre, Scott; Grant, Igor



A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy.  


Hereditary spastic paraplegias (HSPs) include a group of neurodegenerative diseases, and so far 46 SPG loci have been mapped and 17 genes isolated. Among the autosomal dominant HSPs (AD-HSPs), SPG10 is a rare form due to mutations in KIF5A gene (locus 12q13.3). We describe the clinical, neurophysiological, morphological and genetic study of an Italian family with AD-HSP. The proband presented with an adult onset spastic paraparesis and diffuse paresthesias where neurophysiological and nerve biopsy morphological studies revealed an axonal neuropathy. Molecular genetic analysis identified a new missense mutation (c.608C>G) of KIF5A gene resulting in a serine to cysteine substitution, S203C, located in a highly conserved domain of the protein. This pedigree confirms the occurrence of an axonal peripheral neuropathy in SPG10. PMID:21107874

Musumeci, Olimpia; Bassi, Maria Teresa; Mazzeo, Anna; Grandis, Marina; Crimella, Claudia; Martinuzzi, Andrea; Toscano, Antonio



Mouse mtDNA mutant model of Leber hereditary optic neuropathy.  


An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress. PMID:23129651

Lin, Chun Shi; Sharpley, Mark S; Fan, Weiwei; Waymire, Katrina G; Sadun, Alfredo A; Carelli, Valerio; Ross-Cisneros, Fred N; Baciu, Peter; Sung, Eric; McManus, Meagan J; Pan, Billy X; Gil, Daniel W; Macgregor, Grant R; Wallace, Douglas C



Role of Metabolic Syndrome Components in HIV Associated Sensory Neuropathy  

PubMed Central

Objectives Sensory neuropathy (SN) is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy. Metabolic syndrome (MetS), a cluster of risk factors for atherosclerosis and microvascular disease, is associated with SN in HIV-uninfected (HIV?) persons. We examined if MetS or its components predispose individuals to HIV-SN. Design From a prospective multicenter cohort of 1,556 HIV+ subjects, a subgroup (n=130) with fasting laboratory tests and SN assessment was selected. Methods SN was defined by symmetrically decreased reflexes or sensation loss in the legs. MetS was defined by presence of ?3 risk factors: mean arterial pressure (MAP) ?100 mm Hg; triglycerides (TRG) ?150 mg/dl and high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males, <50 mg/dL for females; body mass index (BMI) >25 kg/m2; plasma glucose (GLU) ?100 mg/dl and self-reported diabetes (DM II). Multivariate logistic regression examined the association between HIV-SN and MetS. Results After controlling for HIV-SN risk factors- age, CD4 current, length of HIV infection, use of dideoxynucleoside reverse transcriptase inhibitors and protease inhibitors; MetS was not associated with HIV-SN (p=0.72). However, when each MetS component was assessed, elevated TRG was a significant risk factor for HIV-SN. From the larger cohort, both DM II (OR=1.4, p<0.01) and elevated TRG (OR=1.4, p=0.01) were risk factors for HIV-SN. Conclusion The risk of HIV-SN was increased for DM II and elevated TRG, but not other MetS components. Both increase the risk of SN in HIV- populations, but the mechanism(s) remains unclear.

Ances, Beau M.; Vaida, Florin; Rosario, Debralee; Marquie-Beck, Jennifer; Ellis, Ronald J.; Simpson, David M.; Clifford, David B.; McArthur, Justin C.; Grant, Igor; McCutchan, J. Allen



Vibrotactile perception threshold measurements for diagnosis of sensory neuropathy  

Microsoft Academic Search

Summary Recognition of the fact that impairment of the tactile sense may occur independently of other disturbances in the vibration syndrome has rekindled an interest in developing a diagnostic method for early detection of vibration-induced neuropathy. There is also evidence suggesting that vibrotactile measurements represent a valuable diagnostic tool in compressive neuropathies, such as the carpal tunnel syndrome. The method

R. Lundström; T. Strömberg; G. Lundborg



Acute autonomic sensory and motor neuropathy associated with central nervous system disturbance.  


We report a 45-year-old woman with acute autonomic sensory and motor neuropathy (AASMN) showing central nervous system (CNS) disturbance. She presented with disturbance of consciousness, complex partial seizures with automatisms, autonomic, sensory and motor neuropathy, showing severe orthostatic hypotension and neurogenic bladder. Nerve conduction studies and nerve biopsy indicated axonal degeneration involving both the myelinated and unmyelinated fibers. Muscle biopsy revealed neurogenic muscular atrophy. Electroencephalogram revealed theta wave activities and sharp wave abnormalities in the frontal lobe. Intravenous immunoglobulin therapy resulted in complete recovery of consciousness levels, but no obvious improvement of the other symptoms. Only eight patients with AASMN have been reported. This is the first report of AASMN showing CNS disturbance. Perivascular lymphocytic infiltration into the temporal lobe and brain stem was described in an autonomic neuropathy patient. An inflammatory pathogenesis of the CNS disturbance associated with this autonomic neuropathy was proposed. PMID:16603361

Sakai, Kenji; Matsumoto, Yasuko; Nozaki, Ichiro; Yamada, Masahito



Gastric emptying in hereditary transthyretin amyloidosis: the impact of autonomic neuropathy  

PubMed Central

Background Gastrointestinal (GI) complications are common in hereditary transthyretin amyloidosis and an autonomic dysfunction has been considered to explain these symptoms. The aim of this study was to investigate the impact of autonomic neuropathy on gastric emptying in hereditary transthyretin amyloidosis and to relate these findings to nutritional status, GI symptoms, gender, and age at disease onset. Methods Gastric emptying was evaluated with gastric emptying scintigraphy. Spectral analysis of the heart rate variability and cardiovascular responses after tilt test were used to assess the autonomic function. The nutritional status was evaluated with the modified body mass index (s-albumine × BMI). Key Results Gastric retention was found in about one-third of the patients. A weak correlation was found between the scintigraphic gastric emptying rate and both the sympathetic (rs = ?0.397, P < 0.001) and parasympathetic function (rs = ?0.282, P = 0.002). The gastric emptying rate was slower in those with lower or both upper and lower GI symptoms compared with those without symptoms (median T50 123 vs 113 min, P = 0.042 and 192 vs 113 min, P = 0.003, respectively). Multiple logistic regression analysis showed that age of onset (OR 0.10, CI 0.02–0.52) and sympathetic dysfunction (OR 0.23, CI 0.10–0.51), but not gender (OR 0.76, CI 0.31–1.84) and parasympathetic dysfunction (OR 1.81, CI 0.72–4.56), contributed to gastric retention. Conclusions and Inferences Gastric retention is common in hereditary transthyretin amyloidosis early after onset. Autonomic neuropathy only weakly correlates with gastric retention and therefore additional factors must be involved.

Wixner, J; Karling, P; Rydh, A; Hornsten, R; Wiklund, U; Anan, I; Suhr, O B



Neurofibromatous sensory neuropathy of the thigh in a 7-year-old boy  

Microsoft Academic Search

Neuropathy is considered to be an unusual complication of neurofibromatosis 1 (NF1). Neurofibromatous neuropathy is extremely\\u000a rare in the setting of paediatric age group, pure sensory mononeuropathy and NF1. The following is a description of a 7-year-old\\u000a boy who presented with complains of discomfort and parasthesia on the anterior aspect of his left thigh which is an unusual\\u000a mode of

Gautam M. Shetty; Ashok Shyam Murari; Hae-Ryong Song; Seok Hyun Lee; Jae Hyuk Yang



Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study  

ERIC Educational Resources Information Center

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent



No evidence for ‘skewed’ inactivation of the X-chromosome as cause of Leber's hereditary optic neuropathy in female carriers  

Microsoft Academic Search

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder of the optic nerves. It has been proposed that the specific mutations in the mitochondrial DNA (mtDNA) that are associated with LHON require and X-chromosomally encoded permissive factor in order to become expressed. This would explain both the preponderance of male patients and the fact that most carriers of specific

Roelof-Jan Oostra; Stephan Kemp; Pieter A. Bolhuis; Elisabeth M. Sleeker-Wagemakers



Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study  

ERIC Educational Resources Information Center

|Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent



Haplogroup Effects and Recombination of Mitochondrial DNA: Novel Clues from the Analysis of Leber Hereditary Optic Neuropathy Pedigrees  

Microsoft Academic Search

The mitochondrial DNA (mtDNA) of 87 index cases with Leber hereditary optic neuropathy (LHON) sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, was evaluated in detail. Only seven pairs and three triplets of identical haplotypes were observed, attesting that the large majority of the LHON mutations were due to independent mutational events. Assignment of

Valerio Carelli; Alessandro Achilli; Maria Lucia Valentino; Chiara Rengo; Ornella Semino; Maria Pala; Anna Olivieri; Marina Mattiazzi; Francesco Pallotti; Franco Carrara; Massimo Zeviani; Vincenzo Leuzzi; Carla Carducci; Giorgio Valle; Barbara Simionati; Luana Mendieta; Solange Salomao; Rubens Belfort; Alfredo A. Sadun; Antonio Torroni



Optic disc excavation in the atrophic stage of Leber's hereditary optic neuropathy: comparison with normal tension glaucoma  

Microsoft Academic Search

Background. Abnormal optic disc excavations are reportedly seen in patients with Leber's hereditary optic neuropathy (LHON), a mitochondrial dysfunction disease. We examined the disc morphology in the eyes of patients with LHON at the atrophic stage and compared it to that in eyes with normal-tension glaucoma (NTG). Methods. We studied 15 LHON patients with the 11778 mutation, 15 patients with

Yukihiko Mashima; Itaru Kimura; Yusuke Yamamoto; Hisao Ohde; Yuichirou Ohtake; Tomihiko Tanino; Goji Tomita; Yoshihisa Oguchi



Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies  

Microsoft Academic Search

Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent

Juan M Jimenez-Andrade; Monica B Herrera; Joseph R Ghilardi; Marina Vardanyan; Ohannes K Melemedjian; Patrick W Mantyh



Diagnostic challenges in movement disorders: Sensory Ataxia Neuropathy Dysarthria and Ophthalmoplegia (SANDO) syndrome.  


A woman in her early 60s presented to our Movement Disorders Centre with a 5-year history of progressive peripheral neuropathy, gait instability with falls, blurred vision, cognitive impairment and tremors. The patient was found to have profound sensory ataxia, chronic ophthalmoplegia, dementia with significant deficits in registration and construction and bilateral resting tremor of the hands. Investigations revealed an unremarkable MRI of the brain, negative cerebrospinal fluid studies, and unremarkable chemistries. Nerve conduction studies found a severe sensorimotor axonal polyneuropathy. Genetic testing revealed a compound heterozygous mutation in the POLG1 gene consistent with the diagnosis of Sensory Ataxia Neuropathy Dysarthria and Ophthalmoplegia (SANDO) syndrome. PMID:23997076

Lovan, Alyson; Ihtsham ul Haq; Balakrishnan, Nikhil



A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq26-q27  

SciTech Connect

Twenty-two DNA markers spanning the X chromosome have been analyzed for linkage to the locus causing an unusual form of X-linked recessive hereditary motor and sensory neuropathy in a Pennsylvania family of Italian ancestry. This 3 generation family which was originally reported by Cowchock includes 7 affected males, 3 obligate carrier females, and 4 unaffected males. Males are severely affected at birth or within the first few years of life with areflexia, slowly progressive axonal atrophy, and absence of large myelinated fibers, and they all develop pes cavus and hammer toes. Five of the 7 affected males show associated deafness and 3 of these 5 individuals also presented with mental retardation or social developmental delay. Motor nerve conduction velocities in affected males are normal to mildly delayed and sensory conduction velocities are markedly abnormal. Heterozygous females are asymptomatic. Close linkage to the Xg blood group locus (Xp22) was previously excluded in this family while weak linkage of the disease gene to DXYS1 (Xq13-q21) was suggested. The current study excludes the short arm and the proximal long arm of the X chromosome. Haplotype analysis of markers on the long arm demonstrates that HPRT is a proximal flanking marker and that the disease gene is closely linked to the marker DXS984. Further microsatellite markers are being studied in order to refine the region of the distal long arm of the X chromosome containing the gene causing the motor-sensory neuropathy in this family. This is the first such gene assigned to the distal region of Xq.

Priest, J.M.; Nouri, N.; Keats, B.J.B. [Louisiana State Univ. Medical Center, New Orleans, LA (United States)] [and others



Anterior ischemic optic neuropathy in patient with hereditary spherocytosis and coexisting angioid streaks.  


Purpose. To describe a rare case of hereditary spherocytosis (HE) with angioid streaks that developed anterior ischemic optic neuropathy (AION).?Method. Case report.?Results. A 53-year-old woman with HE had a 3-day history of blurred vision in the lower hemifield in the left eye. At presentation, her visual acuity was 20/20 OD and 20/200 OS. Perimetric testing showed a relative scotoma in the superior parafoveal region in the right eye and an inferior altitudinal field defect in the left eye. Fundus examination demonstrated angioid streaks in both eyes with swelling of the optic disc in the left eye. Both parvovirus B19 immunoglobulin M and immunoglobulin G were identified in her serum. ?Conclusions. This is the first report of AION in HE and coexisting angioid streaks. The infection by parvovirus itself might be involved in the development of AION. PMID:23112036

Sawada, Akira; Oie, Shinya; Mochizuki, Kiyofumi; Yamamoto, Tetsuya



Raised Intraocular Pressure as a Potential Risk Factor for Visual Loss in Leber Hereditary Optic Neuropathy  

PubMed Central

Leber Hereditary Optic Neuropathy (LHON) is an important cause of inherited mitochondrial blindness among young adults. The majority of patients carry one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A and m.14484T>C, all of which affect critical complex I subunits of the mitochondrial respiratory chain. LHON is characterised by marked incomplete penetrance, clearly implying that the mtDNA mutation is insufficient on its own to trigger retinal ganglion cell dysfunction and visual loss. In this case series of three affected patients harbouring the m.11778G>A mutation, we provide evidence suggesting that raised intraocular pressure could be a risk factor triggering visual loss in at-risk LHON carriers.

Thouin, Anais; Griffiths, Philip G.; Hudson, Gavin; Chinnery, Patrick F.; Yu-Wai-Man, Patrick



Teaching NeuroImages: Chiasmal enlargement and enhancement in Leber hereditary optic neuropathy.  


A 19-year-old man was admitted for subacute severe painless bilateral loss of vision. The patient was known to be a healthy carrier of the mitochondrial G11778A mutation, with a family history of Leber hereditary optic neuropathy. Funduscopy revealed bilateral optic disk elevation and hyperemia (figure). Goldmann visual fields demonstrated large central scotomas in both eyes. CSF disclosed normal opening pressure and cytochemical examination. Unexpectedly, brain MRI revealed an asymmetrical chiasmal enlargement and enhancement (figure). Similar cases have rarely been reported.(1,2) These findings would suggest disruption of the blood-brain barrier at the early stage of the disease,(2) likely due to an inflammatory-like mechanism. PMID:24145886

Ong, Elodie; Biotti, Damien; Abouaf, Lucie; Louis-Tisserand, Guy; Tilikete, Caroline; Vighetto, Alain



Clinical and electrophysiological recovery in Leber hereditary optic neuropathy with G3460A mutation.  


To report a case of clinical and electrophysiological recovery in Leber hereditary optic neuropathy (LHON) with G3460A Mutation. A 10-year-old boy with a three-month history of painless bilateral sequential visual loss upon presentation underwent visual acuity (diminished), anterior and posterior segment examination (normal), fluorescein angiography (normal), Goldman kinetic perimetry (bilateral central scotomata), genetic (a point G3460A mutation) and electrophysiological investigation (undetectable pattern visual evoked potentials (VEP); low amplitude, broadened and reduced flash VEPs and loss of the N95 component in the pattern electroretinograms). Diagnosis of LHON was made. Eighteen months later vision and electrophysiological tests results began spontaneously improving. Kinetic perimetry revealed reduced density and size of scotomata. Two years later, there had been further electrophysiological improvement. This report describes both clinical and electrophysiological improvement in LHON with G3460A mutation. PMID:22684678

Sharkawi, Eamon; Oleszczuk, Justyna D; Holder, Graham E; Raina, Joyti



Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.  

PubMed Central

The hereditary ataxias represent a clinically and genetically heterogeneous group of neurodegenerative disorders. Various classification schemes based on clinical criteria are being replaced as molecular characterization of the ataxias proceeds; so far, seven distinct autosomal dominant hereditary ataxias have been genetically mapped in the human genome. We report linkage to chromosome 16q22.1 for one of these genes (SCA4) in a five-generation family with an autosomal dominant, late-onset spinocerebellar ataxia; the gene is tightly linked to the microsatellite marker D16S397 (LOD score = 5.93 at theta = .00). In addition, we present clinical and electrophysiological data regarding the distinct and previously unreported phenotype consisting of ataxia with the invariant presence of a prominent axonal sensory neuropathy.

Flanigan, K.; Gardner, K.; Alderson, K.; Galster, B.; Otterud, B.; Leppert, M. F.; Kaplan, C.; Ptacek, L. J.



Leber's Hereditary Optic Neuropathy Affects Only Female Matrilineal Relatives in Two Chinese Families  

PubMed Central

Purpose. The purpose of this study was to investigate the role of modifier factors in the expression of Leber's hereditary optic neuropathy (LHON). Methods. Thirty-five subjects from two Han Chinese families with maternally transmitted LHON underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. Results. Matrilineal relatives in the two Chinese families exhibited a wide range of severity in visual impairment, from blindness to nearly normal vision. Very strikingly, all nine affected individuals of 21 matrilineal relatives (13 females/8 males) were female, which translates to 33% and 57% of penetrance for optic neuropathy in the two families. The average age at onset was 22 and 25 years. These observations were in contrast with typical features in many LHON pedigrees that have a predominance of affected males. Molecular analysis of their mtDNAs identified the homoplasmic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M1 and M10a. Of other variants, the L175F variant in CO3; the I58V variant in ND6; and the I189V, L292R, and S297A variants in CYTB were located at highly conserved residues of polypeptides. Conclusions. Only female matrilineal relatives with a wide range of penetrance, severity, and age at onset of optic neuropathy in these two Chinese pedigrees showed the involvement of X-linked or autosomal recessive modifier genes in the phenotypic manifestation of the G11778A mutation. Furthermore, mitochondrial haplogroup-specific variants, together with epigenetic and environmental factors, may contribute to the phenotypic manifestation of the primary LHON-associated G11778A mutation in these pedigrees.

Qu, Jia; Wang, Ying; Tong, Yi; Zhou, Xiangtian; Zhao, Fuxin; Yang, Li; Zhang, Shoukang; Zhang, Juanjuan; West, Constance E.; Guan, Min-Xin



Protection From Diabetes-Induced Peripheral Sensory Neuropathy -A Role For Elevated Glyoxalase I?  

PubMed Central

Diabetic neuropathy is a common complication of diabetes mellitus with over half of all patients developing neuropathy symptoms due to sensory nerve damage. Diabetes-induced hyperglycemia leads to the accelerated production of advanced glycation end products (AGEs) that alter proteins, thereby leading to neuronal dysfunction. The glyoxalase enzyme system, specifically glyoxalase I (GLO1), is responsible for detoxifying precursors of AGEs, such as methylglyoxal and other reactive dicarbonyls. The purpose of our studies was to determine if expression differences of GLO1 may play a role in the development of diabetic sensory neuropathy. BALB/cJ mice naturally express low levels of GLO1, while BALB/cByJ express approximately 10-fold higher levels on a similar genetic background due to increased copy numbers of GLO1. Five weeks following STZ injection, diabetic BALB/cJ mice developed a 68% increase in mechanical thresholds, characteristic of insensate neuropathy or loss of mechanical sensitivity. This behavior change correlated with a 38% reduction in intraepidermal nerve fiber density (IENFD). Diabetic BALB/cJ mice also had reduced expression of mitochondrial oxidative phosphorylation proteins in Complex I and V by 83% and 47%, respectively. Conversely, diabetic BALB/cByJ mice did not develop signs of neuropathy, changes in IENFD, or alterations in mitochondrial protein expression. Reduced expression of GLO1 paired with diabetes-induced hyperglycemia may lead to neuronal mitochondrial damage and symptoms of diabetic neuropathy. Therefore, AGEs, the glyoxalase system, and mitochondrial dysfunction may play a role in the development and modulation of diabetic peripheral neuropathy.

Jack, M.M.; Ryals, J.M.; Wright, D.E.



Acute sensory and autonomic neuropathy: possible association with coxsackie B virus infection.  

PubMed Central

This report describes a 26 year old woman with a Coxsackie B virus infection complicated by an acute pandysautonomic and sensory neuropathy. Electrophysiological studies suggested an axonal neuropathy. A sural nerve biopsy performed early in the disease showed axonal degeneration with a virtual absence of unmyelinated fibres and moderate loss of myelinated fibres, mainly affecting the small fibres; this differs from previous reports. An immune-mediated or direct virus action might explain the pathogenesis of this unusual evolution of a viral infection. Images

Pavesi, G; Gemignani, F; Macaluso, G M; Ventrua, P; Magnani, G; Fiocchi, A; Medici, D; Marbini, A; Mancia, D



mtDNA haplogroup distribution in Chinese patients with Leber’s hereditary optic neuropathy and G11778A mutation  

Microsoft Academic Search

Mitochondrial DNA background has been shown to be involved in the penetrance of Leber’s hereditary optic neuropathy (LHON) in western Eurasian populations. To analyze mtDNA haplogroup distribution pattern in Han Chinese patients with LHON and G11778A mutation, we analyzed the mtDNA haplogroups of 41 probands with LHON known to harbor G11778A mutation by sequencing the mtDNA control region hypervariable segments

Yanli Ji; Xiaoyun Jia; Qingjiong Zhang; Yong-Gang Yao



Molecular characterization of six Chinese families with m.3460G>A and Leber hereditary optic neuropathy  

Microsoft Academic Search

The primary mutation m.3460G>A occurs with a very low frequency (?1%) in Chinese patients with Leber hereditary optic neuropathy\\u000a (LHON). Up to now, there is no comprehensive study of Chinese patients harboring this mutation. We characterized six unrelated\\u000a probands with m.3460G>A in this study, which were identified from 1,626 patients with LHON or suspected with LHON. The overall\\u000a penetrance of

Dandan Yu; Xiaoyun Jia; A-Mei Zhang; Xiangming Guo; Ya-Ping Zhang; Qingjiong Zhang; Yong-Gang Yao



[Promising effects of pregabalin in the treatment of oxaliplatin-induced sensory neuropathy in patients with colorectal carcinoma].  


Thirteen patients with metastatic colorectal cancer who suffered from oxaliplatin-induced sensory neuropathy were evaluated to determine the neuropathy Grade before and after the administration of pregabalin. All patients received oxaliplatin as adjuvant or first-line chemotherapy. The mFOLFOX6 and CapeOX groups included 3 and 10 cases, respectively, and the average treatment regimens were 8 and 5 doses, respectively. Before receiving pregabalin, sensory neuropathy was classified as Grade 3 in 2 patients, as Grade 2 in 8 patients, and as Grade 1 in 3 patient. The average amount of pregabalin administered to patients was 237 (range: 150-450) mg. After administering pregabalin, we observed improvements in 8 neuropathy cases (61. 5%)within approximately 2 weeks. All side effects were mild. In this study, pregabalin was shown to positively impact sensory neuropathy resulting from oxaliplatin treatment and to enable the long-term use of oxaliplatin-based chemotherapy. PMID:24047775

Nagahara, Hisashi; Noda, Eiji; Maeda, Kiyoshi; Inoue, Toru; Hirakawa, Toshiki; Hasegawa, Tsuyoshi; Shibutani, Masatsune; Hirakawa, Kosei



Sensory ataxic neuropathy and esophageal achalasia in a patient with Sjogren's syndrome.  


We describe a patient who developed an ataxic sensory syndrome associated with xerophthalmia and progressive dysphagia with regurgitation. Electrophysiological findings were consistent with an axonal sensory neuropathy, and superficial peroneal nerve biopsy showed a reduction in number of myelinated fibers with epineurial inflammation. Rheumatoid factor, anti-SSA/SSB and antinuclear antibodies were positive and a diagnosis of Sjogren's syndrome was made. An endoscopic investigation revealed esophageal achalasia. We suggest that there may be a common autoimmune mechanism directed to different targets on the basis of this rare association. PMID:17221876

Poglio, Fabio; Mongini, Tiziana; Cocito, Dario



A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice  

Microsoft Academic Search

Whereas an important role of free radicals and oxidants in peripheral diabetic neuropathy is well established, the contribution of nitrosative stress and, in particular, of the highly reactive oxidant peroxynitrite, has not been properly explored. Our previous findings implicate peroxynitrite in diabetes-associated motor and sensory nerve conduction deficits and peripheral nerve energy deficiency and poly(ADP-ribose) polymerase activation associated with Type

Viktor R. Drel; Pal Pacher; Igor Vareniuk; Ivan Pavlov; Olga Ilnytska; Valeriy V. Lyzogubov; Jyoti Tibrewala; John T. Groves; Irina G. Obrosova



Sensory neuropathy in human immunodeficiency virus\\/acquired immunodeficiency syndrome patients: Protease inhibitorâ??mediated neurotoxicity  

Microsoft Academic Search

Objective: Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) is a common and disabling disorder, often associated with antiretroviral therapy (ART) use. We investigated the clinical features and associated pathogenic determinants of HIV-SN in a neurological cohort of HIV-infected patients, together with a novel model of HIV-SN. Methods: HIV-infected patients with neurological disease were investigated in terms of clinical and laboratory aspects

Jacqueline A. Pettersen; Gareth Jones; Catherine Worthington; Hartmut B. Krentz; Oliver T. Keppler; Ahmet Hoke; M. John Gill; Christopher Power



?? T cells infiltrating sensory nerve biopsies from patients with inflammatory neuropathy  

Microsoft Academic Search

Sensory nerve biopsy specimens from patients with Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy\\u000a (CIDP), and controls consisting of other neuropathies, were examined in order to characterise the nature and intensity of\\u000a any inflammatory infiltrate. In order to establish whether ?? T cells were present in these infiltrates we examined the expression\\u000a of ?? and ?? T cell receptors

John Winer; Sharon Hughes; Joanne Cooper; Anne Ben-Smith; Caroline Savage



Leber's hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation  

PubMed Central

We report here the clinical, genetic and molecular characterization of three Chinese families with Leber’s hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T14502C (I58V) mutation, which localized at a highly conserved isoleusine at position 58 of ND6, and distinct sets of mtDNA polymorphisms belonging to haplogroups M10a, F1a1 and H2. The occurrence of T14502C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Here, mtDNA variants I187T in the ND1, A122V in CO1, S99A in the in the A6 and V254L in CO3 exhibited an evolutionary conservation, indicating a potential modifying role in the development of visual impairment associated with T14502C mutation in those families. Furthermore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic manifestation of the LHON-associated T14502C mutation in these Chinese.

Zhao, Fuxin; Guan, Minqiang; Zhou, Xiangtian; Yuan, Meixia; Liang, Ming; Liu, Qi; Liu, Yan; Zhang, Yongmei; Yang, Li; Tong, Yi; Wei, Qi-Ping; Sun, Yan-Hong; Qu, Jia; Guan, Min-Xin



Leber's hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation  

PubMed Central

We report here the clinical, genetic and molecular characterization of four Chinese families with Leber’s hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T3394C (Y30H) mutation, which localized at a highly conserved tyrosine at position 30 of ND1, and distinct sets of mtDNA polymorphisms belonging to haplogroups D4b and M9a. The occurrence of T3394C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. However, there was the absence of functionally significant mtDNA mutations in these four Chinese pedigrees carrying the T3394C mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated T3394C mutation.

Liang, Min; Guan, Minqiang; Zhao, Fuxing; Zhou, Xiangtian; Yuan, Meixia; Tong, Yi; Yang, Li; Wei, Qi-Ping; Sun, Yan-Hong; Lu, Fan; Qu, Jia; Guan, Min-Xin



Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside  

PubMed Central

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

Koilkonda, Rajeshwari D.; Guy, John



Leber Hereditary Optic Neuropathy: Do Folate Pathway Gene Alterations Influence the Expression of Mitochondrial DNA Mutation?  

PubMed Central

Background: Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy leading to the loss of central vision. The primary cause of vision loss is mutation in the mitochondrial DNA (mtDNA), however, unknown secondary genetic and/or epigenetic risk factors are suggested to influence its neuropathology. In this study folate gene polymorphisms were examined as a possible LHON secondary genetic risk factor in Iranian patients. Methods: Common polymorphisms in the MTHFR (C677T and A1298C) and MTRR (A66G) genes were tested in 21 LHON patients and 150 normal controls. Results: Strong associations were observed between the LHON syndrome and C677T (P= 0.00) and A66G (P= 0.00) polymorphisms. However, no significant association was found between A1298C (P =0.69) and the LHON syndrome. Conclusion: This is the first study that shows MTHFR C677T and MTRR A66G polymorphisms play a role in the etiology of the LHON syndrome. This finding may help in the better understanding of mechanisms involved in neural degeneration and vision loss by LHON and hence the better treatment of patients.

Aleyasin, A; Ghazanfari, M; Houshmand, M



Hereditary neuropathy with liability to pressure palsies associated with central nervous system myelin lesions.  


Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder most commonly caused by a 1.5-Mb deletion in chromosome 17p11.2 which contains the peripheral myelin protein-22 (PMP22) gene. Mutations resulting in functional loss of one PMP22 gene copy are less frequent. We present a 51-year-old patient with a l.5-Mb deletion in chromosome 17p11.2 who exhibited signs of peripheral as well as central nervous system lesions. He gave a history of recurrent episodes of limb numbness and weakness with spontaneous but incomplete recovery since age 20. His father and two brothers had similar symptoms. Neurological examination revealed signs of multiple mononeuropathy associated with frontal lobe, corticospinal tract and cerebellar dysfunction, as well as signs of initial cognitive impairment. Electrophysiological investigations showed a demyelinating peripheral nerve disease with multiple conduction blocks and conduction disturbances in both optic nerves. Magnetic resonance imaging of the brain revealed multiple subcortical and periventricular foci of myelin lesions. The association of central and peripheral nervous system lesions in this patient indicates a possible role of PMP22 not only in peripheral but also in central nervous system myelin structure. PMID:11784354

Dackovi?, J; Rakocevi?-Stojanovi?, V; Pavlovi?, S; Zamurovi?, N; Dragasevi?, N; Romac, S; Apostolski, S



Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines.  


Leber hereditary optic neuropathy (LHON) is a maternally inherited form of retinal ganglion cell degeneration leading to optic atrophy which is caused by point mutations in the mitochondrial genome (mtDNA). Three pathogenic mutations (positions 11778/ND4, 3460/ND1 and 14484/ND6) account for the majority of LHON cases and they affect genes that encode for different subunits of mitochondrial complex I. Excitotoxic injury to retinal ganglion cells and the optic nerve has been previously hypothesized, especially given the high susceptibility of this neural cell type to glutamate toxicity. Osteosarcoma-derived cytoplasmic hybrids (cybrids) generated from six unrelated LHON patients, two cell lines for each pathogenic mutation, were compared with cybrids obtained from three healthy controls. Molecular and biochemical analyses showed that excitatory amino acid transporter 1 (EAAT1)/GLAST is the most active glutamate transporter in this cellular model. The glutamate uptake maximal velocity was significantly reduced in all LHON cybrids compared with control cybrids. This reduction was correlated in a mutation-specific fashion with the degree of mitochondrial production of reactive oxygen species, which is enhanced in LHON cybrids. Our findings support the hypothesis that the genetically determined mitochondrial dysfunction in LHON patients leads to impaired activity of the EAAT1 glutamate transporter. This observation is particularly relevant since EAAT1 is the major means of glutamate removal in the inner retina and this prevents retinal ganglion cells being damaged as a result of excitotoxicity. PMID:15342361

Beretta, Simone; Mattavelli, Laura; Sala, Gessica; Tremolizzo, Lucio; Schapira, Anthony H V; Martinuzzi, Andrea; Carelli, Valerio; Ferrarese, Carlo



The Role of Advanced Glycation Endproducts and Glyoxalase I in Diabetic Peripheral Sensory Neuropathy  

PubMed Central

Diabetic neuropathy is the most common and debilitating complication of diabetes mellitus with over half of all patients developing altered sensation as a result of damage to peripheral sensory neurons. Hyperglycemia results in altered nerve conduction velocities, loss of epidermal innervation, and the development of painful or painless signs and symptoms in the feet and hands. Current research has been unable to determine if a patient will develop insensate or painful neuropathy or be protected from peripheral nerve damage all together. One of the mechanisms that has been recognized to have a role in the pathogenesis of sensory neuron damage is the process of reactive dicarbonyls forming advanced glycation endproducts (AGEs) as a direct result of hyperglycemia. The glyoxalase system, composed of the enzymes glyoxalase I (GLO1) and glyoxalase II, is the main detoxification pathway involved in breaking down toxic reactive dicarbonyls before producing carbonyl stress and forming AGEs on proteins, lipids, or nucleic acids. This review discusses AGEs, GLO1, their role in diabetic neuropathy, and potential therapeutic targets of the AGE pathway.

Jack, M.M.; Wright, D.E.



Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy.  


Systemic vascular endothelial growth factor inhibition, in combination with chemotherapy, improves the outcome of patients with metastatic cancer. Peripheral sensory neuropathies occurring in patients receiving both drugs are attributed to the chemotherapy. Here, we provide unprecedented evidence that vascular endothelial growth factor receptor inhibitors trigger a painful neuropathy and aggravate paclitaxel-induced neuropathies in mice. By using transgenic mice with altered neuronal vascular endothelial growth factor receptor expression, systemic inhibition of vascular endothelial growth factor receptors was shown to interfere with the endogenous neuroprotective activities of vascular endothelial growth factor on sensory neurons. In vitro, vascular endothelial growth factor prevented primary dorsal root ganglion cultures from paclitaxel-induced neuronal stress and cell death by counteracting mitochondrial membrane potential decreases and normalizing hyperacetylation of ?-tubulin. In contrast, vascular endothelial growth factor receptor inhibitors exerted opposite effects. Intriguingly, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors exerted their effects through a mechanism whereby Hdac6, through Hsp90, controls vascular endothelial growth factor receptor-2-mediated expression of the anti-apoptotic Bcl2. Our observations that systemic anti-vascular endothelial growth factor therapies interfere with the neuroprotective activities of vascular endothelial growth factor may have important implications for the application of anti-vascular endothelial growth factor therapies in cancer patients. PMID:22734125

Verheyen, An; Peeraer, Eve; Nuydens, Rony; Dhondt, Joke; Poesen, Koen; Pintelon, Isabel; Daniels, Anneleen; Timmermans, Jean-Pierre; Meert, Theo; Carmeliet, Peter; Lambrechts, Diether




PubMed Central

Purpose The authors previously presented the results of their 2001 field investigation to rural Brazil to investigate a 336-member pedigree of Leber hereditary optic neuropathy (LHON). The present work describes the yearly field investigations 2001 to 2005, utilizing a variety of highly sophisticated psychophysical and electrophysiologic procedures, in asymptomatic LHON carriers, some of whom converted to affected status. Methods Careful, repeated examinations of 75 carriers of homoplasmic 11778 LHON mtDNA J-haplogroup mutants were performed as part of the field investigation of this pedigree. All subjects underwent a detailed neuro-ophthalmologic investigation, including formal visual fields (Humphrey; HVF) and fundus photography. In addition, many subjects underwent rigorous psychophysical examination, including Cambridge Research Systems color vision and contrast sensitivity testing, OCT, GDx, and multifocal visual evoked response (mfVER) and multifocal electroretinogram (mfERG). Two patients followed as nonsymptomatic LHON carriers converted to affected status. Results Many LHON carriers did, in fact, show subclinical or occult abnormalities. Focal edema was often seen involving the arcuate nerve fiber bundles, and this corresponded with areas of relative paracentral or arcuate scotomas on HVF testing. Compared to controls, LHON carriers had significant losses in color vision affecting mostly the red-green system and reduction in spatial but not temporal contrast sensitivity. The mfVER and mfERG data showed that most carriers had depressed central responses and abnormal interocular asymmetries. Conclusions In this very large pedigree of 11778 LHON, the carriers frequently showed manifestations of optic nerve impairments. Their occult disease reflected low-grade compromise that waxed and waned. In two cases, these changes led to a crescendo of dramatic impairments that characterize conversion to affected status.

Sadun, Alfredo A.; Salomao, Solange R.; Berezovsky, Adriana; Sadun, Federico; DeNegri, Anna Maria; Quiros, Peter A.; Chicani, Filipe; Ventura, Dora; Barboni, Piero; Sherman, Jerome; Sutter, Erich; Belfort, Rubens; Carelli, Valerio



Variation in OPA1 does not explain the incomplete penetrance of Leber hereditary optic neuropathy  

PubMed Central

Purpose Leber hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. These mtDNA pathogenic mutations have variable clinical penetrance. Recent linkage evidence raised the possibility that the nuclear gene optic atrophy 1 (OPA1) determines whether mtDNA mutation carriers develop blindness. To validate these findings we studied OPA1 in three independent LHON cohorts: sequencing the gene in discordant male sib pairs, carrying out a family-based association study of common functional genetic variants, and carrying out a population-based association study of the same genetic variants. Methods We tested 3 hypothesis in three separate study groups. Study group 1: Direct sequencing of OPA1 coding regions was performed using sequencing methodologies (Applied Biosystems, Foster City, CA). Chromatograms were compared with the GenBank reference sequence NM_015560.1. Splice-site prediction was performed using GeneSplicer. Study group 2: Genotyping for rs166850 and rs10451941 was performed by restriction fragment length polymorphism (RFLP) analysis with specific primers for both genotypes, using The restriction enzymes RsaI and FspBI to discriminate genotypes. Study group 3: Genotyping for rs166850 and rs10451941 was performed by primer extension of allele-specific extensions products by matrix-associated laser desorption/ionisation time-of-flight (MALDI-TOF, Seqeunom, San Diego, CA) mass spectrometry. Allele and genotype frequencies were compared using Pearson’s chi-square test. Multiple logistic regression was performed to look for interactions between the variables. All analyses were performed using SPSS software version 17.0 (SPSS Inc.). Results In all three groups we were unable to find an association between OPA1 genetic variation and visual failure in LHON mtDNA mutation carriers. Conclusions Our findings suggest that genetic variation in OPA1 is unlikely to make a major contribution to the risk of blindness in LHON mutation carriers.

