ABSTRACT
BACKGROUND: Single-center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs). METHODS: Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well-defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS). RESULTS: From 86 families with IPNs, 99 patients (59 males) were identified, 85 with sensorimotor neuropathy or CMT (2/3 demyelinating form) and 14 with distal hereditary motor neuropathy (dHMN). Genetic diagnosis was achieved in 79.5% families, with a similar mutation detection rate in the demyelinating (88.7%) and axonal (89.5%) forms, significantly higher than in the dHMN families (27.3%). CMT1A was the most common subtype, followed by those carrying heterozygous mutations in either the GDAP1 or GJB1 genes. Mutations in 15 other genes were identified, including a new pathogenic variant in the ATP1A gene. The CMTPedS detected significant disease progression in all genetic subtypes of CMT, at a rate of 1.84 (±3.7) over 1 year (p < 0.0005, n = 62) and a 2-year rate of 3.6 (±4.4: p < 0.0005, n = 45). Significant disease worsening was also detected for CMT1A over 1 (1.7 ± 3.6, p < 0.05) and 2 years (4.2 ± 4.3, p < 0.0005). CONCLUSIONS: This study highlights the unique spectrum of IPN gene frequencies among pediatric patients in this specific geographic region, identifying the CMTPedS as a sensitive tool to detect significant disease worsening over 1 year that could help optimize the design of clinical trials.
Subject(s)
Hereditary Sensory and Motor Neuropathy , Peripheral Nervous System Diseases , Adolescent , Adult , Age of Onset , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Child , Child, Preschool , Female , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Longitudinal Studies , Male , Mediterranean Region/epidemiology , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/epidemiology , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/physiopathology , Referral and Consultation , Spain/epidemiology , Young AdultABSTRACT
Recently, biallelic variants in the SORD gene were identified as causal for axonal hereditary neuropathy (HN). We ascertained the spectrum and frequency of SORD variants among a large cohort of Czech patients with unknown cause of HN. Exome sequencing data were analysed for SORD (58 patients). The prevalent c.757del variant was tested with fragment analysis (931 patients). Sanger sequencing in additional 70 patients was done. PCR primers were designed to amplify the SORD gene with the exclusion of the pseudogene SORD2P. Sequence differences between gene and pseudogene were identified and frequencies of SNPs were calculated. Eighteen patients from 16 unrelated families with biallelic variants in the SORD gene were found and the c.757del was present in all patients on at least one allele. Three novel, probably pathogenic, variants were detected, always in a heterozygous state in combination with the c.757del on the second allele. Patients presented with a slowly progressive axonal HN. Almost all patients had moderate pes cavus deformity. SORD neuropathy is frequent in Czech patients and the third most common cause of autosomal recessive HN. The c.757del is highly prevalent. Specific amplification of the SORD gene with the exclusion of the pseudogene is essential for a precise molecular diagnostics.
Subject(s)
Hereditary Sensory and Motor Neuropathy , L-Iditol 2-Dehydrogenase/genetics , Adult , Aged , Cohort Studies , Czech Republic/epidemiology , Female , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Humans , Male , Middle Aged , Mutation , Exome SequencingABSTRACT
To date, only one study assessed quality of life (QoL) in patients with hereditary neuropathy with liability to pressure palsies (HNPP). We aimed to fill in this gap by investigating QoL in a cohort of patients with HNPP compared to Charcot-Marie-Tooth type 1A (CMT1A) patients, as well as to analyze sociodemographic and clinical features associated with QoL in HNPP. Eighteen genetically confirmed HNPP patients were age-and gender-matched with 18 CMT1A patients. SF-36 questionnaire was used to assess QoL. Medical Research Council (MRC) Sum Score, CMT Neuropathy Score (CMTNS), Overall Neuropathy Limitation Scale Score (ONLS), Falls Efficacy Score (FES), Visual Analog Pain Scale, Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) were also used in our study. Although HNPP patients were less clinically impaired, no difference was observed in these two cohorts regarding SF-36 scores. Worse QoL in HNPP patients was associated with lower education (p < 0.01), physical work (p < 0.05), higher number of clinically affected nerves during the disease course (p < 0.01), worse MRC-SS score (p < 0.01), worse ONLS score (p < 0.01), and with more severe pain (p < 0.01), depression (p < 0.01), and fatigue (p < 0.01). Worse pain at the moment of testing appeared as a significant independent predictor of worse QoL in HNPP patients (ß = - 0.93, p < 0.001). QoL was similarly impaired in patients with HNPP and patients with CMT1A. We identified different factors associated with QoL in HNPP, and many of these factors are amenable to treatment which is of special interest in these still incurable disease.
