Slowed Motor Nerve Conduction Velocity Research Articles

Disruption of dystonin in Schwann cells results in late-onset neuropathy and sensory ataxia.

Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst-expressing cell type(s) for dt phenotypes have not been well characterized. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0-Cre transgenic mice and Dst gene trap mice. First, we assessed the P0-Cre transgene-dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late-onset neuropathy and sensory ataxia. MAIN POINTS: Dystonin (Dst) disruption in Schwann cells results in late-onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.

Swallowing impairment in older adults: association with sensorimotor peripheral nerve function from the Health, Aging and Body Composition study.

The purpose of this study was to examine whether impairments in sensorimotor peripheral nerve function are associated with a higher likelihood of swallowing impairment in older adults. Health, Aging and Body Composition participants (n = 607, age = 75.8 ± 2.7years, 55.8% women, 32.3% black) underwent peripheral nerve testing at Year 4 and 11 with swallowing difficulty assessed at Year 4 and 15. Nerve conduction amplitude and velocity were measured at the peroneal motor nerve. Sensory nerve function was assessed with the vibration detection threshold and monofilament (1.4-g/10-g) testing at the big toe. Symptoms of lower extremity peripheral neuropathy and difficulty swallowing were collected by self-report. Data analysis was performed using a hierarchical approach. Odds ratios (ORs) were estimated using non-conditional logistic regression. At Year 15 108 (17.8%) participants had swallowing impairments. In fully adjusted models, the peripheral nerve impairments associated with swallowing impairment were numbness (OR 4.67; 95%CI 2.24-9.75) and poor motor nerve conduction velocity (OR 2.26; 95%CI 1.08-4.70). Other peripheral nerve impairments were not related to swallowing. The association between slow motor nerve conduction velocity and numbness and a higher likelihood of swallowing difficulties a decade later in our prospective study identifies an important area for further investigation in older adults.

The role of dietary non-heme iron load and peripheral nerve inflammation in the development of peripheral neuropathy (PN) in obese non-diabetic leptin-deficient ob/ob mice

ABSTRACTIntroduction: Here, we investigated inflammatory signs of peripheral nerves in leptin-deficient obese ob/ob mice and the modulating effects of the exogenous iron load.Methods: Ob/ob and ob/+ control mice were fed with high, standard, or low iron diet for four months.Results: We found intraepidermal nerve fiber degeneration in foot skin and low-grade neuropathic abnormalities including mildly slowed motor and compound sensory nerve conduction velocities and low-grade macrophage and T-cell infiltration without overt neuropathology in sciatic nerves of all ob/ob mice. Low dietary iron load caused more pronounced abnormalities than high iron load in ob/ob mice.Discussion: Our data suggest that dietary non-heme iron deficiency may be a modulating factor in the pathogenesis of peripheral neuropathy in obese ob/ob mice with metabolic syndrome. Once the mechanisms can be further elucidated, how low dietary iron augments peripheral nerve degeneration and dysfunction via pro-inflammatory pathways and new therapeutic strategies could be developed.Abbreviations: CMAP: compound muscle action potential; cSNCV: compound sensory nerve conduction velocity; IENFD: intraepidermal nerve fiber density; LDL: low-density lipoprotein; MetS: metabolic syndrome; MNCV: motor conduction velocity; NCV: nerve conduction velocity; PN: peripheral neuropathy; PNS: peripheral nervous system; STZ: streptozotocin; T2D: type 2 diabetes mellitus; TNF alpha: tumor necrosis factor alpha; WHO: World Health Organization

