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1.
Science ; 373(6559): 1156-1161, 2021 Sep 03.
Article in English | MEDLINE | ID: mdl-34516839

ABSTRACT

Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type­specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.


Subject(s)
Charcot-Marie-Tooth Disease/metabolism , Glycine-tRNA Ligase/metabolism , Protein Serine-Threonine Kinases/metabolism , Stress, Physiological , Tyrosine-tRNA Ligase/metabolism , Activating Transcription Factor 4/genetics , Activating Transcription Factor 4/metabolism , Animals , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Disease Models, Animal , Female , Gene Deletion , Genes, Dominant , Glycine-tRNA Ligase/genetics , Male , Mice , Mice, Mutant Strains , Motor Neurons/physiology , Protein Biosynthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Spinal Cord/physiopathology , Stress, Physiological/drug effects , Stress, Physiological/genetics , Stress, Physiological/physiology , Transcriptome , Tyrosine-tRNA Ligase/genetics
3.
Brain Res ; 1729: 146625, 2020 02 15.
Article in English | MEDLINE | ID: mdl-31899213

ABSTRACT

There has been considerable progress in developing treatments for Charcot-Marie-Tooth disease with a number of therapies either completing or nearing clinical trials. In the case of CMT1A, the commonest subtype of CMT, there have been more than five randomised, double blind placebo-controlled trials. Although these trials were negative for the primary outcome measure, considerable lessons have been learnt leading to the collection of large prospective natural history data sets with which to inform future trial design as well as the development of new and sensitive outcome measures. In this review we summarise the difficulties of conducting clinical trials in a slowly progressive disease such as CMT1A and the requirement for sensitive, reproducible and clinically relevant outcome measures. We summarise the current array of CMT specific outcome measures subdivided into clinical outcome measures, functional outcome measures, patient reported outcome measures, biomarkers of disease burden and treatment specific biomarkers of target engagement. Although there is now an array of CMT specific outcome measures, which collectively incorporate clinically relevant, sensitive and reproducible outputs, a single outcome measure incorporating all three qualities remains elusive.


Subject(s)
Charcot-Marie-Tooth Disease/therapy , Clinical Trials as Topic , Outcome Assessment, Health Care , Biomarkers/analysis , Humans
4.
J Neurol Sci ; 408: 116527, 2020 Jan 15.
Article in English | MEDLINE | ID: mdl-31677558

ABSTRACT

BACKGROUND: Pre-treatment screening for IgA deficiency and close monitoring of full blood count(FBC) and renal function is recommended with intravenous immunoglobulin(IVIg) therapy in neurological diseases. AIMS: To examine the frequency of biochemically defined and clinically significant episodes of treatment associated haemolysis, neutropenia, thrombocytopenia and acute kidney injury(AKI) in a cohort of patients on maintenance Immunoglobulin(Ig) therapy for inflammatory neuropathy. METHODS: A retrospective review of routine blood monitoring in patients from two UK specialist peripheral nerve centres. Accepted definitions for clinically and biochemically significant haemolysis, neutropenia, thrombocytopenia and AKI were used. RESULTS: 1919 infusion episodes in 90 patients were analysed. Age(mean(S.D)) = 58.09(14.4)years, 63% male, 72% CIDP(28% MMN), 97% IVIg(3% SCIg). Dose = 1.57(0.79)g/kg/month or 97.1(37.3)g/infusion, frequency:3.9(1.4) weeks. Relative IgA deficiency was noted in 2 individuals (prevalence:2.2%, 95%C.I.:0-5.2) who received a combined total of 38 infusions(3800 g IVIg) without adverse event. No clinically significant episodes of haemolysis, neutropenia, thrombocytopenia or AKI occurred in relation to treatment. An asymptomatic drop>10 g/L haemoglobin(Hb) occurred in 3.5%(95%CI:2.7-4.3) of treatment episodes in 38 individuals, mean reduction:17.7(7.4)g/L; lowest Hb:86 g/L. Lower pre-treatment haemoglobin correlated with risk of recurrent Ig-related drop(p:0.007). Two patients with chronic renal failure(stage 1 and 3) received 28(IV) and 104(SC) infusions respectively(6416 g) without impact on estimated glomerular filtration rate(eGFR). CONCLUSIONS: No clinically significant Ig-related episodes of haemolysis or AKI were identified in this representative cohort. This suggests that routine monitoring is not essential in long-term Ig use but should be considered when clinically indicated.