Hudson, Gavin; Yu-Wai-Man, Patrick; Griffiths, Phillip G.; Caporali, Leonardo; Salomao, Solange S.; Berezovsky, Adriana; Carelli, Valerio; Zeviani, Massimo



[Spectrum of pathogenic mtDNA mutations in Leber hereditary optic neuropathy families from Siberia].  


The results of clinical, genealogical and molecular investigation of eighteen families with Leber hereditary optic neuropathy (LHON), identified on the territory of Siberia during the period from 1997 to 2005, are presented. Comprehensive analysis of mitochondrial genome variations in probands and their matrilineal relatives revealed the presence of relatively frequent (G11778A, G3460A, and T14484C), as well as rare and new mutations with the established or presumptive pathological effect (T10663C, G363A, C4640T, and A14619G). The G11778A mutation was detected in nine pedigrees (50%), mostly in the families of ethnic Russians. In eight of these families G11778A was found in preferred association with the coding-region substitutions, typical of western Eurasian mtDNA lineage (haplogroup) TJ. On the contrary, the G3460A mutation was detected in the three families belonging to the indigenous Siberian populations (Tuvinians, Altaians, and Buryats). It was associated with clearly different haplotypes of eastern Eurasian haplogroups, C3, D5, and D8. Unexpectedly, the G3460A de novo mutation was found in a large Tuvinian pedigree. At the same time, in eleven out of fourteen families of Caucasoid origin pathogenic mutations in the ND genes were associated with the T4216C and C1542A coding-region mutations, marking the root motif of haplogoup TJ. It is suggested that phylogenetically ancient mutations could have provided their carriers with the adaptive advantages upon the development of Central and Northern Europe at the end of the last glaciation (10 000 to 9 000 years ago), thereby, contributing to the preservation of weekly pathogenic LHON mutations, appearing at specific genetic background. PMID:16523671

Volod'ko, N V; L'vova, M A; Starikovskaia, E B; Derbeneva, O A; Bychkov, I Iu; Mikha?lovskaia, I E; Pogozheva, I V; Fedotov, F F; Soyan, G V; Procaccio, V; Wallace, D C; Sukernik, R I



Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans  

PubMed Central

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a “complex” disease.

Ji, Fuyun; Sharpley, Mark S.; Derbeneva, Olga; Alves, Leonardo Scherer; Qian, Pin; Wang, Yaoli; Chalkia, Dimitra; Lvova, Maria; Xu, Jiancheng; Yao, Wei; Simon, Mariella; Platt, Julia; Xu, Shiqin; Angelin, Alessia; Davila, Antonio; Huang, Taosheng; Wang, Ping H.; Chuang, Lee-Ming; Moore, Lorna G.; Qian, Guisheng; Wallace, Douglas C.



Clinical characterization and mitochondrial DNA sequence variations in Leber hereditary optic neuropathy  

PubMed Central

Purpose Leber hereditary optic neuropathy (LHON), a maternally inherited disorder, results from point mutations in mitochondrial DNA (mtDNA). MtDNA is highly polymorphic in nature with very high mutation rate, 10–17 fold higher as compared to nuclear genome. Identification of new mtDNA sequence variations is necessary to establish a clean link with human disease. Thus this study was aimed to assess or evaluate LHON patients for novel mtDNA sequence variations. Materials and Methods Twenty LHON patients were selected from the neuro-ophthalmology clinic of the All India Institute of Medical Sciences, New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. For structural analysis (molecular modeling and simulation) the MODELER 9.2 program in Discovery Studio (DS 2.0) was used. Results MtDNA sequencing revealed a total of 47 nucleotide variations in the 20 LHON patients and 29 variations in 20 controls. Of 47 changes in patients 21.2% (10/47) were nonsynonymous and the remaining 78.72% (37/47) were synonymous. Five nonsynonymous changes, including primary LHON mutations (NADH dehydrogenase subunit 1 [ND1]:p.A52T, NADH dehydrogenase subunit 6 [ND6]:p.M64V, adenosine triphosphate [ATP] synthase subunit a (F-ATPase protein 6) [ATPase6]:p.M181T, NADH dehydrogenase subunit 4 [ND4]:p.R340H, and cytochrome B [CYB]:p.F181L), were found to be pathogenic. A greater number of changes were present in complex I (53.19%; 25/47), followed by complex III (19.14%; 9/47), then complex IV (19.14%; 9/47), then complex V (8.5%; 4/47). Nonsynonymous variations may impair respiratory chain and oxidative phosphorylation (OXPHOS) pathways, which results in low ATP production and elevated reactive oxygen species (ROS) levels. Oxidative stress is the underlying etiology in various diseases and also plays a crucial role in LHON. Conclusions This study describes the role of mtDNA sequence variations in LHON patients. Primary LHON mutations of mtDNA are main variants leading to LHON, but mutations in other mitochondrial genes may also play an important role in pathogenesis of LHON as indicated in the present study. Certain alleles in certain haplogroups have protective or deleterious roles and hence there is a need to analyze a large number of cases for correlating phenotype and disease severity with mutation and mtDNA haplogroups.

Kumar, Manoj; Kaur, Punit; Kumar, Manoj; Saxena, Rohit; Sharma, Pradeep



Weighted needle pinprick sensory thresholds: a simple test of sensory function in diabetic peripheral neuropathy  

Microsoft Academic Search

A simple device is described, consisting of 12 weighted 23 gauge disposable needles (0.2 to 5.2 g), for testing sensation in busy diabetic clinics. The pinprick sensory threshold (PPT) is the lightest weighted needle which consistently elicits a sharp sensation. The subjects were 48 healthy controls (hospital staff), 44 diabetic patients without neuropathic symptoms, and 35 diabetic patients with chronic

A W Chan; I A MacFarlane; D Bowsher; J A Campbell



Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy  

PubMed Central

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function.

Kennerson, Marina L.; Nicholson, Garth A.; Kaler, Stephen G.; Kowalski, Bartosz; Mercer, Julian F.B.; Tang, Jingrong; Llanos, Roxana M.; Chu, Shannon; Takata, Reinaldo I.; Speck-Martins, Carlos E.; Baets, Jonathan; Almeida-Souza, Leonardo; Fischer, Dirk; Timmerman, Vincent; Taylor, Philip E.; Scherer, Steven S.; Ferguson, Toby A.; Bird, Thomas D.; De Jonghe, Peter; Feely, Shawna M.E.; Shy, Michael E.; Garbern, James Y.



Magnetic resonance imaging, magnetisation transfer imaging, and diffusion weighted imaging correlates of optic nerve, brain, and cervical cord damage in Leber's hereditary optic neuropathy  

Microsoft Academic Search

OBJECTIVESLeber's hereditary optic neuropathy (LHON) is a mitochondrial disease leading to bilateral loss of central vision and severe optic nerve atrophy. A subtype of LHON presents additional clinical and MRI aspects indistinguishable from those of multiple sclerosis (MS) (LHON-MS). In patients with LHON or LHON-MS, an assessment was made of (a) the severity of optic nerve damage, using MRI and

M Inglese; M Rovaris; S Bianchi; L La Mantia; G L Mancardi; A Ghezzi; P Montagna; F Salvi; M Filippi



Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies  

PubMed Central

Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

Jimenez-Andrade, Juan M; Herrera, Monica B; Ghilardi, Joseph R; Vardanyan, Marina; Melemedjian, Ohannes K; Mantyh, Patrick W



Orbital high resolution magnetic resonance imaging with fast spin echo in the acute stage of Leber's hereditary optic neuropathy  

PubMed Central

Some evidence suggests that the primary locus of the lesion in Leber's hereditary optic neuropathy (LHON) may be intraocular rather than retrobulbar. To clarify this issue, the condition of the retrobulbar portion of the optic nerve was evaluated in patients with the acute stage of LHON. High resolution MRI with fast spin echo sequences of the optic nerve complex in the orbit was carried out. Five patients with acute stage LHON were compared with seven patients with acute stage optic neuritis. On T2 weighted fast spin echo MRI, signal changes did not appear in the retrobulbar optic nerve complex in acute stage LHON. By comparison, patients with optic neuritis showed pronounced high signals in the optic nerve. Subsequent orbital MRI in the atrophic stages of the same patients with LHON showed an increase in signal intensity in the optic nerve toward the orbital apex in both eyes. The present results support the hypothesis that a primary lesion in LHON may be intraocular.??

Mashima, Y.; Oshitari, K.; Imamura, Y.; Momoshima, S.; Shiga, H.; Oguchi, Y.



Acute motor-sensory axonal neuropathy associated with active systemic lupus erythematosus and anticardiolipin antibodies.  


Acute motor-sensory axonal neuropathy (AMSAN) is an axonal variant of Guillian-Barré syndrome (GBS) that presents with acute ascending quadriparesis. This has generally been described in association with Campylobacter jejuni infections or with anti-ganglioside antibodies. Known cases have shown a slow recovery and a poor prognosis. We report a case with clinical and electrophysiological evidence of AMSAN in association with active systemic lupus erythematosus (SLE) and anticardiolipin antibodies but not the other associations, with a rapid response to combination immunosuppressant and intravenous immunoglobulin (IVIg) therapy. The association between AMSAN and SLE has not been previously described. This case illustrates that early recognition and the utilization of electrophysiologic techniques may be beneficial in the diagnosis and management of GBS associated with SLE. Fulminant or rapidly progressive cases should be managed in specialized intensive care units. Combination therapy of immunosuppressants and IVIg may be beneficial in non-vasculitic axonal radiculo-neuropathies associated with SLE, resulting in good outcomes. PMID:17039164

Ubogu, E E; Zaidat, O O; Suarez, J I



Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres.  


The aim of this study was to investigate the characteristics of prediabetes (preDM) and early (<3 years) diabetes mellitus type 2 (eDM2)-associated neuropathy and the value of recently proposed diagnostic criteria for diabetic sensorimotor polyneuropathy (DSPN). A prospective case-control study in a group of 48 consecutive patients with eDM2, 16 preDM patients and 40 age- and sex-matched normoglycaemic controls was performed. Clinical and laboratory diagnostic tests were used to detect neuropathic abnormalities; these were further classified in terms of recent diagnostic criteria. Criteria for confirmed DSPN based on abnormal nerve conduction (NC) studies were met in 7 (14.6%) eDM2 patients compared to no control (p < 0.05), and the proportion significantly increased to 37.5% compared to 2.5% controls (p < 0.001), if intraepidermal nerve fibre density (IENFD) was used as an alternative criterion in addition to NC. The subclinical DSPN criteria based on NC abnormalities were met in 4.2% eDM2 patients, while the proportion of preDM and eDM2 cases with subclinical sensory small-fibre involvement documented by IENFD reached 12.5% and 22.9% compared with 2.5% controls (p = 0.005 for eDM2). The absolute IENFD values from distal leg were significantly lower in both eDM2 (p < 0.0001) and preDM patients (p = 0.005) compared to controls. Neuropathy associated with preDM/eDM2 predominantly involves sensory small fibres. PMID:22971096

Divisova, Sarka; Vlckova, Eva; Hnojcikova, Maria; Skorna, Miroslav; Nemec, Martin; Dubovy, Petr; Dusek, Ladislav; Jarkovsky, Jiri; Belobradkova, Jana; Bednarik, Josef



A report of hereditary neuropathy with liability to pressure palsy (HNPP) presenting with brachial plexopathy: the value of complete electrodiagnostic testing.  


Patients with hereditary neuropathy with liability to pressure palsy (HNPP) typically present with a mononeuropathy (particularly peroneal or ulnar palsy) or a brachial plexopathy. Careful electrodiagnostic testing has an important role in establishing the diagnosis of HNPP differentiating this condition from other inherited or acquired neuropathies as well as obviating the need for unnecessary surgeries. We present a case of a patient who presented with a painless brachial plexopathy who was found to have multiple sites of segmental demyelination on nerve conduction studies, consistent with HNPP. We review the clinical and electrodiagnostic features of HNPP including the key electrodiagnostic findings to screen for this disorder. PMID:21988036

Bulusu, Srinivas; McMillan, Hugh J



The Background of Mitochondrial DNA Haplogroup J Increases the Sensitivity of Leber's Hereditary Optic Neuropathy Cells to 2,5-Hexanedione Toxicity  

Microsoft Academic Search

Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778\\/ND4 and 14484\\/ND6 mutations. Recently it was also documented

Anna Ghelli; Anna Maria Porcelli; Claudia Zanna; Sara Vidoni; Stefano Mattioli; Anna Barbieri; Luisa Iommarini; Maria Pala; Alessandro Achilli; Antonio Torroni; Michela Rugolo; Valerio Carelli; Paul Cobine



A Mitochondrial DNA Mutation at Nucleotide Pair 14459 of the NADH Dehydrogenase Subunit 6 Gene Associated with Maternally Inherited Leber Hereditary Optic Neuropathy and Dystonia  

Microsoft Academic Search

A five-generation Hispanic family expressing maternally transmitted Leber hereditary optic neuropathy and\\/or early-onset dystonia associated with bilateral basal ganglia lesions was studied. Buffy coat mitochondrial DNA (mtDNA) from a severely affected child was amplified by the polymerase chain reaction and greater than 90% sequenced. The mtDNA proved to be a Native American haplogroup D genotype and differed from the standard

Albert S. Jun; Michael D. Brown; Douglas C. Wallace



A comparison of nerve conduction velocities and current perception thresholds as correlates of clinical severity of diabetic sensory neuropathy.  

PubMed Central

Nerve conduction velocities (NCVs) are the standard measurements used to confirm the presence or absence of diabetic neuropathy. NCVs were contrasted with the newer technique of measurement of alternating current perception thresholds (CPTs) in assessing the quantitative level of correlation with severity of diabetic sensory neuropathy. A very detailed, scored neurological history (symptoms) and physical examination, emphasising sensory assessment, was conducted on 71 individuals with diabetic neuropathy of varying degrees of severity. Sensory and motor NCVs and CPTs at 5, 250, and 2000 Hz of the upper and lower extremities were determined for these individuals. In addition, vibration thresholds (VTs) were measured as a third modality. Twenty eight individuals underwent repeated evaluations at 2, 6, 10 and 12 months after the initial procedures. Using the results of 169 complete evaluations, correlations were determined between physical scores (PS) and symptoms scores (SS) and NCVs. NCV correlations with the SS were weaker than with the PS. The strongest of the correlations were found between the PS and motor NCVs of the median nerve (rho = 0.29) and the tibial nerve (rho = 0.38). Normal NCVs were present in the face of very significant historical and physical abnormality. Correlations of the SS and PS with both VTs and CPTs were higher than with the NCVs. CPTs proved the more effective as predictors of both symptomatic and physical impairment. NCVs appear to lack the resolving power necessary to evaluate subtle differences in clinical state of diabetic sensory neuropathy. The supplementary use of current perception testing may improve the quantitative assessment of this condition.

Rendell, M S; Katims, J J; Richter, R; Rowland, F



Low penetrance of Leber's hereditary optic neuropathy in ten Han Chinese families carrying the ND6 T11484C mutation  

PubMed Central

We report there the clinical, genetic and molecular characterization of 10 Han Chinese families with Leber’s hereditary optic neuropathy. Clinical evaluation revealed that ten families exhibited extremely low penetrance of visual impairment, with the average of 10%. In particular, ten (8 males/2 females) of 114 matrilineal relatives in these families exhibited the variable severity and age-at-onset in visual dysfunction. The average age-of-onset of vision loss was 19 years old. Molecular analysis of mitochondrial DNA (mtDNA) identified the homoplasmic ND6 T14484C mutation and distinct sets of variants, belonging to the Asian haplogroups B5b, D4, D4g1b, G3a2, R11, R11a and Z3, respectively. However, there was the absence of secondary LHON-associated mtDNA mutations in these ten Chinese families: The low penetrance of vision loss in these Chinese pedigrees strongly indicated that the T14484C mutation was itself insufficient to produce a clinical phenotype. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the T14484C mutation in those Chinese families with low penentrace of vision loss. However, nuclear modifier genes and environmental factors appear to be modifier factors for the phenotypic manifestation of the T14484C mutation in these Chinese families.

Qu, Jia; Zhou, Xiangtian; Zhao, Fuxin; Liu, Xiaoling; Zhang, Minglian; Sun, Yan-Hong; Liang, Min; Yuan, Meixia; Liu, Qi; Tong, Yi; Wei, Qi-Ping; Yang, Li; Guan, Min-Xin



mtDNA haplogroup distribution in Chinese patients with Leber's hereditary optic neuropathy and G11778A mutation.  


Mitochondrial DNA background has been shown to be involved in the penetrance of Leber's hereditary optic neuropathy (LHON) in western Eurasian populations. To analyze mtDNA haplogroup distribution pattern in Han Chinese patients with LHON and G11778A mutation, we analyzed the mtDNA haplogroups of 41 probands with LHON known to harbor G11778A mutation by sequencing the mtDNA control region hypervariable segments and some coding region polymorphisms. Each mtDNA was classified according to the available East Asian haplogroup system. The haplogroup distribution pattern of LHON sample was then compared to the reported Han Chinese samples. Haplogroups M7, D, B, and A were detected in 11 (26.8%), 10 (24.4%), 8 (19.5%), and 5 (12.2%) LHON families, respectively, and accounted for 82.9% of the total samples examined. For the remaining seven mtDNAs, six belonged to M8a, M10a, C, N9a, F1a, and R11, respectively, and one could only be assigned into macro-haplogroup M. The LHON sample was distinguished from other Han Chinese samples in the principal component map based on haplogroup distribution frequency. Our results show that matrilineal genetic components of Chinese LHON patients with G11778A are diverse and differ from related Han Chinese regional samples. mtDNA background might affect the expression of LHON and the G11778A mutation in Chinese population. PMID:17942074

Ji, Yanli; Jia, Xiaoyun; Zhang, Qingjiong; Yao, Yong-Gang



Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy  

PubMed Central

Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits of the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I). Development of gene therapies for LHON has been impeded by genetic heterogeneity and the need to deliver therapies to the mitochondria of retinal ganglion cells (RGCs), the cells primarily affected in LHON. The therapy under development entails intraocular injection of a nuclear yeast gene NADH-quinone oxidoreductase (NDI1) that encodes a single subunit complex I equivalent and as such is mutation independent. NDI1 is imported into mitochondria due to an endogenous mitochondrial localisation signal. Intravitreal injection represents a clinically relevant route of delivery to RGCs not previously used for NDI1. In this study, recombinant adenoassociated virus (AAV) serotype 2 expressing NDI1 (AAV-NDI1) was shown to protect RGCs in a rotenone-induced murine model of LHON. AAV-NDI1 significantly reduced RGC death by 1.5-fold and optic nerve atrophy by 1.4-fold. This led to a significant preservation of retinal function as assessed by manganese enhanced magnetic resonance imaging and optokinetic responses. Intraocular injection of AAV-NDI1 overcomes many barriers previously associated with developing therapies for LHON and holds great therapeutic promise for a mitochondrial disorder for which there are no effective therapies.

Chadderton, Naomi; Palfi, Arpad; Millington-Ward, Sophia; Gobbo, Oliverio; Overlack, Nora; Carrigan, Matthew; O'Reilly, Mary; Campbell, Matthew; Ehrhardt, Carsten; Wolfrum, Uwe; Humphries, Peter; Kenna, Paul F; Jane Farrar, G



[Following sensory neuropathy, anti-Hu antibody-positive paraneoplastic neurological syndrome presenting with limbic encephalitis occurs after complete remission].  


Paraneoplastic limbic encephalitis is a rare neurological disorder that frequently precedes the detection of malignancy. We report the case of a 68-year-old male with small-cell lung cancer who developed paraneoplastic limbic encephalitis associated with presence of the anti-Hu antibody, after achieving complete remission of the tumor by chemotherapy. The patient visited our hospital because of progressive sensory disturbance of the distal extremities at 65 years of age. Though paraneoplastic sensory neuropathy was suspected, we could not find any tumor and he did not improve with steroids or immunoglobulin therapy. Chest computed tomography (CT) revealed large mediastinal lymphadenopathy. He was subsequently diagnosed with small cell lung cancer at one year and three months after the neurological symptoms occurred. As his serum analysis was positive for the anti-Hu antibody, we diagnosed paraneoplastic sensory neuropathy. The lung cancer disappeared with chemotherapy, but he had developed short-term memory loss six months later. Brain fluid attenuated inversion recovery (FLAIR) imaging showed an abnormal high-intensity lesion in the left medial temporal lobe including the hippocampus. We therefore made the diagnosis of paraneoplastic limbic encephalitis following subacute sensory neuropathy associated with the anti-Hu antibody. To our knowledge, this is the first report of a patient presenting with paraneoplastic neurological syndrome in which limbic encephalitis developed after tumor disappearance. So we must recognize the possibility of neurological symptoms occurring during remission. As the mechanism of pathogenesis, delayed neuronal cell damage due to immune responses against the tumor is implicated. PMID:23603543

Fukami, Yuki; Umemura, Toshitaka; Shimono, Tetufumi; Yokoi, Takamasa; Kamijo, Mikiko; Sakakibara, Toshimasa



Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy  

PubMed Central

Sensory neuropathy (HIV-SN) is a common cause of pain in HIV-infected people. Establishing a diagnosis of HIV-SN is important, especially when contemplating opioid use in high risk populations. However physical findings of HIV-SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self-report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV-SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV-SN were measured by a modified Total Neuropathy Score (TNS), composed of 6 objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self-report of DNPP was associated with all 6 TNS items in univariate analysis and with 4 TNS items in multivariate analysis. The sensitivity and specificity of self-report of DNPP in detecting the presence of a sensory abnormality was 52% and 92% respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV-infected patients reporting symptoms consistent with HIV-SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV-SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history.

Robinson-Papp, J.; Morgello, S.; Vaida, F.; Fitzsimons, C.; Simpson, D.M.; Elliott, K.J.; Al-Lozi, M.; Gelman, B.B.; Clifford, D.; Marra, C.M.; McCutchan, J.A.; Atkinson, J.H.; Dworkin, R.H.; Grant, I.; Ellis, R.



Diabetic neuropathy.  


Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the commonest accounting for 75% DN. Asymmetrical neuropathies may involve cranial nerves, thoracic or limb nerves; are of acute onset resulting from ischaemic infarction of vasa nervosa. Asymmetric neuropathies in diabetic patients should be investigated for entrapment neuropathy. Diabetic amyotrophy, initially considered to result from metabolic changes, and later ischaemia, is now attributed to immunological changes. For diagnosis of DN, symptoms, signs, quantitative sensory testing, nerve conduction study, and autonomic testing are used; and two of these five are recommended for clinical diagnosis. Management of DN includes control of hyperglycaemia, other cardiovascular risk factors; alpha lipoic acid and L carnitine. For neuropathic pain, analgesics, non-steroidal anti-inflammatory drugs, antidepressants, and anticonvulsants are recommended. The treatment of autonomic neuropathy is symptomatic. PMID:16461471

Bansal, V; Kalita, J; Misra, U K



Diabetic neuropathy  

PubMed Central

Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the commonest accounting for 75% DN. Asymmetrical neuropathies may involve cranial nerves, thoracic or limb nerves; are of acute onset resulting from ischaemic infarction of vasa nervosa. Asymmetric neuropathies in diabetic patients should be investigated for entrapment neuropathy. Diabetic amyotrophy, initially considered to result from metabolic changes, and later ischaemia, is now attributed to immunological changes. For diagnosis of DN, symptoms, signs, quantitative sensory testing, nerve conduction study, and autonomic testing are used; and two of these five are recommended for clinical diagnosis. Management of DN includes control of hyperglycaemia, other cardiovascular risk factors; ? lipoic acid and L carnitine. For neuropathic pain, analgesics, non?steroidal anti?inflammatory drugs, antidepressants, and anticonvulsants are recommended. The treatment of autonomic neuropathy is symptomatic.

Bansal, V; Kalita, J; Misra, U K



Very high penetrance and occurrence of Leber's hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation  

PubMed Central

We report here the clinical, genetics and molecular characterization of a five-generation Han Chinese family with Leber’s hereditary optic neuropathy (LHON). Strikingly, this family exhibits very high penetrance and occurrence of optic neuropathy. In particular, twenty-five (10 males/15 females) of 30 matrilineal relatives exhibited the variable severity, ranging from profound to mild of visual impairment. This penetrance of optic neuropathy in this Chinese family is much higher than those in many families with LHON worldwide. The age-at-onset for visual impairment in matrilineal relatives in this Chinese family varied from 7 to 24 years old, with the average of 15 years old. Furthermore, the ratio between affected male and female matrilineal relatives is 1:1.5 in the Chinese family. This observation is in contrast with the typical features in LHON pedigrees that there was predominance of affected males in LHON in many families from different ethnic origins. Molecular analysis of mitochondrial genome identified the known ND4 G11778A mutation and 51 variants, belonging to Asian haplogroup C4a1. The absence of other known secondary LHON-associated and functionally significant mtDNA mutations in this Chinese family suggested that mitochondrial variants may not play an important role in the phenotypic manifestation of the G11778A mutation in this Chinese family. Therefore, nuclear modifier gene(s) may be responsible for very high penetrance and occurrence of optic neuropathy in this Chinese pedigree.

Zhou, Xiangtian; Zhang, Hongxing; Zhao, Fuxin; Ji, Yanchun; Tong, Yi; Zhang, Juanjuan; Zhang, Yu; Yang, Li; Qian, Yaping; Lu, Fan; Qu, Jia; Guan, Min-Xin



A 1.5 Mb submicroscopic deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies  

Microsoft Academic Search

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies that was recently associated with a 1.5 Mb deletion in chromosome 17p11.2-p12. Duplication of the same region is known to be associated with Charcot-Marie-Tooth disease type 1A (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity. The CMT1A duplication

D. Lorenzetti; B. B. Roa; N. E. Abbas



A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia.  

PubMed Central

A five-generation Hispanic family expressing maternally transmitted Leber hereditary optic neuropathy and/or early-onset dystonia associated with bilateral basal ganglia lesions was studied. Buffy coat mitochondrial DNA (mtDNA) from a severely affected child was amplified by the polymerase chain reaction and greater than 90% sequenced. The mtDNA proved to be a Native American haplogroup D genotype and differed from the standard "Cambridge" sequence at 40 nucleotide positions. One of these variants, a G-to-A transition at nucleotide pair (np) 14459, changed a moderately conserved alanine to a valine at NADH dehydrogenase subunit 6 (ND6) residue 72. The np 14459 variant was not found in any of 38 Native American haplogroup D mtDNAs, nor was it detected in 108 Asian, 103 Caucasian, or 99 African mtDNAs. Six maternal relatives in three generations were tested and were found to harbor the mutation, with one female affected with Leber hereditary optic neuropathy being heteroplasmic. Thus, the np 14459 G-to-A missense mutation is specific to this family, alters a moderately conserved amino acid in a complex I gene, is a unique mtDNA variant in Native American haplogroup D, and is heteroplasmic, suggesting that it is the disease-causing mutation. Images

Jun, A S; Brown, M D; Wallace, D C



The mitochondrial tRNA Glu A14693G mutation may influence the phenotypic manifestation of ND1 G3460A mutation in a Chinese family with Leber’s hereditary optic neuropathy  

Microsoft Academic Search

We report here the clinical, genetic, and molecular characterization of one Han Chinese family with maternally transmitted Leber’s hereditary optic neuropathy (LHON). Three of seven matrilineal relatives in this family exhibited the variable degree of central vision loss at the age of 12, 14, and 16 years old, respectively. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed

Yi Tong; Yijian Mao; Xiangtian Zhou; Li Yang; Juanjuan Zhang; Wanshi Cai; Fuxing Zhao; Xinjian Wang; Fan Lu; Jia Qu; Min-Xin Guan



Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C.  


Charcot-Marie-Tooth disease type 1C (CMT1C) is a dominantly inherited motor and sensory neuropathy. Despite human genetic evidence linking missense mutations in SIMPLE to CMT1C, the in vivo role of CMT1C-linked SIMPLE mutations remains undetermined. To investigate the molecular mechanism underlying CMT1C pathogenesis, we generated transgenic mice expressing either wild-type or CMT1C-linked W116G human SIMPLE. Mice expressing mutant, but not wild type, SIMPLE develop a late-onset motor and sensory neuropathy that recapitulates key clinical features of CMT1C disease. SIMPLE mutant mice exhibit motor and sensory behavioral impairments accompanied by decreased motor and sensory nerve conduction velocity and reduced compound muscle action potential amplitude. This neuropathy phenotype is associated with focally infolded myelin loops that protrude into the axons at paranodal regions and near Schmidt-Lanterman incisures of peripheral nerves. We find that myelin infolding is often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. Our findings support that SIMPLE mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. The results from this study suggest that myelin infolding and paranodal damage may represent pathogenic precursors preceding demyelination and axonal degeneration in CMT1C patients. PMID:23359569

Lee, Samuel M; Sha, Di; Mohammed, Anum A; Asress, Seneshaw; Glass, Jonathan D; Chin, Lih-Shen; Li, Lian



Association Between Arsenic Exposure and a Measure of Subclinical Sensory Neuropathy in Bangladesh  

Microsoft Academic Search

Objectives: We examined the association between arsenic exposure and peripheral neuropathy in Bangladesh, where the population has been chronically exposed to arsenic in drinking water. Methods: We conducted a cross-sectional study of 137 subjects derived from a larger cohort. Exposure measures included individual water arsenic concentration, cumulative arsenic index, and urinary arsenic concentration taken at two time points (2001 and

Danella M. Hafeman; Habibul Ahsan; Elan D. Louis; Abu B. Siddique; MBBS Vesna Slavkovich; Zhongqi Cheng; Alexander van Geen; Joseph H. Graziano


Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction  

Microsoft Academic Search

Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel-

Sarah J. L. Flatters; Gary J. Bennett



Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells.  


Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ?1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future. PMID:22390282

Iyer, Shilpa; Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R; Bennett, James P



Mitochondrial Gene Therapy Improves Respiration, Biogenesis, and Transcription in G11778A Leber's Hereditary Optic Neuropathy and T8993G Leigh's Syndrome Cells  

PubMed Central

Abstract Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ?1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future.

Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R.



Detection of the mtDNA 14484 mutation on an African-specific haplotype: Implications about its role in causing Leber hereditary optic neuropathy  

SciTech Connect

Leber hereditary optic neuropathy (LHON) is a maternally transmitted disease whose primary clinical manifestation is acute or subacute bilateral loss of central vision leading to central scotoma and blindness. To date, LHON has been associated with 18 mtDNA missense mutations, even though, for many of these mutations, it remains unclear whether they cause the disease, contribute to the pathology, or are nonpathogenic mtDNA polymorphisms. On the basis of numerous criteria, which include the specificity for LHON, the frequency in the general population, and the penetrance within affected pedigrees, the detection of associated defects in the respiratory chain, mutations at three nucleotide positions (nps), 11778 (G{r_arrow}A), 3460 (G{r_arrow}A), and 14484 (T{r_arrow}C) have been classified as high-risk and primary LHON mutations. Overall, these three mutations encompass {ge}90% of the LHON cases. 29 refs., 1 fig.

Torroni, A.; Petrozzi, M.; Terracina, M. [Universita` di Roma (Italy)] [and others



Mice with a mutation in the dynein heavy chain 1 gene display sensory neuropathy but lack motor neuron disease.  


In neurons, cytoplasmic dynein functions as a molecular motor responsible for retrograde axonal transport. An impairment of axonal transport is thought to play a key role in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis, the most frequent motor neuron disease in the elderly. In this regard, previous studies described two heterozygous mouse strains bearing missense point mutations in the dynein heavy chain 1 gene that were reported to display late-onset progressive motor neuron degeneration. Here we show, however, that one of these mutant strains, the so-called Cra mice does not suffer from motor neuron loss, even in aged animals. Consistently, we did not observe electrophysiological or biochemical signs of muscle denervation, indicative of motor neuron disease. The "hindlimb clasping" phenotype of Cra mice could rather be due to the prominent degeneration of sensory neurons associated with a loss of muscle spindles. Altogether, these findings show that dynein heavy chain mutation triggers sensory neuropathy rather than motor neuron disease. PMID:18952079

Dupuis, Luc; Fergani, Anissa; Braunstein, Kerstin E; Eschbach, Judith; Holl, Nathalie; Rene, Frédérique; Gonzalez De Aguilar, Jose-Luis; Zoerner, Björn; Schwalenstocker, Birgit; Ludolph, Albert C; Loeffler, Jean-Philippe



Leber's Hereditary Optic Neuropathy Is Associated with the T3866C Mutation in Mitochondrial ND1 Gene in Three Han Chinese Families  

PubMed Central

Purpose. To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON). Methods. Seventy-one subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included the measurements of the rates of endogenous, substrate-dependent respirations, the adenosine triphosphate (ATP) production and generation of reactive oxygen species using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects. Results. Ten of 41 matrilineal relatives exhibited variable severity and age at onset of optic neuropathy. The average age at onset of optic neuropathy in matrilineal relatives of the three families was 5, 11, and 24 years, respectively. Molecular analysis identified the ND1 T3866C (I187T) mutation and distinct sets of polymorphisms belonging to the Eastern Asian haplogroups D4a, M10a, and R, respectively. The I187T mutation is localized at the highly conserved isoleucine at a transmembrane domain of the ND1 polypeptide. The marked reductions in the rate of endogenous, malate/glutamate-promoted and succinate/glycerol-3-phosphate-promoted respiration were observed in mutant cell lines carrying the T3866C mutation. The deficient respiration is responsible for the reduced ATP synthesis and increased generation of reactive oxygen species. Conclusions. Our data convincingly show that the ND1 T3866C mutation leads to LHON. This mutation may be insufficient to produce a clinical phenotype. Other modifier factors may contribute to the phenotypic manifestation of the T3866C mutation. The T3866C mutation should be added to the list of inherited factors for molecular diagnosis of LHON. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON.

Zhou, Xiangtian; Qian, Yaping; Zhang, Juanjuan; Tong, Yi; Jiang, Pingping; Liang, Min; Dai, Xianning; Zhou, Huihui; Zhao, Fuxin; Ji, Yanchun; Mo, Jun Qin; Qu, Jia; Guan, Min-Xin



A longitudinal study of sensory biomarkers of progression in patients with diabetic peripheral neuropathy using skin biopsies.  


We aimed to identify biomarkers in skin punch biopsies that could be used to monitor progression of diabetic peripheral neuropathy (DPN), and, in future studies, to assess the efficacy of agents that may reduce progression. Patients with DPN were studied with clinical assessments, skin biopsies, quantitative sensory testing (QST), histamine-induced skin flare, nerve conduction studies and contact heat-evoked potentials (CHEPS). Skin biopsies were performed on two visits with a 6 month interval (n=29 patients) to quantify intraepidermal (IENF) and subepidermal (SENF) nerve fibres immunoreactive for: protein gene product 9.5 (PGP9.5), a pan-neuronal marker; transient receptor potential cation channel vanilloid 1 (TRPV1), the heat and capsaicin receptor; and growth associated protein-43 (GAP-43), a marker of regenerating fibres. The IENF were counted along the length of four non-consecutive sections, and results were expressed as fibres per millimetre length of section. SENF were measured by image analysis, and the area of highlighted immunoreactivity was obtained as a percentage (% area) of the field scanned. QST, skin flare and CHEPS were also performed at the two visits. We found that IENF and SENF were significantly reduced for both PGP9.5 and TRPV1 between the first and second skin biopsy over 6months. The annual rate ± standard error of the mean of IENF loss was 3.76 ± 1.46 fibres/mm for PGP9.5, and 3.13 ± 0.58 fibres/mm for TRPV1. The other tests did not show significant changes. Strongly positive GAP-43 nerve fibres were found in deep dermis in the patients with diabetes, even in those with an absence of IENF. We conclude that PGP9.5 and TRPV1 IENF and SENF in skin biopsies are useful markers of progression in DPN, whereas GAP-43 SENF could potentially help detect nerve regeneration in severe neuropathy. PMID:22705139

Narayanaswamy, H; Facer, P; Misra, V P; Timmers, M; Byttebier, G; Meert, T; Anand, P



The Diagnostic Yield of a Standardized Approach to Idiopathic Sensory-Predominant Neuropathy  

Microsoft Academic Search

Background:Peripheralneuropathyisacommonprob- lem that often prompts a lengthy and expensive diag- nostic evaluation. A rational, evidence-based diagnostic approachtoperipheralneuropathyisdesirable.Priorstud- ies have focused on all patients presenting to a tertiary referral center with a diagnosis of unclassified neuropa- thy. However, most patients with peripheral neuropa- thy have primarily sensory symptoms. This study fo- cusesonpatientswithsensory-predominantneuropathy. The goal was to develop a focused diagnostic algorithm

A. Gordon Smith; J. Robinson Singleton



Influence of the diabetic neuropathy on the behavior of electromyographic and sensorial responses in treadmill gait  

Microsoft Academic Search

Objective. We describe and interpret self-cadence treadmill walking by neuropathic diabetic subjects under biomechanical and somatosensorial considerations.Design. EMG variables during stance phase of neuropathic diabetic subjects were acquired and analyzed. We also evaluated sensorial and motor aspects of the feet and legs.Methods. The experimental procedures are divided as follows: (a) determination of the sensitive cronaxie and pain tolerance in selected

I. C. N. Sacco; A. C. Amadio



Painful Peripheral Neuropathies  

PubMed Central

Peripheral neuropathies are a heterogeneous group of diseases affecting peripheral nerves. The causes are multiple: hereditary, metabolic, infectious, inflammatory, toxic, traumatic. The temporal profile includes acute, subacute and chronic conditions. The majority of peripheral neuropathies cause mainly muscle weakness and sensory loss, positive sensory symptoms and sometimes pain. When pain is present, however, it is usually extremely intense and among the most disabling symptoms for the patients. In addition, the neurological origin of the pain is often missed and patients receive inadequate or delayed specific treatment. Independently of the disease causing the peripheral nerve injury, pain originating from axonal pathology or ganglionopathy privileges neuropathies affecting smaller fibres, a clinical observation that points towards abnormal activity within nociceptive afferents as a main generator of pain. Natural activation of blood vessels or perineurial nociceptive network by pathology also causes intense pain. Pain of this kind, i.e. nerve trunk pain, is among the heralding symptoms of inflammatory or ischemic mononeuropathy and for its intensity represents itself a medical emergency. Neuropathic pain quality rekindles the psychophysical experience of peripheral nerves intraneural microstimulation i.e. a combination of large and small fibres sensation temporally distorted compared to physiological perception evoked by natural stimuli. Pins and needles, burning, cramping mixed with numbness, and tingling are the wording most used by patients. Nociceptive pain instead is most often described as aching, deep and dull. Good command of peripheral nerve anatomy and pathophysiology allows timely recognition of the different pain components and targeted treatment, selected according to intensity, type and temporal profile of the pain.