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

BackgroundPrevious studies suggest that dexmedetomidine has a protective effect against local anaesthetic-induced nerve injury in regional nerve blocks. Whether this potentially protective effect exists in the context of diabetes mellitus is unknown. MethodsA diabetic state was established in adult male Sprague–Dawley rats with intraperitoneal injection of streptozotocin. Injections of ropivacaine 0.5%, dexmedetomidine 20 μg kg−1 (alone and in combination), or normal saline (all in 0.2 ml) were made around the sciatic nerve in control and diabetic rats (n=8 per group). The duration of sensory and motor nerve block and the motor nerve conduction velocity (MNCV) were determined. Sciatic nerves were harvested at post-injection day 7 and assessed with light and electron microscopy or used for pro-inflammatory cytokine measurements. ResultsRopivacaine and dexmedetomidine alone or in combination did not produce nerve fibre damage in control non-diabetic rats. In diabetic rats, ropivacaine induced significant nerve fibre damage, which was enhanced by dexmedetomidine. This manifested with slowed MNCV, decreased axon density, and decreased ratio of inner to outer diameter of the myelin sheath (G ratio). Demyelination, axon disappearance, and empty vacuoles were also found using electron microscopy. An associated increase in nerve interleukin-1β and tumour necrosis factor-α was also seen. ConclusionsRopivacaine 0.5% causes significant sciatic nerve injury in diabetic rats that is greatly potentiated by high-dose dexmedetomidine. Although the dose of dexmedetomidine used in this study is considerably higher than that used in clinical practice, our data suggest that further studies to assess ropivacaine (alone and in combination with dexmedetomidine) use for peripheral nerve blockade in diabetic patients are warranted.

Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review

PurposeTo describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. MethodsThe patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. ResultsOne homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. ConclusionIn this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure.

Nerve conduction studies in cases with long-term unintentional exposure to pesticide spraying

Background: Farm workers experience many work-related hazards, including exposure to organophosphorus (OP) compounds during the process of pesticide spraying during their crop season. The recurrent unintentional exposure to OP compounds may lead to motor and sensory nerve neuropathies and also have some delayed neurological sequels. Aims and Objectives: The aims of this study were (1) to find out the toxic effects of OP compound on motor nerve conduction velocity (MNCV) and (2) to compare the MNCV, in selected peripheral nerve (median nerve) of affected population with the normal population. Materials and Methods: A cross-sectional analytical study was conducted by recruiting 60 individuals matched with height, weight, and occupation matched (control group 30 and study group 30). Participants were selected randomly from the outpatient Department of Medical College Hospital with age group between 20 and 40 years, and both sexes were included. The MNCVs were recorded using multichannel polyrite machine. Results: MNCVs were evaluated on median nerves of both the sides. MNCV was recorded on distal stimulation. Our findings show that the motor abnormalities nerve velocities in case of exposed population were significantly less as compared to the controls in tested median nerve. This indicates the presence of abnormalities such as neuropathy in these patients. Conclusion: There was an evidence of peripheral neuropathy to some extent in peripheral nerves as evident by slow MNCVs in median nerve of those farmers who were exposed to the OP pesticide spraying in the farms and its consequent absorption through skin, inhalation, or ingestion as compared to the normal individuals.

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models. Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals. In addition to disease-associated gene expression networks that were restored with ASO treatment, we also identified potential disease biomarkers through transcriptomic profiling. Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy. These results support the use of ASOs as a potential treatment for CMT1A and elucidate potential disease and target engagement biomarkers for use in future clinical trials.

Neuropathy genetics

Charcot-Marie-Tooth disease (CMT) is the most frequent form of hereditary neuropathy. Three genes commonly causing CMT encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). PMP22 duplication causes mainly demyelinating phenotype, known as CMT1A, with slowed motor nerve conduction velocity (MCV). Two distinctive phenotypic subgroups are present in patients with MPZ mutations: one shows preserved MCV and exclusively axonal pathological features, while the other is exclusively demyelinating. Patients with Cx32 mutations show intermediate slowing of MCV. Hereditary neuropathy with liability to pressure palsies (HNPP) usually is associated with a deletion of PMP22, which represents a reciprocal product of CMT1A. Focal thickening of the myelin sheath, known as tomacula, is a characteristic pathological feature in HNPP. Motor conduction studies show age-associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve, suggesting that irreversible axonal damage occurs at entrapment sites in motor nerves in HNPP patients. Familial amyloid polyneuropathy (FAP) is also an important hereditary neuropathy. Although FAP was originally reported in endemic foci of Portugal, Japan, and Sweden, recent progress in diagnostic techniques has revealed that late-onset form of this disease is widely prevalent beyond these conventional endemic foci. Clinicians should consider the possibility of FAP in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis.

