Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.

BACKGROUND AND PURPOSE: Data are reported from the Italian CMT Registry. METHODS: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. RESULTS: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT. CONCLUSIONS: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.

Prevalence and incidence of neuromuscular conditions in the UK between 2000 and 2019: A retrospective study using primary care data.

BACKGROUND: In the UK, large-scale electronic primary care datasets can provide up-to-date, accurate epidemiological information on rarer diseases, where specialist diagnoses from hospital discharges and clinic letters are generally well recorded and electronically searchable. Current estimates of the number of people living with neuromuscular disease (NMD) have largely been based on secondary care data sources and lacked direct denominators. OBJECTIVE: To estimate trends in the recording of neuromuscular disease in UK primary care between 2000-2019. METHODS: The Clinical Practice Research Datalink (CPRD) database was searched electronically to estimate incidence and prevalence rates (per 100,000) for a range of NMDs in each year. To compare trends over time, rates were age standardised to the most recent CPRD population (2019). RESULTS: Approximately 13 million patients were actively registered in each year. By 2019, 28,230 active patients had ever received a NMD diagnosis (223.6), which was higher among males (239.0) than females (208.3). The most common classifications were Guillain-Barre syndrome (40.1), myasthenia gravis (33.7), muscular dystrophy (29.5), Charcot-Marie-Tooth (29.5) and inflammatory myopathies (25.0). Since 2000, overall prevalence grew by 63%, with the largest increases seen at older ages (≥65-years). However, overall incidence remained constant, though myasthenia gravis incidence has risen steadily since 2008, while new cases of muscular dystrophy fell over the same period. CONCLUSIONS: Lifetime recording of many NMDs on primary care records exceed current estimates of people living with these conditions; these are important data for health service and care planning. Temporal trends suggest this number is steadily increasing, and while this may partially be due to better recording, it cannot be simply explained by new cases, as incidence remained constant. The increase in prevalence among older ages suggests increases in life expectancy among those living with NMDs may have occurred.

Functional results and quality of life after joint preserving or sacrificing surgery in Charcot-Marie-Tooth foot deformities.

INTRODUCTION: The purpose of this study was to assess the functional results, quality of life, and complications in two groups of Charcot-Marie-Tooth (CMT) patients according to the type of surgical operations, joint preserving, or joint sacrificing surgery. METHODS: Fifty-two feet in forty-six patients with CMT who had undergone surgical deformity correction were divided into two groups based on the main surgical procedure for the correction: Class I (joint preserving surgery) and class II (joint sacrificing surgery). Foot ankle disability index (FADI) and short form 12 version 2 (SF12V2) were documented pre-operative and 12 months post-operative. The complications of both groups were monitored with a mean follow-up time of 20.5 months (range, 13-71.5). RESULTS: After surgical treatment, FADI scores showed differences (p=0.005) between both groups. The functional improvement was 29 (20-46; p<0.001) in class I and 10 (2-36; p=0.001) in class II. The patients in both groups acquired a better quality of life as demonstrated in physical component summary of SF12 but without statistically difference. Three feet needed reintervention in class I (two for cavovarus recurrence and one for hallux flexus) at the end of follow-up. In contrast, five feet needed a new operation for cavovarus recurrence, claw toes recurrence, and ankle osteoarthritis after the progression of the condition. DISCUSSION: An early surgical intervention to neutralize the deforming forces in CMT patients could be a useful strategy to delay or prevent the need for extensive reconstruction and potential future complications. CONCLUSION: Based on the type of surgical intervention in CMT patients, the joint preserving surgery in addition to soft tissue balancing procedures obtained better functional outcomes and lower rate of complications when compared to the group of joint sacrificing surgery.

Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2.