Marchettini, P; Lacerenza, M; Mauri, E; Marangoni, C



Ankle ROM and stiffness measured at rest and during gait in individuals with and without diabetic sensory neuropathy  

PubMed Central

Introduction The purpose of our study was to examine the relationship between ankle dorsiflexion (DF) range of motion (ROM) and stiffness measured at rest (passively) and plantar loading during gait in individuals with and without diabetes mellitus (DM) and sensory neuropathy. Specifically, we sought to address three questions for this at-risk patient population: (1) Does peak passive DF ROM predict ankle DF ROM used during gait? (2) Does passive ankle stiffness predict ankle stiffness used during gait? (3) Are any of the passive or gait-related ankle measures associated with plantar loading? Methods Ten subjects with DM and 10 age and gender matched non-diabetic control subjects participated in this study. Passive ankle DF ROM and stiffness were measured with the Iowa Ankle ROM device. Kinematic, kinetic and plantar pressure data were collected as subjects walked at 0.89 m/s. Results We found that subjects with DM have reduced passive ankle DF ROM and increased stiffness compared to non-diabetic control subjects, however, subjects with DM demonstrated ankle motion, stiffness and plantar pressures, similar to control subjects, while walking at the identical speed, 0.89 m/s (2 mph). These data indicate that clinical measures of heel cord tightness and stiffness do not represent ankle motion or stiffness utilized during gait. Our findings suggest that subjects with DM utilize strategies such as shortening their stride length and reducing their push-off power to modulate plantar loading.

Rao, Smita; Saltzman, Charles; Yack, H. John



Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene  

PubMed Central

Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNATyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0–11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNATyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNATyr gene is the causative mutation for SAN.

Baranowska, Izabella; Jaderlund, Karin Hultin; Nennesmo, Inger; Holmqvist, Erik; Heidrich, Nadja; Larsson, Nils-Goran; Andersson, Goran; Wagner, E. Gerhart H.; Hedhammar, Ake; Wibom, Rolf; Andersson, Leif



Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade.  


Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger ?-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or ?-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists. PMID:23477783

Trevisan, Gabriela; Materazzi, Serena; Fusi, Camilla; Altomare, Alessandra; Aldini, Giancarlo; Lodovici, Maura; Patacchini, Riccardo; Geppetti, Pierangelo; Nassini, Romina



Sensory neuropathy associated with aggressive cauterization using a bipolar radiofrequency device in primary TKA.  


Because significant postoperative blood loss can result in many complications, hemostasis remains a critical part of successful joint replacement outcomes. Advanced techniques, such as electrocautery use after optimally timed tourniquet release, focus on desired patient blood loss outcomes. The purposes of this study were to report the incidence of nerve injury, identify associated risk factors following the use of bipolar electrocautery for hemostasis in the posterior knee during primary total knee arthroplasty, and compare that rate with the rate seen using a standard electrocautery device. Clinical and operative data were retrospectively reviewed for an association with postoperative nerve injury in 241 consecutive patients when using bipolar electrocautery between July 2007 and October 2008. A comparison group of 192 demographically similar consecutive patients between November 2008 and October 2009 was also evaluated to establish a surgeon-specific benchmark when using standard electrocautery. Seven (2.9%) of 241 patients in the bipolar electrocautery group reported documented neuropathies compared with 1 (0.52%) of 192 patients using standard electrocautery. In addition, female sex and rheumatoid arthritis were associated with postoperative nerve injury following bipolar electrocautery. Although the bipolar radiofrequency device is effective in achieving hemostasis, the authors recommend judicious use of this procedure in women or patients with rheumatoid arthritis and cautious, nonaggressive use of posterior compartment bipolar radiofrequency ablation in the remaining patient populations. PMID:23379925

Lyons, Steven; Morrison, Kurt; Tejiram, Shawn; Levering, Melissa; Polikandriotis, John A; Bernasek, Thomas



Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation  

PubMed Central

We report here the clinical, genetic, and molecular characterization of five Han Chinese families with Leber's hereditary optic neuropathy (LHON). Strikingly, there were very low penetrances of visual impairment in these Chinese families, ranging from 4.2% to 22.2%, with an average of 10.2%. In particular, only 7 (4 males/3 females) of 106 matrilineal relatives in these families exhibited the variable severity and age-at-onset in visual dysfunction. The age-at-onset for visual impairment in matrilineal relatives in these families, varied from 20 to 25 years, with an average of 21.8 years old. Molecular analysis of mitochondrial genomes identified the homoplasmic ND1 G3460A mutation and distinct sets of variants, belonging to the Asian haplogroups B5b, C4a1, D5, F1, and R9, respectively. This suggests that the G3640A mutation occurred sporadically and multiplied through evolution of the mtDNA in China. However, there was the absence of known secondary LHON-associated mtDNA mutations in these Chinese families. Very low penetrance of visual loss in these five Chinese pedigrees strongly indicated that the G3640A mutation was itself insufficient to develop the optic neuropathy. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G3640A mutation in those Chinese families with low penetrance of vision loss. However, nuclear modifier genes, epigenetic and environmental factors appear to be modifier factors for the phenotypic manifestation of the G3640A mutation in these Chinese families.

Tong, Yi; Sun, Yan-Hong; Zhou, Xiangtian; Zhao, Fuxin; Mao, Yijian; Wei, Qi-ping; Yang, Li; Qu, Jia; Guan, Min-Xin



[A case of acute autonomic, sensory and motor neuropathy with swelling and gadolinium enhancement of bilateral trigeminal nerve on MRI and dissociation between superficial and deep sensation disturbance].  


We report a case of a 46-year old man with acute autonomic, sensory and motor neuropathy (AASMN). He developed severe orthostatic hypotension, anuria,anhydrosis, tonic pupil with dysarthria, dysphagia, jaw claudication, and dysesthesia and sharp pain several days after symptom of upper respiratory infection. Neurological examination revealed severely decreased superficial sensation with normal deep sensation. Brain MRI findings showed bilateral trigeminal nerve swelling with gadolinium (Gd) enhancement. His motor and sensory symptoms and MRI abnormality were improved after the administration of intravenous immunoglobulin and intravenous methylprednisolone therapy; however his autonomic symptoms scarcely reacted to these immunotherapies. As long as we investigated in AASMN cases, bilateral trigeminal nerve swelling with Gd enhancement and dissociation between superficial and deep sensation disturbance have not reported, suggesting that the present case mainly disrupted C nerve fibers distributing postganglionic autonomic and temperature-pain sensory nerves. PMID:23470893

Naito, Hiroyuki; Doi, Hikaru; Inamizu, Saeko; Ito, Hijiri; Araki, Takehisa



X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant  

SciTech Connect

Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model of mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.

Pegoraro, E.; Hoffman, E.P. [Univ. of Pittsburgh School of Medicine, PA (United States); Carelli, V.; Cortelli, P. [Univ. of Bologna (Italy)] [and others



X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: Evidence from segregation analysis for dependence on X chromosome inactivation  

SciTech Connect

Leber hereditary optic neuropathy (LHON) has been shown to involve mutation(s) of mitochondrial DNA, yet there remain several confusing aspects of its inheritance not explained by mitochondrial inheritance alone, including male predominance, reduced penetrance, and a later age of onset in females. By extending segregation analysis methods to disorders that involve both a mitochondrial and a nuclear gene locus, the authors show that the available pedigree data for LHON are most consistent with a two-locus disorder, with one responsible gene being mitochondrial and the other nuclear and X chromosome-linked. Furthermore, they have been able to extend the two-locus analytic method and demonstrate that a proportion of affected females are likely heterozygous at the X chromosome-linked locus and are affected due to unfortunate X chromosome inactivation, thus providing an explanation for the later age of onset in females. The estimated penetrance for a heterozygous female is 0.11{plus minus}0.02. The calculated frequency of the X chromosome-linked gene for LHON is 0.l08. Among affected females, 60% are expected to be heterozygous, and the remainder are expected to be homozygous at the responsible X chromosome-linked locus.

Xiangdong Bu; Rotter, J.I. (Cedars-Sinai Medical Center, Los Angeles, CA (United States) Univ. of California, Los Angeles (United States))



Hip dysplasia associated with a hereditary sensorimotor polyneuropathy mimics a myopathic process.  


Some orthopedic complications have been reported in the hereditary neuropathies. However, the association of the hip dysplasia with this category of neuropathy is rarely recognized. We present a 13-year-old boy with the progressive weakness of the lower extremities, difficulty in walking, climbing stairs, and rising from floor; a wide-based, hyper-extended and waddling gait similar to a myopathic process. Hip radiography showed dysplastic acetabulae with hip subluxation, broken Shenton's lines, and valgus femoral necks. In electrodiagnosis, there was a significant neuropathic process (absent all evoked sensory potentials, abnormal evoked motor responses, and neurogenic electeromyography) which eventually was found to be a hereditary mixed axonal and demyelinating sensorimotor polyneuropathy with concomitant hip dysplasia confirmed with thorough physical examination and the electrodiagnostic study. In patients with gait difficulties such as waddling gait mimicking a myopathic process, hereditary polyneuropathy complicated with hip dysplasia should be considered as well. PMID:22919197

Hadianfard, Mohammad Javad; Ashraf, Alireza



Hip dysplasia associated with a hereditary sensorimotor polyneuropathy mimics a myopathic process  

PubMed Central

Some orthopedic complications have been reported in the hereditary neuropathies. However, the association of the hip dysplasia with this category of neuropathy is rarely recognized. We present a 13-year-old boy with the progressive weakness of the lower extremities, difficulty in walking, climbing stairs, and rising from floor; a wide-based, hyper-extended and waddling gait similar to a myopathic process. Hip radiography showed dysplastic acetabulae with hip subluxation, broken Shenton's lines, and valgus femoral necks. In electrodiagnosis, there was a significant neuropathic process (absent all evoked sensory potentials, abnormal evoked motor responses, and neurogenic electeromyography) which eventually was found to be a hereditary mixed axonal and demyelinating sensorimotor polyneuropathy with concomitant hip dysplasia confirmed with thorough physical examination and the electrodiagnostic study. In patients with gait difficulties such as waddling gait mimicking a myopathic process, hereditary polyneuropathy complicated with hip dysplasia should be considered as well.

Hadianfard, Mohammad Javad; Ashraf, Alireza



Phrenic nerve conduction study in demyelinating neuropathies and open-heart surgery  

Microsoft Academic Search

Objectives: The aim of this study was to determine normal values of phrenic nerve conduction (PNC) in healthy individuals; to evaluate the subclinical extent of phrenic nerve involvement in Guillain–Barré syndrome (G-B) and hereditary motor and sensory neuropathy-I (HMSN-I), and to evaluate phrenic nerve damage after cardiac surgery.Materials and methods: PNC was performed by transcutaneous stimulation in the neck and

A Cruz-Martinez; A Armijo; A Fermoso; S Moraleda; I Maté; M Mar??n



Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells  

Microsoft Academic Search

Paclitaxel-induced peripheral neuropathy (PN) can be a significant problem for patients receiving chemotherapeutic regimens for the treatment of breast, ovarian, and lung cancer as PN can influence the quality of life and survivorship in these patients. To begin to understand the cellular changes that occur within the peripheral and central nervous system as PN develops, we intravenously infused rats with

Christopher M. Peters; Juan Miguel Jimenez-Andrade; Beth M. Jonas; Molly A. Sevcik; Nathan J. Koewler; Joseph R. Ghilardi; Gilbert Y. Wong; Patrick W. Mantyh



Experimental diabetic neuropathy: an update  

Microsoft Academic Search

Diabetic neuropathy consists of several clinical syndromes affecting motor, sensory and autonomic nerves. Of these the most\\u000a common is distal symmetric sensory polyneuropathy usually referred to as diabetic neuropathy. Animal studies, mainly in diabetic\\u000a rodents, have contributed tremendously to our understanding of this disease. From these it is clear that the pathogenesis\\u000a of diabetic neuropathy is multifactorial involving sequentially occurring

A. A. F. Sima; K. Sugimoto



Complete mitochondrial DNA sequence analysis in two southern Chinese pedigrees with Leber hereditary optic neuropathy revealed secondary mutations along with the primary mutation  

PubMed Central

AIM To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS Two unrelated southern Chinese families with LHON and 10 matched healthy controls were recruited, and their entire mitochondrial DNA (mtDNA) was amplified and sequenced with the universal M13 primer. Then DNA sequence analysis and variation identification were perfomed by DNAssist and Chromas 2 software and compared with authoritative databases such as Mitomap. RESULTS Mutational analysis of mtDNA in these two Chinese pedigrees revealed one common LHON-associated mutation, G11778A (Arg?His), in the MT-ND4 gene. In addition, there were two secondary mutations in Pedigree 1: C3497T (Ala?Val), and C3571T (Leu?Phe) in the MT-ND1 gene, which have not been reported; and two secondary mutations occurred in Pedigree 2: A10398G (Thr?Ala) in the MT-ND3 gene, and T14502C (Ile?Val) in the MT-ND6 gene. Three polymorphisms, A73G, G94A and A263G in the mtDNA control region, were also found. CONCLUSION Our study confirmed that the known MT-ND4*G11778A mutation is the most significant cause of LHON. The C3497T and C3571T mutations in Pedigree 1 were also both at hot-spots of MT-ND1; they may affect the respiratory chain in coordination with the primary mutation G11778A. In Pedigree 2, the two secondary mutations A10398G of MT-ND3 and T14502C of MT-ND6 may influence mitochondrial respiratory complex I, leading to the mitochondrial respiratory chain dysfunction which results in optic atrophy together with G11778A. Therefore, not only the common primary LHON mutation is responsible for the visual atrophy, but other secondary mtDNA mutations should also be considered when giving genetic counseling.

Shu, Lei; Zhang, Yong-Ming; Huang, Xiao-Xiao; Chen, Chun-Yue; Zhang, Xian-Ning



Chemotherapy-induced peripheral neuropathy  

Microsoft Academic Search

The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known\\u000a about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful\\u000a neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the\\u000a autonomic nervous system (with vincristine, taxol, suramin)

Stefan Quasthoff; Hans Peter Hartung



Coexistence of Charcot-Marie-Tooth disease type 1A and anti-MAG neuropathy.  


At age 35, a man with a genetic diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM-kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti-myelin associated glycoprotein (anti-MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a "double hit". Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate. PMID:23781967

Piscosquito, Giuseppe; Salsano, Ettore; Ciano, Claudia; Palamara, Luisa; Morbin, Michela; Pareyson, Davide



KCNS1, but not GCH1, is associated with pain intensity in a black southern African population with HIV-associated sensory neuropathy: a genetic association study.  


KCNS1 and GCH1 were investigated for their association with pain intensity in black Southern Africans with HIV-associated sensory neuropathy. Previously associated single nucleotide polymorphisms (SNPs) were supplemented with population-specific tagSNPs. No SNPs in KCNS1 were individually associated with pain intensity. However, several haplotypes of population-specific tagSNPs correlated with pain intensity on univariate analysis and after correcting for age, gender, and CD4 T-cell count. This suggests that the haplotypes incorporate the causative SNP(s). No SNPs or haplotypes in GCH1 were associated with pain intensity. The study shows the importance of conducting association analyses in different ethnic groups, using population-based marker selection. PMID:23314412

Hendry, Liesl; Lombard, Zané; Wadley, Antonia; Kamerman, Peter



[Screening for hereditary neuromuscular disorders with molecular genetic methods in the Roma population of Hungary].  


Recent medical genetic research has identified a number of novel, or previously known, but rare conditions, caused by private founder mutations. The Finnish and Ashkenazi Jew populations provide the best examples for identifying genes in unique genetic disorders. In these populations, research efforts and high-level medical services resulted in intense improvements of medical care and in organization of population-based screening programs. Hereditary disorders of the Roma populations are known for a long time. The genetic background of these diseases has been established by extensive molecular genetic studies. The Romas represent 6% of the Hungarian population and live under extremely bad health conditions. Therefore, our aim was to map the incidence of the hereditary neuromuscular disorders among the Hungarian Roma population. Moreover, we intended to provide proper information, genetic counseling and possible prevention strategies for the families at risk, which should represent a primer task in public health. Because of our experience in neuromuscular disorders, we choose six, frequent, autosomal recessive disorders for these clinical and genetic studies: hereditary motor and sensory neuropathy type Lom (HMSNL), hereditary motor and sensory neuropathy type Russe (HMSNR), congenital cataracts facial dysmorphism syndrome (CCFDN), limb-girdle muscular dystrophy 2C (LGMD2C), congenital myasthenic syndrome (CMS) and spinal muscular atrophy (SMA). Following identification of the founder mutations, the possibility of prenatal diagnosis and carrier screening for family members will contribute to the decrease of the recurrence risk for these severe, mostly untreatable disorders. PMID:19070320

Herczegfalvi, Agnes; Pikó, Henriett; Karcagi, Veronika



Uremic neuropathy.  


Polyneuropathy is a common complication of end-stage renal failure especially when treatment with periodic hemodialysis is started too late. Large myelinated fibers bear the brunt of the many biological changes associated with renal failure. Nerve conduction slowing is common in this setting. Compression of the median nerve in the carpal tunnel commonly occurs in these patients, as a result of amyloid deposits at this site. End-stage renal failure in diabetic patients is often associated with severe distal motor and sensory deficits. Improved quality of periodic hemodialysis and renal transplantation have dramatically reduced the prevalence and severity of peripheral neuropathy in these patients. PMID:23931805

Said, Gérard



Diabetic Neuropathy  


NINDS Diabetic Neuropathy Information Page Table of Contents (click to jump to sections) What is Diabetic Neuropathy? Is there any treatment? ... Organizations Additional resources from MedlinePlus What is Diabetic Neuropathy? Diabetic neuropathy is a peripheral nerve disorder caused ...


Hereditary elliptocytosis  


... red blood cells are abnormally shaped. See also: Hereditary spherocytosis Hereditary ovalocystosis ... Most persons with hereditary elliptocytosis have no problems, and are unaware of their condition.


Diabetic neuropathy  

Microsoft Academic Search

Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the commonest accounting for 75% DN. Asymmetrical neuropathies may involve cranial nerves, thoracic or limb nerves; are of acute onset resulting from ischaemic infarction of vasa nervosa. Asymmetric neuropathies in diabetic patients

V Bansal; J Kalita; U K Misra



Diabetic neuropathy  


Nerve damage - diabetic; Diabetes - neuropathy ... the heart, bladder, stomach, and intestines (called autonomic neuropathy) ... develop: Bladder or kidney infection Diabetes foot ulcers Neuropathy that may hide the symptoms of angina, chest ...


Peripheral neuropathy associated with the sicca syndrome  

Microsoft Academic Search

Three patients with the sicca syndrome and chronic sensory neuropathy are described; in two of them neuropathy was the presenting feature of the disease. The sicca syndrome can give rise to a characteristic neurological syndrome comprising areflexia and asymmetrical sensory loss, particularly of proprioception, in the limbs. This is often associated with tonic pupils and trigeminal anaesthesia.

R P Kennett; A E Harding



Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies  

PubMed Central

Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein–protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling.

Zimon, Magdalena; Baets, Jonathan; Auer-Grumbach, Michaela; Berciano, Jose; Garcia, Antonio; Lopez-Laso, Eduardo; Merlini, Luciano; Hilton-Jones, David; McEntagart, Meriel; Crosby, Andrew H.; Barisic, Nina; Boltshauser, Eugen; Shaw, Christopher E.; Landoure, Guida; Ludlow, Christy L.; Gaudet, Rachelle; Houlden, Henry; Reilly, Mary M.; Fischbeck, Kenneth H.; Sumner, Charlotte J.; Timmerman, Vincent; Jordanova, Albena



Electroacupuncture Zusanli (ST36) on Release of Nitric Oxide in the Gracile Nucleus and Improvement of Sensory Neuropathies in Zucker Diabetic Fatty Rats  

PubMed Central

The purpose of these studies was to examine the effects of electroacupuncture (EA) Zusanli (ST36) on release of nitric oxide (NO) in the gracile nucleus (GN) and determine if functional neuropathic changes were modified by EA ST36-induced NO in the nucleus in Zucker diabetic fatty (ZDF) rats. The foot withdrawal responses to mechanical, thermal and cold stimuli were measured before and after EA stimulation. A microdialysis probe was implanted in the GN and dialysate samples were collected 20 min before, during and after EA ST36. Total nitrate and nitrite (NOx?) concentrations in the samples were quantified by using chemiluminescence. The baseline dialysate NOx? concentrations in the GN were decreased in ZDF rats compared to lean control (LC) rats (P < .05). In ZDF rats, dialysate NOx? releases in the GN were markedly increased during EA ST36, whereas in LC rats, the releases were moderately enhanced at 20–40?min after EA ST36. The withdrawal latencies to mechanical, cold and thermal stimuli were significantly improved 20?min after EA ST36 both in LC and ZDF rats, but not altered by non-acupoint stimulation. The withdrawal latencies to EA ST36 were further potentiated by 3-morpholinyl-sydnoneimine and inhibited by NG-Propyl-l-arginine infused into the GN in ZDF rats (P < .05). These results show that EA ST36 increases NO release in the GN, and NO in the nucleus modifies withdrawal latencies to mechanical, cold, and thermal nociception stimuli. Data suggest that EA ST36 induces NO release in the GN, which contributes to improvement of sensory neuropathies in rats.

Rong, Pei-Jing; Ma, Sheng-Xing



Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.  


Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy. PMID:20557422

Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin



Reduction in Voltage-Gated K+ Channel Activity in Primary Sensory Neurons in Painful Diabetic Neuropathy: Role of Brain-Derived Neurotrophic Factor  

PubMed Central

Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. Here we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA), and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced ~50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pretreatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin



Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy  

PubMed Central

Background Mitochondrial DNA (mtDNA) mutations are known to cause Leber hereditary optic neuropathy (LHON). However, the co-occurrence of double pathogenic mutations with different pathological significance in pedigrees is a rare event. Methods Detailed clinical investigation and complete mtDNA sequencing analysis was performed for two Indian families with LHON. The haplogroup was constructed based on evolutionarily important mtDNA variants. Results We observed the existence of double pathogenic mutations (m.11778G>A and m.1555A>G) in two Indian LHON families, who are from different haplogroup backgrounds (M5a and U2e1), with different clinical penetrance of the disease (visual impairment). The m.11778G>A mutation in the MT-ND4 gene is associated primarily with LHON; whereas, m.1555A>G in the 12S rRNA gene has been reported with aminoglycoside-induced non-syndromic hearing loss. Conclusions The absence of hearing abnormality and widely varying clinical expression of LHON suggest additional nuclear modifier genes, environmental factors, and population heterogeneity might play an important role in the expression of visual impairment in these families.

Khan, Nahid Akhtar; Govindaraj, Periyasamy; Jyothi, Vuskamalla; Meena, Angamuthu K



Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.  

PubMed Central

mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. High-resolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoid-specific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three primary mutations. The 3460 mutations are distributed randomly along the phylogenetic trees, without any preferential association with the nine haplogroups (H, I, J, K, T, U, V, W, and X) that characterize European populations, whereas the 11778 and 14484 mutations show a strong preferential association with haplogroup J. This finding suggests that one ancient combination of haplogroup J-specific mutations increases both the penetrance of the two primary mutations 11778 and 14484 and the risk of disease expression.

Torroni, A; Petrozzi, M; D'Urbano, L; Sellitto, D; Zeviani, M; Carrara, F; Carducci, C; Leuzzi, V; Carelli, V; Barboni, P; De Negri, A; Scozzari, R



TRP channels: new potential therapeutic approaches in CNS neuropathies.  


More than 30 different Transient Receptor Potential channels (TRP) have been identified in mammals and are grouped in 6 families. Members of these subunit families, specifically of the vanilloid TRP (TRPV), melastatin TRP (TRPM), ankyrin TRP (TRPA), polycystin TRP (TRPP) and canonical or classical TRP (TRPC) family, are considered relevant in central nervous system neurodegenerative diseases. In fact, TRP channels have received increased attention in recent years, since they are involved in a broad array of pathways and respond to different environmental stimuli. Preclinical research has identified TRPs involved in hereditary neuropathies as well as in a heterogeneous group of neuronal disorders. Moreover, changes in TRP channel expression and functionality have been associated to diabetic thermal hyperalgesia, painful neuropathies and headache. At the molecular level, TRPs are involved in a wide range of mechanisms regulating osmosis, thermal, stretch, chemical and sensory signaling, highlighting TRPs as potential targets for pharmacological intervention. The area of small molecule TRP agonists/antagonists drug development is moving rapidly. This review will evaluate current evidence that supports particular TRP channels as targets for novel drugs, summarizing the current perspectives for the therapeutic potential of TRP agonists and antagonists in the treatment of a wide range of neuropathies, along with potential adverse effects that may limit drug development. PMID:23469844

Morelli, Maria Beatrice; Amantini, Consuelo; Liberati, Sonia; Santoni, Matteo; Nabissi, Massimo



Leprous neuropathy.  


Leprous neuropathy, which is due to infection of nerve cells by Mycobacterium leprae, still affects millions of people in many developing countries. The clinical and pathological manifestations are determined by the natural resistance of the host to invasion of M. Leprae. Failure of early detection of leprosy often leads to severe disability in spite of eradication of mycobacterium at a later date. In the lepromatous type, bacilli are easily found in the skin and in nerve cells including Schwann cells, endothelial cells, and macrophages. In the tuberculoid type, a strong cell-mediated immune reaction leads to formation of granulomas and destruction of cells harboring bacilli and neighboring nerve fibers. In many cases, treatment of patients with the multibacillary leprosy is complicated by reversal reaction and further nerve damage. Nerve lesions lead to a symmetrical, pseudo-polyneuritic pattern in most cases of lepromatous leprosy, which is usually associated with typical skin lesions, but pure neuritic forms occur in up to 10% of patients with lepromatous leprosy. In the pure neuropathic cases, only nerve biopsy permits diagnosis. The multifocal pattern is more common in tuberculoid leprosy. Treatment is currently based on multidrug therapy with dapsone, rifampicin, and clofazimine. The use of corticosteroids can reduce or prevent nerve damage in reversal reactions. It is important to remember that sequelae, especially sensory loss, are extremely common, which can lead to secondary trophic changes due to repeated trauma in painless areas. PMID:23931798

de Freitas, Marcos R G; Said, Gérard



Electrophysiological studies in diabetic neuropathy  

PubMed Central

In 30 patients with diabetic neuropathy sensory potentials in the median nerve, motor conduction in the lateral popliteal and median nerves, and electromyographic findings in distal and proximal muscles were compared with the severity of symptoms and signs. All patients had abnormalities in at least one of the electrophysiological parameters. The sensory potentials were the most sensitive indicator of subclinical involvement; abnormalities were found in 24 patients, 12 of whom had no sensory symptoms or signs and five of whom had no other clinical or electrophysiological evidence of neuropathy in the upper extremities. This indicates that sensory nerve fibres may be affected before motor. The next most sensitive parameter was the presence of fibrillation potentials, found in more than half the distal muscles examined. Slowing in motor conduction in the lateral popliteal nerve was the only electrophysiological change correlated to the severity of the neuropathy, and no other electrophysiological parameter was correlated to the duration or the severity of the neuropathy or the diabetes. An onset of neuropathy before or simultaneously with the manifestations of the diabetes, as well as the frequent occurrence of asymptomatic changes in sensory conduction, support the evidence at hand that the neuropathy develops concomitantly with and as an integral part of the metabolic disturbance rather than as a consequence of the vascular complications of diabetes. Of three patients with clinical signs or symptoms of a diabetic amyotrophy, two had asymptomatic electrophysiological abnormalities in distal nerves and muscles, consistent with widespread involvement of the peripheral nerves. The third patient had electromyographic changes in the medial vastus muscles suggestive of a myopathy. Motor and sensory conduction in distal and proximal nerves were normal. Images

Lamontagne, Albert; Buchthal, Fritz



Inflammatory neuropathies.  


Inflammatory neuropathies are acquired disorders of peripheral nerves and occasionally of the central nervous system that can affect individuals at any age. The course can be monophasic, relapsing, or progressive. Inflammatory neuropathies are classified as acute or chronic. The acute form reaches a nadir by 4 weeks and the chronic form over 8 weeks or greater. The most common example of an acute inflammatory neuropathy is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is part of the Guillain-Barré syndrome (GBS). The most common chronic inflammatory neuropathy is chronic inflammatory demyelinating polyradiculopathy (CIDP). Other chronic inflammatory neuropathies are multifocal motor neuropathy (MMN) and the Lewis-Sumner syndrome. The Fisher syndrome and Bickerstaff brainstem encephalitis occur acutely and have clinical overlap with AIDP. PMID:20941668

Whitesell, Jackie



Acquired neuropathies.  


Acquired neuropathies represent most of the neuropathies encountered in clinical practice. Hundreds of causes have been identified even though up to 41 % of patients are still classified as idiopathic (Rajabally and Shah in J Neurol 258:1431-1436, 1). Routine evaluation relies on comprehensive medical history taking, clinical examination, nerve conduction studies and laboratory tests. Other investigations such as nerve biopsy or nerve or muscle imaging are performed in specific settings. This review focuses on recent advances in acquired neuropathies. PMID:23771508

Lozeron, Pierre; Trocello, Jean-Marc; Kubis, Nathalie



Diabetic Neuropathy  

Microsoft Academic Search

Polyneuropathy is one of the commonest complications of the diabetes and the commonest form of neuropathy in the developed\\u000a world. Diabetic polyneuropathy encompasses several neuropathic syndromes, the most common of which is distal symmetrical neuropathy,\\u000a the main initiating factor for foot ulceration. The epidemiology of diabetic neuropathy has recently been reviewed in reasonable\\u000a detail (1). Several clinic- (2,3) and populationbased

Solomon Tesfaye


Peripheral Neuropathy  


... diet, correcting vitamin deficiencies, and limiting or avoiding alcohol consumption -- can reduce the physical and emotional effects of peripheral neuropathy. Systemic diseases frequently require more complex ...


Multifocal motor neuropathy.  


Multifocal motor neuropathy (MMN) is a chronic immune-mediated neuropathy that is particular for its asymmetric, multifocal, purely motor clinical presentation, often related to the distribution of individual nerves. Upper limbs are usually primarily and more severely affected, but lower limbs may be involved during the course of the disease. The hallmark of the disease is the presence, in electrophysiological studies, of persistent conduction blocks in the affected motor nerves, located outside the usual sites of nerve compression, contrasting with normal sensory nerve conduction velocities. The most typical laboratory finding is the presence of high levels of serum IgM antibodies to the ganglioside GM1, and less frequently to asialo-GM1, GD1a or GM2. These striking features may help distinguishing this neuropathy from both motor neuron disease and other chronic immune-mediated neuropathies. Several randomized controlled trials (RCT) have established the efficacy of high-dose intravenous immunoglobulin (IVIg), as well as subcutaneous immunoglobulin (SCIg). However, this therapy has a short-lasting effect, and need to be maintained with periodic infusions. This disappointing status has led to the search of other immune therapies whose efficacy has not been so far confirmed in RCT. This review intends to summarize current contents in the diagnosis and the treatment of MMN. PMID:23623583

Guimarães-Costa, Raquel; Bombelli, Francesco; Léger, Jean-Marc



Multiple myeloma, painful neuropathy, acupuncture?  


Thalidomide and bortezomib are remarkably efficacious in the treatment of multiple myeloma. Unfortunately, their use can cause sensory neuropathy, a common and serious adverse event that frequently limits dose and duration of treatment. Although the relationship between peripheral neuropathy and therapeutic dose is controversial, many authors have demonstrated a positive correlation between neuropathy and cumulative dose, dose intensity, and length of therapy. Peripheral neuropathic pain is the most troublesome symptom of neuropathy. Spontaneous pain, allodynia, hyperalgesia, and hyperpathia are often associated with decreased physical activity, increased fatigue, mood, and sleep problems. Symptoms are often difficult to manage, and available treatment options rarely provide total relief. Moreover, the adverse effects of these treatments often limit their use. Several studies have demonstrated the efficacy of acupuncture, with fewer adverse effects than analgesic drugs, in the treatment of painful diabetic and human immunodeficiency virus-related neuropathy. However, the effectiveness of acupuncture in treating toxic neuropathy has not been assessed. Although its putative mechanisms remain elusive, acupuncture has strong potential as an adjunctive therapy in thalidomide- or bortezomib-induced painful neuropathy, and a better understanding might guide its use in the management of chemotherapy-induced neuropathic pain. Well-designed clinical trials with adequate sample size and power are warranted. PMID:19887992

Zhou, Yuhong; Garcia, M Kay; Chang, David Z; Chiang, Joseph; Lu, Jin; Yi, Qing; Romaguera, Jorge; Delasalle, Kay; Guo, Ying; Forman, Arthur; Fang, Wenjing; Wang, Michael



[Genetic diagnosis and molecular pathology of inherited neuropathy].  


Recent advances in genetic analysis technology have enabled a surprising progress in genetic diagnosis in the field of neurological disease research. High-throughput molecular biology techniques, such as microarrays and next-generation sequencing, are the major contributors to this progress and to new discoveries. Charcot-Marie-Tooth disease (CMT), a known hereditary motor and sensory neuropathy, is clinically and genetically heterogeneous. Genetic studies have revealed at least 35 disease causing-genes responsible for Charcot-Marie-Tooth disease. Genetic studies have revealed that abnormalities in the following factors are the cause of inherited neuropathies: myelin components, transcription factors controlling myelination, myelin maintenance system, differentiation factors related to the peripheral nerve, neurofilaments, protein transfer system, mitochondrial proteins, DNA repair, RNA/protein synthesis, ion channels, and aminoacyl-tRNA synthetase. On the other hand concomitant with the increase in the number of genes that must be screened for mutations, the labor and reagent costs for molecular genetic testing have increased significantly. Therefore, new methodology for detecting gene mutations is required. Based on the recent progress in DNA analysis methods, resequencing microarray appears to be an economical and highly sensitive method for detecting mutations. We have been screening CMT patients for mutations using originally designed microarray DNA chips since 2007, thencehaving identified disease causing mutations in MPZ, GJB1, PMP22, EGR2, MFN2, NEFL, PRX, AARS, GARS, DNM2, and SETX genes in CMT patients. PMID:22790800

Takashima, Hiroshi



Hereditary Xanthinuria  

Microsoft Academic Search

Three patients with hereditary xanthinuria are presented and the pertinent literature is reviewed. In two siblings the disease has been asymptomatic; in the third urolithiasis has developed. Xanthine stone formation is the clinical hallmark of the disease. Hereditary xanthinuria seems to be relatively prevalent in Lebanon.Copyright © 1977 S. Karger AG, Basel

Rida A. Frayha; Ibrahim S. Salti; Amin Arnaout; Avedis Khatchadurian; Suhayl M Uthman



Hereditary spherocytosis  

Microsoft Academic Search

Hereditary spherocytosis is a common hemolytic disorder characterized by a defect or deficiency in one or more of the proteins composing red blood cell membrane. As a result, red blood cells have an abnormal shape, higher metabolic requirements, and are prematurely trapped and destroyed in the spleen. Hereditary spherocytosis, including the very mild or subclinical forms, is the most common

A. Iolascon; R. A. Avvisati; C. Piscopo



Inherited Neuropathy Can Cause Postpartum Foot Drop  

Microsoft Academic Search

Postpartum neurological complications occur in up to 1% of deliveries. Often prior anesthetic procedures are blamed, with medicolegal implications. We de- scribe a young woman who presented with postpar- tum foot drop diagnosed as an iatrogenic L5 root le- sion after uncomplicated epidural anesthesia. After neurological assessment some 5 mo later she tested positive for the common hereditary neuropathy with



Treatment of Diabetic Sensory Polyneuropathy  

Microsoft Academic Search

Opinion statement  No current disease-modifying treatments have been shown definitively in randomized clinical trials to reduce or reverse diabetic\\u000a sensory polyneuropathy (DSP). It is increasingly recognized that individuals with “prediabetes” or impaired glucose regulation\\u000a can already have a “small-fiber” neuropathy, or mild DSP, in which sensory axons of both small and larger diameter are damaged.\\u000a Small-fiber neuropathy is frequently associated with

Lindsay Zilliox; James W. Russell



Peripheral Neuropathy  


... long fiber that extends out from the main nerve cell body). Some neuropathies are caused by inflammation resulting ... the ability to regenerate, as long as the nerve cell itself has not been killed. Symptoms often can ...


Alcoholic neuropathy  


... and the effect of poor nutrition associated with alcoholism. Up to half of all long-term heavy ... alcoholic neuropathy include: Long-term, heavy alcohol use Alcoholism that is present for 10 years or more


[Neuropathy pain: tactic of treatment].  