P 43 A novel deletion in two exons of the SH3TC2 gene with mutation in the DPYD gene in Charcot-Marie-Tooth disease type 4C

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating neuropathy associated with SH3TC2 mutations. More than 60 variants including nonsense, frameshift, and splice site variants have been reported in families of different ethnic origins as well as in sporadic patients. CMT4C is clinically characterised by early onset neuropathy, cranial nerve involvement and spine deformities. We present a family from Kuwait with a novel deletion of exons 13 and 14 in the SH3TC2 gene combined with a novel homozygous mutation in the DPYD gene. The 40 year-old male patient had foot deformities in infancy and delayed walking after the age of two. He first required walking aids when ten years old and became wheelchair-bound since the age of 18. He had progressive hearing loss over five years. Walking difficulties and wheelchair-dependency were reported in his father as well as a cousin of his mother while there were no symptoms reported in his own siblings and child. Clinical examination showed hypoacusis requiring the use of hearing aids, marked widespread symmetric muscular atrophies with weakness, and areflexia. He could walk a few steps with bilateral support. He had sensory neuropathy with skin atrophy and loss of hair on the lower legs. Spinal examination and X-ray showed slight hyperkyphosis of the thoracic spine but no signs of kyphoscoliosis. Electrophysiological studies showed severe motor and sensory neuropathy with very low amplitudes, markedly prolonged distal motor latencies and very slow motor nerve conduction velocities in the ulnar nerve. Needle electromyography detected fibrillations, positive sharp waves and complex repetitive discharges. High resolution sonography of the median nerve at the wrist showed a few enlarged fascicles with only moderately raised cross sectional area. Creatin kinase levels were constantly and significantly raised. Genetic testing revealed a homozygous large deletion in the SH3TC2 gene comprising exons 13 and 14 that had not been described before. Furthermore a second homozygous novel mutation (c.680+1G>T;p.?) was found in the DPYD gene. The same combination in heterozygous form was detected in the asymptomatic eight year old daughter. This newly described family with CMT4C broadens the spectrum of genetic causes and underlines the clinical variability of phenotypes as the absence of scoliosis does not exclude mutations in the SH3TC2 gene even in patients with severe disabling Azzedine et al., 2006 , Azzedine et al., 2016 , Varley et al., 2015 , Inherited Peripheral Neuropathies Mutation Database, 2016 .

Hereditary neuropathy with liability to pressure palsy in patients under 30 years old: Neurophysiological data and proposed electrodiagnostic criteria.

In young patients with mononeuropathy who lack family history and precipitating factors, hereditary neuropathy with liability to pressure palsy (HNPP) may be a possibility. Our objective is to propose neurophysiological criteria for HNPP in patients <30 years of age. We conducted a national multicenter retrospective clinical and neurophysiological study in patients under 30 with genetically confirmed HNPP. All of the 51 patients included in the study had at least 1 demyelinating pattern in 2 asymptomatic nerves, and 3 abnormalities were found in almost 90%, including slowed motor nerve conduction velocity across the elbow in at least 1 ulnar nerve (97.5%), increased distal motor latency (DML) in at least 1 fibular nerve (95.8%), and increased DML in both median nerves (89%). Age influenced DML slightly only in the fibular nerve. Dissemination of nerve involvement in HNPP incites to perform a complete nerve conduction study. including bilateral ulnar, fibular, and median nerves. Muscle Nerve 57: 217-221, 2018.