Mutations in TRPV4 are linked to a group of clinically distinct, but also overlapping axonal neuropathies, including Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. The incidence of TRPV4-linked cases ranges from 0 to 7% in overall axonal neuropathy cohorts from European countries and Australia. However, the data from other areas remain largely unknown. In this study, we screened for TRPV4 mutations in a well-characterized USA cohort of 62 unrelated CMT2 patients without mutations in MFN2, GARS, NEFL, and GDAP1. All 15 coding exons of TRPV4 were analyzed by Sanger-sequencing. Clinical features of TRPV4-linked patients were compared with those lacking TRPV4 mutations. We identified two TRPV4 mutations in two patients. A TRPV4-R316C was identified in a patient with family history, while a TRPV4-R269C in an apparently sporadic case. Marked clinical variations were observed in the patients with TRPV4 mutations. Our data suggest that TRPV4-linked CMT2C accounts for a sizable fraction in this USA cohort of CMT2; it has a wide phenotypic spectrum, and vocal cord paralysis, scapular weakness and wasting, skeletal dysplasia, and hearing loss are suggestive signs for TRPV4-linked CMT2C.

Prevalence and orthopedic management of foot and ankle deformities in Charcot-Marie-Tooth disease.

INTRODUCTION: Foot deformities are frequent complications in Charcot-Marie-Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. METHODS: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. RESULTS: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. DISCUSSION: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57: 255-259, 2018.

Hereditary neuropathies: An update.

Hereditary neuropathies are the most common inherited neuromuscular diseases. Charcot-Marie-Tooth (CMT) disease represents the most common form with an average prevalence ranging from 1/2500 to 1/1200, depending on the studies. To date and with the advances of the latest generation sequencing, more than 80 genes have been identified. Although the common clinical phenotype comprises a progressive distal muscle weakness and sensory loss, foot deformities and decreased or absent tendon reflexes, clinical and electrophysiological phenotypes exhibit great variability. Moreover, atypical phenotypes are arising, overlapping with spastic paraplegia, hereditary sensory neuropathies or amyotrophic lateral sclerosis. The causative genes are involved in various biological processes such as myelin development and maintenance, biosynthesis and degradation of proteins, neuronal structural maintenance, axonal transport, endocytosis, membrane dynamics, ion-channel function and the mitochondrial network. An accurate genetic diagnosis is important for appropriate genetic counselling and treatment options. Therapeutic advances, particularly small interfering RNA therapy, are encouraging in hereditary transthyretin amyloid neuropathy.

Idiopathic Hypereosinophilic Syndrome With Cutaneous Manifestations and Flame Figures: A Spectrum of Eosinophilic Dermatoses Whose Features Overlap With Wells' Syndrome.

IMPORTANCE: Wells syndrome (WS) (eosinophilic cellulitis) is an uncommon eosinophilic dermatitis that has been rarely described in association with, but distinct from, hypereosinophilic syndrome (HES). OBSERVATIONS: We report a case of an eosinophilic dermatosis with flame figures in association with idiopathic HES, manifested by inflammatory myocarditis, asthma, and peripheral blood eosinophilia. CONCLUSIONS AND RELEVANCE: The diagnoses of WS and HES, rather than being distinct findings, may represent 2 entities on a spectrum of hypereosinophilic diseases. The diagnosis of WS should be made with caution and should prompt a thorough investigation that includes a work-up for a systemic eosinophilic disorder.