Subject(s)
Drug Monitoring/methods , Immunoglobulins, Intravenous/blood , Immunoglobulins, Intravenous/therapeutic use , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/blood , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Drug Monitoring/trends , Female , Humans , Male , Middle Aged , Polyradiculoneuropathy/blood , Polyradiculoneuropathy/diagnosis , Polyradiculoneuropathy/drug therapy , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Retrospective Studies , Young Adult
5.
Hum Mol Genet ; 28(21): 3528-3542, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31411673

ABSTRACT

X-linked Charcot-Marie-Tooth disease (CMT1X), one of the commonest forms of inherited demyelinating neuropathy, results from GJB1 gene mutations causing loss of function of the gap junction protein connexin32 (Cx32). The aim of this study was to examine whether delayed gene replacement therapy after the onset of peripheral neuropathy can provide a therapeutic benefit in the Gjb1-null/Cx32 knockout model of CMT1X. After delivery of the LV-Mpz.GJB1 lentiviral vector by a single lumbar intrathecal injection into 6-month-old Gjb1-null mice, we confirmed expression of Cx32 in lumbar roots and sciatic nerves correctly localized at the paranodal myelin areas. Gjb1-null mice treated with LV-Mpz.GJB1 compared with LV-Mpz.Egfp (mock) vector at the age of 6 months showed improved motor performance at 8 and 10 months. Furthermore, treated mice showed increased sciatic nerve conduction velocities, improvement of myelination and reduced inflammation in lumbar roots and peripheral nerves at 10 months of age, along with enhanced quadriceps muscle innervation. Plasma neurofilament light (NEFL) levels, a clinically relevant biomarker, were also ameliorated in fully treated mice. Intrathecal gene delivery after the onset of peripheral neuropathy offers a significant therapeutic benefit in this disease model, providing a proof of principle for treating patients with CMT1X at different ages.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/therapy , Connexins/genetics , Genetic Therapy , Animals , Charcot-Marie-Tooth Disease/metabolism , Charcot-Marie-Tooth Disease/pathology , Connexins/metabolism , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin Sheath/metabolism , Spinal Nerve Roots/metabolism , Spinal Nerve Roots/pathology , Gap Junction beta-1 Protein
6.
J Neuromuscul Dis ; 6(2): 267-270, 2019.
Article in English | MEDLINE | ID: mdl-30856118

ABSTRACT

Here we describe a patient with genetically confirmed ATTR, a family history of the disease and histological confirmation following carpal tunnel release surgery but no other manifestations. The first major neurological or systemic manifestation was cauda equina syndrome with ATTR deposits contributing to lumbar spinal stenosis. Recent gene therapy trials showed improvement in the neuropathy in TTR amyloidosis. This case highlights the need for awareness of the heterogeneous neurological phenotype seen in ATTR to aid earlier diagnosis especially now that disease modifying therapies are available.


Subject(s)
Amyloid Neuropathies, Familial/complications , Spinal Stenosis/etiology , Adult , Carpal Tunnel Syndrome/etiology , Female , Humans , Lumbosacral Region , Middle Aged
7.
Neuromuscul Disord ; 28(9): 757-765, 2018 09.
Article in English | MEDLINE | ID: mdl-30072201

ABSTRACT

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable chronic disorder of the peripheral nervous system. We retrospectively studied 30 children with a suspected diagnosis of CIDP. The diagnosis of CIDP was compared against the childhood CIDP revised diagnostic criteria 2000. Of the 30 children, five did not meet the criteria and four others met the criteria but subsequently had alternative diagnosis, leaving a total of 21 children (12 male) with CIDP as the final diagnosis. Thirteen children presented with chronic symptom-onset (>8 weeks). The majority presented with gait difficulties or pain in legs (n = 16). 12 children (57%) met the neurophysiological criteria and 18/19 (94%) met the cerebrospinal fluid criteria. Nerve biopsy was suggestive in 3/9 (33%), with magnetic resonance imaging supportive in 9/20 (45%). Twenty-one children received immuno-modulatory treatment at first presentation, of which majority (n = 19, 90%) received IVIG (immunoglobulin) monotherapy with 13 (68%) showing a good response. 8 children received second line treatment with either IVIG or steroids or plasmapharesis (PE) and 4 needed other immune-modulatory agents. During a median follow-up of 3.6 years, 9 (43%) had a monophasic course and 12 (57%) had a relapsing-remitting course. At last paediatric follow up 7 (33%) were off all treatment, 9 (43%) left with no or minimal residual disability and 6 (28%) children were walking with assistance (n = 3) or were non-ambulant (n = 3). Our review highlights challenges in the diagnosis and management of paediatric CIDP. It also confirms that certain metabolic disorders may mimic CIDP.