Thirty Years Later, Case Closed: A Case of PMP22 Triplication From Anticipation

A 19-year-old woman was brought by her 46-year-old mother for evaluation of a chronic neuropathy present since childhood. The case was described by Dyck et al1Dyck P.J. Karnes J.L. Windebank A.J. Sparks M. Stevens J.C. O'Brien P.C. Minimal pathologic expression of a mutant gene for hereditary motor and sensory neuropathy.Mayo Clin Proc. 1983; 58: 419-425Google Scholar in Mayo Clinic Proceedings in 1983. The daughter had high arches and hammertoes since infancy. During childhood, she had delayed motor milestones with progressive lower- and upper-limb weakness. At the time of her initial evaluation, she had sensory loss over the distal aspect of all extremities, distal greater than proximal weakness, and diffuse areflexia with difficulty walking. Her cerebrospinal fluid protein level was elevated (168 mg/dL; <45 mg/dL is normal). Electromyography and nerve conduction studies showed markedly slowed motor nerve conduction velocities indicative of a primary demyelinating neuropathy. The mother was asymptomatic apart from reduced to absent ankle reflexes. Sural nerve biopsies revealed abnormal Schwann cell morphology with fibroblast proliferation and collagen deposition around nerve fibers (onion bulbs), mild in mother but severe in her daughter, supporting an inherited cause (Figure). The daughter's condition worsened and she developed progressive motor and neuromuscular respiratory weakness, leading to her death at age 53 years, whereas her mother at age 80 years has minimal clinical and electromyographic findings. Modern copy number genetic analysis has now revealed that the mother has a PMP22 duplication whereas her daughter had a triplication of the same region on chromosome 17p11.2 where PMP22 resides. This allowed for the diagnosis of hereditary motor and sensory neuropathy type 1A, also known as Charcot-Marie-Tooth 1A, by triplication. PMP22 duplications are the most common known cause of hereditary neuropathy (∼1:2500 persons in the population). Triplications of PMP22 from incomplete crossover during meiosis of parents with PMP22 duplication have recently been reported by Lupski et al2Liu Pengfei Gelowani V. Zhang F. et al.Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication.Am J Hum Genet. 2014; 94: 462-469Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar as an explanation for why children may be much more severe by genetic anticipation in successive generations. Application of modern DNA sequencing and copy number technologies has helped to close this long-standing previously unsolved case. We acknowledge Peter J. Dyck, MD, and James Klaas, MD, for providing important clinical information related to this case, and Erik Thorland, PhD, for verifying the mutation discussed in the clinical laboratory using CytoScan technology.

Adiponectin, markers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes.

Subclinical inflammation has been implicated in the development of diabetic sensorimotor polyneuropathy (DSPN), but studies using electrophysiological assessment as outcomes are scarce. Therefore, we aimed to investigate associations of biomarkers reflecting different aspects of subclinical inflammation with motor and sensory nerve conduction velocity (NCV) in individuals with diabetes. Motor and sensory NCV was assessed in individuals with recently diagnosed type 2 (n=352) or type 1 diabetes (n=161) from the baseline cohort of the observational German Diabetes Study. NCV sum scores were calculated for median, ulnar and peroneal motor as well as median, ulnar and sural sensory nerves. Associations between inflammation-related biomarkers, DSPN and NCV sum scores were estimated using multiple regression models. In type 2 diabetes, high serum interleukin (IL)-6 was associated with the presence of DSPN and reduced motor NCV. Moreover, higher levels of high-molecular weight (HMW) adiponectin, total adiponectin and their ratio were associated with prevalent DSPN and both diminished motor and sensory NCV, whereas no consistent associations were observed for C-reactive protein, IL18, soluble intercellular adhesion molecule-1 and E-selectin. In type 1 diabetes, only HMW and total adiponectin showed positive associations with motor NCV. Our results point to a link between IL6 and both DSPN and slowed motor NCV in recently diagnosed type 2 diabetes. The reverse associations between adiponectin and NCV in type 1 and type 2 diabetes are intriguing, and further studies should explore whether they may reflect differences in the pathogenesis of DSPN in both diabetes types.

Motor nerve conduction parameters in patients with iron deficiency anemia

Background: Worldwide, iron deficiency anemia (IDA) is the most common nutritional problem. Iron is very essential and has many important functions in brain energy metabolism, neurotransmitter function, and myelin formation. IDA may cause nerve dysfunctions. Aims and Objectives: The purpose of the present study was to investigate the effects of IDA on peripheral motor nerve function. Materials and Methods: A total of 40 individuals (25 females and 15 males) with IDA in the age range of 20-50 years from the Department of Medicine, SRM Medical College, as the study group and 30 participants (20 females and 10 males) without anemia as the control group were enrolled into this cross-sectional study. Patients with history of diabetes mellitus, neuromuscular, metabolic, vasculitic, or rheumatologic diseases and those taking medications that may alter central or peripheral nerve function were excluded from the study. The motor nerve conduction parameters, viz., distal latency, amplitude of compound muscle action potential (CMAP), and motor nerve conduction velocity (MNCV) were recorded bilaterally in median, ulnar, and posterior tibial nerves using standard protocols and settings. Values from patients were compared with those of controls by unpaired student’s t-test and one-way ANOVA. Results: The observations revealed significantly prolonged distal motor latencies, reduced CMAP amplitudes, and slowed MNCV in the peripheral nerves in IDA. Conclusion: The results indicated that the alteration in motor conduction parameters in IDA might be due to various functional and structural changes in peripheral nerves associated with iron deficiency.