Subject(s)
Arthrogryposis/epidemiology , Arthrogryposis/psychology , Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/psychology , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/psychology , Quality of Life/psychology , Adult , Arthrogryposis/diagnosis , Charcot-Marie-Tooth Disease/diagnosis , Cohort Studies , Cross-Sectional Studies , Female , Hereditary Sensory and Motor Neuropathy/diagnosis , Humans , Longitudinal Studies , Male , Middle Aged , Serbia/epidemiologyABSTRACT
Pathogenic variants in the HINT1 gene lead to hereditary axonopathy with neuromyotonia. However, many studies show that neuromyotonia may remain undiagnosed, while axonopathy is the major clinical finding. The most common cause of neuromyotonia and axonopathy, especially in patients of Slavic origin, is a c.110G>C (p.Arg37Pro) pathogenic variant in homozygous or compound heterozygous state. In this study, we analyzed a peripheral neuropathy caused by pathogenic variants in the HINT1 gene and evaluated its contribution to the hereditary neuropathy structure. The studied group included 1596 non-related families diagnosed with hereditary motor and sensory neuropathy (HMSN). The results show that HINT1 gene pathogenic variants make a significant contribution to the hereditary neuropathy epidemiology in Russian patients. They account for at least 1.9% of all HMSN cases and 9% of axonopathy cases. The most common HINT1 pathogenic variant in Russian patients is the c.110G>C (p.Arg37Pro) substitution. Its allelic frequency is 0.2% (95% CI 0.19-0.21%), carrier frequency is 1 in 250 people in Russian Federation, and the estimated disease incidence is 1 in 234,000 individuals. It was determined that the cause of this pathogenic variant's prevalence is the founder effect.
Subject(s)
Genes, Recessive , Hereditary Sensory and Motor Neuropathy/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Gene Frequency/genetics , Haplotypes/genetics , Hereditary Sensory and Motor Neuropathy/epidemiology , Heterozygote , Humans , Linkage Disequilibrium/genetics , Microsatellite Repeats/genetics , RussiaABSTRACT
BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is a rare neuropathy with a heterogeneous clinical profile. Painless recurrent palsies are the usual presentation, but neuropathic pain could be predominant or inaugural. Browsing the medical literature, we only found two articles reffering to this important clinical feature. Whether there are differences between patients with or without pain is unclear. The main objective of this study was to compare the clinical and electrophysiological features of these patients and to evaluate the impact on their disability. METHODS: All patients diagnosed with HNPP at the Limoges University Hospital Centre were included and separated into two groups according to the presence or absence of neuropathic pain. In each case, the clinical, genetic, electrodiagnostic, therapeutic features and the modified Rankin Scale (mRS) were evaluated. RESULTS: Out of 23 patients, 52% presented with neuropathic pain. There was no difference between groups regarding to clinical and electrophysiological features, except for the amplitude of the ulnar sensory nerve (p < 0,003). The amplitudes of sensory nerve action potentials (SNAPs) seemed to be higher in patients with pain, but were below the lower limit of normal. Patients with pain had a higher mRS than patients without pain (p < 0,007). CONCLUSION: This study supports previous published results and highlights a trend for higher sensory amplitudes in HNPP patients with pain. We found a prevalence of neuropathic pain of 52% in patients with HNPP, underlining the need to systematically assess pain in such patients in order to improve their management.
Subject(s)
Arthrogryposis/diagnosis , Arthrogryposis/physiopathology , Electrophysiological Phenomena/physiology , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/physiopathology , Pain/diagnosis , Pain/physiopathology , Adolescent , Adult , Aged , Arthrogryposis/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Hereditary Sensory and Motor Neuropathy/epidemiology , Humans , Male , Middle Aged , Pain/epidemiology , Retrospective Studies , Young AdultABSTRACT
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder mainly due to a deletion of chromosome 17p11.2 including PMP22 (PMP22 Del HNPP). The prevalence of HNPP is estimated to be 0.84 to 16 per 100,000, but could be underestimated because of the mild symptoms of HNPP. In this study, we estimated the prevalence of PMP22 Del HNPP in a Korean newborn population who underwent next-generation sequencing (NGS)-based copy number variation (CNV) analysis. Of the 11,885 newborns tested by NGS-based CNV analysis, 17p11.2 deletions were found in seven samples. The prevalence of PMP22 Del HNPP was estimated to be 58.9 per 100,000 (95% confidence interval (CI), 25.8-116.5) or 1 in 1698 (95% CI, 1/909-1/5000). Our data suggest that PMP22 Del HNPP might not be uncommon at least in the Korean population.