Diagnostics of neuropathy pain is presented in the article, where most essential are methods of clinical estimation with the use of questionnaires and scales for verification and quantitative estimation of pain. The neurological inspection of patients with suspicion on neuropathy pain must plug in itself of the motive, sensory and vegetative phenomena with the purpose of authentication of all signs of neurological dysfunction. If on a background immunotherapy it is not succeeded fully a pain syndrome preparations of the first row, setting of combined pharmacotherapy allows to promote efficiency of treatment at the less dosages of preparations and reduce the risk of development of by-effects. PMID:23373387

Murashko, N K



Threshold for detection of diabetic peripheral sensory neuropathy using a range of research grade monofilaments in persons with Type 2 diabetes mellitus  

PubMed Central

Aims To identify the threshold of reduced sensory perception in Type 2 diabetes mellitus (Type 2 DM) using a range of research grade monofilaments. Methods Three groups of participants were recruited into a between subject, cross-sectional study. Group 1(NEW), persons with Type 2 DM diagnosed for less than 2 years (n = 80); Group 2 (EST) persons with Type 2 DM diagnosed for more than 2 years (n = 91), and Group 3, a Comparison group without Type 2 DM (n = 73), resulted in a total study population, n = 244. Research grade monofilaments (2, 4, 6, 8 and 10-gram) were employed using standardised protocol, at 6 sites on the plantar aspect of both feet. The demographic and anthropometric measures of gender, age, height, weight, body mass index (BMI), blood pressure and duration of Type 2 DM since diagnosis (if applicable) of the participants were analysed. Results Perception of the research grade monofilaments differed significantly between the 3 groups (p < 0.05). The 6-gram monofilament was found to be the threshold of normal perception, based on 90% of the Comparison group perceiving the 6-gram monofilament at all sites in contrast to 64% of NEW and 48% of EST groups. Conclusion The 6-gram monofilament was identified as the threshold of normal sensory perception. Inability to perceive the 6-gram monofilament indicates, when using the method described in this study, that diminution of sensory perception is evident. Employing a range of monofilaments, 6, 8 and 10-grams in Type 2 DM foot screening would allow the clinical detection of deteriorating sensory perception and enable implementation of foot protection strategies at an earlier stage than is currently practised.

Thomson, Mary P; Potter, Julia; Finch, Paul M; Paisey, Richard B



Hereditary hemochromatosis.  


Hereditary hemochromatosis is an autosomal recessive disorder that disrupts the body's regulation of iron. It is the most common genetic disease in whites. Men have a 24-fold increased rate of iron-overload disease compared with women. Persons who are homozygous for the HFE gene mutation C282Y comprise 85 to 90 percent of phenotypically affected persons. End-organ damage or clinical manifestations of hereditary hemochromatosis occur in approximately 10 percent of persons homozygous for C282Y. Symptoms of hereditary hemochromatosis are nonspecific and typically absent in the early stages. If present, symptoms may include weakness, lethargy, arthralgias, and impotence. Later manifestations include arthralgias, osteoporosis, cirrhosis, hepatocellular cancer, cardiomyopathy, dysrhythmia, diabetes mellitus, and hypogonadism. Diagnosis requires confirmation of increased serum ferritin levels and transferrin saturation, with or without symptoms. Subtyping is based on genotypic expression. Serum ferritin measurement is the most useful prognostic indicator of disease severity. Liver biopsy is performed to stage the degree of fibrosis with severe ferritin elevation or transaminitis, or to diagnose nonclassical hereditary hemochromatosis in patients with other genetic defects. Treatment of hereditary hemochromatosis requires phlebotomy, and the frequency is guided by serial measurements of serum ferritin levels and transferrin saturation. Iron avidity can result from overtreatment. If iron avidity is not suspected, it may mimic undertreatment with persistently elevated transferrin saturation. Dietary modification is generally unnecessary. Universal screening for hereditary hemochromatosis is not recommended, but testing should be performed in first-degree relatives of patients with classical HFE-related hemochromatosis, those with evidence of active liver disease, and patients with abnormal iron study results. Screening for hepatocellular carcinoma is reserved for those with hereditary hemochromatosis and cirrhosis. PMID:23418762

Crownover, Brian K; Covey, Carlton J



The Spectrum of Diabetic Neuropathies  

PubMed Central

Diabetes mellitus is associated with many different neuropathic syndromes, ranging from a mild sensory disturbance as can be seen in a diabetic sensorimotor polyneuropathy, to the debilitating pain and weakness of a diabetic lumbosacral radiculoplexus neuropathy. The etiology of these syndromes has been extensively studied, and may vary among metabolic, compressive, and immunological bases for the different disorders, as well as mechanisms yet to be discovered. Many of these disorders of nerve appear to be separate conditions with different underlying mechanisms, and some are directly caused by diabetes mellitus, whereas others are associated with it but not caused by hyperglycemia. We discuss a number of the more common disorders of nerve found with diabetes mellitus. We discuss the symmetrical neuropathies, particularly generalized diabetic polyneuropathy, and then the focal or asymmetrical types of diabetes-associated neuropathy.

Tracy, Jennifer A.; Dyck, P. James B.



Hereditary spherocytosis.  


Hereditary spherocytosis is a common hemolytic disorder characterized by a defect or deficiency in one or more of the proteins composing red blood cell membrane. As a result, red blood cells have an abnormal shape, higher metabolic requirements, and are prematurely trapped and destroyed in the spleen. Hereditary spherocytosis, including the very mild or subclinical forms, is the most common cause of non-immune hemolytic anemia among people of Northern European ancestry, with a prevalence of approximately 1 in 2000. However very mild forms of the disease may be much more common. Hereditary spherocytosis is inherited in a dominant fashion in 75% of cases, whereas the remaining are truly recessive cases and de novo mutations. This review reports current concepts on red cell membrane structure and it will attempt to clarify molecular defects leading to spherocyte and their consequences. PMID:20655264

Iolascon, A; Avvisati, R A; Piscopo, C



Quantitative and integrative proteome analysis of peripheral nerve myelin identifies novel myelin proteins and candidate neuropathy loci.  


Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel myelin constituents using immuno-based methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during myelin biogenesis and maturation. By differential myelin proteome analysis, we found that the abundance of septin 9, the protein affected in hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion protein. Finally, the systematic comparison of our compendium with the positions of human disease loci allowed us to identify several candidate genes for hereditary demyelinating neuropathies. These results illustrate how the integration of unbiased proteome, transcriptome, and genome data can contribute to a molecular dissection of the biogenesis, cell biology, metabolism, and pathology of myelin. PMID:22072688

Patzig, Julia; Jahn, Olaf; Tenzer, Stefan; Wichert, Sven P; de Monasterio-Schrader, Patricia; Rosfa, Susanne; Kuharev, Jörg; Yan, Kuo; Bormuth, Ingo; Bremer, Juliane; Aguzzi, Adriano; Orfaniotou, Foteini; Hesse, Dörte; Schwab, Markus H; Möbius, Wiebke; Nave, Klaus-Armin; Werner, Hauke Bernhard



Hereditary Hyperlipoproteinemias  

ERIC Educational Resources Information Center

|Evidence and research indicate that the majority of cases of coronary artery disease represent familial disorders which are best explained by a polygenic hereditary predisposition interacting with emotional triggers such as diet and stress. Early identification is judged necessary. (Authors/JA)|

Nora, James J.; And Others



Diabetic Neuropathies  

Microsoft Academic Search

Diabetic neuropathies (DN) are a heterogeneous group of disorders that include a wide range of abnormalities. They can be\\u000a focal or diffuse, proximal or distal, affecting both peripheral and autonomic nervous systems, causing morbidity with significant\\u000a impact on the quality of life of the person with diabetes, resulting in early mortality. Distal symmetric polyneuropathy,\\u000a the most common form of DN,

Aaron I. Vinik


[Applications of 'quantitative sensory testing'].  


Quantitative sensory testing (QST) consists of several non-invasive, standardised tests aimed at examining different aspects of the entire somatosensory nervous system. Important advantages of QST over existing supplementary tests such as electromyography are the ability to test the function of thin and unmyelinated nerve fibres as well as the subjective sensation of a somatosensory stimulus. QST is validated in diagnosing small fibre neuropathy, diabetic neuropathy chemotherapy-induced peripheral neuropathy and neuropathic pain. In scientific research, QST is useful in the study into pathophysiological mechanisms of diseases and syndromes with sensory symptoms and in the evaluation of the effect of analgesic treatment on the function of the somatosensory nervous system. In the future, QST could be a useful diagnostic and prognostic test in more forms of neuropathy and in other clinical conditions such as chronic unexplained pain syndromes (e.g. fibromyalgia and whiplash-associated disorder. PMID:23369816

Verberne, Wouter R; Snijders, Tom J; Liem, K Seng; Baakman, Anne Catrien; Veldhuijzen, Dieuwke S



Light chain deposition disease neuropathy resembling amyloid neuropathy in a multiple myeloma patient  

Microsoft Academic Search

A 65-year-old man with IgG lambda multiple myeloma developed severe polyneuropathy with prominent thermal-pain sensory impairment\\u000a and autonomic failure. Although the clinical presentation suggested amyloid neuropathy, nerve biopsy showed the immunohistochemical\\u000a and ultrastructural features typical of light chain deposition disease (LCDD). A precise morphologic and clinical description\\u000a of LCDD neuropathy is given for the first time in the present report.

M. P. Grassi; F. Clerici; C. Perin; M. Borella; A. Mangoni; A. Gendarini; A. Quattrini; R. Nemni



Therapeutic Angiogenesis Inhibits or Rescues Chemotherapy-induced Peripheral Neuropathy: Taxol and Thalidomide-induced Injury of Vasa Nervorum is Ameliorated by VEGF  

Microsoft Academic Search

Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of

Rudolf Kirchmair; Anne B Tietz; Eleftheria Panagiotou; Dirk H Walter; Marcy Silver; Young-Sup Yoon; Peter Schratzberger; Alberto Weber; Kengo Kusano; David H Weinberg; Allan H Ropper; Jeffrey M Isner; Douglas W Losordo



[Spontaneous acquired localized neuropathies in childhood].  


Acquired non-surgical, non-traumatic localized neuropathies, excluding cranial nerve disorders, are rare in infancy. We review the clinical histories of six children, studied for this disorders amongst a total of 2,105 children seen in the Neuropediatric Department of the Hospital Miguel Servet in Zaragoza. Two were diagnosed as familial neuropathy with pressure sensitive paralysis. Two plexopathies were considered to be familial brachial plexopathy with minor dysmorphic features. One case was diagnosed as idiopathic radial neuropathy and a further case as idiopathic lumbosacral plexopathy. We emphasize that although rare in pediatrics, spontaneous localized neuropathies often show constitutional pathology, frequently hereditary. Idiophatic cases may also be hereditary, and it may be difficult to confirm the diagnosis if there is no family history or phenotypic characteristics. Diagnosis depends on the personal and family history, physical examination, neurophysiological study, absence of abnormal neuroimaging findings and awareness of the possibility of this diagnosis. These disorders probably occur more often than is generally believed. PMID:9244623

Peña, J L; Marco, M; Gros, L; López Pisón, J



Diagnosis and Management of Diabetic Peripheral Neuropathy  

Microsoft Academic Search

Diabetic peripheral neuropathy (DPN) is one of the most commonly occurring major complications of diabetes. The disease may manifest in several clinical patterns: most frequently as distal symmetrical sensory polyneuropathy. Guidelines are available for the diagnosis of DPN by the primary care physician. These recommend that a review of diabetic patients, including a questionnaire and inspection and neurological examination of

Isabel Illa



Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management.  


Microtubule inhibitor (MTI)-based chemotherapies used in the treatment of breast cancer--including vinca alkaloids, taxanes, and epothilones--are known to be associated with peripheral neuropathy. The incidence and severity of neuropathy, most frequently sensory in nature, depend on the agent used, absolute and cumulative drug dose, administration schedule, and presence of comorbidities. Although some first-generation vinca alkaloids, such as vincristine, were associated with severe mixed sensory/motor neuropathy, the deficits associated with newer agents in this class (eg, vinflunine) are generally milder and limited to distal sensory signs and symptoms. Among the taxanes, sensory neuropathy is reported more often with administration of paclitaxel and albumin-bound paclitaxel and less frequently with docetaxel. Epothilones, a new class of MTI, may be associated with grade 3/4 peripheral neuropathy; however, the neuropathy associated with ixabepilone, a novel epothilone B analog, is generally mild to moderate and reversible to baseline or grade 1 levels. The neuropathy induced by MTI therapy is best managed with dose adjustments and/or treatment delay. This article provides an overview of the incidence, characteristics, and management of MTI-associated neurotoxicities for known vinca alkaloids and taxanes, as well as newer agents, such as vinflunine and ixabepilone. PMID:18567992

Swain, Sandra M; Arezzo, Joseph C



Bladder dysfunction in peripheral neuropathies.  


Normal bladder function depends on the complex interaction of sensory and motor pathways. Bladder dysfunction can develop as a result of several neurological conditions. It can happen in a number of ways, including diabetic cystopathy, detrusor overactivity, bladder outlet obstruction, and urge and stress urinary incontinence. Diabetic neuropathy is the most common cause of peripheral neuropathy-associated bladder dysfunction. Guillain-Barré syndrome (GBS), human immunodeficiency virus (HIV)-associated neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), and amyloid neuropathy are other major causes. The diagnosis of bladder dysfunction should be established by the history of neurological symptoms, neurological examination, and urological evaluation. Functional evaluation of the lower urinary tract includes cystometry, sphincter electromyography, uroflowmetry, and urethral pressure profilometry. Management of urinary symptoms in patients with bladder dysfunction is usually supportive. In some cases, alpha-blocker and/or anti-muscarinic agents are needed to help improve urinary dysfunction. Intermittent self-catheterization is needed occasionally for patients with slow and/or poor recovery. PMID:22190298

Burakgazi, Ahmet Z; Alsowaity, Bander; Burakgazi, Zeynep Aydin; Unal, Dogan; Kelly, John J



The variable clinical manifestations of ulnar neuropathies at the elbow  

Microsoft Academic Search

In twenty-five cases of ulnar neuropathy at the elbow, the involvement of the fibres from three sensory and to four motor branches were examined clinically and, where possible, electrophysiologically. Of the sensory fibres, those from the terminal digital nerves were most commonly involved. The fibres to the hand muscles were much more frequently involved than those to the forearm muscles.

J D Stewart



Hereditary ataxia.  


The hereditary ataxias, also referred to as the spinocerebellar degenerations, comprise a series of clinical manifestations that include ataxia and dysmetria, resulting from the predominant involvement of the cerebellum and its afferent and efferent pathways. These disorders are system degenerations; many of them are specific entities clearly inherited as autosomal dominant or autosomal recessive traits. Although the clinical manifestations and neuropathologic findings of cerebellar disease dominate the spinocerebellar degenerations, there may also be characteristic changes in the basal ganglia, optic atrophy, retinitis pigmentosa, or peripheral nerve disease. There are many gradations from pure cerebellar manifestations to mixed cerebellar and brain-stem disorders, cerebellar and basal ganglia syndromes, and spinal syndromes or peripheral nerve disease. The clinical picture may be consistent in one family, but sometimes there is a characteristic syndrome in the majority of family members and an entirely different disorder in one or several members. PMID:2564162

Rosenberg, R N; Grossman, A



Retinitis pigmentosa, ataxia, and peripheral neuropathy.  

PubMed Central

The clinical features of four patients with retinitis pigmentosa, ataxia and peripheral neuropathy but with no increase in serum phytanic acid are reported. Three patients also had sensorineural deafness and radiological evidence of cerebellar atrophy. Nerve conduction studies revealed abnormalities of sensory conduction and normal or only mild slowing of motor conduction velocity. Sural nerve biopsy demonstrated a reduction in the density of myelinated fibres. There were no onion bulb formations. These cases clinically resemble Refsum's disease, but differ in having no detectable biochemical abnormality, and a peripheral neuropathy which is not hypertrophic in type. They may represent unusual cases of spinocerebellar degeneration. Images

Tuck, R R; McLeod, J G



Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy?  


Dominant mutations in the receptor calcium channel gene TRPV4 have been associated with a family of skeletal dysplasias (metatropic dysplasia, pseudo-Morquio type 2, spondylometaphyseal dysplasia, Kozlowski type, brachyolmia, and familial digital arthropathy) as well as with dominantly inherited neuropathies (hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy). While there is phenotypic overlap between the various members of each group, the two groups were considered to be totally separate with the former being strictly a structural skeletal condition and the latter group being confined to the peripheral nervous system. We report here on fetal akinesia as the presenting feature of severe metatropic dysplasia, suggesting that certain TRPV4 mutations can cause both a skeletal and a neuropathic phenotype. Three cases were detected on prenatal ultrasound because of absent movements in the second trimester. Case 4 presented with multiple joint contractures and absent limb movements at birth and was diagnosed with "fetal akinesia syndrome". Post-interruption and post-natal X-rays showed typical features of metatropic dysplasia in all four. Sequencing of the TRPV4 gene confirmed the presence of de novo heterozygous mutations predicting G78W (Case 1), T740I (Cases 2 and 3), and K276E (Case 4). Although some degree of restriction of movements is not uncommon in fetuses with skeletal dysplasia, akinesia as leading sign is unusual and suggests that certain TRPV4 mutations produce both chondrodysplasia and a peripheral neuropathy resulting in a severe "overlap" phenotype. PMID:21964829

Unger, Sheila; Lausch, Ekkehart; Stanzial, Franco; Gillessen-Kaesbach, Gabriele; Stefanova, Irina; Di Stefano, Cristina Maria; Bertini, Enrico; Dionisi-Vici, Carlo; Nilius, Bernd; Zabel, Bernhard; Superti-Furga, Andrea



Sciatic neuropathy as first sign of metastasising prostate cancer  

PubMed Central

Peripheral neuropathies are among the most common neurological diseases and have numerous causes, including diabetes, alcohol, hereditary, toxic, metabolic, infectious, inflammatory, ischaemic and paraneoplastic. Often, however, no definitive cause is identified and the condition is termed idiopathic neuropathy. Here we describe a patient who was initially diagnosed with idiopathic sciatic neuropathy but who was eventually diagnosed with prostate cancer. This is an uncommon manifestation of prostate cancer, and the diagnostic was difficult because prostate-specific antigen (PSA) was normal and the positron emission tomography scan negative. Changes in PSA should always raise the suspicion of prostate cancer, just as idiopathic progressive neuropathy should always raise the suspicion of an underlying malignancy, even when standard diagnostics fail to explain the patient's symptoms.

Hansen, Jakob M?ller; Rasti, Zoreh; Smith, Torben; Lassen, Lisbeth Hjorth



Peripheral neuropathy with microtubule-targeting agents: occurrence and management approach.  


Microtubule-targeting agents (MTAs), which include vinca alkaloids, taxanes, and the recently introduced epothilone, ixabepilone, are widely used chemotherapeutic agents for treatment of patients with cancer. MTAs interfere with the normal structure and function of microtubules, leading to cell-cycle arrest and tumor cell death. Microtubule function is critical to normal neuronal function, thus MTA therapy is commonly associated with some form of neuropathy. There is poor agreement between tools for clinical assessment of MTA-associated peripheral neuropathy, and standardization of grading scales is needed to reduce variability. For a majority of patients, MTA-associated neuropathy is mild to moderate in intensity and reversible, but it can be severe and resolve incompletely. The incidence and severity of MTA-associated neuropathy is drug, dose, and schedule dependent. The first-generation vinca alkaloids (eg, vincristine) are associated with severe mixed sensory and motor neuropathy, whereas the newer vinca alkaloids (eg, vinorelbine, vinflunine) induce a milder sensory neuropathy. Taxane-associated sensory neuropathy occurs more often with standard (polyoxyethylated castor oil-based) and albumin-bound paclitaxel than with docetaxel. The incidence and presentation of peripheral neuropathy with ixabepilone, alone or in combination with capecitabine, are similar to that with taxanes. Management of neuropathy may involve reducing or delaying the MTA dose, or in severe persistent or disabling cases discontinuing treatment. Reversal of neuropathy after dosage intervention appears to be more rapid with ixabepilone than with other MTAs. PMID:21569993

Carlson, Karen; Ocean, Allyson J



[Molecular genetics of inherited neuropathies].  


Inherited neuropathies are clinically and genetically heterogeneous. At least 28 genes and 12 loci have been associated with Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Most causes of inherited neuropathy have been discovered by positional cloning technique and in the past two years, the pace of CMT gene discovery has accelerated. Genetic studies have revealed the following gene mutations as the causes of inherited neuropathies; PMP22, MPZ, EGR2, SOX10, SIMPLE/LITAF, ARHGEF10 for CMT1 (autosomal dominant demyelinating form); GDAP1, MTMR2, SBF2/MTMR13, KIAA1985, NDRG1 PRX for CMT4 (autosomal recessive demyelinating form), MFN2, KIF1B, RAB7, GARS, NEFL, HSPB1, HSPB8 for CMT2 (autosomal dominant axonal form); LMNA, GAN1, KCC3, TDP1, APTX, SETX for AR-CMT2 (autosomal recessive axonal form); GIB1 for CMTX (X-linked CMT); DNM2 for CMT-DI (autosomal dominant CMT with intermediate nerve conduction velocities); and DHH for minifascicular neuropathy. These discovered CMT causing genes/proteins include those which show unpredictable correlations with the peripheral nervous system. However, these genes/proteins are definitely important for the peripheral nerve, and their discovery should pave the way for dramatic progress in the understanding of peripheral nerve biology. On the other hand, genotype-phenotype correlations of these genes are also important in order to understand the pathomechanisms of inherited neuropathy. Because, based on mutation studies, a large number of genes associated with both the CMT1/4 and CMT2 forms have been identified, it is usually difficult to predict the causative gene based on clinical information from patients without specific complications. To clarify the specific features and molecular mechanisms of five diseases that we previously reported, we reviewed recent progress in HMSN-P linked to chromosome 3, CMT4F caused by PRX, CMT4A caused by GDAP1, CMT4B2 caused by SBF2/MTMR13, and SCAN1 caused by TDP1. HMSN-P is characterized by late onset, proximal dominant severe muscle weakness, fasciculations, muscle cramp and sensory involvement. HMSN-P is a primary neuronopathy. Mutations in periaxin are associated with a broad spectrum of demyelinating neuropathies including DSS, a sensory dominant form and early onset slowly progressive CMT. Pathologically, loss of myelinated fibers, demyelination, small onion bulb formations, tomacula formation and myelin foldings were seen in sural nerves. Absence of septate like junction in the paranodal loop suggests that periaxin could be required for the adhesion complex. GDAP1 is a relatively common cause of CMT4. Half of reported patients showed the demyelinating form, while the rest showed the axonal form. The typical feature of CMT4A is paresis of the vocal cords and diaphragm. CMT4B2 is characterized by autosomal recessive, juvenile onset glaucoma and focally folded myelin in sural nerves. SBF2/MTMR13 mutations cause CMT4B2. Early onset glaucoma was seen in patients with nonsense mutations. SBF2/MTMR13 and MTMR2, which is the cause of CMT4B1, could be acting on the same 3-phosphoinositide signaling pathway. Clinical phenotypes of patients with TDP1, APTX, or SETX mutations share common clinical findings, namely cerebellar ataxia and axonal neuropathy. TDP1 and aprataxin both act on the single strand break repair pathway, with TDP1 working specifically on topoisomerase I related SSBR. Senataxin is a RNA helicase acting on RNA maturation and termination in yeast. Since these three proteins share a common pathway, disruption in any of them could induce a delay in the transcription process. The low rate of protein supply could lead to deaths of large neuronal cells. PMID:16541790

Takashima, Hiroshi



Evaluation of thermal and vibration sensation in diabetic neuropathy  

Microsoft Academic Search

Summary  Sensory evaluation of diabetic neuropathy was undertaken by a new technique for assessment of thermal sensitivity. The method is simple and reproducible, and the mean normal value of the lateral border of the foot was 6.0 °C (3.6–9.8 °C, 95% confidence limits). Four groups of patients with diabetic neuropathy were examined: 22 with neuropathic ulcers and\\/or Charcot joints (groups 1

R. J. C. Guy; C. A. Clark; P. N. Malcolm; P. J. Watkins



Chronic demyelinating neuropathy and intra-axonal polyglucosan bodies  

Microsoft Academic Search

In this study we evaluated the relationship between polyglucosan bodies and peripheral nerve lesions. The biopsied sural nerve from a patient with late-onset chronic sensori-motor neuropathy showed many intra-axonal polyglucosan bodies and segmental demyelination\\/remyelination. The formation of Schwann cell hyperplasia around the demyelinated axons was found at the sites of polyglucosan bodies. These findings suggest that demyelinating neuropathy is a

K. Matsumuro; S. Izumo; Y. Minauchi; M. Inose; I. Higuchi; M. Osame



Pediatric sciatic neuropathies due to unusual vascular causes.  


Four cases of pediatric sciatic neuropathies due to unusual vascular mechanisms are reported. Pediatric sciatic neuropathies were seen after umbilical artery catheterization, embolization of arteriovenous malformation, meningococcemia, and hypereosinophilic vasculitis. Electrophysiologic studies demonstrated abnormalities in motor studies of peroneal and tibial nerves. Sensory studies demonstrated abnormalities of sural and superficial peroneal nerves. Results of needle electromyography were abnormal in sciatic-innervated muscles. Prognosis was variable and depended on the severity of the initial nerve injury. PMID:18658074

Srinivasan, Jayashri; Escolar, Diane; Ryan, Monique; Darras, Basil; Jones, H Royden



Hereditary Spastic Paraplegia  


... What is Hereditary Spastic Paraplegia? Hereditary spastic paraplegia (HSP), also called familial spastic paraparesis (FSP), refers to ... typically slowly progress so that eventually individuals with HSP may require the assistance of a cane, walker, ...


Ulnar neuropathy associated with subdermal contraceptive implant.  


Side effects are a common occurrence in the use of subdermal contraceptive implants (Norplant); approximately 70% to 80% of women using the device report abnormal uterine bleeding, headaches, acne, mastalgia, nervousness, appetite changes, and weight gain. Local implant site reactions range from 0.4% to 4.7%, with pain being the most common. Other insertion site complications include infection and implant expulsion. Only three cases have been described in the literature concerning implant site-related neuropathy, involving the sensory branch of the musculocutaneous nerve (lateral cutaneous nerve) in two cases and the antebrachial cutaneous nerve in the third case. We believe our report is the first case of an axonal loosing motor and sensory ulnar neuropathy associated with the removal of a subdermal contraceptive implant (Norplant). We review insertion site complications and their most likely causes. Also, we discuss alternative removal techniques for difficult-to-remove implants. PMID:9743065

Marin, R; McMillian, D



Hereditary Pancreatic Cancer  

Microsoft Academic Search

Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and\\/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma

Henry T. Lynch; Randall E. Brand; Carolyn A. Deters; Trudy G. Shaw; Jane F. Lynch



Hereditary chin trembling or hereditary chin myoclonus?  

PubMed Central

Hereditary chin trembling is a rare autosomal dominant disease often considered as an "essential tremor variant". The clinical and neurophysiological data obtained in a new white family lead to the suggestion that this abnormal involuntary movement is a focal variant of hereditary essential myoclonus.??

Destee, A; Cassim, F; Defebvre, L; Guieu, J



Hereditary chin trembling or hereditary chin myoclonus?  

Microsoft Academic Search

Hereditary chin trembling is a rare autosomal dominant disease often considered as an “essential tremor variant”. The clinical and neurophysiological data obtained in a new white family lead to the suggestion that this abnormal involuntary movement is a focal variant of hereditary essential myoclonus.

A Destee; F Cassim; L Defebvre; J D Guieu



Protein misfolding and clearance in demyelinating peripheral neuropathies  

PubMed Central

Peripheral neuropathies such as Charcot-Marie-Tooth disease (CMT) are a group of neurological disorders that affect the peripheral nervous system. Although demyelinating CMT is the most prevalent hereditary peripheral neuropathy, there are currently no effective treatments for patients suffering from this disease. Recent studies by our group and others have provided a link between protein misfolding and demyelinating CMT and indicate that impairment of the proteasome and aggresome-autophagy pathways may contribute to CMT pathogenesis. These studies suggest that targeting protein quality control systems involved in cytoprotection against CMT-associated misfolded proteins could have therapeutic benefits for treating demyelinating CMT.

Lee, Samuel M.



Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study  

Microsoft Academic Search

Bortezomib is a new chemotherapeutic agent approved for the treatment of relapsed\\/refractory and newly diagnosed multiple\\u000a myeloma. One of the major side effects of bortezomib is a peripheral length-dependent sensory axonal neuropathy and, less\\u000a frequently, a small fiber neuropathy. Autonomic symptoms like postural dizziness, syncope, diarrhoea, ileus, impotence and\\u000a urinary disturbances have been reported, nevertheless, autonomic neuropathy has never been

Maria Pia Giannoccaro; Vincenzo Donadio; Carolina Gomis Pèrez; Walter Borsini; Vitantonio Di Stasi; Rocco Liguori



[Original articles on axonal neuropathy in 2010].  


During 2010, 15 articles were published which focused on chronic sensorimotor axonal neuropathy; some will be discussed in this review. Clinical diagnosis from signs and symptoms seems to be excessively variable, often overestimating the incidence of diabetic sensorimotor polyneuropathy. Long-term use of Metformin is associated with malabsorption of vitamin B12. Metformin exposure may be a iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. The neuroprotective role of vitamin E against cisplatinperipheral neurotoxicity has been suggested by a phase III study. Metallosis after hip arthroplasty with a cobalt-chromium alloy prosthesis can cause progressive sensory disturbance, hearing loss and hypothyroidism. The effects of electrical stimulation on neuromuscular recovery after nerve crush injury in rats do not support a benefit of the tested protocol using electrical stimulation during the period of motor nerve recovery following injury. The rate of motor vehicle accidents in patients with neuropathy, based on surveys from 260 subjects, demonstrated that 40.6% were involved in traffic accidents. Accident frequency and discomfort with driving are higher in neuropathy patients compared to age-matched national statistics. Peripheral neuropathy in primary (AL) amyloidosis may be the cause of stepwise progressive, multiple upper limb mononeuropathies. PMID:22100324

Attarian, S



Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol ® ): Double blind crossover trial  

Microsoft Academic Search

Summary  A double blind crossover study with placebo and carbamazepine was done in 30 diabetic patients who presented diverse clinical types of peripheral diabetic neuropathy. The active drug offered symptomatic relief of all sensory manifestations in 28 cases. No effort was made to assess the action of carbamazepine upon motor or visceral manifestations of neuropathy. There were two complete failures. Untoward

J. A. Rull; R. Quibrera; H. González-Millán; O. Lozano Castañeda



Diabetic neuropathy in the upper limb and the effect of twelve months sorbinil treatment  

Microsoft Academic Search

Summary  Clinical and neurophysiological studies were undertaken, with particular reference to the arms, in 39 patients with diabetic neuropathy. The effects of an aldose reductase inhibitor, sorbinil, on neuropathy in these patients were studied in a 12 month double blind placebo controlled trial. Neurophysiological measurements, particularly of sensory amplitude, were considerably more sensitive than measurements of temperature and vibration sensation and

R. J. C. Guy; S. G. Gilbey; M. Sheehy; P. Asselman; P. J. Watkins



Three ulnar nerve conduction studies in patients with ulnar neuropathy at the elbow  

Microsoft Academic Search

Objective: Ulnar neuropathy at the elbow is often difficult to localize by standard electrophysiologic testing. This study compared three ulnar nerve conduction studies to determine which was more sensitive in localizing ulnar neuropathy at the elbow.Methods: Motor studies to the first dorsal interosseous and the abductor digiti quinti and a mixed ulnar nerve sensory study across the elbow.Results: Motor studies

Milind J. Kothari; Michele Heistand; Seward B. Rutkove



Disease mechanisms in inherited neuropathies  

Microsoft Academic Search

Inherited neuropathies are caused by dominant or recessive mutations in genes that are expressed by neurons and\\/or Schwann cells. In demyelinating neuropathies, the deleterious effects originate primarily in myelinating Schwann cells. In axonal neuropathies, neurons (axons) are initially affected. In demyelinating neuropathies, the axonal cytoskeleton is altered and axonal transport is disrupted. In some axonal neuropathies, genes that are directly

Steven S. Scherer; Ueli Suter



HIV neuropathy: Insights in the pathology of HIV peripheral nerve disease  

Microsoft Academic Search

HIV-associated neuropathies (HIV-N) have become the most frequent neuro- logical disorder associated with HIV infection. The most common forms of HIV-N are the distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathies (ATN), disorders characterized mostly by sensory symptoms that include spontaneous or evoked pain that follow a subacute or chronic course. The main pathological features that characterize DSP and ATN

Carlos A. Pardo; Justin C. McArthur; John W. Griffin



Surrogate markers of small fiber damage in human diabetic neuropathy.  


Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy. PMID:17513704

Quattrini, Cristian; Tavakoli, Mitra; Jeziorska, Maria; Kallinikos, Panagiotis; Tesfaye, Solomon; Finnigan, Joanne; Marshall, Andrew; Boulton, Andrew J M; Efron, Nathan; Malik, Rayaz A



Brachial plexus neuropathy  

PubMed Central

Branchial plexus neuropathy is characterized by acute onset of intense pain in the shoulder or arm followed shortly by focal muscle weakness. This presentation may mislead the clinician into diagnosing shoulder or cervical spine pathology. Although brachial plexus neuropathy is not common, it should be considered in the differential diagnosis of pain and weakness of the arm. We present a patient with brachial plexus neuropathy who was originally misdiagnosed as having a cervical disc herniation. ImagesFigure 1Figure 2Figure 3

Hubka, Michael J; King, Laurie; Cassidy, J David; Donat, JR



Diabetic Peripheral Neuropathy  

Microsoft Academic Search

Diabetic peripheral neuropathy is the most prevalent peripheral neuropathy in the Western world. It has been reported to affect\\u000a nearly 50% of people with diabetes (1,2). It is responsible for a significant proportion of the mortality and morbidity that accompany diabetes and ranks third in\\u000a lifetime expenditures associated with diabetic complications (3). Diabetic peripheral neuropathy was until recently thought to

Rachel Nardin; Roy Freeman


Peripheral nerve involvement in hereditary cerebellar and multisystem degenerative disorders.  


Hereditary ataxias (HA) encompass an increasing number of degenerative disorders characterized by progressive cerebellar ataxia usually accompanied by extracerebellar semeiology including peripheral nerve involvement. Classically, HA were classified according to their pathological hallmark comprising three main forms: (1) spinal form predominantly with degeneration of spinocerebellar tracts, posterior columns, and pyramidal tracts (Friedreich's ataxia, FA); (2) olivopontocerebellar atrophy (OPCA); and (3) cortical cerebellar atrophy (CCA). In the 1980s Harding proposed a clinico-genetic classification based upon age of onset, modality of transmission, and clinical semeiology. The main categories in this classification were as follows: (1) early onset cerebellar ataxia (EOCA) with age of onset below 25 years and usually with autosomal recessive (AR) transmission (this group encompasses FA and syndromes different from FA); (2) autosomal dominant cerebellar ataxia (ADCA) with adult onset and with either cerebellar-plus syndrome or pure cerebellar semeiology; and (3) idiopathic late onset onset cerebellar ataxia (ILOCA). With the advent of molecular genetics, the nosology of HA has been in a state of constant flux. At present EOCA comprises at least 17 genotypes (designated with the acronym of ARCA derived from AR cerebellar ataxia), whereas under the umbrella of ADCA 30 genotypes have been reported. In this chapter we will review peripheral nerve involvement in classical pathological entities (OPCA and CCA), ARCA, ADCA, and ILOCA paying special attention to the most prevalent syndromes in each category. As a general rule, nerve involvement is relatively common in any form of ataxia except ILOCA, the most common pattern being either sensory or sensorimotor neuronopathy with a dying-back process. An exception to this rule is AR spastic ataxia of Charlevoix-Saguenay where nerve conduction studies show the characteristic pattern of intermediate neuropathy implying that sacsin mutation causes both axonal and Schwann cell dysfunction. PMID:23931821

Berciano, José; García, Antonio; Infante, Jon



Dyslipidemia as a contributory factor in etiopathogenesis of diabetic neuropathy  

PubMed Central

Objectives: The pathogenesis of neuropathy in type 2 diabetes mellitus is multifactorial.Dyslipidemia may contribute to the development of diabetic neuropathy. This study aimed to assess the atherogenic lipid indices in type 2 diabetic patients with neuropathy. Material and Methods: Fifty-one patients with type 2 diabetes mellitus and 31 healthy subjects were studied in the Unit of Neurophysiology at the University Hospital of Medical College, Al-Nahrin University in Baghdad, Iraq, from January 2002 to January 2003. Neuropathy total symptom score (NTSS), neuropathy impairment score in the lower leg (NIS-LL), and electrophysiological study of sensory (ulnar and sural) and motor (ulnar and common peroneal) nerves were used to assess nerve function. Fasting venous blood was obtained from each participant for determination of lipid profile and atherogenic lipid ratios. Results: The frequency of high blood pressure was significantly higher in neuropathic patients. The electrophysiology study revealed significant decrease in conduction velocity of ulnar (sensory and motor components), sural, and common peroneal nerves. The minimum F-wave latency of motor nerve was significantly prolonged. Among the lipid fractions, only high-density lipoprotein–cholesterol was significantly reduced by 14% of healthy participant's value. Atherogenic lipid ratios were significantly higher in diabetic patients than corresponding healthy ratios. Conclusion: Metabolic lipid disturbances in terms of atherogenicity co-existwith neuropathy in type 2 diabetes mellitus, irrespective of duration of disease.

Al-Ani, Fakhir S.; Al-Nimer, Marwan S.; Ali, Fatima S.



Voriconazole-Induced Neuropathy  

Microsoft Academic Search

Background: Fungal infections are common and life threatening among immunosupressive patients. Rare side effects may occur related to the use of voriconazole, which is the drug of choice in invasive aspergillosis. Patients and Methods: Neuropathy was determined through clinical and electromyographic findings during the course of voriconazole therapy in 2 patients developing invasive aspergillosis. Results: Since examinations revealed no neuropathy

Firdevs Aksoy; Elif Akdogan; Kemalettin Aydin; Mustafa Yilmaz; Vildan Altunayoglu; Ebru Emel Sozen; Serdar Bedii Omay; Iftihar Koksal



Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study.  