Electromyoneurographic findings in patient with congenital muscular dystrophy

Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of inherited muscle disorders defined by early onset of hypotonia and muscle weakness. They are the second most common myopathic cause of floppy infant syndrome, following the group of congenital myopathies. The main CMD are classified by involved protein function and gene in which causative mutations occur. Merosin-negative muscle dystrophy is the most common CMD, characterized by early onset hypotonia, delayed motor milestones, contractures, normal cognitive abilities and diffuse brain white matter changes. Some forms of CMD are characterized by mental retardation, eye involvement, epileptic seizures and structural brain abnormalities. The diagnosis of CMD is based on clinical findings, elevated muscle enzymes, brain imaging, muscle biopsy histology and immunohistochemical staining and molecular genetic testing. The vast majority of patients have myopathic findings on electromyography (EMG). Slowed motor and sensory nerve conduction velocities could be found in patients with merosin deficiency. Electromyography has a significant role in the primary assessment of patients with muscle weakness. Myopathic EMG findings ruled out other causes of floppy infant syndrome and led to a muscle biopsy and focused genetic tests. An associated demyelinating neuropathy could focus the investigation on primary or secondary merosin deficit.

Motor conduction parameters in recently diagnosed and untreated hypothyroidism.

The severity of neuromuscular symptoms and signs in hypothyroidism is known to be related to the duration and degree of hormone deficiency. The present study was aimed to assess whether recently diagnosed and untreated hypothyroidism affects peripheral nervous system. The study included a total of 120 female subjects with age ranging from 20 to 45 years. The motor nerve conduction parameters viz. Distal latency (DL), amplitude of compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) were recorded bilaterally in median, ulnar and posterior tibial nerves using standard protocols and settings. The observations revealed significantly prolonged distal motor latencies, reduced CMAP amplitudes and slowed MNCV in the peripheral nerves in hypothyroid. The results indicated that the alteration in motor conduction parameters in recently diagnosed and untreated hypothyroidism might be due to various functional and structural changes in peripheral nerves associated with deficiency of thyroid hormones.

Intermediate Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

Electrodiagnostic Testing and Histopathologic Changes Confirm Peripheral Nervous System Myelin Abnormalities in the Feline Model of Niemann-Pick Disease Type C

Niemann-Pick disease type C (NPC disease) is an incurable, neurodegenerative, autosomal recessive disease caused by mutations in either the NPC1 or the NPC2 gene. These mutations affect the intracellular trafficking of lipids and cholesterol, resulting in the intralysosomal accumulation of unesterified cholesterol and glycosphingolipids. These abnormalities are associated with clinical ataxia and impaired motor and intellectual development, and death frequently occurs in adolescence. The incidence of peripheral neuropathy in NPC patients is not known. We investigated peripheral nerves in the naturally occurring feline model of NPC disease, which has proven to be critical for understanding both disease pathogenesis and for evaluating experimental therapies. Electrodiagnostic studies revealed significantly slowed motor and sensory nerve conduction velocities in affected cats in the absence of altered M-wave amplitude. Histologic and ultrastructural analyses showed thin myelin sheaths, membranous debris, myelin figures, lipid vacuolization of Schwann cell cytoplasm, and expanded paranodal areas. Axonal degeneration was not identified. There was a shift to small myelinated fibers in affected cats, and there were significant decreases in fiber diameter, axon diameter, and myelin thickness. These changes were similar to those described in the murine NPC disease model and in rare patients in whom nerve biopsy has been performed. Characterization of the demyelinating neuropathy is necessary for evaluating clinical trials that target only the CNS aspects of NPC.