Subject(s)
Gait/physiology , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Plasmapheresis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Adolescent , Child , Child, Preschool , Disease Progression , Female , Humans , Magnetic Resonance Imaging , Male , Neural Conduction/physiology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/physiopathology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/therapy , Retrospective Studies , Treatment Outcome
8.
Eur J Neurol ; 25(1): 154-163, 2018 01.
Article in English | MEDLINE | ID: mdl-29029362

ABSTRACT

BACKGROUND AND PURPOSE: Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. METHODS: We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. RESULTS: The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. CONCLUSIONS: Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration.


Subject(s)
DNA-Binding Proteins/genetics , Heat-Shock Proteins/genetics , Hereditary Sensory and Motor Neuropathy/genetics , Protein Serine-Threonine Kinases/genetics , Adult , Age of Onset , Alternative Splicing , Biopsy , Disease Progression , Female , Hereditary Sensory and Motor Neuropathy/diagnostic imaging , Hereditary Sensory and Motor Neuropathy/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Molecular Chaperones , Muscle, Skeletal/pathology , Neural Conduction , Pedigree , RNA/metabolism , TDP-43 Proteinopathies/genetics
9.
Eur J Neurol ; 23(10): 1566-71, 2016 10.
Article in English | MEDLINE | ID: mdl-27412484

ABSTRACT

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. METHODS: Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency (DML), motor (MNCV) and sensory (SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot-Marie-Tooth Examination Score (CMTES). RESULTS: NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. CONCLUSIONS: This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients.


Subject(s)
Action Potentials/physiology , Charcot-Marie-Tooth Disease/physiopathology , Neural Conduction/physiology , Adolescent , Adult , Aged , Female , Humans , Italy , Male , Middle Aged , Young Adult
10.
J Neurol Neurosurg Psychiatry ; 87(6): 620-7, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26243339

ABSTRACT

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group. METHODS: We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset. RESULTS: Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used. CONCLUSION: The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history.


Subject(s)
Amyloid Neuropathies, Familial/diagnosis , Peripheral Nervous System Diseases/diagnosis , Adenine , Adult , Aged , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/physiopathology , Cohort Studies , DNA Mutational Analysis , Disease Progression , Female , Genes, Dominant , Humans , Male , Middle Aged , Mutation, Missense , Neural Conduction/physiology , Neurologic Examination , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/physiopathology , Phenotype , Prealbumin/genetics , Retrospective Studies , Tyrosine/genetics
11.
Semin Neurol ; 35(4): 407-23, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26502764

ABSTRACT

Hereditary neuropathies (HNs) are among the most common inherited neurologic disorders and are diverse both clinically and genetically. Recent genetic advances have contributed to a rapid expansion of identifiable causes of HN and have broadened the phenotypic spectrum associated with many of the causative mutations. The underlying molecular pathways of disease have also been better delineated, leading to the promise for potential treatments. This chapter reviews the clinical and biological aspects of the common causes of HN and addresses the challenges of approaching the diagnostic workup of these conditions in a rapidly evolving genetic landscape.


Subject(s)
Genetic Predisposition to Disease , Peripheral Nervous System Diseases/genetics , Adolescent , Child, Preschool , Female , Humans , Male , Neural Conduction/genetics , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology
12.
Eur J Neurol ; 22(12): 1556-63, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26227902

ABSTRACT

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive-to-change outcome measures (OMs) are urgently needed. METHODS: The relative responsiveness of clinical scales of the Italian-UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness). RESULTS: Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM -0.31 and -0.38, respectively). Amongst the other measures, the nine-hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28). CONCLUSIONS: Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients.


Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Exercise Test/methods , Outcome Assessment, Health Care/methods , Adult , Charcot-Marie-Tooth Disease/drug therapy , Clinical Trials as Topic , Exercise Test/standards , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care/standards
13.
Neuromuscul Disord ; 25(7): 589-92, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25958339

ABSTRACT

We report a rare case of myofasciitis and meningitis with deafness caused by systemic enterovirus infection in the setting of hypogammaglobulinaemia induced by rituximab. Whilst effective and generally safe, anti- CD 20 antibody therapy is increasingly recognised to result in unusual infectious complications to be considered in a treated patient presenting with neurological symptoms. These cases may pose diagnostic difficulties and can have atypical presentations. We present this rare complication of rituximab therapy, with histopathological confirmation of myofasciitis. In the older literature, enterovirus associated myofasciitis may have erroneously been termed dermatomyositis and we review the literature to demonstrate this important nosological point.


Subject(s)
Antineoplastic Agents/adverse effects , Enterovirus Infections/etiology , Fasciitis/etiology , Meningitis, Viral/etiology , Myositis/etiology , Rituximab/adverse effects , Adult , Antineoplastic Agents/therapeutic use , Deafness/etiology , Deafness/pathology , Enterovirus Infections/pathology , Enterovirus Infections/physiopathology , Enterovirus Infections/therapy , Fasciitis/pathology , Fasciitis/therapy , Humans , Lymphoma, Follicular/drug therapy , Male , Meningitis, Viral/pathology , Meningitis, Viral/therapy , Muscle, Skeletal/pathology , Myositis/pathology , Myositis/therapy , Rituximab/therapeutic use
14.
Neuromuscul Disord ; 25(6): 511-5, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25819286

ABSTRACT

Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment.