Bortezomib is a new chemotherapeutic agent approved for the treatment of relapsed/refractory and newly diagnosed multiple myeloma. One of the major side effects of bortezomib is a peripheral length-dependent sensory axonal neuropathy and, less frequently, a small fiber neuropathy. Autonomic symptoms like postural dizziness, syncope, diarrhoea, ileus, impotence and urinary disturbances have been reported, nevertheless, autonomic neuropathy has never been characterized. We describe by means of immunofluorescence, the involvement of autonomic skin nerve fibers in three patients with small fiber neuropathy induced by bortezomib treatment. PMID:21290160

Giannoccaro, Maria Pia; Donadio, Vincenzo; Gomis Pèrez, Carolina; Borsini, Walter; Di Stasi, Vitantonio; Liguori, Rocco



The role of copper on ethambutol's antimicrobial action and implications for ethambutol-induced optic neuropathy.  


The principal side effect of the antimycobacterial agent ethambutol (EMB) is an optic neuropathy with clinical features very similar to a mitochondrial hereditary optic neuropathy (Leber's). The mechanism of EMB-induced optic neuropathy may be EMB's chelation of copper, thereby precluding normal cytochrome c oxidase activity and mitochondrial metabolism in the optic nerve. Before attempting to use therapeutic copper to replenish endogenous stores in an attempt to preclude EMB-induced optic neuropathy, we wished to determine whether EMB is still effective against mycobacteria in the presence of copper. EMB and copper, alone and in combination, were tested against six strains of Mycobacterium tuberculosis and five strains of Mycobacterium avium using a radiometric broth macrodilution assay. Copper did not effect EMB's antimicrobial actions against either species of mycobacteria. This in vitro study suggests that if copper were given to patients to prevent EMB-induced optic neuropathy, it would not compromise EMB's bacteriostatic properties. PMID:9554173

Kozak, S F; Inderlied, C B; Hsu, H Y; Heller, K B; Sadun, A A



Hereditary Congenital External Ophthalmoplegia  

Microsoft Academic Search

Several members of a large pedigree suffering from hereditary congenital external ophthalmoplegia, an autosomal hereditary disorder of ocular movements, were examined and surgically treated. From nystagmographic findings it was concluded that the main cause of this disorder is of supranuclear origin. Specimen of the inferior oblique muscle revealed no abnormalities or showed decrease of type I muscle fibers.

W. A. Houtman; T. W. van Weerden; P. H. Robinson; B. de Vries; Tj. U. Hoogenraad



Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy  

PubMed Central

Objective In HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated. Design Prospective, comparative, single-center, cross-sectional cohort study. Methods Clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression. Results Of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (? 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ? 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4–5.5). Conclusions Elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.

Banerjee, Sugato; McCutchan, J. Allen; Ances, Beau M.; Deutsch, Reena; Riggs, Patricia K.; Way, Lauren; Ellis, Ronald J.



Dystonin/Bpag1 is a necessary endoplasmic reticulum/nuclear envelope protein in sensory neurons  

SciTech Connect

Dystonin/Bpag1 proteins are cytoskeletal linkers whose loss of function in mice results in a hereditary sensory neuropathy with a progressive loss of limb coordination starting in the second week of life. These mice, named dystonia musculorum (dt), succumb to the disease and die of unknown causes prior to sexual maturity. Previous evidence indicated that cytoskeletal defects in the axon are a primary cause of dt neurodegeneration. However, more recent data suggests that other factors may be equally important contributors to the disease process. In the present study, we demonstrate perikaryal defects in dorsal root ganglion (DRG) neurons at stages preceding the onset of loss of limb coordination in dt mice. Abnormalities include alterations in endoplasmic reticulum (ER) chaperone protein expression, indicative of an ER stress response. Dystonin in sensory neurons localized in association with the ER and nuclear envelope (NE). A fusion protein ofthe dystonin-a2 isoform, which harbors an N-terminal transmembrane domain, associated with and reorganized the ER in cell culture. This isoform also interacts with the NE protein nesprin-3{alpha}, but not nesprin-3{beta}. Defects in dt mice, as demonstrated here, may ultimately result in pathogenesis involving ER dysfunction and contribute significantly to the dt phenotype.

Young, Kevin G. [Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, K1H 8L6 (Canada); University of Ottawa Center for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario (Canada); Kothary, Rashmi [Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, K1H 8L6 (Canada); University of Ottawa Center for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario (Canada); Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario (Canada); Department of Medicine, University of Ottawa, Ottawa, Ontario (Canada)], E-mail:



Genetics Home Reference: Distal hereditary motor neuropathy, type V  


... type V is a progressive disorder that affects nerve cells in the spinal cord. It results in muscle ... accumulation likely damages and kills motor neurons (specialized nerve cells in the brain and spinal cord that control ...


Genetics Home Reference: Distal hereditary motor neuropathy, type II  


... type II is a progressive disorder that affects nerve cells in the spinal cord. It results in muscle ... cells throughout the body and are abundant in nerve cells. In nerve cells, heat shock protein beta-1 ...


Obesity and peripheral neuropathy risk: a dangerous liaison.  


This study investigates motor (MNCS) and sensory (SNCS) nerve conduction in a sample of non-diabetic obese people without symptoms suggestive of neuropathy and looks for a possible metabolic alteration. Twenty-one patients and 20 age-matched controls underwent (a) MNCS (median, ulnar, peroneal, and tibial) and SNCS (median, ulnar, and sural); (b) quantitative sensory testing to measure sensory threshold for vibration, warm and cold sensation (WS-CS), heat and cold-induced pain; and (c) blood sample analysis to evaluate glucose and insulin levels and calculate the quantitative insulin-sensitivity check index (QUICKI). The obese group showed significantly decreased compound muscle action potential amplitude of tibial and peroneal nerves and decreased sensory action potential amplitude of all nerves. Most of the sensory thresholds were altered in obese patients. Insulin serum levels were significantly increased while QUICKI decreased in obese patients. WS and CS from the index and little fingers and WS from the big toe significantly correlated with QUICKI. Thermal and pain thresholds from the index and thermal thresholds from the little finger correlated with QUICKI values. The non-diabetic obese patients showed a subclinical involvement of different diameter sensory fibers. Such impairment was related to hyperinsulinemia and insulin sensitivity. The increase in sensory threshold of obese patients might be due to a metabolic alteration, potentially leading to a future clinical neuropathy. PMID:16279984

Miscio, Giacinta; Guastamacchia, Giulia; Brunani, Amelia; Priano, Lorenzo; Baudo, Silvia; Mauro, Alessandro



Neuropathy secondary to drugs  


... weakness. Many medications may affect the development of neuropathy, including: Heart or blood pressure medications Amiodarone Hydralazine Perhexiline Drugs used to fight cancer Cisplatin Docetaxel Paclitaxel Suramin Vincristine Drugs used to fight infections ...


Additional Types of Neuropathy  


Complications Heart Disease Ketoacidosis (DKA) Men's Health Women's Health Eye Complications Foot Complications Hearing Loss Neuropathy Skin Complications High Blood Pressure (Hypertension) Stroke Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS) Gastroparesis ...


Occupational Peripheral Neuropathies  

PubMed Central

Neither clinical nor laboratory evaluation can distinguish occupational neuropathies from neuropathies due to other causes. A worker may suffer either from mechanical injury of individual nerves or from a toxic polyneuropathy that is usually axonal in type. A thorough occupational and environmental history and the recognition of clusters of cases are important in determining the diagnosis. Electrophysiologic studies are helpful in detecting neuropathies in patients who have been occupationally exposed to neurotoxins but have no symptoms. Prevention of occupational neuropathies depends on clinical vigilance, industrial hygiene surveys, biologic monitoring and periodic examination of workers exposed to neurotoxic chemicals. The development of more sophisticated methods of prevention and early detection of peripheral nerve involvement depend on understanding the mechanisms of action of toxins and the pathophysiology of the lesions they cause.

Lotti, Marcello; Becker, Charles E.; Aminoff, Michael J.



Leprosy neuropathy: clinical presentations.  


Leprosy is a chronic infectious peripheral neuropathy caused by Mycobacterium leprae. The different clinical presentations of the disease are determined by the quality of the host immune response. Early detection of leprosy and treatment by multidrug therapy are the most important steps in preventing deformity and disability. Thus the early recognition of the clinical leprosy presentation is essential. Mononeuritis, mononeuritis multiplex (MM), polyneuritis (MM summation) are the most frequent. The frequent anesthetic skin lesions are absent in the pure neuritic leprosy presentation form. Isolated peripheral nerve involvement is common, including the cranial ones. Arthritic presentation is occasionally seen, usually misdiagnosed as rheumatoid arthritis. Attention should be given to autonomic dysfunctions in leprosy. There are clinical presentations with severe neuropathic pain - painful small-fiber neuropathy. Leprous late-onset neuropathy (LLON) clinical presentation should be considered facing a patient who develop an inflammatory neuropathy many years after a previous skin leprosy treatment. PMID:24141500

Nascimento, Osvaldo J M



[Paraneoplastic neuropathy with positive anti-Hu].  


The case of a 72-year-old woman presenting sensory neuropathy and anti-Hu antibodies is reported. She was admitted in November 1995 with a one year history of sensory neuropathy. Her first symptoms were painful numbness and dysesthesias in both feet. She experienced progression of the sensory symptoms affecting upper limbs, and clumsiness of gait. One month before admission she complained of diminished strength in both hands. The neurologic examination showed anicocoric fixed pupils, with no reaction to light; convergence miosis was evident in the right eye (Argyll-Robertson pupil). In the lower limbs she had very mild distal weakness, and tendon reflexes were universally abolished. Pin and touch sensation, position sense and pallesthesia were absent in all four limbs. Romberg test was elicited, and a tabetic gait was patent. Pseudoathetotic movements were observed in hands and feet. An ulcer was present in the fifth finger of the right foot. Routine blood biochemistry and hematology showed a ESR of 105 and an increased IgG in the immune-electrophoretic run. Neurophysiologic evaluation disclosed a mild demyelinating neuropathy. Positive anti-Hu antibodies were found in the serum (Western blot - Athena Diagnostics); CSF was normal but not tested for anit-Hu. An abdominal CT scan disclosed multiple hypodense nodules in liver, right adrenal gland and peritoneum. A chest CT scan showed a hyperdense mass in the lower right pulmonary lobe and enlarged retrocava-pretracheal lymph nodes. A biopsy of the peritoneal nodule was performed, showing a metastatic small cell carcinoma. The patient died eight days after discharge. Although multiple organs were affected, she was independent until death, showing an indolent clinical course. PMID:9706256

Casas Parera, I; Fischman, D; Paz, L; Lehkuniec, E; Muchnik, S



Nuclear matrix proteins and hereditary diseases.  


The review summarizes literature data on alterations of structure or expression of different nuclear matrix proteins in hereditary syndromes. From the point of view of involvement of nuclear matrix proteins in etiology and pathogenesis of the disease hereditary pathologies can be classified in pathologies with pathogenesis associated with defects of nuclear matrix proteins and pathologies associated to changes of the nuclear matrix protein spectrum. The first group includes laminopathies, hereditary diseases with abnormal nuclear-matrix associated proteins and triplet extension diseases associated with accumulation of abnormal proteins in the nuclear matrix. Laminopathies are hereditary diseases coupled to structural defects of the nuclear lamina. These diseases include Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy (DCM) with conduction system disease, familial partial lipodystrophy (FPLD), autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disorder type 2, CMT2), mandibuloacral dysplasia (MAD), Hutchison Gilford Progeria syndrome (HGS), Greenberg Skeletal Dysplasia, and Pelger-Huet anomaly (PHA). Most of them are due to mutations in the lamin A/C gene, one - to mutations in emerin gene, some are associated with mutations in Lamin B receptor gene. In Werner's, Bloom's, Cockayne's syndromes, Fanconi anemia, multiple carboxylase deficiency mutations in nuclear matrix protein or enzyme gene lead to deficient DNA repair, abnormal regulation of cell growth and differentiation or other specific metabolic functions. Proteins with a long polyglutamic tract synthesized in the cells of patients with dentato-rubral and pallido-luysian atrophy, myotonic dystrophy and Huntington disease interfere with transcription on the nuclear matrix. Down's syndrome is a representative of the group of diseases with altered nuclear matrix protein spectrum. PMID:15865282

Sjakste, N; Sjakste, T



Chemotherapy-induced neuropathy  

Microsoft Academic Search

Peripheral neuropathy is a common dose-limiting toxicity of chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN)\\u000a causes numerous debilitating symptoms, impairs functional capacity, and results in dose reductions or possible cessation of\\u000a chemotherapy. Analgesic or neurotropic agents are only modestly effective in treating neuropathic symptoms. Animal and human\\u000a studies into the pathogenesis of CIPN have demonstrated heterogeneity in the mechanism(s) of nerve injury

Anjali Bhagra; Ravi D. Rao



Neuropathological alterations in diabetic truncal neuropathy: evaluation by skin biopsy  

PubMed Central

OBJECTIVES—To describe the neuropathological features in skin biopsies from patients with diabetic truncal neuropathy.?METHODS—Three patients with diabetic truncal neuropathy underwent skin biopsies from both symptomatic and asymptomatic regions of the chest and trunk. After local anaesthesia, biopsies were performed using a 3 mm diameter punch device (Acupunch). Intraepidermal nerve fibres (IENFs), the most distal processes of small myelinated and unmyelinated nerve fibres, were identified after staining with PGP 9.5 as previously described.?RESULTS—Diabetes was diagnosed at the time of the neurological presentation in two, and one was a known diabetic patient. All three had associated sensory-motor polyneuropathy. In all, skin biopsies showed a marked reduction of both epidermal and dermal nerve fibres in the symptomatic dermatomes, compared with skin from asymptomatic truncal areas. In one patient, a follow up skin biopsy when symptoms had improved showed a return of IENFs.?CONCLUSIONS—In diabetic truncal neuropathy, skin biopsies from symptomatic regions show a loss of IENFs. After clinical recovery, there is a return of the IENF population, suggesting that improvement occurs by nerve regeneration. These findings suggest that sensory nerve fibre injury in diabetic truncal neuropathy is distal to or within the sensory ganglia. Skin biopsy provides a possible tool for understanding the pathophysiology of the disease.??

Lauria, G.; McArthur, J.; Hauer, P.; Griffin, J.; Cornblath, D.



[Occupational toxic neuropathies: morphology in peripheral nerve biopsies].  


Many peripheral neuropathies are caused by the (acute or chronic) toxic action of metals, solvents, pesticides, and other occupational and environmental contaminants. These agents often reproduce the anatomoclinical pictures of hereditary (e.g., Charcot-Marie-Tooth disease), autoimmune (Guillain-Barrè syndrome), or dysmetabolic (thiamine deficiency, diabetic neuropathy) forms. Toxic peripheral neuropathies can be classified on the basis of etiology, clinical features (sensitive, motor, sensitive-motor), or histopathology: neuronopathies (uncommon, mostly secondary to retrograde axonal degeneration; e.g., arsenic, thallium), axonopathies (acrylamide, esacarbons, CS2, organophosphate-induced delayed neuropathy), myelinopathies (trichloroethylene), mixed forms (axonal and demyelinating: lead). For many substances, experimental research has led to the identification of the molecular and cellular targets of neurotoxicity. Several compounds are active by biotransformation (e.g., the esacarbons n-hexane and MnBK are neurotoxic since they are metabolized to 2,5-hexanedione), Genetic, physiological and environmental factors determine the individual metabolic set-up, and they may give origin to differences in the workers' sensitivity. Cessation of exposure is often followed by (microscopically observable) regenerative phenomena and clinical improvement. The morphology of neuropathies can be studied through peripheral nerve biopsy. Samples of sural nerve (or other nervous trunks of the limbs), adequately fixed, sectioned, and stained, allow the observation of alterations in axonal fibres (e.g., giant-axonal neuropathy, dying back neuropathy), myelin (demyelination), Schwann cells, interstitium, and blood vessels; possible inflammatory infiltrates; fibre density; regenerative phenomena (growth cone, remyelination). In occupational medicine, biopsy is indicated when the anamnestic-clinical picture, laboratory tests, and instrumental exams leave doubts about the nature, type, and entity of the neurological damage. In such cases, current optical and electron microscopy techniques can be very useful for injury evaluation, prognosis, and follow-up. PMID:23477107

Scelsi, Roberto; Candura, Stefano M


Hereditary Hemorrhagic Telangiectasia - HHT  


... IR Treatments Abdominal aortic aneurysms Angiography Angioplasty and stent placement Cancer - bone Cancer - breast Cancer - kidney Cancer - ... Causes Life-threatening Malformations in Blood Vessels Throughout Body Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder ...


Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy.  


Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I-mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-L-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy-induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts. PMID:22947198

Zheng, H; Xiao, W H; Bennett, G J



Comparison of efficiencies of michigan neuropathy screening instrument, neurothesiometer, and electromyography for diagnosis of diabetic neuropathy.  


Aim. This study compares the effectiveness of Michigan Neuropathy Screening Instrument (MNSI), neurothesiometer, and electromyography (EMG) in detecting diabetic peripheral neuropathy in patients with diabetes type 2. Materials and Methods. 106 patients with diabetes type 2 treated at the outpatient clinic of Ankara Numune Education and Research Hospital Department of Endocrinology between September 2008 and May 2009 were included in this study. Patients were evaluated by glycemic regulation tests, MNSI (questionnaire and physical examination), EMG (for detecting sensorial and motor defects in right median, ulnar, posterior tibial, and bilateral sural nerves), and neurothesiometer (for detecting alterations in cold and warm sensations as well as vibratory sensations). Results. According to the MNSI score, there was diabetic peripheral neuropathy in 34 (32.1%) patients (score ?2.5). However, when the patients were evaluated by EMG and neurothesiometer, neurological impairments were detected in 49 (46.2%) and 79 (74.5%) patients, respectively. Conclusion. According to our findings, questionnaires and physical examination often present lower diabetic peripheral neuropathy prevalence. Hence, we recommend that in the evaluation of diabetic patients neurological tests should be used for more accurate results and thus early treatment options to prevent neuropathic complications. PMID:23818897

Mete, Turkan; Aydin, Yusuf; Saka, Mustafa; Cinar Yavuz, Halise; Bilen, Sule; Yalcin, Yavuz; Arli, Berna; Berker, Dilek; Guler, Serdar



The Role of Copper on Ethambutol’s Antimicrobial Action and Implications for Ethambutol-induced Optic Neuropathy 1 1 Grant support for this research: NIH (R01EY 11396-01A1 and AI25140)  

Microsoft Academic Search

The principal side effect of the antimycobacterial agent ethambutol (EMB) is an optic neuropathy with clinical features very similar to a mitochondrial hereditary optic neuropathy (Leber’s). The mechanism of EMB-induced optic neuropathy may be EMB’s chelation of copper, thereby precluding normal cytochrome c oxidase activity and mitochondrial metabolism in the optic nerve. Before attempting to use therapeutic copper to replenish

Scott F Kozak; Clark B Inderlied; Hugo Y Hsu; Keith B Heller; Alfredo A Sadun



Neuropathy and monoclonal gammopathy.  


The association of neuropathy with monoclonal gammopathy has been known for several years, even if the clinical and pathogenetic relevance of this association is not completely defined. This is not a marginal problem since monoclonal gammopathy is present in 1-3% of the population above 50 years in whom it is often asymptomatic, and in at least 8% of patients is associated with a symptomatic neuropathy, representing one of the leading causes of neuropathy in aged people. Monoclonal gammopathy may result from malignant lymphoproliferative diseases including multiple myeloma or solitary plasmocytoma, Waldenström's macroglobulinemia (WM), other IgM-secreting lymphoma or chronic lymphocytic leukemia, and primary systemic amyloidosis (AL). In most instances it is not associated with any of these disorders and is defined monoclonal gammopathy of undetermined significance (MGUS) for its possible, though infrequent, evolution into malignant forms. Several data support the pathogenetic role of the monoclonal gammopathy in the neuropathy particularly when of IgM isotype where IgM reactivity to several neural antigens has been reported. Increased levels of VEGF have been implicated in POEMS syndrome. However, there are as yet no defined therapies for these neuropathies, as their efficacy has not been confirmed in randomized trials. PMID:23931795

Nobile-Orazio, Eduardo



Clinical research for neuropathies.  


The National Institutes of Health (NIH) has a long-standing commitment to neuropathy research. From 2005-2009, the NIH has committed US $115 million each year. A collaborative effort between researchers and patients can accelerate the translation of pre-clinical discoveries into better treatments for neuropathy patients. Clinical trials are needed to test these new treatments, but they can only be implemented in a timely fashion if patients with neuropathies are willing to participate. This perspective focuses on the value of having various outlets for informing both the patients and the physicians about existing clinical research opportunities and on the potential benefit of establishing patient registries to help with trial recruitment. Once data have been collected, there is a need to broadly share the data in order to inform future trials, and a first step would be to harmonize data collection by using Common Data Elements (CDEs). PMID:22548622

Kaufmann, Petra



Alcohol-induced stress in painful alcoholic neuropathy.  


Chronic alcohol consumption induces a painful small-fiber peripheral neuropathy, the severity of which increases during alcohol withdrawal. Chronic alcohol consumption also produces a sustained increase in stress hormones, epinephrine and corticosterone, that is exacerbated during alcohol withdrawal. We report that adrenal medullectomy and administration of a glucocorticoid receptor antagonist, mifepristone (RU 38486), both prevented and reversed a model of painful peripheral neuropathy in alcohol binge-drinking rats. Chronic administration of stress levels of epinephrine to rats that had undergone adrenal medullectomy and were being fed the alcohol diet reconstituted this phenotype. Intrathecal administration of oligodeoxynucleotides antisense to the beta(2)-adrenergic- or glucocorticoid-receptor also prevented and reversed the pro-nociceptive effects of ethanol. Our results suggest a convergence of the effects of mediators of the hypothalamic-pituitary- and sympathoadrenal-stress axes on sensory neurons in the induction and maintenance of alcohol-induced painful peripheral neuropathy. PMID:18093169

Dina, Olayinka A; Khasar, Sachia G; Alessandri-Haber, Nicole; Green, Paul G; Messing, Robert O; Levine, Jon D



Defining risks of taxane neuropathy: insights from randomized clinical trials.  


Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin-bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes. PMID:23817688

Kudlowitz, David; Muggia, Franco



Axonal neuropathy associated with interferon-? treatment for hepatitis C: HLA-DR immunoreactivity in Schwann cells  

Microsoft Academic Search

A 44-year-old man developed a peripheral neuropathy during treatment with interferon-? for chronic hepatitis C. The onset\\u000a was insidious, beginning symmetrically in the hands with paresthesia. Neurophysiological investigation revealed a predominantly\\u000a sensory axonal neuropathy. A sural nerve biopsy confirmed primary axonal damage. Immunofluorescence studies showed increased\\u000a expression of HLA-DR molecules prevalently on Schwann cells of non-myelin-forming type.

Angelo Quattrini; Giancarlo Comi; Raffaello Nemni; Vittorio Martinelli; Antonello Villa; Marco Caimi; Lawrence Wrabetz; Nicola Canal



Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice  

Microsoft Academic Search

Bortezomib, a proteasome inhibitor, is an antineoplastic drug to treat multiple myeloma and mantle cell lymphoma. Its most clinically significant adverse event is peripheral sensory neuropathy. Our objective was to characterize the neuropathy induced by bortezomib in a mouse model. Two groups were used; one group received vehicle solution and another bortezomib (1mg\\/kg\\/twice\\/week) for 6weeks (total dose as human schedule).

Jordi Bruna; Esther Udina; Albert Alé; Jorge J. Vilches; Ann Vynckier; Johan Monbaliu; Lee Silverman; Xavier Navarro



Thermal Biofeedback and Lower Extremity Blood Flow in Adults with Diabetes: Is Neuropathy a Limiting Factor?  

Microsoft Academic Search

Thermal biofeedback may be a useful adjunctive technique for enhancing cutaneous blood flow in patients with lower-extremity vascular complications of diabetes. However, autonomic, sensory, and\\/or motor neuropathies may impair vasomotion and limit the ability to alter blood flow and achieve significant foot warming with thermal biofeedback. We examined nerve function associated with four common types of diabetic neuropathy (sympathetic–autonomic, vagal–autonomic,

Patricia L. Fiero; Daniel I. Galper; Daniel J. Cox; Lawrence H. Phillips II; David A. Fryburg



Genome-wide screen identifies drug-induced regulation of the gene giant axonal neuropathy (Gan) in a mouse model of antiretroviral-induced painful peripheral neuropathy.  


Painful peripheral neuropathy is a debilitating complication of the treatment of HIV with nucleoside reverse transcriptase inhibitors (NRTIs). Patients are living longer with these drugs; however many develop excruciating, unremitting, and often treatment-limiting neuropathy that is resistant to conventional pain management therapies. Improving patient comfort and quality of life is paramount and depends on a clearer understanding of this devastating side effect. The mechanisms underlying the development of NRTI-induced neuropathy, however, remain unclear. Using a mouse model of NRTI-induced neuropathy, the authors conducted an unbiased whole-genome microarray screen to identify molecular targets in the spinal dorsal horn, which is the location where integration of ascending sensory transmission and descending modulatory effects occur. Analysis of the microarray data identified a change in the gene giant axonal neuropathy 1 (Gan1). Mutation of this gene has been linked to the development of giant axonal neuropathy (GAN), a rare autosomal recessive condition characterized by a progressive sensorimotor neuropathy. Gan1 has not been previously linked to nerve pathologies in other populations. In this study, downregulation of the Gan1 gene and the gene protein product, gigaxonin, was validated via quantitative polymerase chain reaction ([qPCR] gene expression) and Western blot analyses (protein level). Our report is the first to suggest that Gan1 might be a novel molecular target in the development of NRTI-induced peripheral neuropathy with implications for new therapeutic approaches to preventing or reducing a significant side effect of HIV treatment. PMID:19398414

Dorsey, Susan G; Leitch, Carmen C; Renn, Cynthia L; Lessans, Sherrie; Smith, Barbara A; Wang, Xiao M; Dionne, Raymond A



Clinicopathological features of neuropathy associated with lymphoma.  


Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain. PMID:23884813

Tomita, Minoru; Koike, Haruki; Kawagashira, Yuichi; Iijima, Masahiro; Adachi, Hiroaki; Taguchi, Jun; Abe, Takenori; Sako, Kazuya; Tsuji, Yukiko; Nakagawa, Masanori; Kanda, Fumio; Takeda, Fusako; Sugawara, Masashiro; Toyoshima, Itaru; Asano, Naoko; Sobue, Gen



Treatment of Diabetic Sensory Polyneuropathy  

PubMed Central

Opinion statement No current disease-modifying treatments have been shown definitively in randomized clinical trials to reduce or reverse diabetic sensory polyneuropathy (DSP). It is increasingly recognized that individuals with “prediabetes” or impaired glucose regulation can already have a “small-fiber” neuropathy, or mild DSP, in which sensory axons of both small and larger diameter are damaged. Small-fiber neuropathy is frequently associated with pain, and these patients may present to a neurologist for evaluation before the underlying glucose dysregulation has been diagnosed. It is important to identify these individuals, because aggressive diabetic control and lifestyle interventions can delay the onset of diabetes and may reverse small-fiber neuropathy associated with early diabetes mellitus. Although treatment currently focuses on pain associated with DSP, attention should be paid to potential risk factors for neuropathy. For example, glycemic control and hyperlipidemia should be improved with diet, exercise, and medications. Hypertension that is a risk marker for more severe neuropathy should be treated. Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers not only treat hypertension but also may directly reduce the progression of neuropathy. Class I or II clinical studies support the use of sodium valproate, pregabalin, duloxetine, amitriptyline, gabapentin, venlafaxine, opioids, and topical capsaicin in treating diabetic neuropathic pain. Pregabalin and gabapentin are relatively well tolerated and have few medication interactions. Sodium valproate has been shown to be effective but is not recommended for use in women of childbearing potential, and patients must be monitored for hepatotoxicity and thrombocytopenia. Tricyclic antidepressants such as amitriptyline are often used for nocturnal pain but require caution in the elderly or anyone with cardiac disease. Venlafaxine and duloxetine successfully treat neuropathic pain independently of their effect on depression. Opioid medications are associated with a high rate of adverse effects but with careful monitoring, they can be effective in treating resistant neuropathic pain. Capsaicin is an effective topical treatment that lacks systemic side effects. The lidocaine patch is effective in relieving pain associated with postherpetic neuralgia, but only class III evidence supports its use for diabetic neuropathic pain. No current Class I or II studies support other treatment modalities.

Zilliox, Lindsay; Russell, James W.



Hereditary angio-oedema.  


Hereditary angio-oedema is caused by a heterozygous deficiency of C1 inhibitor. This inhibitor regulates several inflammatory pathways, and patients with hereditary angio-oedema have intermittent cutaneous or mucosal swellings because of a failure to control local production of bradykinin. Swellings typically evolve in several hours and persist for a few days. In addition to orofacial angio-oedema, painless swellings affect peripheries, which causes disfigurement or interference with work and other activities of daily living. Angio-oedema affecting the gastrointestinal tract or abdominal viscera causes severe pain often with vomiting due to oedematous bowel obstruction. About 2% of swellings involve the larynx and can be fatal if untreated. About 50% of patients have laryngeal swellings that are potentially fatal despite prophylaxis. In this Seminar we review the clinical features, diagnosis, and management of hereditary angio-oedema, with specific emphasis on the new treatments available for acute swellings. PMID:22305226

Longhurst, Hilary; Cicardi, Marco



Sensory syndromes.  


Somatosensory deficit syndromes represent a common impairment following stroke and have a prevalence rate of around 80% in stroke survivors. These deficits restrict the ability of survivors to explore and manipulate their environment and are generally associated with a negative impact on quality of life and personal safety. Sensory impairments affect different sensory modalities in diverse locations at varying degrees, ranging from complete hemianesthesia of multiple modalities to dissociated impairment of somatosensory submodalities within a particular region of the body. Sensory impairments induce typical syndromal patterns which can be differentiated by means of a careful neurological examination, allowing the investigator to deduce location and size of the underlying stroke. In particular, a stroke located in the brainstem, thalamus, and the corticoparietal cortex result in well-differentiable sensory syndromes. Sensory function following stroke can be regained during rehabilitation even without specific sensory training. However, there is emerging evidence that specialized sensory interventions can result in improvement of somatosensory and motor function. Herein, we summarize the clinical presentations, examination, differential diagnoses, and therapy of sensory syndromes in stroke. PMID:22377851

Klingner, Carsten M; Witte, Otto W; Günther, Albrecht



Immune modulation therapy in the management of bortezomib-induced peripheral neuropathy  

PubMed Central

Peripheral neuropathy (PN) is one of the most common side effects of bortezomib therapy. The majority of bortezomib-related PN is a sensory neuropathy of mild to moderate degree, and is reversible after dose reduction or discontinuation. However, occasionally bortezomib-induced neuropathy can be severe and affects motor and/or autonomic nerves, and may be mediated by immune process. The role of immune modulation therapy in the management of bortezomib-induced PN was not well established. Here, we reported a case of bortezomib-induced severe PN that responded well to plasma exchange and steroid treatment.



Immune modulation therapy in the management of bortezomib-induced peripheral neuropathy.  


Peripheral neuropathy (PN) is one of the most common side effects of bortezomib therapy. The majority of bortezomib-related PN is a sensory neuropathy of mild to moderate degree, and is reversible after dose reduction or discontinuation. However, occasionally bortezomib-induced neuropathy can be severe and affects motor and/or autonomic nerves, and may be mediated by immune process. The role of immune modulation therapy in the management of bortezomib-induced PN was not well established. Here, we reported a case of bortezomib-induced severe PN that responded well to plasma exchange and steroid treatment. PMID:23211009

Jeter, Ashley; Kang, Yubin



Toxic optic neuropathy  

PubMed Central

Toxic optic neuropathy (TON) is a disease entity which is not only underdiagnosed, but also often diagnosed at a stage when recovery of vision is not possible. This article gives an overview of common causes, clinical features, and management of TON.

Sharma, Pradeep; Sharma, Reena



Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy.  

PubMed Central

Five siblings of a Danish family with slowly progressive involvement of the trigeminal, facial, glossopharyngeal, accessory, and hypoglossal nerves beginning at the age of 55-65 years were examined. All had asymptomatic corneal lattice dystrophy. Clinical and electrophysiological investigations also showed evidence of slight neurogenic involvement of the limbs. Conduction velocity along sensory nerves was normal but amplitude of sensory potentials was severely reduced suggesting an axonal affection which was confirmed by sural nerve biopsy. The neuropathy was secondary to amyloidosis revealed by skin and sural nerve biopsies. Images

Boysen, G; Galassi, G; Kamieniecka, Z; Schlaeger, J; Trojaborg, W



Neuropathy Associated with Microtubule Inhibitors: Diagnosis, Incidence, and Management  

Microsoft Academic Search

Microtubule inhibitor (MTI)-based chemotherapies used in the treatment of breast cancer—including vinca alkaloids, taxanes, and epothilones—are known to be associated with peripheral neuro- pathy. The incidence and severity of neuropathy, most frequently sensory in nature, depend on the agent used, absolute and cumulative drug dose, administration schedule, and presence of comorbidities. Although some first-generation vinca alkaloids, such as vincristine, were

Sandra M. Swain; Joseph C. Arezzo


Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies  

Microsoft Academic Search

Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established.The clinical symptoms localized in a stocking-glove distribution may be explained by a length depen- dent neuronopathy or by a distal axonopathy.To study whether the whole neuron or the distal axon was primar- ily affected, we have carried out serial clinical and

A. Krarup-Hansen; S. Helweg-Larsen; H. Schmalbruch; M. Rrth; C. Krarup



Endoplasmic reticulum stress contributes to prediabetic peripheral neuropathy.  


Growing evidence suggests that prediabetes and metabolic syndrome are associated with increased risk for the development of microvascular complications including retinopathy, nephropathy, and, most commonly, peripheral painful neuropathy and/or autonomic neuropathy. The etiology of these disabling neuropathies is unclear, and several clinical and experimental studies implicated obesity, impaired fasting glycemia/impaired glucose tolerance, elevated triglyceride and non-esterified fatty acids, as well as oxidative-nitrative stress. Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins and leading to the impairment of metabolism, transcriptional regulation, and gene expression, is emerging as a key mechanism of metabolic diseases including obesity and diabetes. We evaluated the role for this phenomenon in prediabetic neuropathy using two animal models i.e., Zucker (fa/fa) rats and high-fat diet fed mice which displayed obesity and impaired glucose tolerance in the absence of overt hyperglycemia. Endoplasmic reticulum stress manifest in upregulation of the glucose-regulated proteins BiP/GRP78 and GRP94 of unfolded protein response was identified in the sciatic nerve of Zucker rats. A chemical chaperone, trimethylamine oxide, blunted endoplasmic reticulum stress and alleviated sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. A selective inhibitor of eukaryotic initiation factor-2? dephosphorylation, salubrinal, improved glucose intolerance and alleviated peripheral nerve dysfunction in high-fat diet fed mice. Our findings suggest an important role of endoplasmic reticulum stress in the neurobiology of prediabetic peripheral neuropathy, and identify a new therapeutic target. PMID:23142188

Lupachyk, Sergey; Watcho, Pierre; Obrosov, Alexander A; Stavniichuk, Roman; Obrosova, Irina G



Inherited Optic Neuropathies  

Microsoft Academic Search

? Inherited optic neuropathies are a diverse group of conditions presenting with mild to severe visual loss, colour vision\\u000a deficits, central\\/paracentral visual field defects, optic disc pallor and in many cases a positive family history. \\u000a \\u000a ? Modes of inheritance are dominant, recessive, X-linked and mitochondrial. \\u000a \\u000a \\u000a ? The absence of a family history does not exclude this diagnosis as there are

Marcela Votruba


Painful diabetic neuropathy management.  


Diabetic neuropathy is the most common complication of diabetes as it affects a significant number of patients. The management of patients with diabetic neuropathy is complicated by several factors including the varied symptoms and response to the various treatments available. Strict blood glucose control remains the key to the management thus far nonetheless; it is associated with complications such as hypoglycaemia. In order to provide the most up-to-date evidence-based clinical recommendations pertinent to the management of diabetic neuropathy, several databases and clinical practice guidelines were searched for this evidence-based report. The main outcome measures are reduction in pain associated with diabetic neuropathy and the number of withdrawal rates due to adverse effects of the medications both of which are discussed in this report. Various pharmacological and non-pharmacological treatments are available with varying degrees of success in pain relief. The current evidence suggests that use of tricyclics antidepressants and conventional anticonvulsants for the short term of pain relief is beneficial. Combination therapy of opioids and anticonvulsants has also been found to be superior to monotherapy. Other treatment modalities such as the use of alpha-lipoic acid as an antioxidant and evening primrose oil through increased PGE1 synthesis have also been trialled with evidence of improvement in neuropathic pain. Evidence also supports non-pharmacological treatment such as the use of percutaneous electrical nerve stimulation. There is a scope for further improvement of the reporting of rating pain scales and including various outcomes measures such as quality of life and physical function when trialling new therapies for better evaluation of future treatments. PMID:23448333

Khalil, Hanan



Folate responsive neuropathy.  