Early Electrodiagnostic Abnormalities in Guillain-Barre Syndrome (P01.200)

Objective: To provide data on early electrodiagnostic (EDX) abnormalities observed in early Guillain-Barre syndrome (GBS). Background GBS is a potentially life-threatening affection requiring early diagnosis and treatment. In this context, relevant EDX criteria are required for the early diagnosis of GBS. Design/Methods: We retrospectively reviewed the clinical and EDX data of GBS patients investigated in our department in whom EDX studies had been performed 7 days or less after the onset of clinical signs. Patients with a previously known polyneuropathy or a condition such as diabetes, alcoholism, and chronic kidney disease, were excluded. Motor nerve conduction velocities (MNCV), sensory nerve conduction velocities (SNCV), distal motor latencies (DML), sensory nerve action potential (SNAP) amplitudes, compound muscle action potential (CMAP) amplitudes, H reflexes, F waves, conduction block and temporal dispersion were investigated in all patients. Results: Forty patients were included in our study. Ninety-two percents of patients had abnormal H reflexes, 77% had slowed MNCV, 67% had delayed DML, 61% had abnormal F waves, 52% had reduced CMAP amplitude, and 50% had reduced SNAP amplitude. Conduction blocks were observed in 42% of patients, and temporal dispersion in 30%. When combining all EDX parameters, abnormalities were observed in 97% of patients with early GBS. Conclusions: Exhaustive EDX studies in patients with GBS at the early stage are crucial for diagnosis and management of this condition. The H reflex is the most sensitive test for early GBS, followed by slowed MNCV, delayed DML, and abnormal F waves. Disclosure: Dr. Chanson has nothing to disclose. Dr. De Seze has received personal compensation for activities with Bayer Schering, Biogen Idec, LFB, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience.Dr. De Seze has received personal compensation in an editorial capacity for Elsevier. Dr. Echaniz-Laguna has nothing to disclose.

Phenotypic characterization of hypomyelination and congenital cataract

To define the clinical and laboratory findings in a novel autosomal recessive white matter disorder called hypomyelination and congenital cataract, recently found to be caused by a deficiency of a membrane protein, hyccin, encoded by the DRCTNNB1A gene located on chromosome 7p21.3-p15.3. We performed neurological examination, neurophysiological, neuroimaging, and neuropathological studies on sural nerve biopsy in 10 hypomyelination and congenital cataract patients from 5 unrelated families. The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation. Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times. Neuroimaging studies demonstrated a diffuse supratentorial hypomyelination, with in some patients, additional areas of more prominent signal change in the frontal region. Sural nerve biopsy showed a slight-to-severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin. Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous system.

Comparison of CMT1A and CMT2: similarities and differences

To evaluate the clinical and electrophysiological similarities and differences between two large groups of patients with Charcot-Marie-Tooth disease, i.e. CMT1A and CMT2, we performed a post hoc comparison of clinical and electrophysiological data. Most CMT1A and CMT2 patients had the classical CMT phenotype. Age of onset was significantly later in CMT2. Total areflexia was present in approximately half of the CMT1A patients whereas it was rare in CMT2. Foot deformities and weakness of knee extensor and foot dorsal flexor muscles were more frequent in CMT1A. Median nerve motor nerve conduction velocities (MNCV) were always less than 38 m/s in CMT1A patients, whereas this was also the case in 16% of the CMT2 patients. Sensory nerve conduction velocities showed less overlap. In both CMT1A and CMT2 CMAP and SNAP amplitudes were often reduced or not obtainable in the legs. In CMT1A, SNAP amplitude was more reduced and SNAP duration more prolonged than in CMT2. We conclude that there are no robust clinical signs or symptoms that differentiate between CMT1A and CMT2 patients. Electrodiagnostical studies show a length-dependent motor and sensory axonal dysfunction in both CMT-types. Additional SNAP and SNCV evaluation may be helpful in focusing molecular genetic analysis in the occasional case of CMT2 showing slow motor nerve conduction velocities overlapping with CMT1A values. The reduction of CMAP and SNAP amplitudes in CMT1A is probably a combined effect of demyelination and axonal dysfunction.