Genetic epidemiology of Charcot-Marie-Tooth disease.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The frequency of different CMT genotypes has been estimated in clinic populations, but prevalence data from the general population is lacking. Point mutations in the mitofusin 2 (MFN2) gene has been identified exclusively in Charcot-Marie-Tooth disease type 2 (CMT2), and in a single family with intermediate CMT. MFN2 point mutations are probably the most common cause of CMT2. The CMT phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P(0) ) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. X-linked Charcot-Marie Tooth disease (CMTX) is caused by mutations in the connexin32 (cx32) gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions. AIMS: Estimate prevalence of CMT. Estimate frequency of Peripheral Myelin Protein 22 (PMP22) duplication and point mutations, insertions and deletions in Cx32, Early growth response 2 (EGR2), MFN2, MPZ, PMP22 and Small integral membrane protein of lysosome/late endosome (SIMPLE) genes. Description of novel mutations in Cx32, MFN2 and MPZ. Description of de novo mutations in MFN2. MATERIAL AND METHODS: Our population based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist, and classified clinically, neurophysiologically and genetically. Two-hundred and thirty-two consecutive unselected and unrelated CMT families with available DNA from all regions in Norway were included in the MFN2 study. We screened for point mutations in the MFN2 gene. We describe four novel mutations, two in the connexin32 gene and two in the MPZ gene. RESULTS: A total of 245 affected from 116 CMT families from the general population of eastern Akershus county were included in the genetic epidemiological survey. In the general population 1 per 1214 persons (95% CI 1062-1366) has CMT. Charcot-Marie-Tooth disease type 1 (CMT1), CMT2 and intermediate CMT were found in 48.2%, 49.4% and 2.4% of the families, respectively. A mutation in the investigated genes was found in 27.2% of the CMT families and in 28.6% of the affected. The prevalence of the PMP22 duplication and mutations in the Cx32, MPZ and MFN2 genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations, insertions or deletions in the EGR2, PMP22 or SIMPLE genes. Four known and three novel mitofusin 2 (MFN2) point mutations in 8 unrelated Norwegian CMT families were identified. The novel point mutations were not found in 100 healthy controls. This corresponds to 3.4% (8/232) of CMT families having point mutations in MFN2. The phenotypes were compatible with CMT1 in two families, CMT2 in four families, intermediate CMT in one family and distal hereditary motor neuronopathy (dHMN) in one family. A point mutation in the MFN2 gene was found in 2.3% of CMT1, 5.5% of CMT2, 12.5% of intermediate CMT and 6.7% of dHMN families. Two novel missense mutations in the MPZ gene were identified. Family 1 had a c.368G>A (Gly123Asp) transition while family 2 and 3 had a c.103G>A (Asp35Asn) transition. The affected in family 1 had early onset and severe symptoms compatible with Dejerine-Sottas syndrome (DSS), while affected in family 2 and 3 had late onset, milder symptoms and axonal neuropathy compatible with CMT2. Two novel connexin32 mutations that cause early onset X-linked CMT were identified. Family 1 had a deletion c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247 while family 2 had a c.536G>A (Cys179Tyr) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade and the nerve conduction velocities were in the intermediate range. DISCUSSION: Charcot-Marie-Tooth disease is the most common inherited neuropathy. At present 47 hereditary neuropathy genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is likely that at least 30-50 CMT genes are yet to be identified. The identified known and novel point mutations in the MFN2 gene expand the clinical spectrum from CMT2 and intermediate CMT to also include possibly CMT1 and the dHMN phenotypes. Thus, genetic analyses of the MFN2 gene should not be restricted to persons with CMT2. The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and DSS, while milder changes cause the phenotypes CMT1 and CMT2. The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode. CONCLUSION: Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 1214. CMT1 and CMT2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de novo mutations in CMT families was estimated to be 22.7%. Genotype- phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described. Two novel phenotypes were ascribed to the MFN2 gene, however further studies are needed to confirm that MFN2 mutations can cause CMT1 and dHMN.

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.

Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIAA1985, was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2(DeltaEx1/DeltaEx1) animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2(DeltaEx1/DeltaEx1) animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.

Late onset axonal Charcot-Marie-Tooth phenotype caused by a novel myelin protein zero mutation.

A late onset axonal Charcot-Marie-Tooth phenotype is described, resulting from a novel mutation in the myelin protein zero (MPZ) gene. Comparative computer modelling of the three dimensional structure of the MPZ protein predicts that this mutation does not cause a significant structural change. The primary axonal disease process in these patients points to a function of MPZ in maintenance of the myelinated axons, apart from securing stability of the myelin layer.