The literature on folate related neuropathy has been reviewed. Twenty patients fulfilled the following criteria (a) they presented with neurological findings for which no other cause could be found (b) the serum or red cell and/or the CSF folate was low (c) the serum vitamin B12 or vitamin B12 absorption was normal and (d) they showed a significant response to folic acid. Ten presented with a peripheral neuropathy, eight with subacute combined degeneration of the cord and two with a myelopathy. In two patients the neuropathy occurred when treatment for congenital malabsorption of folate--an isolated lesion affecting folate alone--lapsed. Two patients with subacute combined degeneration died and posterio-lateral sclerosis of the cord was confirmed at autopsy. Three patients were mentally retarded and nine showed mental changes which also responded to folate in addition to the neurological disorder. A single biochemical reaction, the methionine synthetase reaction, is suggested as the basis for the neurological as well as the haematological consequences of both vitamin B12 and folate deficiency. The pitfalls in diagnosis are discussed and a greater awareness of the condition urged. PMID:8177846

Parry, T E



Docetaxel neuropathy: a distal axonopathy  

Microsoft Academic Search

Docetaxel has been implicated as a causative agent in peripheral neuropathy, but pathological changes in peripheral nerve\\u000a have not been described. During docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy when the overall\\u000a docetaxel dosage was 540 mg\\/m2. Neurophysiological investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve biopsy showed an axonal\\u000a neuropathy with a preferentially loss of large

Raffaella Fazio; Angelo Quattrini; Angelo Bolognesi; Gianni Bordogna; Eugenio Villa; Stefano Previtali; Nicola Canal; Raffaello Nemni



Autonomic and sensory nerve dysfunction in primary biliary cirrhosis  

Microsoft Academic Search

AIM: Cardiovascular autonomic and peripheral sensory neuropathy is a known complication of chronic alcoholic and non-alcoholic liver diseases. We aimed to assess the prevalence and risk factors for peripheral sensory nerve and autonomic dysfunction using sensitive methods in patients with primary biliary cirrhosis (PBC). METHODS: Twenty-four AMA M2 positive female patients with clinical, biochemical and histological evidence of PBC and

Katalin Keresztes; Ildikó Istenes; Aniko Folhoffer; Peter L Lakatos; Andrea Horvath; Timea Csak; Peter Varga; Peter Kempler; Ferenc Szalay; Lakatos PL


MBK neuropathy among spray painters.  


It has been suggested that the solvent methyl N-butyl ketone (MBK) may cause peripheral neuropathy in humans. An investigation was undertaken after two cases of peripheral neuropathy among spray painters at one work site were reported to the National Institute for Occupational Safety and Health. Twenty-six painters were interviewed and examined. Two were found to have definite peripheral neuropathy and one had a probable case. Although one of these men had been exposed to lead in the past, there are strong reasons to believe that MBK was responsible for his neuropathy. There was nothing to suggest excessive lead absorption in the other two men. PMID:176479

Mallov, J S



The role of aberrant mitochondrial bioenergetics in diabetic neuropathy.  


Diabetic neuropathy is a neurological complication of diabetes that causes significant morbidity and, because of the obesity-driven rise in incidence of type 2 diabetes, is becoming a major international health problem. Mitochondrial phenotype is abnormal in sensory neurons in diabetes and may contribute to the etiology of diabetic neuropathy where a distal dying-back neurodegenerative process is a key component contributing to fiber loss. This review summarizes the major features of mitochondrial dysfunction in neurons and Schwann cells in human diabetic patients and in experimental animal models (primarily exhibiting type 1 diabetes). This article attempts to relate these findings to the development of critical neuropathological hallmarks of the disease. Recent work reveals that hyperglycemia in diabetes triggers nutrient excess in neurons that, in turn, mediates a phenotypic change in mitochondrial biology through alteration of the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) signaling axis. This vital energy sensing metabolic pathway modulates mitochondrial function, biogenesis and regeneration. The bioenergetic phenotype of mitochondria in diabetic neurons is aberrant due to deleterious alterations in expression and activity of respiratory chain components as a direct consequence of abnormal AMPK/PGC-1? signaling. Utilization of innovative respirometry equipment to analyze mitochondrial function of cultured adult sensory neurons from diabetic rodents shows that the outcome for cellular bioenergetics is a reduced adaptability to fluctuations in ATP demand. The diabetes-induced maladaptive process is hypothesized to result in exhaustion of the ATP supply in the distal nerve compartment and induction of nerve fiber dissolution. The role of mitochondrial dysfunction in the etiology of diabetic neuropathy is compared with other types of neuropathy with a distal dying-back pathology such as Friedreich ataxia, Charcot-Marie-Tooth disease type 2 and human immunodeficiency virus-associated distal-symmetric neuropathy. PMID:22446165

Chowdhury, Subir K Roy; Smith, Darrell R; Fernyhough, Paul



[Implication of alpha-lipoic acid preparations in the treatment of diabetic neuropathy].  


Twenty-eight patients, 17 women and 11 men, aged 40-70 years, with distal sensory-motor diabetic neuropathy of the lower extremities were treated with berlition, an alpha-lipoic acid preparation, in dosage 600 mg daily during 3 months. The treatment resulted in the significant reduction of clinical (sensory and motor) and neurological changes of lower extremity peripheral nerves. PMID:18427500

Al'-Zamil', M Kh; Brezheva, E V



Hereditary Nonmelanoma Skin Cancer  

PubMed Central

Cutaneous basal and squamous cell carcinomas are among the most frequent malignancies in the white population, with the annual incidence estimates ranging from 1 million to 3.5 million cases in the United States. These tumors can occur either sporadically or in the context of hereditary genodermatoses with cancer predisposition, such as basal cell nevus syndrome, xeroderma pigmentosum, epidermolysis bullosa, or oculocutaneous albinism. Different genes and signaling pathways have been shown to play a central role in the development and growth of these tumors. This article overviews the clinical features, diagnostic criteria, and the most recent data on genetic routes of the major hereditary syndromes predisposed to the development of nonmelanoma skin cancer.

Nikolaou, Vasiliki; Stratigos, Alexander J.; Tsao, Hensin



Hereditary spherocytosis and hemochromatosis  

Microsoft Academic Search

A 37-year-old male, splenectomized at the age of 1 year, was admitted to the ward with severe chest pain and signs of cardiogenic shock. Clinical investigations revealed the presence of both hemochromatosis and hereditary spherocytosis (HS). HLA typing showed A3,B7 and A24,B57 haplotypes and genetic analysis revealed homozygosity for the C282Y mutation. A family study was performed. The parents and

J. Brandenberg; F. Demarmels Biasiutti; H. Lutz; W. Wuillemin



Dysfunction in Multiple Primary Afferent Fiber Subtypes Revealed By Quantitative Sensory Testing in Patients with Chronic Vincristine-Induced Pain  

Microsoft Academic Search

Vincristine is one of the frontline chemotherapy drugs for the treatment of numerous lymphoid neoplasias. The main dose-limiting complication of vincristine is the development of painful peripheral neuropathy. Although clinical reports have appeared in the literature detailing the symptoms of vincristine neuropathy, quantitative sensory testing data that might yield insight to dysfunction in subsets of primary afferents are lacking. In

Patrick M. Dougherty; Juan P. Cata; Allen W. Burton; Khanh Vu; Han-Rong Weng



Sensory systems.  


Research on the senses spans the enormous range from analysis of individual molecules involved in sensory transduction to the attempted elucidation of conscious sensation. Because the variety of conceptual and experimental approaches varies so broadly across the field, it is impossible to delineate a single direction for future research. Two trends are nonetheless apparent. At the reductionistic end of the spectrum, in the analysis of sensory transduction, studies on all the senses will increasingly be driven by the techniques of molecular biology. The advent of techniques for producing cDNA libraries from small ensembles of receptor cells, or even from individual cells, will permit the recognition of new constituents of receptor cells and of factors involved in their specification, differentiation, and maintenance. In the integrative realm of sensory neurobiology, future studies will increasingly rely on optical techniques for the study of activity patterns on the surfaces of sensory areas of the cerebral cortex and on noninvasive functional imaging for the investigation of neural responses in human subjects. These techniques will continue to strengthen our understanding of the relation between neuronal activity and conscious sensory experience. PMID:9751666

Hudspeth, A J; Tanaka, K



Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.  


We report on a large four-generation Austrian family with autosomal dominant distal hereditary motor neuronopathy type V (distal HMN V). Forty-seven at-risk family members, of whom 21 were definitely affected, underwent detailed clinical, electrophysiological and genetic studies. The age at onset was in the second decade of life in most affected individuals, but clinical presentation was rather variable. While the majority of patients were primarily disabled by progressive asymmetrical wasting of the thenar and the first dorsal interosseus muscles, others had marked foot deformity and gait disturbance with the occasional absence of hand involvement. Sensation sense was normal except for the reduced response to vibration. Many individuals showed brisk tendon reflexes and some elevated muscle tone in the lower limbs, but extensor plantar responses were rarely observed. Electrophysiological evaluation revealed normal or reduced motor nerve conduction velocities, normal or prolonged distal motor latencies, and low compound motor action potentials, depending on the degree of muscle wasting. Sensory nerve studies were usually within the normal range or slightly to moderately abnormal in older or severely affected persons. Electromyography showed high-amplitude motor unit potentials and reduced recruitment compatible with anterior horn cell degeneration. Central motor conduction times were prolonged in two-thirds of the patients. Molecular genetic studies excluded Charcot-Marie-Tooth 1A syndrome and proximal spinal muscular atrophy linked to chromosome 5q as well as the known gene loci for distal HMN II on chromosome 12q, HMN V on chromosome 7p and juvenile amyotrophic lateral sclerosis on chromosome 9q. The findings in this family thus provide detailed clinical and electrophysiological information on HMN V and demonstrate broad phenotypic variability in this disorder. Hallmark features are discussed that appear to be most reliable to differentiate this type of HMN V from other variants of hereditary neuropathies, and a set of diagnostic criteria is proposed. Furthermore, this is the first report of prolonged central motor conduction times in HMN V, which indicates additional involvement of the central motor pathways in this disease. Finally, molecular genetic studies demonstrate genetic heterogeneity, suggesting the existence of at least a second genetic subtype in HMN V. PMID:10908191

Auer-Grumbach, M; Löscher, W N; Wagner, K; Petek, E; Körner, E; Offenbacher, H; Hartung, H P



Distinct elements of the peripheral myelin protein 22 (PMP22) promoter regulate expression in Schwann cells and sensory neurons  

Microsoft Academic Search

Genetic disease mechanisms in the demyelinating peripheral neuropathies Charcot-Marie-Tooth disease type 1A (CMTA) and hereditary neuropathy with liability to pressure palsies (HNPP) as well as transgenic animals with altered PMP22 gene dosage revealed that alterations in PMP22 gene expression have profound effects on the development and maintenance of peripheral nerves. Consequently, the regulation of PMP22 is a crucial aspect in

Marcel Maier; François Castagner; Philipp Berger; Ueli Suter



Diabetic Radiculoneuropathy: Clinical patterns of sensory loss and distal paresthesias  

Microsoft Academic Search

It is the purpose of this review article to draw attention to some of the patterns of sensory abnormalities which occur in diabetic radiculoneuropathy. (The term 'radiculoneuropathy' is used in preference to the more commonly used term 'neuropathy' since, as noted below, there is considerable evidence that spinal roots, as well as peripheral nerves, are involved pathologically in diabetes mellitus:3).

Stephen G. Waxman



[Hereditary angioedema--neglected diagnosis].  


Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare autosomal dominant inherited disorder. It is characterized by recurrent episodes of potentially life-threatening swellings without itching localized in the dermis and submucosa. We report a case of 41 years old woman with hereditary angioedema manifested as episodes of localized skin swellings and painful gastrointestinal colics. This report underlines the fact that hereditary angioedema is underdiagnosed in differential diagnoses. If hereditary angioedema is correctly diagnosed, effective treatment highly improving patients' quality of life is available. PMID:21137180

Králicková, P; Buresová, E; Freiberger, T; Tachecí, I



Genetics Home Reference: Hereditary angioedema  


... and Families Resources for Health Professionals What glossary definitions help with understanding hereditary angioedema? autosomal ; autosomal dominant ; blood clotting ; bradykinin ; cell ; clotting ; coagulation ; deficiency ; edema ; ...


[Hereditary and non-hereditary cutaneous amyloidoses].  


Amyloid and amyloidosis describes a heterogeneous group of diseases which are characterized by the pathological extracellular deposition of autologous proteins. Basically, amyloidoses can be divided into systemic or organ-limited (e.g. cutaneous) forms and can be acquired or hereditary in nature. The subclassification discriminates between primary amyloidosis (in the absence of an obvious predisposing disease) and secondary amyloidosis (if caused by a certain underlying disease). The subclassification of amyloidoses is based on the main protein constituent and therefore on the chemical composition of the amyloid fibrils. However, the exact etiopathogenesis of amyloid formation remains unclear. In addition to the clinical presentation, histology, electron microscopy and biochemical-immunological differentiation are also decisive for a proper diagnosis. In cutaneous amyloidosis the deposition of amyloid either occurs along reticulin fibers and the basal membrane (perireticulary amyloidoses) or along collagen fibers (pericollagenous amyloidosis). The purpose of this article is to provide an up-to-date overview on the different kinds of cutaneous amyloidoses. PMID:19319536

Schreml, S; Schroeder, J; Eder, F; Szeimies, R M; Landthaler, M; Babilas, P



Hypertrophic changes in diabetic neuropathy  

Microsoft Academic Search

Observations have been made on 10 consecutive nerve biopsies from patients with diabetic neuropathy. 1 patient showed the typical appearances of hypertrophic neuropathy on light and electron microscopy. 5 displayed typical hypertrophic changes visible only on electron microscopy and minor abnormalities of a similar nature were seen in 2 others. It was considered that they were likely to have resulted

R. H. M. Ballin; P. K. Thomas



A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy  

Microsoft Academic Search

The onset of diabetic neuropathy, a complication of diabetes mellitus, has been linked to poor glycemic control. We tested the hypothesis that the mitogen-activated protein kinases (MAPK) form transducers for the damaging effects of high glucose. In cultures of adult rat sensory neurons, high glucose activated JNK and p38 MAPK but did not result in cell damage. However, oxidative stress




Acupuncture treatment for chemotherapy-induced peripheral neuropathy – a case series  

Microsoft Academic Search

Chemotherapy induced peripheral neuropathy (CIPN) occurs in 10 to 20% of cancer patients treated with neurotoxic chemotherapy. A mixture of sensory, sensorimotor and autonomic nervous system dysfunction can occur, resulting in deterioration in function and worsened quality of life. A major feature is discomfort and pain. Early termination of treatment and dose reduction of chemotherapy may be necessary. The clinical

Raimond Wong; Stephen Sagar



Early diagnosis of diabetic neuropathy using double-shock stimulation of peripheral nerves  

Microsoft Academic Search

Objective: The purpose of this study was to determine the changes in the amplitudes of a sensory nerve action potential (NAP) to a conditioning stimulus given prior to a test stimulus at 2–8 ms intervals in healthy subjects and patients with diabetes mellitus with no clinical signs of neuropathy and normal nerve conduction velocities (NCVs), to be able to diagnose

Meliha Tan; Uner Tan



Severe neuropathy in a patient with acquired immune deficiency syndrome (AIDS)  

Microsoft Academic Search

A patient with acquired immune deficiency syndrome (AIDS) developed a progressive neuromuscular disorder which included a sensory component, severe weakness and muscle wasting, and fasciculations. At autopsy, there was evidence of severe peripheral neuropathy, as well as widespread cytomegalovirus (CMV) infection within the central and peripheral nervous system. Although the anterior horn cell complement within the spinal cord appeared normal,

M. E. Robert; J. J. Geraghty; S. A. Miles; M. E. Cornford; H. V. Vinters



Fatal exacerbation of peripheral neuropathy during lamivudine therapy: evidence for iatrogenic mitochondrial damage.  


A 57-year-old man with mild neuropathy who was positive for hepatitis B and C viruses was treated with lamivudine 300 After 3 months he presented with dysphonia and progressive muscle weakness. Subsequently, he developed tetraparesis followed by acute respiratory failure requiring mechanical ventilation, which was complicated by sudden cardiac arrest. After lamivudine was stopped, the neuropathy improved and respiratory capacity improved. Unfortunately, the patient died suddenly in spite of haemodynamic, ventilatory and metabolic support. Electrophysiological studies showed evidence of a sensory-motor axonal neuropathy. Nerve biopsy, muscle biopsy, biochemistry and mitochondrial DNA molecular genetics suggested possible widespread iatrogenic mitochondrial damage. Mitochondrial DNA dysfunction could be a potential cause of the sudden cardiac arrest. Stopping lamivudine treatment sooner after the onset of peripheral neuropathy or its exacerbation is important as continued therapy could lead to acute respiratory failure requiring mechanical ventilation and intensive care unit admission. PMID:16029231

Fodale, V; Mazzeo, A; Praticò, C; Aguennouz, M; Toscano, A; Santamaria, L B; Vita, G



Delayed Neuropathy Due to Organophosphate Insecticide Injection in an Attempt to Commit Suicide  

PubMed Central

Organophosphates (OPs) are commonly used as pesticides throughout the world. Exposures to OPs cause a significant number of poisonings and deaths every year. Organophosphate-induced delayed polyneuropathy is a sensory-motor distal axonopathy which usually occurs after exposure of certain OP insecticides. Neuropathies due to ingestion of OPs have rarely been reported in the literature. Moreover, until now, there is no report of a patient developing organophosphorus injection-induced delayed neuropathy in the literature. We report a patient with serious organophosphorus-induced delayed neuropathy due to malathion injection. The patient was a 32-year-old female who self-injected undetermined amounts of malathion over the median nerve trace on the forearm crease in a suicide attempt which resulted in peripheral neuropathy.

Ozturk, Kahraman; Su, Ozlem; Basar Gursoy, Esra; Ugurad, Is?l; Yuksel, Goksen



Toxic peripheral neuropathy associated with commonly used chemotherapeutic agents.  


Peripheral neuropathy ranks among the most common non-haematological adverse effects of a number of effective chemotherapeutic agents, including platinum compounds, taxanes and vinca alkaloids. Newer agents, such as bortezomib, thalidomide and lenalidomide, frequently exert similar neurotoxic effects on peripheral nerves. Chemotherapy-induced peripheral neuropathy (CIPN) may result from a variety of mechanisms and may be related to causal factors, such as single dose per course, cumulative dose and risk factors including treatment schedule, prior or concomitant administration of other neurotoxic agents, age and pre-existing peripheral neuropathy of other causes. The symptoms usually begin during chemotherapy and they may even worsen after cessation of treatment. In most of the cases, patients experience positive (pain, paresthesias) or negative (numbness) sensory symptoms in distal extremities in a stocking-and-glove distribution with less prominent motor and autonomic involvement. To date, several neuroprotective agents including thiols, neurotrophic factors, anticonvulsants and antioxidants have been tested in preclinical models and clinical open label or randomized controlled trials for their ability to prevent or treat symptoms of CIPN. Although several of these agents hold promise as possible neuroprotective factors, clinical data are still controversial and none have as yet robustly been proven effective against CIPN. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of peripheral neuropathy associated with commonly used chemotherapeutic agents. We also highlight areas of future research to pursue. PMID:20941808

Argyriou, A A; Zolota, V; Kyriakopoulou, O; Kalofonos, H P


Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.  


Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens. PMID:22889832

Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H; Ehrlich, Barbara E



Skin biopsy for the diagnosis of peripheral neuropathy.  


Skin biopsy has become an accepted tool for investigating small nerve fibres, which are invisible to conventional neurophysiological tests even though they are affected early on in peripheral neuropathies of varying aetiology. Morphometric analysis of epidermal and dermal nerves has proved to be reliable, reproducible and unaffected by the severity of neuropathy, making skin biopsy useful for diagnosing small fibre neuropathy (SFN) in clinical practice. The possibility of obtaining skin biopsy specimens from different sites of the body, to repeat them within the area of the same sensory nerve, to distinguish between somatic and autonomic nerves and to investigate the expression of nerve-related proteins has widened the potential applications of this technique to clinical research. Skin biopsy performed using a minimally invasive disposable punch is a safe and painless procedure. Using specific antibodies with bright-field immunohistochemistry or immunofluorescence technique, it is possible to investigate unmyelinated fibres innervating the epidermis of hairy and glabrous skin, large myelinated fibres supplying specialized corpuscles in glabrous skin, and autonomic fibres innervating sweat glands, blood vessels and arrector pilorum muscles. This review discusses the features of skin innervation in hairy and glabrous skin, the functional properties of skin nerve fibres and their changes in peripheral neuropathies. PMID:18637969

Lauria, G; Lombardi, R; Camozzi, F; Devigili, G



Metabolic neuropathies and myopathies.  


Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are ?-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain-Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, ?-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney. Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are excercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney. PMID:23622366

D'amico, Adele; Bertini, Enrico



Management of Hereditary Hypercoagulable Disorders  

Microsoft Academic Search

The clinical management of individuals with hereditary hypercoaguable disorders has evolved from initial broad recommendations of lifelong anticoagulation after first event of venous thromboembolism to a more intricate individualized risk-benefit analysis as studies have begun to delineate the complexity of interactions of acquired and hereditary factors which determine the predilection to thrombosis. The contri- bution of thrombophilic disorders to risk

Paula L. Bockenstedt


Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.  


Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), "mutilating sensory neuropathy with spastic paraplegia" owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders. PMID:23897027

Fink, John K



Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy.  


Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy. PMID:21907196

Zheng, Huaien; Xiao, Wen Hua; Bennett, Gary J



Botulinum toxin type a (150 kDa) decreases exaggerated neurotransmitter release from trigeminal ganglion neurons and relieves neuropathy behaviors induced by infraorbital nerve constriction  

Microsoft Academic Search

Many patients with trigeminal neuropathies suffer severe chronic pain which is inadequately alleviated with centrally-acting drugs. These drugs also possess severe side effects making compliance difficult. One strategy is to develop new treatments without central side effects by targeting peripheral sensory neurons, since sensory neuron excitability and neurotransmitter release increase in chronic pain states. Such treatments may include the highly

Y. Kitamura; Y. Matsuka; I. Spigelman; Y. Ishihara; Y. Yamamoto; W. Sonoyama; T. Kuboki; K. Oguma



[Peripheral neuropathy in infantile and juvenile diabetes. A neurophysiological study].  


We report on the results of a study on the peripheral nerve function in 40 patients with type I diabetes mellitus with onset in pediatric age. Results have shown a significant decrease in motor and sensory nerve conduction velocities (NCV) in a high percentage of cases, correlated with the degree of metabolic control. The finding of NCV slowing also in patients with a history of diabetes of less than 10 years and the presence in these cases of a high number of complications (autonomic neuropathy, nephropathy, retinopathy) may suggest that peripheral neuropathy is an early-onset complication and that its prompt recognition through neurophysiological investigations can have some predictive value in forecasting other complications. This hypothesis is to be verified through prospective studies. PMID:1947399

Campea, L; Benedetti, P; Srouji, W; Camerota, V; Costantino, F; Turbacci, M; Emanuelli, O; Pelliccia, A


A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa - the NARP syndrome.  


The archetypal NARP syndrome is almost exclusively associated with the m.8993T>C/G mutation in the sixth subunit of the mitochondrial ATP synthase, whereas other mutations in the MT-ATP6 gene primarily associate with Leigh syndrome or Leber's hereditary optic neuropathy (LHON). We report a novel mitochondrial point mutation, m.8989G>C, in a patient presenting with neuropathy, ataxia and retinitis pigmentosa constituting the classical NARP phenotype. This mutation alters the amino acid right next to canonical NARP mutation. We suggest that classic NARP syndrome relates to a defined dysfunction of p.MT-ATP6. PMID:23266623

Duno, Morten; Wibrand, Flemming; Baggesen, Kirsten; Rosenberg, Thomas; Kjaer, Niels; Frederiksen, Anja L



Persistence of tropical ataxic neuropathy in a Nigerian community  

PubMed Central

OBJECTIVES—The term tropical ataxic neuropathy (TAN) is currently used to describe several neurological syndromes attributed to toxiconutritional causes. However, TAN was initially proposed to describe a specific neurological syndrome seen predominantly among the Ijebu speaking Yorubas in south western Nigeria. In this study, the prevalence of TAN was determined in Ososa, a semiurban community in south western Nigeria described as endemic for TAN in 1969, and its neurological features were compared with Strachan's syndrome, prisoners of war neuropathy, the epidemic neuropathy in Cuba, and konzo.?METHODS—A census of Ososa was followed by door to door screening of all subjects aged 10 years and above with a newly designed screening instrument. Subjects who screened positive had a neurological examination, and the diagnosis of TAN was made if any two or more of bilateral optic atrophy, bilateral neurosensory deafness, sensory gait ataxia, or distal symmetric sensory polyneuropathy were present.?RESULTS—A total of 4583 inhabitants were registered in the census. Of these, 3428 subjects aged 10 years and above were screened. The diagnosis of TAN was made in 206 of 323 subjects who screened positive for TAN. The prevalence of TAN was 6.0%, 3.9% in males and 7.7% in females. The highest age specific prevalence was 24% in the 60-69 years age group in women.?CONCLUSION—The occurrence of TAN in Ososa continues at a higher prevalence than was reported 30 years ago. Its neurological features and natural history do not resemble those described for Strachan syndrome, epidemic neuropathy in Cuba, or konzo. The increasing consumption of cassava foods linked to its causation makes TAN of public health importance in Nigeria, the most populous African country.??

Oluwole, O; Onabolu, A; Link, H.; Rosling, H.



Radiation optic neuropathy  

SciTech Connect

Following surgery for pituitary adenoma, radiation therapy is an accepted treatment in reducing tumor recurrence. However, a potential therapeutic complication is delayed radionecrosis of perisellar neural structures, including the optic nerves and chiasm. This particular cause of visual loss, radiation optic neuropathy (RON), has not been emphasized in the ophthalmologic literature. Four cases of RON seen in the past five years are reported. Diagnostic criteria include: (1) acute visual loss (monocular or binocular), (2) visual field defects indicating optic nerve or chiasmal dysfunction, (3) absence of optic disc edema, (4) onset usually within three years of therapy (peak: 1-1 1/2 years), and (5) no computed tomographic evidence of visual pathway compression. Pathologic findings, differential diagnosis and therapy will be discussed in outlining the clinical profile of RON.

Kline, L.B.; Kim, J.Y.; Ceballos, R.



Compression and entrapment neuropathies.  


Peripheral nerve entrapments are frequent. They usually appear in anatomical tunnels such as the carpal tunnel. Nerve compressions may be due to external pressure such as the fibular nerve at the fibular head. Malignant or benign tumors may also damage the nerve. For each nerve from the upper and lower limbs, detailed clinical, electrophysiological, imaging, and therapeutic aspects are described. In the upper limbs, carpal tunnel syndrome and ulnar neuropathy at the elbow are the most frequent manifestations; the radial nerve is less frequently involved. Other nerves may occasionally be damaged and these are described also. In the lower limbs, the fibular nerve is most frequently involved, usually at the fibular head by external compression. Other nerves may also be involved and are therefore described. The clinical and electrophysiological examination are very important for the diagnosis, but imaging is also of great use. Treatments available for each nerve disease are discussed. PMID:23931789

Bouche, P



There is No Association between Cardiovascular Autonomic Dysfunction and Peripheral Neuropathy in Chronic Hemodialysis Patients  

PubMed Central

Background and Purpose The potential association between the severity of autonomic dysfunction and peripheral neuropathy has not been extensively investigated, with the few studies yielding inconsistent results. We evaluated the relationship between autonomic dysfunction and peripheral neuropathy in chronic hemodialysis patients in a cross-sectional study. Methods Cardiovascular autonomic function was assessed in 42 consecutive patients with chronic renal failure treated by hemodialysis, using a standardized battery of 5 cardiovascular reflex tests. Symptoms of autonomic dysfunction and of peripheral neuropathy were evaluated using the Autonomic Neuropathy Symptom Score (ANSS) and the Neuropathy Symptoms Score. Neurological deficits were assessed using the Neuropathy Disability Score. Conduction velocities along the sensory and motor fibers of the sural and peroneal nerves were measured. Thermal thresholds were documented using a standardized psychophysical technique. Results Parasympathetic and sympathetic dysfunction was prevalent in 50% and 28% of cases, respectively. Peripheral neuropathy was identified in 25 cases (60%). The prevalence of peripheral neuropathy did not differ between patients with impaired (55%) and normal (75%) autonomic function (p=0.297; Fisher's exact test). The electrophysiological parameters for peripheral nerve function, neuropathic symptoms, abnormal thermal thresholds, age, gender, and duration of dialysis did not differ significantly between patients with and without autonomic dysfunction. Patients with autonomic dysfunction were more likely to have an abnormal ANSS (p=0.048). The severity of autonomic dysfunction on electrophysiological testing was positively correlated with ANSS (r=0.213, p=0.036). Conclusions The present data indicate that although cardiovascular autonomic dysfunction is prevalent among patients with chronic renal failure, it is not associated with the incidence of peripheral neuropathy.

Stamboulis, Elefterios; Voumvouraki, Konstantinos; Zambelis, Thomas; Andrikopoulou, Athina; Vlahakos, Demetrios; Tsivgoulis, Athanasios; Rallis, Demetrios



NSE, a Potential Biomarker, Is Closely Connected to Diabetic Peripheral Neuropathy.  


OBJECTIVE To explore the relationship between serum neuron-specific enolase (NSE) levels and diabetic neuropathy. RESEARCH DESIGN AND METHODS Type 1 or 2 diabetic and healthy control subjects (n = 568) were randomly enrolled in a cross-sectional study. Diabetic neuropathy status was documented by the presence of clinical symptoms or signs, electromyography, quantitative sensory tests, and cardiac autonomic neuropathy tests. The severity of the neuropathy was staged by composite scores. Serum NSE was measured using electrochemiluminescence immunoassay. The demographic and clinical variables were obtained through an interviewer questionnaire. RESULTS Serum NSE levels increased slightly in diabetic subjects compared with normal subjects (9.1 [1.5] vs. 8.7 [1.7], P = 0.037), and the levels increased greatly in diabetic subjects with neuropathy compared with those without (10.8 [2.8] vs. 9.1 [1.5], P = 0.000). The association of NSE with diabetic neuropathy was independent of the hyperglycemic state (fasting blood glucose, HbA1c, duration, and the type of diabetes) and other potential confounders affecting NSE levels (e.g., age, sex, and renal status) (odds ratio 1.48 [1.13-1.74], P = 0.001). In addition, NSE levels increased with and were closely correlated to the stages of neuropathy (r = 0.63 [0.52-0.74], P = 0.000). The optimal cutoff point for serum NSE levels to distinguish patients with diabetic neuropathy from those without was 10.10 ?g/L, with a sensitivity of 66.3% and a specificity of 72.5%. CONCLUSIONS Serum NSE levels are closely associated with peripheral neuropathy in patients with diabetes. Future studies are warranted to clarify the relationship. PMID:23846809

Li, Jianbo; Zhang, Hongman; Xie, Min; Yan, Lingfei; Chen, Jiawei; Wang, Hongxing



Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study.  


The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinson's disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (?3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P?neuropathy was 2.38 higher in the LELD group than in the control group (P?=?0.022; OR, 2.38; 95% CI, 1.130-5.014). In a comparison between patients with and without neuropathy (Student's t test), the levodopa dose was higher (P?neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical-neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa. © 2013 International Parkinson and Movement Disorder Society. PMID:23836370

Ceravolo, Roberto; Cossu, Giovanni; Bandettini di Poggio, Monica; Santoro, Lucio; Barone, Paolo; Zibetti, Maurizio; Frosini, Daniela; Nicoletti, Valentina; Manganelli, Fiore; Iodice, Rosa; Picillo, Marina; Merola, Aristide; Lopiano, Leonardo; Paribello, Alessandra; Manca, Davide; Melis, Maurizio; Marchese, Roberta; Borelli, Paolo; Mereu, Alessandra; Contu, Paolo; Abbruzzese, Giovanni; Bonuccelli, Ubaldo



Early Treatment of Diabetic Neuropathy.  

National Technical Information Service (NTIS)

Treatment of diabetic neuropathy is a difficult clinical problem. In this paper, clinical experience on managing 120 newly discovered, untreated, noninsulin dependent cases is presented. Besides strict control of diabetes, the therapeutic effect of differ...

X. Zhong B. Zheng G. Hu X. Zhu Z. Hu



Effect of Atibalamula and Bhumyamalaki on thirty-three patients of diabetic neuropathy  

PubMed Central

Diabetic neuropathy is a relatively early and common complication affecting approximately 30% of diabetic patients. According to Ayurvedic principles there is involvement of Vata and Pitta Dosa in diabetic neuropathy. Bhumyamalaki (Phyllanthus niruri) is a plant which shows possibility to pacify these two Dosas. Another plant Atibala (Abutilon indicum) has also Vata pacifying qualities. Present study has been carried out to study the effects of Bhumyamalaki and Atibala on 33 patients of diabetic neuropathy. All the patients have been given Bhumyamalaki Churna 3 g twice a day and decoction of 10 g of Atibala-mula twice a day for 30 days. Neuropathy analyzer machine has been used for exact recording of sensory perception of vibration, cold and hot sensations before and after treatment. Changes in numbness, tingling, burning sensation and pain in lower limbs have also been assessed before and after treatment. Results have been analyzed statistically by applying the ‘t’ test. It can be stated from the results that use of Bhumyamalaki and Atibalamula in the patients of diabetic neuropathy can revert the diminished sensory perception and can reduce the symptoms significantly.

Patel, Kalapi; Patel, Manish; Gupta, S N



Posttraumatic childhood lumbosacral plexus neuropathy.  


A 13-month-old male received crush injury to the abdomen resulting in paraparesis due to lumbosacral plexus neuropathy. The child was monitored with serial clinical examinations and electromyography/nerve conduction studies. He had complete clinical recovery. Lumbosacral plexus neuropathy is unusual in childhood and has not been previously reported as a result of abdominal trauma. This patient is presented with details of the clinical course, electrodiagnostic studies, discussion, and literature review. PMID:7748364

Egel, R T; Cueva, J P; Adair, R L



Hereditary Angioedema: Not An Allergy  

PubMed Central

Hereditary angioedema is a genetic disorder due to a deficiency or malfunction of C1 esterase inhibitor. We herein describe a case of 25-year-old male who presented with swelling over face since one day. There was history of similar episodes since two years with gradual subsidence of swelling without any treatment. Investigations revealed grossly reduced complement C4 and C1 esterase inhibitor level. Patient was diagnosed to have hereditary angioedema type 1 and started on stanozolol 2 mg three times a day with no recurrence in one year of follow-up. Hereditary angioedema resembles angioedema of an allergic reaction. However, the cause is different.

Bhivgade, Sanjay; Melkote, Shubha; Ghate, Smita; Jerajani, H R



Pathophysiology of Hereditary Hemochromatosis  

PubMed Central

Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.

Fleming, Robert E.; Britton, Robert S.; Waheed, Abdul; Sly, William S.; Bacon, Bruce R.



Peripheral neuropathy in patients with diabetes mellitus presenting as Bell's palsy.  


The aim of this study is to evaluate the peripheral nerves in diabetes mellitus with or without peripheral facial paralysis (PFP). A total of 49 diabetic patients with PFP within the last year (23 females, mean age 60.3 +/- 9.3), and 83 diabetic patients without PFP (41 females, mean age 59.5 +/- 9.9) were enrolled. The neurological examination, eye-blinking response, needle EMG and electrophysiological parameters of peripheral nerves were evaluated. The neuropathic pain, other positive and negative sensory symptoms were statistically more frequent in controls than the PFP group, while no difference was noted in total neuropathy score. Sural sensorial nerve action potential amplitudes were same in both groups, but median nerve amplitudes were significantly lower in the PFP group. It is suggested that PFP is not a part of multifocal neuropathy in diabetes mellitus. However, at least some parts of the nerve conduction studies were involved, focal neuropathies were more frequent while sensory neuropathies with small nerve fiber involvement were less frequent in diabetes patients with PFP. PMID:17933462

Kiziltan, Meral E; Akalin, M Ali; Sahin, Rahsan; Uluduz, Derya



Mitochondrial optic neuropathies - Disease mechanisms and therapeutic strategies  

PubMed Central

Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (DOA) are the two most common inherited optic neuropathies in the general population. Both disorders share striking pathological similarities, marked by the selective loss of retinal ganglion cells (RGCs) and the early involvement of the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations; m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in DOA, the majority of affected families harbour mutations in the OPA1 gene, which codes for a mitochondrial inner membrane protein. Optic nerve degeneration in LHON and DOA is therefore due to disturbed mitochondrial function and a predominantly complex I respiratory chain defect has been identified using both in vitro and in vivo biochemical assays. However, the trigger for RGC loss is much more complex than a simple bioenergetic crisis and other important disease mechanisms have emerged relating to mitochondrial network dynamics, mtDNA maintenance, axonal transport, and the involvement of the cytoskeleton in maintaining a differential mitochondrial gradient at sites such as the lamina cribosa. The downstream consequences of these mitochondrial disturbances are likely to be influenced by the local cellular milieu. The vulnerability of RGCs in LHON and DOA could derive not only from tissue-specific, genetically-determined biological factors, but also from an increased susceptibility to exogenous influences such as light exposure, smoking, and pharmacological agents with putative mitochondrial toxic effects. Our concept of inherited mitochondrial optic neuropathies has evolved over the past decade, with the observation that patients with LHON and DOA can manifest a much broader phenotypic spectrum than pure optic nerve involvement. Interestingly, these phenotypes are sometimes clinically indistinguishable from other neurodegenerative disorders such as Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and multiple sclerosis, where mitochondrial dysfunction is also thought to be an important pathophysiological player. A number of vertebrate and invertebrate disease models has recently been established to circumvent the lack of human tissues, and these have already provided considerable insight by allowing direct RGC experimentation. The ultimate goal is to translate these research advances into clinical practice and new treatment strategies are currently being investigated to improve the visual prognosis for patients with mitochondrial optic neuropathies.

Yu-Wai-Man, Patrick; Griffiths, Philip G.; Chinnery, Patrick F.