Subject(s)
Amyloid Neuropathies, Familial/pathology , Amyloid Neuropathies, Familial/physiopathology , Heart Diseases/complications , Amyloid Neuropathies, Familial/complications , Heart Diseases/pathology , Heart Diseases/physiopathology , Humans , Male , Middle Aged , Muscle, Skeletal/pathology , Myocardium/pathology , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/diagnosis
15.
J Neurol Neurosurg Psychiatry ; 86(8): 873-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25430934

ABSTRACT

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.


Subject(s)
Charcot-Marie-Tooth Disease/classification , Adaptor Proteins, Signal Transducing , Cell Cycle Proteins , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/pathology , Charcot-Marie-Tooth Disease/physiopathology , Connexins/genetics , Cost of Illness , Cross-Sectional Studies , Female , GTP Phosphohydrolases/genetics , Humans , Male , Mitochondrial Proteins/genetics , Mutation/genetics , Myelin P0 Protein/genetics , Myelin Proteins/genetics , Nuclear Proteins , Proteins/genetics , Gap Junction beta-1 Protein
16.
J Neurol ; 262(1): 228-34, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25488473

ABSTRACT

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.


Subject(s)
Amyloid Neuropathies, Familial , Meninges/pathology , Adult , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/pathology , Amyloid Neuropathies, Familial/physiopathology , Humans , Leucine/genetics , Male , Mutation/genetics , Nigeria , Proline/genetics
17.
Pract Neurol ; 14(6): 399-408, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25035142

ABSTRACT

The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is usually straightforward, but atypical presentations can represent a significant diagnostic challenge. This review highlights the clinical and electrophysiological 'red flags' that should make one consider an alternative diagnosis.


Subject(s)
Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Humans
18.
J Neurol Neurosurg Psychiatry ; 85(12): 1354-8, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24659795

ABSTRACT

BACKGROUND: In overwork weakness (OW), muscles are increasingly weakened by exercise, work or daily activities. Although it is a well-established phenomenon in several neuromuscular disorders, it is debated whether it occurs in Charcot-Marie-Tooth disease (CMT). Dominant limb muscles undergo a heavier overload than non-dominant and therefore if OW occurs we would expect them to become weaker. Four previous studies, comparing dominant and non-dominant hand strength in CMT series employing manual testing or myometry, gave contradictory results. Moreover, none of them examined the behaviour of lower limb muscles. METHODS: We tested the OW hypothesis in 271 CMT1A adult patients by comparing bilateral intrinsic hand and leg muscle strength with manual testing as well as manual dexterity. RESULTS: We found no significant difference between sides for the strength of first dorsal interosseous, abductor pollicis brevis, anterior tibialis and triceps surae. Dominant side muscles did not become weaker than non-dominant with increasing age and disease severity (assessed with the CMT Neuropathy Score); in fact, the dominant triceps surae was slightly stronger than the non-dominant with increasing age and disease severity. DISCUSSION: Our data does not support the OW hypothesis and the consequent harmful effect of exercise in patients with CMT1A. Physical activity should be encouraged, and rehabilitation remains the most effective treatment for CMT patients.


Subject(s)
Charcot-Marie-Tooth Disease/complications , Muscle Weakness/etiology , Adolescent , Adult , Aged , Charcot-Marie-Tooth Disease/physiopathology , Cumulative Trauma Disorders/etiology , Cumulative Trauma Disorders/physiopathology , Female , Functional Laterality/physiology , Hand Strength/physiology , Humans , Male , Middle Aged , Muscle Strength/physiology , Muscle Weakness/physiopathology , Muscle, Skeletal/physiopathology , Young Adult
19.
PharmaNutrition ; 1(1): 10-12, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23525455

ABSTRACT

Charcot-Marie-Tooth 1A disease (CMT1A) is a disease for which no drug treatments are available. In 2004, it was reported that ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing PMP22, an animal model of human CMT1A, compared with untreated mice. Based on those results, clinical trials were undertaken at different centers worldwide and four of them have been completed, but none of them resulted in significant improvements. Based on the pharmacokinetics of ascorbic acid, we propose that the randomized clinical trial carried out thus far confirmed the tight control of ascorbic acid's absorption and proved its tolerability at one and two years. The pharmacokinetic considerations discussed in this article might largely explain the disappointing results of the recent CMT1A trials.

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