Subject(s)
Arthrogryposis/genetics , Asian People/genetics , Hereditary Sensory and Motor Neuropathy/genetics , Myelin Proteins/genetics , Arthrogryposis/epidemiology , Gene Deletion , Hereditary Sensory and Motor Neuropathy/epidemiology , Humans , Infant, Newborn , Republic of Korea/epidemiologyABSTRACT
INTRODUCTION: There have been few reports on subtypes of Guillain-Barré syndrome (GBS) in children. We compared clinical and laboratory findings of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). METHODS: One hundred forty children with GBS were included. Based on nerve conduction study (NCS) findings, patients were subclassified as AIDP, AMAN, acute motor sensory axonal neuropathy (AMSAN), and equivocal. RESULTS: Clinically, 72.1% of patients had pure motor, 24.3% motor sensory, and 3.4% Miller Fisher syndrome. Based on NCS, 67.8% of patients had AIDP, 23.6% had AMAN, and 4.3% had AMSAN. By 3 months, 2.1% patients had died, 47.1% had complete recovery, and 24.3% had poor recovery (wheelchair-bound). Children with AMAN had more frequent lower limb weakness (P = 0.02) and a lower probability of complete recovery (P = 0.01) at 3 months than children with AIDP (56% vs. 30%). DISCUSSION: AIDP is the most common GBS subtype in children. It is characterized by better recovery at 3 months when compared with AMAN. Muscle Nerve 57: 761-765, 2018.
Subject(s)
Guillain-Barre Syndrome/complications , Guillain-Barre Syndrome/epidemiology , Hereditary Sensory and Motor Neuropathy/complications , Hereditary Sensory and Motor Neuropathy/epidemiology , Neural Conduction/physiology , Adolescent , Child , Disease Management , Female , Follow-Up Studies , Guillain-Barre Syndrome/classification , Guillain-Barre Syndrome/therapy , Humans , India/epidemiology , Male , Neurologic Examination , Proportional Hazards Models , Prospective Studies , Treatment OutcomeABSTRACT
Hereditary neuropathy with liability to pressure palsy (HNPP) has historically been considered a pain-free condition, though some people with HNPP also complain of pain. This study characterised persistent pain in people with HNPP. Participants provided cross-sectional demographic data, information on the presence of neurological and persistent pain symptoms, and the degree to which these interfered with daily life. The painDETECT and Central Sensitization Inventory questionnaires were used to indicate potential neuropathic, central sensitisation and musculoskeletal (nociceptive) pain mechanisms. Additionally, participants were asked if they thought that pain was related to/part of HNPP. 32/43 (74%) subjects with HNPP had persistent pain and experience this pain in the last week. Of those with pain, 24 (75%) were likely to have neuropathic pain and 27 (84%) were likely to have central sensitisation. All 32 participants felt that their pain could be related to/part of their HNPP. Significant negative impact of the pain was common. Pain characterisation identified neuropathic pain and/or central sensitisation as common, potential underlying processes. Pain may plausibly be directly related to the underlying pathophysiology of HNPP. Further consideration of including pain as a primary symptom of HNPP is warranted.
Subject(s)
Arthrogryposis/complications , Hereditary Sensory and Motor Neuropathy/complications , Pain/etiology , Adult , Arthrogryposis/epidemiology , Cohort Studies , Cross-Sectional Studies , Female , Hereditary Sensory and Motor Neuropathy/epidemiology , Humans , Male , Middle Aged , Neurologic Examination , Pain/epidemiology , Pain MeasurementABSTRACT
BACKGROUND: Hereditary motor-sensory neuropathy 1X (ÐÐСР1X) is the second frequent form of hereditary motor-sensory neuropathies caused by mutations in the GJB1 gene (gap junction B1 type). The authors have established earlier that the Ñ.259C>G (Ñ.P87A) mutation is the most frequent cause of ÐÐСР1Ð¥ (92%) in patients from the Republic of Bashkortostan. AIM: To study in details the territorial ethnic distribution and clinical manifestations of the Ñ.259C>G (Ñ.P87A) in the GJB1 gene in patients with ÐÐСР1Ð¥ from the Republic of Bashkortostan. MATERIAL AND METHODS: Clinical/neurological data were assessed in 52 patients (32 men and 20 women) from 13 families with this ÐÐСР1Ð¥ mutation in accordance to the diagnostic criteria of the European neuromuscular center. Twenty-three patients underwent standard electroneuromyographic study ('Nicolet Viking quest') using cutaneous electrodes. Data analysis was performed with Statistica ver.6.0 ('Stat Soft, Inc.', 2003) software. RESULTS: The Ñ.259C>G (Ñ.P87A) mutation was more frequent in Bashkir (61%) and Russian (31%) families from 6 areas of the Republic of Bashkortostan. The age-at-onset was 13.24±4.33 years in men. In women, the age-at-onset varied from 7 to 45 years, it was difficult to detect this parameter in several patients due to the absence of complaints and symptoms of disease. A comparative analysis revealed the higher degree of peripheral nerve lesions in men compared to women. There was the distinct difference in electrophysiological parameters (excitation spreading velocity and M-response amplitude) along motor fibers of the middle nerves between men and women that indicated the predominantly demyelinating character of the pathological process in men and the axonal character in women. CONCLUSION: Clear clinical/electrophysiological sex differences (intra- and inter family) were shown in patients with ÐÐСРIX with the Ñ.259C>G (Ñ.P87A) mutation in the GJB1 gene. The disease was less severe and often with the absence of symptoms in women. Genetic testing for mutations in the GJB1 gene, including the Ñ.259C>G (Ñ.P87A) mutation, can be recommended to female patients with excitation spreading velocity >38m/s.