Quality of life in patients with Charcot-Marie-Tooth disease.

The authors evaluated quality of life in Charcot-Marie-Tooth disease by administering the Medical Outcome Study Short Form-36 (SF-36) questionnaire to 121 Italian patients. Patients scored lower on all of the SF-36 scales compared with Italian normative data. Scores were lower in nonworking vs working patients, women vs men, and older vs younger patients, but not between patients with demyelinating vs axonal forms or between patients who had undergone orthopedic foot surgery vs those who had not.

Hearing loss as the first feature of late-onset axonal CMT disease due to a novel P0 mutation.

A Czech family with three individuals carrying a novel mutation, 290 A-->T (Glu97Val), in the myelin protein zero gene (P0) is reported. The two eldest carriers developed progressive sensorineural hearing loss and abnormal pupillary reaction at age 18. These preceded the onset of the classic signs of Charcot-Marie-Tooth disease (CMT) by more than a decade. Sural nerve biopsy and nerve conduction studies were compatible with the axonal type of CMT. The authors show that progressive hearing loss can be the first symptom in P0 mutation carriers.

Vincristine-induced neuropathy as the initial presentation of charcot-marie-tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE: After profound peripheral neurotoxicity during induction chemotherapy for acute lymphoblastic leukemia (ALL) in the index patient with Charcot-Marie-Tooth hereditary neuropathy (CMT), study coordinators of the Pediatric Oncology Group (POG) front-line ALL protocols reviewed patient registrations to identify any other patients with possible CMT. The goal was to provide preliminary information about patients with undiagnosed CMT who develop ALL. PATIENTS AND METHODS: Five children with ALL who were enrolled in POG B-precursor or T-cell ALL protocols from 1994 to 1999 subsequently were determined to have CMT hereditary neuropathy. Their clinical presentations and treatment records were reviewed in detail. Records of all patients entered on POG 9201 (lesser-risk ALL) were reviewed to identify all cases of significant vincristine toxicity noted in the first 6 months of treatment. RESULTS: The five identified patients all had substantial peripheral neurotoxicity that required alteration in treatment and/or orthopedic/physical therapy evaluation and follow-up. The POG 9201 review identified 25 of 686 patients (3.6%) with significant peripheral neuropathy. Three of 25 were diagnosed with CMT; the others have had no testing reported. CONCLUSIONS: A family history of CMT or other peripheral neuropathy should be sought at the time of diagnosis of ALL. Testing for CMT should be considered in any child with substantial vincristine-induced peripheral neurotoxicity. Treatment of such patients must be individualized. Testing of all patients with significant peripheral neuropathy would be necessary to determine the percentage of such neuropathy explained by underlying CMT.

[Clinical phenotype of Charcot-Marie-Tooth disease (CMT) and familial amyloid polyneuropathy (FAP)].

A nationwide study of CMT and FAP has been performed. In FAP TTR Met30 families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms, consistent with pathological findings. In contrast, families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction. Demyelinating versus axonal phenotypes are major issues in CMT. CMT1A duplication caused mainly demyelinating phenotype, while axonal features were variably present. In CMT1B, two distinctive phenotypic subgroups were present: one showed exclusively axonal features; and another was exclusively demyelinating. CMTX showed intermediate slowing of MCV, predominantly axonal features, and relatively mild demyelinating pathology. Differing from CMT1B, these axonal and demyelinating features were concomitantly present in individual patients in variable extent. Median nerve MCVs were well maintained independently of age, disease duration, and severity of clinical and pathologic abnormalities. Amplitude of CMAPs was correlated significantly with distal muscle strength, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. CMT patients with demyelinating and/or axonal features, together with FAP patients with axonal feature and scattered distribution, are supposed to increase according to the development of genetic diagnosis for hereditary neuropathy that verifies late-onset, de novo and asymptomatic patients.