Bioenergetics in Diabetic Neuropathy- What We Need to Know  

PubMed Central

Progress in developing treatments for diabetic neuropathy is slowed by our limited understanding of how disturbances in metabolic substrates- glucose and fatty acids- produce nerve injury. In this review, we present the current oxidative stress hypothesis and experimental data that support it. We identify weaknesses in our understanding of diabetes-disordered metabolism in the neurovascular unit; i.e. in critical cell types of the microvascular endothelium, peripheral sensory neurons, and supporting Schwann cells. Greater understanding of peripheral nervous system bioenergetics may provide insight into new drug therapies or improvements in dietary interventions in diabetes or even pre-diabetes.

Hinder, Lucy M.; Vincent, Andrea M.; Burant, Charles F.; Pennathur, Subramaniam; Feldman, Eva L.



Overview of Hereditary Metabolic Disorders  


... Disorders Overview of Hereditary Metabolic Disorders Disorders of Carbohydrate Metabolism Disorders of Amino Acid Metabolism Disorders of Lipid ... Diabetes Mellitus in Children(DM) Next: Disorders of Carbohydrate Metabolism Audio Figures Photographs Pronunciations Sidebar Tables Videos Copyright © ...


Hereditary familial vestibular degenerative diseases.  


Identification of genes involved in hereditary vestibular disease is growing at a remarkable pace. Mutant mouse technology can be an important tool for understanding the biological mechanism of human vestibular diseases. PMID:11710498

Sun, J C; Van Alphen, A M; Wagenaar, M; Huygen, P; Hoogenraad, C C; Hasson, T; Koekkoek, S K; Bohne, B A; De Zeeuw, C I



Successful treatment of infliximab-associated immune-mediated sensory polyradiculopathy with intravenous immunoglobulin.  


Infliximab, a tumor necrosis factor-alpha antagonist, is used to treat many inflammatory diseases. Various forms of demyelinating neuropathies have been reported as neurological complications associated with infliximab use. There have been few reports of pure sensory neuropathy associated with infliximab. We report the clinical, electrophysiological, and pathological findings of a patient with subacute sensory polyradiculopathy 1month after infliximab therapy for psoriasis vulgaris. Immune-mediated pathogenesis was suggested by positive anti-ganglioside antibodies and rapid response to intravenous immunoglobulin. This is the first reported case of sensory polyradiculopathy with positive anti-ganglioside antibodies following infliximab therapy. Our findings suggest the clinical importance of immunological investigations and treatment in demyelinating neuropathies following infliximab therapy. PMID:23906523

Naruse, Hiroya; Nagashima, Yu; Maekawa, Risa; Etoh, Takafumi; Hida, Ayumi; Shimizu, Jun; Kaida, Ken-Ichi; Shiio, Yasushi



Hereditary pancreatitis presenting with ascites.  

PubMed Central

We report a case of an adolescent girl who presented with painless massive ascites secondary to chronic pancreatitis and a ductal fistula. The diagnosis was delayed and an unnecessary laparotomy was performed, as initial evaluation of ascites did not include measurement of serum and ascitic amylase. Evidence of pancreatic abnormalities in asymptomatic relatives suggested an underlying hereditary pancreatitis. Hereditary pancreatitis presenting as pancreatic ascites, to our knowledge, has not been described previously.

Rao, S. S.; Riley, S. A.; Foster, P. N.; Losowsky, M. S.; Stone, W. D.



Cardiac Involvement in Hereditary Ataxias  

PubMed Central

Although much attention has been focused on the neurological sequelae of the hereditary ataxias, patients with these conditions also may develop cardiac complications that represent a significant cause of disability and even death. In this paper, we describe the hereditary ataxias with known cardiac involvement, discuss underlying causes, and review guidelines for screening and treatment. Continued progress will require coordinated clinical trial networks, interdisciplinary care teams, and team science.

Moore, Sean; Raman, Subha V.



Compression neuropathy of the radial palmar thumb nerve.  


Compression neuropathy of a single digital nerve is a rare entity. We report the case of a patient with numbness in the distribution of the radial digital nerve of the thumb caused by the use of a walking stick. The nerve was compressed between the handle of the stick, the loop and the radial sesamoid bone of the first metacarpophalangeal joint. The site of the lesion was confirmed by electrophysiologic examination. Orthodromic recording of the sensory response from the radial palmar digital nerve of the thumb documented a complete absence of nerve action potential whereas the ulnar digital thumb nerve showed a normal response. Sensory function was restored when a padded ski glove was used to protect the area of the metacarpophalangeal joint whilst using the stick. PMID:15071968

Hug, U; Burg, D; Baldi, S V; Meyer, V E



Crucifixion and median neuropathy  

PubMed Central

Crucifixion as a means of torture and execution was first developed in the 6th century B.C. and remained popular for over 1000 years. Details of the practice, which claimed hundreds of thousands of lives, have intrigued scholars as historical records and archaeological findings from the era are limited. As a result, various aspects of crucifixion, including the type of crosses used, methods of securing victims to crosses, the length of time victims survived on the cross, and the exact mechanisms of death, remain topics of debate. One aspect of crucifixion not previously explored in detail is the characteristic hand posture often depicted in artistic renditions of crucifixion. In this posture, the hand is clenched in a peculiar and characteristic fashion: there is complete failure of flexion of the thumb and index finger with partial failure of flexion of the middle finger. Such a “crucified clench” is depicted across different cultures and from different eras. A review of crucifixion history and techniques, median nerve anatomy and function, and the historical artistic depiction of crucifixion was performed to support the hypothesis that the “crucified clench” results from proximal median neuropathy due to positioning on the cross, rather than from direct trauma of impalement of the hand or wrist.

Regan, Jacqueline M; Shahlaie, Kiarash; Watson, Joseph C



WNK1/HSN2 Mutation in Human Peripheral Neuropathy Deregulates KCC2 Expression and Posterior Lateral Line Development in Zebrafish (Danio rerio)  

PubMed Central

Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare pathology characterized by an early onset of severe sensory loss (all modalities) in the distal limbs. It is due to autosomal recessive mutations confined to exon “HSN2” of the WNK1 (with-no-lysine protein kinase 1) serine-threonine kinase. While this kinase is well studied in the kidneys, little is known about its role in the nervous system. We hypothesized that the truncating mutations present in the neural-specific HSN2 exon lead to a loss-of-function of the WNK1 kinase, impairing development of the peripheral sensory system. To investigate the mechanisms by which the loss of WNK1/HSN2 isoform function causes HSANII, we used the embryonic zebrafish model and observed strong expression of WNK1/HSN2 in neuromasts of the peripheral lateral line (PLL) system by immunohistochemistry. Knocking down wnk1/hsn2 in embryos using antisense morpholino oligonucleotides led to improper PLL development. We then investigated the reported interaction between the WNK1 kinase and neuronal potassium chloride cotransporter KCC2, as this transporter is a target of WNK1 phosphorylation. In situ hybridization revealed kcc2 expression in mature neuromasts of the PLL and semi-quantitative RT–PCR of wnk1/hsn2 knockdown embryos showed an increased expression of kcc2 mRNA. Furthermore, overexpression of human KCC2 mRNA in embryos replicated the wnk1/hsn2 knockdown phenotype. We validated these results by obtaining double knockdown embryos, both for wnk1/hsn2 and kcc2, which alleviated the PLL defects. Interestingly, overexpression of inactive mutant KCC2-C568A, which does not extrude ions, allowed a phenocopy of the PLL defects. These results suggest a pathway in which WNK1/HSN2 interacts with KCC2, producing a novel regulation of its transcription independent of KCC2's activation, where a loss-of-function mutation in WNK1 induces an overexpression of KCC2 and hinders proper peripheral sensory nerve development, a hallmark of HSANII.

Bercier, Valerie; Brustein, Edna; Liao, Meijiang; Dion, Patrick A.; Lafreniere, Ronald G.; Rouleau, Guy A.; Drapeau, Pierre



Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies.  


Mitochondrial optic neuropathies, that is, Leber hereditary optic neuropathy and dominant optic atrophy, selectively affect retinal ganglion cells, causing visual loss with relatively preserved pupillary light reflex. The mammalian eye contains a light detection system based on a subset of retinal ganglion cells containing the photopigment melanopsin. These cells give origin to the retinohypothalamic tract and support the non-image-forming visual functions of the eye, which include the photoentrainment of circadian rhythms, light-induced suppression of melatonin secretion and pupillary light reflex. We studied the integrity of the retinohypothalamic tract in five patients with Leber hereditary optic neuropathy, in four with dominant optic atrophy and in nine controls by testing the light-induced suppression of nocturnal melatonin secretion. This response was maintained in optic neuropathy subjects as in controls, indicating that the retinohypothalamic tract is sufficiently preserved to drive light information detected by melanopsin retinal ganglion cells. We then investigated the histology of post-mortem eyes from two patients with Leber hereditary optic neuropathy and one case with dominant optic atrophy, compared with three age-matched controls. On these retinas, melanopsin retinal ganglion cells were characterized by immunohistochemistry and their number and distribution evaluated by a new protocol. In control retinas, we show that melanopsin retinal ganglion cells are lost with age and are more represented in the parafoveal region. In patients, we demonstrate a relative sparing of these cells compared with the massive loss of total retinal ganglion cells, even in the most affected areas of the retina. Our results demonstrate that melanopsin retinal ganglion cells resist neurodegeneration due to mitochondrial dysfunction and maintain non-image-forming functions of the eye in these visually impaired patients. We also show that in normal human retinas, these cells are more concentrated around the fovea and are lost with ageing. The current results provide a plausible explanation for the preservation of pupillary light reaction despite profound visual loss in patients with mitochondrial optic neuropathy, revealing the robustness of melanopsin retinal ganglion cells to a metabolic insult and opening the question of mechanisms that might protect these cells. PMID:20659957

La Morgia, Chiara; Ross-Cisneros, Fred N; Sadun, Alfredo A; Hannibal, Jens; Munarini, Alessandra; Mantovani, Vilma; Barboni, Piero; Cantalupo, Gaetano; Tozer, Kevin R; Sancisi, Elisa; Salomao, Solange R; Moraes, Milton N; Moraes-Filho, Milton N; Heegaard, Steffen; Milea, Dan; Kjer, Poul; Montagna, Pasquale; Carelli, Valerio



Sensory symptoms in restless legs syndrome: the enigma of pain.  


Restless legs syndrome (RLS) is a common sensorimotor condition characterized by an urge to move the legs, worsening of symptoms at rest and during the evening/night, and improvement of symptoms with movement. Our review explores the role and impact of sensory symptoms in RLS. The phenomenology of RLS is discussed, highlighting the difficulty patients have in describing their sensations and in differentiating between sensory and motor symptoms. Sensory symptoms have a significant impact on quality of life but remain much less well understood than motor symptoms and sleep disturbances in RLS. Although RLS symptoms usually are not described as painful, sensory manifestations in RLS do share some similarities with chronic pain sensations, and RLS frequently occurs in chronic pain and neuropathic conditions. Peripheral neuropathies may account for some of the sensory disturbances in secondary RLS, while alterations in central somatosensory processing may be a more viable explanation for the sensory disturbances in primary RLS. The effectiveness of analgesics in treating RLS supports the concept of abnormal sensory modulation in RLS and suggests an overlap between pain modulatory pathways and sensory disturbances. Future studies are needed to better understand the experiential and biologic aspects of altered sensory experiences in RLS. PMID:23948222

Winkelman, John W; Gagnon, Alison; Clair, Andrew G



Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer  

PubMed Central

Objective: To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapy-induced peripheral neuropathy in an experimental animal model and in a randomized, double-blinded, controlled trial in patients with non-small-cell lung cancer (NSCLC). Methods: Forty male Wistar rats were randomized in 5 groups: group A, control; groups B and C, treated with cisplatin; and groups D and E, treated with paclitaxel. ATRA (20 mg/kg PO) was administered for 15 days in groups C and E. We evaluated neuropathy and nerve regeneration–related morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)–? and RAR-? expression. In addition, 95 patients with NSCLC under chemotherapy treatment were randomized to either ATRA (20 mg/m2/d) or placebo. Serum NGF, neurophysiologic tests, and clinical neurotoxicity were assessed. Results: The experimental animals developed neuropathy and axonal degeneration, associated with decreased NGF levels in peripheral nerves. Treatment with ATRA reversed sensorial changes and nerve morphology; this was associated with increased NGF levels and RAR-? expression. Patients treated with chemotherapy had clinical neuropathy and axonal loss assessed by neurophysiology, which was related to decreased NGF levels. ATRA reduced axonal degeneration demonstrated by nerve conduction velocity and clinical manifestations of neuropathy grades ?2. Conclusions: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-? expression in nerve. In patients, reduction of NGF in serum was associated with the severity of neuropathy; ATRA treatment reduced the electrophysiologic alterations. Classification of evidence: This study provides Class II evidence that ATRA improves nerve conduction in patients with chemotherapy-induced peripheral neuropathy. Neurology® 2011;77:987–995

Hernandez-Pedro, N.; Fernandez-Gonzalez- Aragon, M.C.; Saavedra-Perez, D.; Campos-Parra, A.D.; Rios-Trejo, M.A.; Ceron-Lizarraga, T.; Martinez-Barrera, L.; Pineda, B.; Ordonez, G.; Ortiz-Plata, A.; Granados-Soto, V.; Sotelo, J.



PARP inhibitors attenuate chemotherapy-induced painful neuropathy.  


Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity of chemotherapy treatment for which no therapy is approved. Poly(ADP-ribose) polymerase (PARP)1/2 are nuclear enzymes activated upon DNA damage, and PARP1/2 inhibition provides resistance against DNA damage. A role for PARP inhibition in sensory neurotransmission has also been established. PARP inhibitors attenuate pain-like behaviors and neuropathy-associated decreased peripheral nerve function in diabetic models. The hypothesis tested was that PARP inhibition protects against painful neuropathy. The objective of this study was to investigate whether the novel, selective PARP1/2 inhibitors (ABT-888 and related analogues) would attenuate development of mechanical allodynia in vincristine-treated rats. PARP inhibitors were dosed for 2 days, and then co-administered with vincristine for 12 days. Mechanical allodynia was observed in rats treated with vincristine. PARP1/2 inhibition significantly attenuated development of mechanical allodynia and reduced poly ADP-ribose (PAR) activation in rat skin. The data presented here show that PARP inhibition attenuates vincristine-induced mechanical allodynia in rats, and supports that PARP inhibition may represent a novel therapeutic approach for CIPN. PMID:22971094

Brederson, Jill-Desiree; Joshi, Shailen K; Browman, Kaitlin E; Mikusa, Joseph; Zhong, Chengmin; Gauvin, Donna; Liu, Xuesong; Shi, Yan; Penning, Thomas D; Shoemaker, Alex R; Giranda, Vincent L



Hereditary fructose intolerance.  

PubMed Central

Hereditary fructose intolerance (HFI, OMIM 22960), caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase, EC, is a recessively inherited condition in which affected homozygotes develop hypoglycaemic and severe abdominal symptoms after taking foods containing fructose and cognate sugars. Continued ingestion of noxious sugars leads to hepatic and renal injury and growth retardation; parenteral administration of fructose or sorbitol may be fatal. Direct detection of a few mutations in the human aldolase B gene on chromosome 9q facilitates the genetic diagnosis of HFI in many symptomatic patients. The severity of the disease phenotype appears to be independent of the nature of the aldolase B gene mutations so far identified. It appears that hitherto there has been little, if any, selection against mutant aldolase B alleles in the population: in the UK, approximately 1.3% of neonates harbour one copy of the prevalent A149P disease allele. The ascendance of sugar as a major dietary nutrient, especially in western societies, may account for the increasing recognition of HFI as a nutritional disease and has shown the prevalence of mutant aldolase B genes in the general population. The severity of clinical expression correlates well with the immediate nutritional environment, age, culture, and eating habits of affected subjects. Here we review the biochemical, genetic, and molecular basis of human aldolase B deficiency in HFI, a disorder which responds to dietary therapy and in which the principal manifestations of disease are thus preventable. Images

Ali, M; Rellos, P; Cox, T M



Hereditary hyperferritinaemia/ cataract syndrome.  


In mammalian cells, cellular iron homeostasis is maintained by the co-ordinated regulation of transferrin receptor and ferritin synthesis that occurs at the translational level. This regulation is mediated by iron-responsive elements (IREs) that are found within the untranslated regions (UTRs) of mRNA and by cytoplasmic mRNA-binding proteins, known as iron regulatory proteins (IRPs). When cellular iron is scarce, IRPs are available for binding the 5' IRE of ferritin mRNA, initiation of translation is prevented and ferritin synthesis is inhibited. By contrast, the presence of abundant intracellular iron prevents binding of the IRPs to the 5' IRE and allows efficient mRNA translation to proceed. Hereditary hyperferritinaemia/cataract syndrome (HHCS) arises as a result of various point mutations or deletions within a protein binding sequence in the 5'-UTR of the L-ferritin mRNA, which results in increased efficiency of L-ferritin translation. Each unique mutation confers a characteristic degree of hyperferritinaemia and severity of cataract in affected individuals. This exemplifies a new paradigm in which mutations in mRNA cis-acting elements may be responsible for phenotypic variability in disease states. PMID:12401313

Cazzola, Mario



Hereditary ataxias: overview.  


The hereditary ataxias are a highly heterogeneous group of disorders phenotypically characterized by gait ataxia, incoordination of eye movements, speech, and hand movements, and usually associated with atrophy of the cerebellum. There are more than 35 autosomal dominant types frequently termed spinocerebellar ataxia and typically having adult onset. The most common subtypes are spinocerebellar ataxia 1, 2, 3, 6, and 7, all of which are nucleotide repeat expansion disorders. Autosomal recessive ataxias usually have onset in childhood; the most common subtypes are -Friedreich, ataxia-telangiectasia, ataxia with oculomotor apraxia type 1, and ataxia with oculomotor apraxia type 2. Four autosomal recessive types have dietary or biochemical treatment modalities (ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, Refsum, and coenzyme Q10 deficiency), whereas there are no specific treatments for other ataxias. Diagnostic genetic testing is complicated because of the large number of relatively uncommon subtypes with extensive phenotypic overlap. However, the best testing strategy is based on assessing relative frequencies, ethnic predilections, and recognition of associated phenotypic features such as seizures, visual loss, or associated movement abnormalities.Genet Med 15 9, 673-683.Genetics in Medicine (2013); 15 9, 673-683. doi:10.1038/gim.2013.28. PMID:23538602

Jayadev, Suman; Bird, Thomas D



Update on medication-induced peripheral neuropathy  

Microsoft Academic Search

Despite improvements in the identification of causes of peripheral neuropathy, idiopathic polyneuropathy remains common. Medication\\u000a and toxic neuropathy account for a small but important percentage of potentially preventable or reversible causes of neuropathy.\\u000a New drugs that can induce neuropathy have been approved over the past several years, including the anticancer agents bortezomib,\\u000a ixabepilone, and oxaliplatin. We review the neurotoxic effects

Louis H. Weimer; Noor Sachdev



Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat  

Microsoft Academic Search

While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The

Xiaojie Chen; Jon D Levine



A case of myelopathy, myopathy, peripheral neuropathy and subcortical grey matter degeneration associated with recessive compound heterozygous POLG1 mutations  

Microsoft Academic Search

This 54year old woman presented with symptoms of sensory ataxic neuropathy, with cerebellar features. She developed further weakness, visual disturbances with diplopia, dysarthria and dysphasia. After her death at 66years, she was found to have compound heterozygous mutations of POLG1 gene in muscle, and Southern blot showed low levels of multiple deletions of mitochondrial DNA. Neuropathological examination showed profound dorsal

P. McKelvie; R. Marotta; D. R. Thorburn; J. Chin; S. Punchihewa; S. Collins


Peripheral neuropathy in mitochondrial disorders.  


Why is peripheral neuropathy common but mild in many mitochondrial disorders, and why is it, in some cases, the predominant or only manifestation? Although this question remains largely unanswered, recent advances in cellular and molecular biology have begun to clarify the importance of mitochondrial functioning and distribution in the peripheral nerve. Mutations in proteins involved in mitochondrial dynamics (ie, fusion and fission) frequently result in a Charcot-Marie-Tooth phenotype. Peripheral neuropathies with different phenotypic presentations occur in mitochondrial diseases associated with abnormalities in mitochondrial DNA replication and maintenance, or associated with defects in mitochondrial respiratory chain complex V. Our knowledge of mitochondrial disorders is rapidly growing as new nuclear genes are identified and new phenotypes described. Early diagnosis of mitochondrial disorders, essential to provide appropriate genetic counselling, has become crucial in a few treatable conditions. Recognising and diagnosing an underlying mitochondrial defect in patients presenting with peripheral neuropathy is therefore of paramount importance. PMID:24050734

Pareyson, Davide; Piscosquito, Giuseppe; Moroni, Isabella; Salsano, Ettore; Zeviani, Massimo



Reversible Neuropathy in Chronic Renal Failure  

Microsoft Academic Search

Chronic renal failure is associated with distal symmetrical axonal neuropathy. We report a 50-year-old man who suffered from chronic renal failure due to benign enlargement of the prostate. He presented with fever and rapidly developing pure motor neuropathy. The nerve conduction velocity was slow and the F response delayed, suggestive of demyelinating neuropathy. A sural nerve biopsy specimen was also

A. Roy; J. Kalita; N. Gayathri; S. K. Shankar; U. K. Misra



Emerging toxic neuropathies and myopathies.  


There is a daunting list of toxins that can affect the peripheral nervous system, with new drugs and chemicals added to this list every year. This article focuses on some of the more recent toxic neuropathies and myopathies that have emerged from the medical literature. Among these are toxic myopathies caused by statins, daptomycin, imatinib, hydroxychloroquine, and highly active antiretroviral therapy; neuromuscular junction toxicity caused by tandutinib; toxic peripheral neuropathies caused by bortezomib, angel's trumpet, cisplatin, oxaliplatin, tumor necrosis factor ? antagonists, cobalt-chromium, and ixabepilone; and a unique syndrome reported in workers exposed to aerosolized porcine neural tissue. PMID:21803218

Kushlaf, Hani A



[Metabolic neuropathies: overview in 2011].  


Metabolic diseases constitute a frequent etiologic group of axonal and small-fiber neuropathies. Recent works in this field are dominated by diabetic neuropathy (clinical presentation, prognostic factors) because of its prevalence. Vitamin B12 deficiency aroused several studies in 2011. This renewed interest for this well known entity ensues from the lack of sensibility of its biological markers underestimating its prevalence, its clinical spectrum and therefore, access to its therapy. Finally, 2011 highlighted the growing interest of the measure of the intra-epidermic nerve fibers density by skin biopsy for some metabolic disorders such as infra-clinical hypothyroïdism, chronic renal failure or Fabry disease. PMID:23107883

Franques, J; Verschueren, A



Gabapentin in painful HIV-related neuropathy: a report of 19 patients, preliminary observations.  


The objective of this study was to assess the efficacy and safety of Gabapentin as the sole analgesic in patients with HIV-related painful neuropathy. Nineteen patients with HIV-related painful neuropathy were administered Gabapentin. Efficacy was evaluated with two 100-mm Visual Analogue Scales (VAS) (0: no symptom; 100: worst symptom), rating pain and interference of pain with sleep, performed at baseline and monthly intervals. Main Pain VAS score decreased from a baseline of 55.7 +/- 19.1 mm to a final 14.7 +/- 18.6 mm (ANOVA P = 0.0001) and mean Sleep Interference VAS score decreased from a baseline of 60.4 +/- 31.9 mm to a final 15.5 +/- 27.7 mm (ANOVA P = 0.0001). Gabapentin provided significant pain relief in our patients with HIV-associated painful sensory neuropathy. PMID:11509084

La Spina, I; Porazzi, D; Maggiolo, F; Bottura, P; Suter, F



Neuroprotective effects of Kv7 channel agonist, retigabine, for cisplatin-induced peripheral neuropathy.  


Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of many commonly used chemotherapeutic agents. One mechanism underlying this neuronal damage is via drug-induced membrane depolarization. Accordingly, one potential approach for preventing chemotherapy-induced neuropathy is via the forced maintenance of normal membrane potential during exposure to the toxic drug. More specifically, intentional elevation of the slow K(+) current, via activation of Kv7 channels with a resultant hyperpolarizing shift, could be theoretically neuroprotective. In this study, in vivo nerve excitability testing in sensory nerves in mice was used to evaluate the potential therapeutic role of retigabine, a Kv7 channel activator, in the prevention of cisplatin-induced neurodegeneration. It was found that cisplatin caused membrane depolarization and peripheral axon loss that were partially prevented by retigabine pretreatment. These results support the general concept that chemotherapy-induced neuropathy can be partially inhibited via Kv7 channel activation. PMID:21945947

Nodera, Hiroyuki; Spieker, Andrew; Sung, Minhee; Rutkove, Seward



Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy  

PubMed Central

Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18–52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations at the heterozygous state might predispose to late-onset neurodegenerative disorders, mimicking autosomal dominant inheritance. Finally, a novel missense SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family, indicating that some SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause of isolated optic neuropathy. Altogether, these results emphasize the clinical variability associated with SPG7 mutations, ranging from optic neuropathy to spastic paraplegia, and support the view that SPG7 screening should be carried out in both conditions.

Klebe, Stephan; Depienne, Christel; Gerber, Sylvie; Challe, Georges; Anheim, Mathieu; Charles, Perrine; Fedirko, Estelle; Lejeune, Elodie; Cottineau, Julien; Brusco, Alfredo; Dollfus, Helene; Chinnery, Patrick F.; Mancini, Cecilia; Ferrer, Xavier; Sole, Guilhem; Destee, Alain; Mayer, Jean-Michel; Fontaine, Bertrand; de Seze, Jerome; Clanet, Michel; Ollagnon, Elisabeth; Busson, Philippe; Cazeneuve, Cecile; Stevanin, Giovanni; Kaplan, Josseline; Rozet, Jean-Michel; Brice, Alexis



Progressive cerebellar atrophy: hereditary ataxias and disorders with spinocerebellar degeneration.  


The hereditary ataxias with onset in childhood are a group of heterogeneous disorders, usually with autosomal recessive inheritance. In many of them, magnetic resonance imaging (MRI) shows cerebellar atrophy. The most prominent exception to this is Friedreich's ataxia, where MRI shows normal cerebellar volume, but sometimes spinal cord atrophy. In several of the hereditary ataxias, the causative gene plays an important role in DNA repair: ataxia telangiectasia and ataxia telangiectasia-like disorder, and ataxia with oculomotor apraxia type I and II. Mitochondrial metabolism is impaired in another group of inherited ataxias including the emergent group of defects in coenzyme Q10 synthesis. Few of these disorders are amenable to effective treatment, the most important of these being vitamin E-responsive ataxia. The autosomal dominant spinocerebellar ataxias are rare in childhood. Some of them, especially SCA7 and SCA2, may begin in childhood or even infancy, family history being positive in these cases. Additional clinical clues such as presence or absence of neuropathy or oculomotor apraxia still help in making a definitive diagnosis albeit there are still many unsolved cases. In pontocerebellar hypoplasia, a neurodegenerative disease with prenatal onset, the genetic basis of the different subtypes has recently been elucidated and involves genes with different functions. PMID:23622410

Wolf, Nicole I; Koenig, Michel



Screening for hereditary haemochromatosis.  


Hereditary haemochromatosis (HH) is a common autosomal recessive disorder of iron overload in Caucasian populations. Clinical manifestations usually occur in individuals homozygous for the C282Y mutation in the HFE gene product and who have developed significant iron loading. Current screening methods can detect affected individuals either prior to or early during disease evolution, enabling early introduction of phlebotomy treatment that can normalise life expectancy. Evaluation of possible iron overload, via measurement of serum transferrin saturation and ferritin level, is the most appropriate initial test for those subjects presenting clinically for evaluation. HFE genotyping, when combined with serum biochemical measurements, defines the presence of likely iron overload and the underlying genetic disorder and is the preferred initial screening modality for families of an affected individual. Definitive proof of iron overload requires measurement of hepatic iron concentration or total iron burden via therapeutic phlebotomy; elevated serum ferritin level alone is not adequate. We now recognise that the natural history of HH is not as discrete as previously believed, because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical expression of HH. In fact, a minority of C282Y homozygotes develop classical 'iron overload disease', although it has recently emerged that the disorder may predispose to breast and colorectal cancer. Uncertainties as to the true clinical impact of the condition at a population level lead to current recommendations of cascade screening of families of affected patients, case-finding in high-risk groups, such as patients with clinical manifestations consistent with the diagnosis, and a high level of clinical awareness in the community to facilitate early diagnosis. Generalised population screening is not presently recommended. PMID:22198253

Nadakkavukaran, Itty M; Gan, Eng K; Olynyk, John K



Hereditary gastrointestinal polyposis syndromes.  


Hereditary gastrointestinal polyposis syndromes can be divided into adenomatous and hamartomatous types. Familial adenomatous polyposis coli (FAPC) is the prototype adenomatous polyposis syndrome and is defined by the autosomal dominant transmission of multiple (more than 100) colorectal adenomas. Virtually all affected patients develop colorectal carcinoma if untreated. Adenomas may develop also in the stomach and small bowel in FAPC patients, but the incidence of carcinoma in these sites is low. A variety of extracolonic manifestations has been reported in FAPC, with the name Gardner's syndrome applied to kindreds with osteomas of the skull and mandible, multiple epidermal cysts, and other skin and soft-tissue lesions. In Turcot's syndrome, brain tumors are present. The distinction between Gardner's and Turcot's syndromes and classical FAPC has become blurred because of marked overlap between them; some authorities consider them to be varying manifestations of a single genetic defect. The hamartomatous polyposes include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, intestinal ganglioneuromatosis, and the Ruvalcaba-Myrhe-Smith syndrome. The incidence of gastrointestinal cancer in patients with Peutz-Jeghers syndrome and familial juvenile polyposis exceeds that in the normal population, but is relatively low. In Cowden's disease, the gastrointestinal tract may be the site of multiple hamartomas, but there is no associated increase in the incidence of gastrointestinal cancers; instead, there is an increased incidence of carcinoma of the breast and thyroid. Intestinal ganglioneuromatosis occurs in von Recklinghausen's disease, in association with multiple endocrine neoplasia, type 2b, or as an isolated abnormality. Patients with ganglioneuromatosis do not appear to have an increased risk of developing gastrointestinal cancer. Ruvalcaba-Myrhe-Smith syndrome comprises macrocephaly, mental deficiency, an unusual craniofacial appearance, hamartomatous intestinal polyposis, and pigmented macules on the penis. No increased risk of developing cancer has been identified in the few reported cases. PMID:3024515

Haggitt, R C; Reid, B J



Genetics Home Reference: Hereditary hemorrhagic telangiectasia  


... serious problems may arise from hemorrhages in the brain, liver, lungs, or other organs. Forms of hereditary hemorrhagic telangiectasia include type 1, type 2, type 3, and juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. People with type ...


Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel.  


Anti-neoplastic agents in the platinum-complex, taxane, vinca alkaloid, and proteasome-inhibitor classes induce a dose-limiting, chronic, distal, symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Clinical descriptions suggest that these conditions are very similar, but clinical data are insufficient to determine the degree of similarity and to determine if they share common pathophysiological mechanisms. Animal models do not have the limitations of clinical studies and so we have characterized a rat model of chronic painful peripheral neuropathy induced by a platinum-complex agent, oxaliplatin, in order to compare it with a previously characterized model of chronic painful peripheral neuropathy induced by a taxane agent, paclitaxel. The oxaliplatin model evokes mechano-allodynia, mechano-hyperalgesia, and cold-allodynia that have a delayed onset, gradually increasing severity, a distinct delay to peak severity, and duration of about 2.5 months. There is no effect on heat sensitivity. Electron microscopy (EM) analyses found no evidence for axonal degeneration in peripheral nerve, and there is no upregulation of activating transcription factor-3 in the lumbar dorsal root ganglia. There is a statistically significant loss of intraepidermal nerve fibers in the plantar hind paw skin. Oxaliplatin treatment causes a significant increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons, but not in their Schwann cells. Nerve conduction studies found significant slowing of sensory axons, but no change in motor axons. Single fiber recordings found an abnormal incidence of A- and C-fibers with irregular, low-frequency spontaneous discharge. Prophylactic dosing with two drugs that are known to protect mitochondria, acetyl-l-carnitine and olesoxime, significantly reduced the development of pain hypersensitivity. Our results are very similar to those obtained previously with paclitaxel, and support the hypothesis that these two agents, and perhaps other chemotherapeutics, produce very similar conditions because they have a mitotoxic effect on primary afferent neurons. PMID:22200546

Xiao, W H; Zheng, H; Bennett, G J



Sensory Integration Dysfunction  

Microsoft Academic Search

\\u000a Sensory integration dysfunction (SID) (also known as regulatory sensory processing disorder, sensory processing dysfunction,\\u000a or sensory processing dysfunction) is a neurological disorder that involves impairment in processing data from the different\\u000a senses (vision, auditory, touch, olfaction, and taste), the vestibular system (movement), and proprioception (body awareness).

Mark L. Goldstein; Stephen Morewitz


Natura non facit saltus in anti-ganglioside antibody-mediated neuropathies.  


Natura non facit saltus (Latin for "nature does not make jumps") is a maxim expressing the idea that natural things and properties change gradually, in a continuum, rather than suddenly. In biomedical sciences, for taxonomic purposes, we make jumps that emphasize differences more than similarities. Among the dysimmune neuropathies, 2 disorders, characterized by the presence of antibodies to gangliosides GM1 and GD1a and a peculiar, exclusive motor involvement, have been identified: acute motor axonal neuropathy (AMAN) and multifocal motor neuropathy (MMN). However, anti-GM1 or -GD1a antibodies are also associated with acute motor and sensory axonal motor neuropathy (AMSAN). We review the results of recent clinical and experimental studies showing that AMAN and MMN are not exclusively motor. We discuss the possible explanations for the greater resistance of sensory fibers to antibody attack to finally suggest that AMAN, AMSAN, and MMN belong to a continuous spectrum with a common pathophysiological mechanism. Muscle Nerve 48: 484-487, 2013. PMID:23625341

Uncini, Antonino; Notturno, Francesca; Capasso, Margherita



Subclinical peripheral neuropathy is a common finding in colorectal cancer patients prior to chemotherapy  

PubMed Central

Purpose Of the numerous complications associated with cancer and cancer treatment, peripheral neuropathy is a deleterious and persistent patient complaint commonly attributed to chemotherapy. The present study investigated the occurrence of subclinical peripheral neuropathy in patients with colorectal cancer prior to the initiation of chemotherapy. Experimental Design Fifty-two (52) patients underwent extensive quantitative sensory testing (QST) prior to receiving chemotherapy. Changes in multiple functions of primary afferent fibers were assessed and compared to a group of healthy control subjects. Skin temperature, sensorimotor function, sharpness detection, and thermal detection were measured, as was touch detection, using both conventional (von Frey monofilaments) and novel (Bumps detection test) methodology. Results Patients had subclinical deficits, especially in sensorimotor function, detection of thermal stimuli, and touch detection that were present prior to the initiation of chemotherapy. The measured impairment in touch sensation was especially pronounced when using the Bumps detection test. Conslusions The colorectal cancer patients in this study exhibited deficits in sensory function prior to undergoing chemotherapy treatment, implicating the disease itself as a contributing factor in chemotherapy induced peripheral neuropathy. The widespread nature of the observed deficits further indicated that cancer is affecting multiple primary afferent subtypes. Specific to the finding of impaired touch sensation, results from this study highlight the use of newly employed methodology, the Bumps detection test, as a sensitive and useful tool in the early detection of peripheral neuropathy.

Boyette-Davis, Jessica A.; Eng, Cathy; Wang, Xin S.; Cleeland, Charles S.; Wendelschafer-Crabb, Gwen; Kennedy, William R.; Simone, Donald A.; Zhang, Haijun; Dougherty, Patrick M.



Study on Corporate Hereditary Central Dogma  

Microsoft Academic Search

Based on analyzing the central dogma of biology, this paper raises hypothesis, using the analogism method to set up the corporate hereditary central dogma. It analyzes the differences between the Corporate hereditary central dogma and the central dogma of biology, which explains the significance of research on Corporate hereditary central dogma; it discusses the meanings of all factors of Corporate

Li Xianbai



Radiation-induced optic neuropathy  

Microsoft Academic Search

Radiation-induced optic neuropathy (RION) is a devastating late complication of radiotherapy to the anterior visual pathway resulting in acute, profound, irreversible visual loss. It is thought to be a result of radiation necrosis of the anterior visual pathway. Visual loss may be unilateral or bilateral; simultaneous or sequential. RION occurs commonly between 10-20 months, with an average of 18 months

Helen V. Danesh-Meyer



Congenital Cataracts – Facial Dysmorphism – Neuropathy  

Microsoft Academic Search

Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a complex developmental disorder of autosomal recessive inheritance. To date, CCFDN has been found to occur exclusively in patients of Roma (Gypsy) ethnicity; over 100 patients have been diagnosed. Developmental abnormalities include congenital cataracts and microcorneae, primary hypomyelination of the peripheral nervous system, impaired physical growth, delayed early motor and intellectual development,

Luba Kalaydjieva



Peripheral Neuropathy in Cockayne's Syndrome  

Microsoft Academic Search

A detailed study has been made of a typical case of Cockayne's syndrome. An associated peripheral neuropathy has been demonstrated by slow nerve conduction velocities and by evidence of segmental demyelination on sural nerve biopsy. Cockayne's syndrome is probably a leucodystrophy.

A. Moosa; V. Dubowitz



Ethambutol-induced optic neuropathy linked to OPA1 mutation and mitochondrial toxicity.  


Ethambutol (EMB), widely used in the treatment of tuberculosis, has been reported to cause Leber's hereditary optic neuropathy in patients carrying mitochondrial DNA mutations. We study the effect of EMB on mitochondrial metabolism in fibroblasts from controls and from a man carrying an OPA1 mutation, in whom the drug induced the development of autosomal dominant optic atrophy (ADOA). EMB produced a mitochondrial coupling defect together with a 25% reduction in complex IV activity. EMB induced the formation of vacuoles associated with decreased mitochondrial membrane potential and increased fragmentation of the mitochondrial network. Mitochondrial genetic variations may therefore be predisposing factors in EMB-induced ocular injury. PMID:19900585

Guillet, Virginie; Chevrollier, Arnaud; Cassereau, Julien; Letournel, Franck; Gueguen, Naïg; Richard, Laurence; Desquiret, Valérie; Verny, Christophe; Procaccio, Vincent; Amati-Bonneau, Patrizia; Reynier, Pascal; Bonneau, Dominique



Profound and persistent painful paclitaxel peripheral neuropathy in a premenopausal patient  

PubMed Central

The authors herein report the case of a 35-year-old woman undergoing adjuvant therapy for node positive breast cancer, who presented with short and rapidly progressive history of bilateral lower limb symptoms of peripheral neuropathy following therapy with paclitaxel. MRI of her neural axis revealed no leptomeningeal enhancement or focal metastatic lesions. Neurophysiological tests favoured toxic sensory axonal polyneuropathy. She remains symptomatic following discontinuation of therapy 20 months ago, and is under review with pain management.

Quintyne, K I; Mainstone, P; McNamara, B; Boers, P; Wallis, F; Gupta, R K



An animal model of nociceptive peripheral neuropathy following repeated cisplatin injections  

Microsoft Academic Search

We report the assessment of motor and sensory behaviors using an electrophysiologic and an histologic approach, in a rat model of cisplatin peripheral neuropathy. Cisplatin was injected intraperitoneally one (3 mg\\/ kg), two (2 mg\\/kg), or three (1 mg\\/kg) times a week up to a cumulative dose of 15 or 20 mg\\/kg. With regard to nociceptive signs, we observed mechanical

Nicolas Authier; Jean-Pierre Gillet; Joseph Fialip; Alain Eschalier; François Coudore



Multifocal conduction block in a patient with sarcoid neuropathy: successful treatment with intravenous immunoglobulin.  


A 54-year-old-woman with sarcoidosis presented with progressive symmetric, predominantly distal weakness and sensory dysfunction with areflexia in all four limbs. Nerve conduction studies showed multifocal conduction blocks in several nerves. Oral steroids were ineffective; however, intravenous immunoglobulin (IVIG) therapy rapidly and repeatedly improved the patient's neurologic symptoms with a resolution of the conduction blocks. Multifocal conduction blocks are not frequently reported in patients with sarcoid neuropathy, but they may respond to early treatment with IVIG. PMID:23648721

Kono, Yu; Omoto, Shusaku; Sengoku, Renpei; Yaguchi, Hiroshi; Sonoo, Masahiro; Inoue, Kiyoharu; Mochio, Soichiro



Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice.  


Bortezomib, a proteasome inhibitor, is an antineoplastic drug to treat multiple myeloma and mantle cell lymphoma. Its most clinically significant adverse event is peripheral sensory neuropathy. Our objective was to characterize the neuropathy induced by bortezomib in a mouse model. Two groups were used; one group received vehicle solution and another bortezomib (1mg/kg/twice/week) for 6weeks (total dose as human schedule). Tests were performed during treatment and for 4weeks post dosing to evaluate electrophysiological, autonomic, pain sensibility and sensory-motor function changes. At the end of treatment and after washout, sciatic and tibial nerves, dorsal ganglia and intraepidermal innervation were analyzed. Bortezomib induced progressive significant decrease of sensory action potential amplitude, mild reduction of sensory velocities without effect in motor conductions. Moreover, it significantly increased pain threshold and sensory-motor impairment at 6weeks. According to these data, histopathological findings shown a mild reduction of myelinated (-10%; p=0.001) and unmyelinated fibers (-27%; p=0.04), mostly involving large and C fibers, with abnormal vesicular inclusion body in unmyelinated axons. Neurons were also involved as shown by immunohistochemical phenotypic switch. After washout, partial recovery was observed in functional, electrophysiological and histological analyses. These results suggest that axon and myelin changes might be secondary to an initial dysfunctional neuronopathy. PMID:20188093

Bruna, Jordi; Udina, Esther; Alé, Albert; Vilches, Jorge J; Vynckier, Ann; Monbaliu, Johan; Silverman, Lee; Navarro, Xavier



Electrolyte imbalance triggering relapse of inflammatory neuropathy.  


Electrolyte imbalance is a well-known cause of acute neurological deterioration in the central and peripheral nervous systems. Rapid correction of hyponatraemia1 can cause central pontine myelinolysis, and in muscle tetany may result from hypocalcaemia. However the role of electrolyte imbalance in peripheral neuropathy although well-described is encountered less frequently. We describe a case of a 71 year old female with a fourteen year history of chronic inflammatory demyelinating polyneuropathy (CIDP) and stable monoclonal gammopathy, normally maintained on three-weekly intravenous immunoglobulin (IVIG) therapy. At her best baseline, she has a normal motor examination and reduced vibration sense only to the ankles. She presented with a four week history of progressive numbness and paresthesiae in all four limbs, reduced balance, a decline in mobility with frequent falls and reduced hand function. The deterioration developed after a week of non-bloody diarrhoea with night sweats but continued to progress through two courses of her regular IVIG. She also had a past history of breast cancer, hypertension and a duodenal ulcer. On examination she had a profound sensory ataxia and pseudo-athetosis of the upper limbs. Power was preserved. Pinprick was reduced to the forearm and thighs. Vibration sense was present only at the sternum. Proprioception was reduced to the shoulders and hips. She was areflexic. General examination was normal. Blood investigations showed hypomagnesaemia of 0.1 (range 0.6-1.0), hypocalcaemia of 1.75 (range 2.15-2.55), mild hypokalaemia of 3.2 (range 3.5-5.1) but stable renal function. Nerve conduction studies showed a length-dependent demyelinating sensorimotor neuropathy with significant deterioration from previous studies. Her paraprotein level was stably low. Thus we considered the metabolic disturbance as a potential cause of her acute severe relapse of her CIDP. The diarrhoea resolved spontaneously and potassium and calcium levels normalised after oral treatment. However the hypomagnesaemia required high-dose oral and intravenous supplementation. Investigations for a malabsorption syndrome were negative. She was taking two medications known to be associated with hypomagnesaemia. After stopping indapamide, a thiazide-like diuretic, her urine magnesium output was low, so a renal cause was unlikely. Omeprazole, which had been doubled in the last year after the diagnosis of her duodenal ulcer, is known in multiple case series to be associated with severe symptomatic hypomagnesaemia that is thought to be a class effect of proton pump inhibitors (PPIs).(2) This prompted us to halve the dose of omeprazole. Her serum magnesium level stabilised in the low-to-normal range and she was treated with two further courses of 2 g/kg IVIG. She had a marked improvement in sensory examination and functional ability. Her proprioceptive loss and sensory ataxia resolved. A logical approach to investigating for reversible causes for her deterioration pointed to drug-induced hypomagnesaemia as a potentially important cause of acute decompensation in CIDP. Her severe relapse remained refractory to treatment until her metabolic disturbance was normalised, after which she showed an excellent response. PMID:24108985

Keshavan, A; Gandhi, S; Lunn, Mp; Reilly, Mm



Standing Balance and Trunk Position Sense in Impaired Glucose Tolerance (IGT)-Related Peripheral Neuropathy  

PubMed Central

Type 2 diabetes mellitus (T2DM) and pre-diabetes or impaired glucose tolerance (IGT) affects a large segment of the population. Peripheral neuropathy (PN) is a common complication of T2DM, leading to sensory and motor deficits. While T2DM-related PN often results in balance- and mobility-related dysfunction which manifests as gait instability and falls, little is known about balance capabilities in patients who have evidence of PN related to IGT (IGT-PN). We evaluated patients with IGT-PN on commonly-used clinical balance and mobility tests as well as a new test of trunk position sense and balance impairment, trunk repositioning errors (TREs). Eight participants aged 50–72 years with IGT-PN, and eight age and gender matched controls underwent balance, mobility and trunk repositioning accuracy tests at a university neurology clinic and mobility research laboratory. Compared to controls, IGT-PN participants had as much as twice the magnitude of TREs and stood approximately half as long on the single leg balance test. People with IGT-PN exhibit deficits in standing balance and trunk position sense. Furthermore, there was a significant association between performance on commonly-used clinical balance and mobility tests, and electrophysiological and clinical measures of neuropathy in IGT-PN participants. Because IGT-related neuropathy represents the earliest stage of diabetic neuropathy, deficits in IGT-PN participants highlights the importance of early screening in the dysglycemic process for neuropathy and associated balance deficits.

Goldberg, Allon; Russell, James William; Alexander, Neil Burton



Corneal confocal microscopy to assess diabetic neuropathy: an eye on the foot.  


Accurate detection and quantification of human diabetic peripheral neuropathy are important to define at-risk patients, anticipate deterioration, and assess new therapies. Easily performed clinical techniques such as neuro-logical examination, assessment of vibration perception or insensitivity to the 10 g monofilament only assess advanced neuropathy, i.e., the at-risk foot. Techniques that assess early neuropathy include neurophysiology (which assesses only large fibers) and quantitative sensory testing (which assesses small fibers), but they can be highly subjective while more objective techniques, such as skin biopsy for intra-epidermal nerve fiber density quantification, are invasive and not widely available. The emerging ophthalmic technique of corneal confocal microscopy allows quantification of corneal nerve morphology and enables clinicians to diagnose peripheral neuropathy in diabetes patients, quantify its severity, and potentially assess therapeutic benefit. The present review provides a detailed critique of the rationale, a practical approach to capture images, and a basis for analyzing and interpreting the images. We also critically evaluate the diagnostic ability of this new noninvasive ophthalmic test to diagnose diabetic and other peripheral neuropathies. PMID:24124944

Tavakoli, Mitra; Petropoulos, Ioannis N; Malik, Rayaz A




PubMed Central

Peripheral neuropathy develops in human subjects with prediabetes and metabolic syndrome, prior to overt hyperglycemia. The contributions of impaired glucose tolerance and insulin signaling, hypertriglyceridemia and/or increased NEFA, and hypercholesterolemia to this condition remain unknown. Niacin and its derivatives alleviate dyslipidemia with a minor effect on glucose homeostasis. This study evaluated the roles of impaired glucose tolerance versus dyslipidemia in prediabetic neuropathy using Zucker fatty (fa/fa) rats and the niacin derivative acipimox, as well as the interplay of hypertriglyceridemia, increased NEFA, and oxidative-nitrosative stress. 16 wk-old Zucker fatty rats with impaired glucose tolerance, obesity, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and increased NEFA, displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. Acipimox (100 mgkg?1d?1, 4 weeks) reduced serum insulin, NEFA, and triglyceride concentrations without affecting glucose tolerance and hypercholesterolemia. It alleviated sensory nerve conduction velocity deficit, changes in behavioral measures of sensory function, and corrected oxidative-nitrosative stress, but not impaired insulin signaling, in peripheral nerve. Elevated NEFA increased total and mitochondrial superoxide production and NAD(P)H oxidase activity in cultured human Schwann cells. In conclusion, hypertriglyceridemia and/or increased NEFA concentrations cause prediabetic neuropathy through oxidative-nitrosative stress. Lipid-lowering agents and antioxidants may find use in management of this condition.

Lupachyk, Sergey; Watcho, Pierre; Hasanova, Nailia; Julius, Ulrich; G.Obrosova, Irina



Mitochondrial enzymes in hereditary ataxias  

Microsoft Academic Search

As a test of the hypothesis that mitochondrial abnormalities are common in patients with hereditary ataxias, the activities of two mitochondrial enzymes were studied in platelets from an unselected series of patients. For the group of ataxies, the activity of the pyruvate dehydrogenase complex (PDHC) was 68% of the control (P P 2 SD below the control mean. Immunoblots of

Kwan-Fu Rex Sheu; John P. Blass; Jesse M. Cedarbaum; Young-Tai Kim; Bradford J. Harding; Joseph DeCicco



Cyclopism as a Hereditary Malformation  

Microsoft Academic Search

CYCLOPISM is a malformation which has been recognized for many years and which may have furnished the model for the Homeric monsters. It has been suggested that this developmental disorder is hereditary, but until recently there has been no proof of this.

Peter Pfitzer; Horst Müntefering



Drug therapy for hereditary cancers  

PubMed Central

Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies.



Calciphylaxis and bilateral optic neuropathy.  


A 51-year-old woman on hemodialysis for chronic renal failure complained of visual loss in her right eye. Right optic disc edema was observed on fundus examination. An arteritic optic neuropathy was suspected. However, a first biopsy did not reveal any inflammatory cells. Two months later, the patient experienced sudden visual loss in her left eye and presented with necrotic cutaneous lesions at the distal phalanges of several fingers of the right hand. Necrotic lesions also appeared on the inner aspect of the thighs. Biopsy of the cutaneous lesions revealed calcification in the wall of a small artery. A new biopsy of the temporal artery showed large calcium deposits in the artery's tunica media. The diagnosis of optic neuropathy secondary to calciphylaxis was made. A temporal artery biopsy should be repeated if the first one is inconclusive. An early diagnosis leading to appropriate treatment may help to prevent an irreversible loss of vision in these patients. PMID:21680055

Huerva, V; Sánchez, M C; Ascaso, F J; Craver, L; Fernández, E



Focal neuropathies following percutaneous nephrolithotomy (PCNL) - preliminary study  

PubMed Central

Introduction: Postoperative neurological complications in pelvic and renal surgery are a well-known clinical problem and their morbidities are important. We designed this study to determine prevalence and risk factors of such complications after percutaneous nephrolithotomy (PCNL) surgery. Material and methods: A cross-sectional study was performed during February and July 2011 on 68 PCNL cases. Demographic data and surgery reports were gathered and comprehensive neurological physical examination carried out before and after surgery. Then, data was analyzed using software SPSS 18. Results: The ultimate sample included 30 (46.2%) male and 35 (53.8%) female patients with a mean age of 47.9 ± 11.47 years. In intercostal and lumbosacral plexus area, sensory neurological complications occurred in 8 patients (12.31%), 4 men and 4 women. The most common involved dermatomes and nerves were T12 (8 cases). There was a significant correlation between prolonged duration of surgery and prevalence of sensory complications (p<0.010). The highest hemoglobin value drop after surgery occurred in patients with neurological complications (p<0.001). There were no correlations between age, tracts used, diabetes mellitus, BMI, hypertension, positioning of patients and side of surgery with incidence of sensory neurological complications. No motor neurological complications occurred. Conclusion: Prolonged duration of PCNL and increased value of hemoglobin drop may lead to increased risk of neuropathy. Larger prospective studies with retroperitoneal imagings and patients’ follow up is suggested for better understanding of this complication.

Nasseh, Hamidreza; Pourreza, Farshid; Saberi, Alia; Kazemnejad, Ehsan; Kalantari, Behnam Behmardi; Falahatkar, Siavash



Congenital Cataracts - Facial Dysmorphism - Neuropathy  

Microsoft Academic Search

Key words Disease name\\/synonyms Definition\\/diagnostic criteria Epidemiology Abstract Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a complex developmental disorder of autosomal recessive inheritance. CCFDN is a genetically homogeneous condition in which all patients are homozygous for the same ancestral mutation in the CTDP1 gene. To date, it has been found to occur exclusively in patients of Roma (Gypsy) ethnicity;

Marianne de Visser


Pathogenesis of Human Diabetic Neuropathy  

Microsoft Academic Search

Experimental studies have provided multiple mechanisms for the development of diabetic neuropathy, yet very few findings have\\u000a been replicated in patients. Hyperglycemia mediated nerve damage may begin very early even prior to overt diabetes as evidenced\\u000a by several recent studies in patients with impaired glucose tolerance. Polyol pathway abnormalities have been exhaustively\\u000a explored in animals, but studies in man are

Rayaz Ahmed Malik; Aristides Veves


Treatment of Painful Diabetic Neuropathy  

Microsoft Academic Search

Up to 50% of patients with chronic sensorimotor diabetic neuropathy will experience painful or uncomfortable symptoms, and\\u000a of these a significant minority may require pharmacological therapy. As painful symptomatology may be worsened by a sudden\\u000a change in glycaemic control, the first step in management should be the quest for stable, near normal glycaemic control avoiding\\u000a glycaemic flux. Of all the

Andrew J. M. Boulton


Peripheral Neuropathy: Symptoms and Signs  


... At first, you may notice numbness, tingling, abnormal sensations, or pain in your feet. Some people feel ... these nerves and their location: Sensory Nerves: affect sensation Autonomic Nerves: affect internal organ functions; and, Motor ...


Bilateral isolated cut of sensory branch of radial nerve.  


Bilateral injuries of the sensory branch of the radial nerve (SBRN) usually occur as a result of tight-handcuff neuropathy. In this case we aimed to present bilateral isolated cut of SBRN resulting an injury mechanism that has not been reported in the literature previously. A male twenty-four years old, a worker in a glass factory, presented to our clinic. The dorsolateral skin of his wrists were cut by breaking of the glass as a result of occupational accident and was primarily sutured in a healthcare center. The patient sought additional care after a month because of lingering numbness and pain, and surgery was planned. During surgery, scar tissue and neuroma at the cut ends of SBRN were excised, and bilateral SBRN cuts were repaired. Four weeks after operation, mild sensory deficit on the dorsal side of bilateral thumbs, and left first web space and flexion limitation on the right wrist were detected. At the 3rd month postoperative, right wrist joint range of motion was full, and sensory deficits, and hyperesthesia were decreased. The SBRN elicits the sensory innervation of the thumb dorsum and its injury does not cause important functional deficit. However because of susceptibility of SBRN to develop painful neuroma, diagnosis, treatment and follow up of isolated SBRN injury would be worthwhile for prevention of possible painful neuropathy disturbing quality of life. PMID:23599208

Akkaya, Nuray; Özcan, Hakan Ramazan; Gökalan Kara, Inci; Sahin, Füsun



Fetal sensory competencies  

Microsoft Academic Search

A growing body of evidence is available about the functioning of fetal sensory systems during gestation. This article aims at reviewing data concerning (i) the presence of potential sensory stimulation in the fetal milieu, (ii) the sequential functional development of the sensory systems and (iii) physiological and behavioral responses of fetuses to various types of stimulation. Human data are compared

Jean-Pierre Lecanuet; Benoist Schaal



Sensory Assessment Manual.  

ERIC Educational Resources Information Center

|This manual is intended to provide information leading to reliable assessment of vision and hearing capabilities of children considered to have dual sensory impairments. Ongoing sensory assessment is necessary to determine the extent of residual sensory abilities that should be considered in educational programming decisions and to determine any…

Cress, Pamela J.


Electrophysiological features of the mouse tail nerves and their changes in chemotherapy induced peripheral neuropathy (CIPN).  


Electrophysiology of tail nerves in rodents has been demonstrated a reliable method to investigate models of peripheral neuropathies. Nevertheless, data concerning mouse models are lacking. We assessed the normal features of sensory and motor conduction of tail nerves in adult mice. We found that, as in rats, a sensory compound action potential and motor responses could be recorded with the non invasive and highly reliable technique proposed, especially if bipolar derivations were used. We also investigated the changes related to chemotherapy induced peripheral neuropathy (CIPN) after paclitaxel treatment (times 1 and 2), compared to pre-treatment (time 0) and to controls. It was found that only the sensory compound action potential was involved in CIPN, with decrease in amplitude and conduction velocity, suggesting a significant reduction in number of fast conducting fibres and a correspondent increase in the number of slow conducting ones, although the total amount of active myelinated fibres was deemed to be unchanged through time 0, time 1 and time 2. The results obtained in CIPN provide new functional evidence about the involvement of sensory fibres and may help in better understanding the underlying mechanisms. PMID:22800858

Leandri, Massimo; Ghignotti, Mariaisabella; Emionite, Laura; Leandri, Silia; Cilli, Michele



Hereditary angioedema in a family.  


Hereditary angioedema is an uncommon clinical condition. Life-long episodic brawny and non-itchy swelling of the extremities, face and trunk, with episodic abdominal pain and familial occurrence are the typical features. Oedema causing obstruction of airways may lead to suffocation and even death. The diagnosis can be confirmed by finding low levels of C1 esterase inhibitor, C4 and C2. Therapy with synthetic androgenic agents can ameliorate the condition to a large extent. PMID:1452538

Singh, Y N; Chanana, B B; Kumar, A; Malaviya, A N



Monilethrix: a rare hereditary condition.  


Monilethrix is a rare hereditary condition generally considered to be an autosomal-dominant disorder with variable penetrance. Here, we report a case of monilethrix in a 13-year-old boy with an affected sibling. A therapeutic trial with oral N-acetyl cysteine was attempted. There was slight improvement after 2 months of therapy. The hair density, however, did not show any further improvement subsequently. Monilethrix remains as a therapeutic challenge for dermatologists. PMID:23723505

Vikramkumar, Adaikalampillai Ganapathy; Kuruvila, Sheela; Ganguly, Satyaki



Imaging of Hereditary Hemorrhagic Telangiectasia  

Microsoft Academic Search

This pictorial review is based on our experience of the follow-up of 120 patients at our multidisciplinary center for hereditary\\u000a hemorrhagic telangiectasia (HHT). Rendu-Osler-Weber disease or HHT is a multiorgan autosomal dominant disorder with high penetrance,\\u000a characterized by epistaxis, mucocutaneous telangiectasis, and visceral arteriovenous malformations (AVMs). The research on\\u000a gene mutations is fundamental and family screening by clinical examination, chest

Marie-France Carette; Cosmina Nedelcu; Marc Tassart; Jean-Didier Grange; Marie Wislez; Antoine Khalil



Hereditary hyperferritinemia-cataract syndrome.  


Hereditary hyperferritinemia-cataract syndrome (HHCS) is a recently recognized syndrome characterized by dominantly inherited, early-onset cataracts and elevated serum ferritin. The opacities are caused by elevated ferritin protein within the crystalline lens and usually become symptomatic in the second to fourth decade of life. Routine laboratory tests can establish this diagnosis. We report two unrelated cases that presented in the United States. PMID:17572344

Christiansen, Gregory; Mohney, Brian G



Hereditary Adenomatous Colorectal Cancer Syndromes  

Microsoft Academic Search

\\u000a Colorectal cancer (CRC) is one of the most common cancer diagnoses that a digestive disease specialist or primary care physician\\u000a will encounter in a patient in their practice [1]. While fewer than 10% of the cases occur within the setting of a hereditary\\u000a colorectal cancer syndrome (HCCS), the burden of the disease to the patient, family, and provider is greater

Maqsood Khan; Carol A. Burke


Movement-related cerebellar activation in the absence of sensory input.  


Movement-related cerebellar activation may be due to sensory or motor processing. Ordinarily, sensory and motor processing are obligatorily linked, but in patients who have severe pansensory neuropathies with normal muscle strength, motor activity occurs in isolation. In the present study, positron emission tomography and functional magnetic resonance imaging in such patients showed no cerebellar activation with passive movement, whereas there was prominent movement-related cerebellar activation despite absence of proprioceptive or visual input. The results indicate that motor processing occurs within the cerebellum and do not support the recently advanced view that the cerebellum is primarily a sensory organ. PMID:10400975

Weeks, R A; Gerloff, C; Honda, M; Dalakas, M C; Hallett, M



Hereditary deafness and phenotyping in humans.  


Hereditary deafness has proved to be extremely heterogeneous genetically with more than 40 genes mapped or cloned for non-syndromic dominant deafness and 30 for autosomal recessive non-syndromic deafness. In spite of significant advances in the understanding of the molecular basis of hearing loss, identifying the precise genetic cause in an individual remains difficult. Consequently, it is important to exclude syndromic causes of deafness by clinical and special investigation and to use all available phenotypic clues for diagnosis. A clinical approach to the aetiological investigation of individuals with hearing loss is suggested, which includes ophthalmology review, renal ultrasound scan and neuro-imaging of petrous temporal bone. Molecular screening of the GJB2 (Connexin 26) gene should be undertaken in all cases of non-syndromic deafness where the cause cannot be identified, since it is a common cause of recessive hearing impairment, the screening is straightforward, and the phenotype unremarkable. By the same token, mitochondrial inheritance of hearing loss should be considered in all multigeneration families, particularly if there is a history of exposure to aminoglycoside antibiotics, since genetic testing of specific mitochondrial genes is technically feasible. Most forms of non-syndromic autosomal recessive hearing impairment cause a prelingual hearing loss, which is generally severe to profound and not associated with abnormal radiology. Exceptions to this include DFNB2 (MYO7A), DFNB8/10 (TMPRSS3) and DFNB16 (STRC) where age of onset may sometimes be later on in childhood, DFNB4 (SLC26A4) where there may be dilated vestibular aqueducts and endolymphatic sacs, and DFNB9 (OTOF) where there may also be an associated auditory neuropathy. Unusual phenotypes in autosomal dominant forms of deafness, include low frequency hearing loss in DFNA1 (HDIA1) and DFNA6/14/38 (WFS1), mid-frequency hearing loss in DFNA8/12 (TECTA), DFNA13 (COL11A2) and vestibular symptoms and signs in DFNA9 (COCH) and sometimes in DFNA11 (MYO7A). Continued clinical evaluation of types and course of hearing loss and correlation with genotype is important for the intelligent application of molecular testing in the next few years. PMID:12324385

Bitner-Glindzicz, Maria



[Case of chronic progressive encephalo-myelo-radiculo-neuropathy].  


A 65-year-old man developed urinary impairment and gait disturbance over a period of four months. On admission, neurological examinations revealed paraplegia, decreased deep tendon reflexes in the extremities, bilateral positive Babinski and Chaddock signs, superficial and deep sensory disturbances and neurogenic bladder. Cerebrospinal fluid examination disclosed a total cell count of 70/mm3, and protein of 76 mg/dl. Nerve conduction studies and somatosensory evoked potential suggested demyelinating neuropathy and myelopathy. Brain MRI revealed irregular-shaped white matter lesions distributed over the bilateral cerebral hemispheres and the brain stem. In addition spinal MRI disclosed long spinal cord lesions disseminated from the higher cervical to the lower thoracic spine. A 1 microm-thick epon-embedded section and teased fiber preparations of a biopsied sural nerve showed segmental demyelination and remyelination. Treatments using intravenous methylprednisolone and IVIg were both effective. The positive responses to immunological treatment, along with the findings, strongly suggested that the demyelinating lesions occurred in both the central and peripheral nervous systems. We regarded this case as one of chronic progression of Encephalo-myelo-radiculo-neuropathy. PMID:20535982

Kutoku, Yumiko; Inoue, Ken; Murakami, Tatsufumi; Sunada, Yoshihide



Acute motor axonal neuropathy cases in Van region.  


Acute motor axonal neuropathy (AMAN) is a form of Guillain Barré Syndrome (GBS) seen in summer months in Northern China to cause epidemics. This form of the disease, which is also sporadically observed in other countries, constitutes less than 5% of GBS in Western countries. It usually develops with motor findings. No sensory findings are observed. In some of the cases, the severe impairments in tissues improve however slowly and inadequately. In the motor conduction studies of cases with AMAN, motor action potential values are lowered. On needle electromyography (EMG), motor unit potential (MUP) activity is diminished with spontaneous denervation findings. Investigations were conducted on nerve conduction of patients with GBS aged from 1 to 77 years. AMAN was detected in 25 of these patients. In our investigation, AMAN as a GBS variant was detected in 39.7% of the patients. The conduction velocities of motor nerves were in normal ranges whereas combined muscle action potentials were significantly lower. No F response could be obtained. Although AMAN is a rare variant of GBS and shows different clinical courses, it has been brought under intense scrutiny since there is high prevalance of acute inflammatory neuropathies in our region (Tab. 1, Ref. 7). PMID:21682081

Sayin, R; Tombul, T; Gulec, T C; Anlar, O; Akbayram, S; Caksen, H



Guideline of transthyretin-related hereditary amyloidosis for clinicians  

PubMed Central

Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.



[Peripheral neuropathy, myelopathy, cerebellar ataxia, and subclinical optic neuropathy associated with copper deficiency occurring 23 years after total gastrectomy].  


We report a 61-year-old man with slowly progressive gait disturbance and paresthesia in the lower extremities following a total gastrectomy for gastric cancer 23 years previously. The patient presented with hyperreflexia, peripheral sensory neuropathy, and cerebellar ataxia. Magnetic resonance imaging showed atrophy of the cerebellum, and electrophysiological findings suggested the presence of disorder in both sides of the pyramidal tract, dorsal column, peripheral nerves, and optic nerve. Laboratory findings revealed anemia, neutropenia, and a remarkably low serum copper level (10 microg/dl; normal: 68-128). His serum vitamin E was slightly low and his serum vitamin B12 was within the normal limits. After administering an oral copper supplement, his symptoms improved with normalization of the serum copper level. We need to pay attention to myeloneuropathy caused by copper deficiency if the patient has a past history of total gastrectomy. PMID:21735733

Inaba, Meiko; Torii, Takako; Shinoda, Koji; Yamasaki, Ryo; Ohyagi, Yasumasa; Kira, Jun-ichi



[Compression neuropathy of upper limbs in miners].  


The authors analyzed prevalence of individual types of upper limb compression neuropathy in miners of coal and iron-ore mines. Medical examination covered main mining occupations exposed to suchhazards as local vibration, cooling microclimate, functional overstrain. Some types of compression neuropathies appeared to depend on duration of exposure to the hazards and on the occupation hands disease stage. PMID:16898248

Rodin, S I; Matveeva, O V



Bortezomib-induced severe autonomic neuropathy.  


Peripheral neuropathy is a known side effect of bortezomib therapy. Acute autonomic neuropathy may also follow treatment with this cytotoxic agent used for treatment of multiple myeloma. Here, we report clinical characteristics and patterns of autonomic involvement in a 75-year-old patient who presented with recurring syncopes. PMID:22532274

Stratogianni, A; Tosch, M; Schlemmer, H; Weis, J; Katona, I; Isenmann, S; Haensch, C A



Alcoholic vagal neuropathy: recovery following prolonged abstinence  

Microsoft Academic Search

Cardiac vagal reflexes were studied in 11 alcoholic subjects, 1 to 6 weeks after withdrawal and again after up to 27 months of continued abstinence. On initial investigation six subjects had vagal neuropathy. On the second occasion only two subjects had vagal neuropathy and significant improvement was seen in the total patient group with regard to heart rate responses to

E T Tan; R H Johnson; D G Lambie; E A Whiteside



Problems of etiology in femoral neuropathies  

Microsoft Academic Search

29 cases of femoral mononeuropathy are reported. While the clinical features of the femoral neuropathy are easily identified, the etiology is often hard to establish. The cases reported tend to fall into three general categories: 1) cases without major diagnostic difficulties (e.g. diabetic neuropathy); 2) those in which the definite diagnosis results from combined evidence of laboratory and instrumental data

L. Compagnoni; A. Lanzetti; A. Laterza; A. Nappo



Diagnosis and treatment in inflammatory neuropathies  

Microsoft Academic Search

The inflammatory neuropathies are a large diverse group of immune-mediated neuropathies that are amenable to treatment and may be reversible. Their accurate diagnosis is essential for informing the patient of the likely course and prognosis of the disease, informing the treating physician of the appropriate therapy and informing the scientific community of the results of well-targeted, designed and performed clinical

M P T Lunn; H J Willison



Management of ischemic optic neuropathies  

PubMed Central

Ischemic optic neuropathies (IONs) consist primarily of two types: anterior ischemic optic neuropathy (AION) and posterior ischemic optic neuropathy (PION). AION comprises arteritic AION (A-AION: due to giant cell arteritis) and non-arteritic AION (NA-AION: due to other causes). PION consists of arteritic PION (A-PION: due to giant cell arteritis), non-arteritic PION (NA-PION: due to other causes), and surgical PION (a complication of several systemic surgical procedures). These five types of ION are distinct clinical entities etiologically, pathogenetically, clinically and from the management point of view. In the management of AION, the first crucial step with patients aged 50 and over is to identify immediately whether it is arteritic or not because A-AION is an ophthalmic emergency and requires urgent treatment with high-dose steroid therapy to prevent any further visual loss in one or both eyes. Patients with NA-AION, when treated with systemic corticosteroid therapy within first 2 weeks of onset, had significantly better visual outcome than untreated ones. Systemic risk factors, particularly nocturnal arterial hypotension, play major roles in the development of NA-AION; management of them is essential in its prevention and management. NA-PION patients, when treated with high-dose systemic steroid therapy during the very early stages of the disease, showed significant improvement in visual acuity and visual fields, compared to untreated eyes. A-PION, like A-AION, requires urgent treatment with high-dose steroid therapy to prevent any further visual loss in one or both eyes. There is no satisfactory treatment for surgical PION, except to take prophylactic measures to prevent its development.

Hayreh, Sohan Singh



Hereditary proctalgia fugax and constipation: report of a second family.  

PubMed Central

A second family with hereditary proctalgia fugax and internal anal sphincter hypertrophy associated with constipation is described. Anorectal ultrasonography, manometry, and sensory tests were conducted in two symptomatic and one asymptomatic subjects within the same family and further clinical information was obtained from other family members. The inheritance would correspond to an autosomal dominant condition with incomplete penetration, presenting after the second decade of life. Physiological studies showed deep, ultraslow waves and an absence of internal anal sphincter relaxation on rectal distension in the two most severely affected family members, suggesting the possibility of a neuropathic origin. Both of these patients had an abnormally high blood pressure. After treatment with a sustained release formulation of the calcium antagonist, nifedipine, their blood pressure returned to normal, anal tone was reduced, and the frequency and intensity of anal pain was suppressed. These together improved the quality of the patients' sleep, which had previously been very troubled because of night time attacks of anal pain.

Celik, A F; Katsinelos, P; Read, N W; Khan, M I; Donnelly, T C



HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy  

PubMed Central

We examined the utility of herpes simplex virus (HSV) vector-mediated gene transfer of vascular endothelial growth factor (VEGF) in a mouse model of diabetic neuropathy. A replication-incompetent HSV vector with VEGF under the control of the HSV ICP0 promoter (vector T0VEGF) was constructed. T0VEGF expressed and released VEGF from primary dorsal root ganglion (DRG) neurons in vitro, and following subcutaneous inoculation in the foot, expressed VEGF in DRG and nerve in vivo. At 2 weeks after induction of diabetes, subcutaneous inoculation of T0VEGF prevented the reduction in sensory nerve amplitude characteristic of diabetic neuropathy measured 4 weeks later, preserved autonomic function measured by pilocarpine-induced sweating, and prevented the loss of nerve fibers in the skin and reduction of neuropeptide calcitonin gene-related peptide and substance P in DRG neurons of the diabetic mice. HSV-mediated transfer of VEGF to DRG may prove useful in treatment of diabetic neuropathy.

Chattopadhyay, M; Krisky, D; Wolfe, D; Glorioso, JC; Mata, M; Fink, DJ



Dual Angiogenic and Neurotrophic Effects of Bone Marrow-Derived Endothelial Progenitor Cells on Diabetic Neuropathy  

PubMed Central

Background Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs. Methods and Results We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow–derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves. A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC-conditioned media. Conclusions We demonstrate for the first time that bone marrow-derived EPCs could reverse various manifestations of diabetic neuropathy. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy.

Jeong, Jin-Ok; Kim, Mee-Ohk; Kim, Hyongbum; Lee, Min-Young; Kim, Sung-Whan; Ii, Masaaki; Lee, Jung-uek; Lee, Jiyoon; Choi, Yong Jin; Cho, Hyun-Jai; Lee, Namho; Silver, Marcy; Wecker, Andrea; Kim, Dong-Wook; Yoon, Young-sup



Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature.  


Bortezomib has demonstrated significant activity in clinical trials, mainly against recurrent or newly diagnosed multiple myeloma (MM). Peripheral neuropathy is a significant toxicity of bortezomib, requiring dose modification and potential changes in the treatment plan when it occurs. The mechanism underlying bortezomib-induced peripheral neuropathy (BIPN) is unknown. Metabolic changes resulting from the accumulation of bortezomib in the dorsal root ganglia cells, mitochondrial-mediated disregulation of Ca(++) homeostasis, and disregulation of neurotrophins may contribute to the pathogenesis of BIPN. It is increasingly recognized that BIPN may be a proteasome inhibitor class effect, producing primarily a small fiber and painful, axonal, sensory distal neuropathy. Incidence of BIPN is mainly related to various risk factors, including cumulative dose and evidence of preexisting neuropathy. Assessment of BIPN is based primarily on neurologic clinical examination and neurophysiologic methods. To date, apart from the use of dose reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for BIPN. Analgesics, tricyclic antidepressants, anticonvulsants, and vitamin supplements have been used as symptomatic treatment against bortezomib-associated neuropathic pain with some success. This review looks critically at the pathogenesis, incidence, risk factors, diagnosis, characteristics, and management of BIPN, and highlights areas for future research. PMID:18574024

Argyriou, Andreas A; Iconomou, Gregoris; Kalofonos, Haralabos P



Quantitative thermal sensory testing and sympathetic skin response in primary Restless legs syndrome - A prospective study on 57 Indian patients.  


Patients with restless leg syndrome present with sensory symptoms similar to peripheral neuropathy. While there is evidence of abnormalities of dopaminergic pathways, the peripheral nervous system has been studied infrequently. We studied conventional nerve conduction studies, quantitative thermal sensory testing and sympathetic skin response in 57 patients with primary restless leg syndrome. Almost two third patients demonstrated abnormalities in the detailed testing of the peripheral nervous system. Sbtle abnormalities of the peripheral nervous system may be more common than previously believed. PMID:23349589

Shukla, Garima; Goyal, Vinay; Srivastava, Achal; Behari, Madhuri



Therapeutic angiogenesis inhibits or rescues chemotherapy-induced peripheral neuropathy: taxol- and thalidomide-induced injury of vasa nervorum is ameliorated by VEGF.  


Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder. PMID:17164777

Kirchmair, Rudolf; Tietz, Anne B; Panagiotou, Eleftheria; Walter, Dirk H; Silver, Marcy; Yoon, Young-Sup; Schratzberger, Peter; Weber, Alberto; Kusano, Kengo; Weinberg, David H; Ropper, Allan H; Isner, Jeffrey M; Losordo, Douglas W