[A family of early childhood-onset Charcot-Marie-Tooth disease type 2].

We reported a man and his son with Charcot-Marie-Tooth disease (CMT) type 2. Their age at onset was about 5 years. Their clinical examinations revealed muscle atrophy and weakness of both distal lower limbs, foot-drop, a reduction of the reflex in both Achilles tendons and sensory impairment of the glove and stocking type. Nerve conduction studies revealed remarkably low amplitude of compound muscle action potential compared to conduction velocity. The nerve biopsy of their sural nerves revealed loss of large myelinated fiber. We presumed that the clinical features of their disease were compatible with CMT2A or 2B. DNA analysis of our family members performed with microsatellite markers linked to the candidate regions of CMT2A and 2B, did not show apparent positive results. We speculate that this family was a novel gene locus of CMT type 2.

Peripheral neuropathies of childhood.

This article has provided a brief overview of the most common inherited and acquired peripheral nerve diseases encountered in childhood. The diagnostic approach of peripheral neuropathies in children often relies on some combination of careful history taking, physical examination findings, a careful determination of family history, electrodiagnostic studies, molecular genetic studies, sural nerve biopsy, and occasionally metabolic laboratory studies. Although pediatric mononeuropathies may have different causes than those observed in adults, the clinical presentations, diagnostic evaluation, and management of mononeuropathies are frequently similar in adults and children. Encouraging progress is being made in the management of acute inflammatory demyelinating polyneuropathy (AIDP), which is the most common acquired neuropathy of childhood. Rapid advances in molecular genetics over the past decade have had a significant impact on our diagnostic approach to hereditary motor sensory neuropathy in particular. In the future it is likely that the sequencing of genes, characterization of protein structure and function, and further elucidation of pathophysiology will have significant impacts on the treatment of many inherited peripheral neuropathies of childhood.

Inherited early onset severe axonal polyneuropathy with respiratory failure and autonomic involvement.

We report dizygotic twins who first presented at the age of 6 months with severe diaphragmatic weakness and marked abnormalities of autonomic function. A female sibling had earlier died from a disorder with similar clinical features. Both twins had a severe axonal polyneuropathy with generalized hypotonic limb weakness together with diaphragmatic paralysis resulting in respiratory failure. Associated features were tachycardia, increased sweating, elevated body temperature, and hypertension, suggesting autonomic dysfunction. Nerve conduction studies indicated an axonopathy affecting both motor and sensory nerve fibres. Sural nerve biopsy in one twin performed at the age of 7 months showed a reduced population of myelinated nerve fibres, particularly those of larger diameter, with no indication of hypomyelination, demyelination or axonal atrophy. Examples of axonal forms of hereditary motor and sensory neuropathy (HMSN) with onset in infancy are very rare and autonomic involvement associated with this condition has not so far been described.

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.

Doença de Charcot-Marie-Tooth / Charcot-Marie-Tooth disease

A doença de Charcot-Marie-Tooth (CMT) é a mais frequente das doenças neuromusculares hereditárias. Várias casuísticas mundiais confirmam esta alta prevalência. O tipo I (desmielinizante) é mais frequente do que o tipo II (axonal), porém em alguns países esta relaçäo se inverte. Além da herança autossômica dominante (mais comum) e da autossômica recessiva há famílias de hereditariedade ligada ao cromossomo X, dominante ou recessiva. Recentemente verificou-se que a maoiria das famílias de doença de CMT I dominante está ligada ao cromossomo 17; algumas poucas famílias têm ligaçäo com o cromossomo I e em algumas näo se descobriu a ligaçäo cromossômica. Apesar do tipo I ser desmielinizante alguns pensam estar a lesäo inicial no axônio. Entretando, parece que há uma alteraçäo da proteína PMP22 mapeada na regiäo da duplicaçäo da doença de CMT I. Este gen seria responsável por desencadeamento da desmielinizaçäo e remielinizaçäo deste tipo de doença