Subject(s)
Connexins/genetics , Hereditary Sensory and Motor Neuropathy , Adolescent , Adult , Aged , Bashkiria/epidemiology , Female , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Male , Middle Aged , Mutation , Sex Factors , Young Adult , Gap Junction beta-1 ProteinABSTRACT
OBJECTIVE: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. METHODS: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). RESULTS: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. CONCLUSIONS: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.
Subject(s)
Charcot-Marie-Tooth Disease/epidemiology , Genetic Heterogeneity , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Mutation/genetics , Adolescent , Adult , Aged , Analysis of Variance , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Cohort Studies , Connexins/genetics , DNA Mutational Analysis , Electromyography , England/epidemiology , Family Health , Female , GTP Phosphohydrolases/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Male , Middle Aged , Mitochondrial Proteins/genetics , Myelin Proteins/genetics , Neural Conduction/genetics , Young Adult , Gap Junction beta-1 ProteinABSTRACT
Recessive mutations in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1) were recently shown to cause a motor-predominant Charcot-Marie-Tooth neuropathy. About 80% of the patients exhibit neuromyotonia, a striking clinical and electrophysiological hallmark that can help to distinguish this disease and to guide diagnostic screening. HINT1 neuropathy has worldwide distribution and is particularly prevalent in populations inhabiting central and south-eastern Europe. With 12 different mutations identified in more than 60 families, it ranks among the most common subtypes of axonal Charcot-Marie-Tooth neuropathy. This article provides an overview of the present knowledge on HINT1 neuropathy with the aim to increase awareness and spur interest among clinicians and researchers in the field. We propose diagnostic guidelines to recognize and differentiate this entity and suggest treatment strategies to manage common symptoms. As a recent player in the field of hereditary neuropathies, the role of HINT1 in peripheral nerves is unknown and the underlying disease mechanisms are unexplored. We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies of this peculiar Charcot-Marie-Tooth subtype.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Hereditary Sensory and Motor Neuropathy/genetics , Isaacs Syndrome/genetics , Myotonia/genetics , Nerve Tissue Proteins/genetics , Peripheral Nervous System Diseases/genetics , Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/pathology , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/pathology , Humans , Isaacs Syndrome/epidemiology , Isaacs Syndrome/pathology , Myotonia/epidemiology , Myotonia/pathology , Peripheral Nervous System Diseases/epidemiology , Peripheral Nervous System Diseases/pathologyABSTRACT
BACKGROUND: No epidemiological studies on the prevalence of compressive neuropathy have been undertaken in Arab countries. The aim of the study was to estimate the prevalence of the most common types of compressive neuropathies in Qena governorate/Egypt. METHODS: The study was part of a community-based survey carried out to assess the prevalence of neuromuscular disorders among the Qena population. A random sampling of 10 districts, 5,039 inhabitants aged ≥20. There were 3,050 urban residents (60.5%) and 1,989 (39.5%) from the rural community. Patients were diagnosed using a screening questionnaire for diagnosis of entrapment neuropathies. Positive cases were referred to the Qena University Hospital. They were given full clinical, electrophysiological and laboratory investigations. RESULTS: Compressive neuropathy was recorded in 165 cases giving a CPR = 3.3% of population at risk (≥20 years). Carpal tunnel syndrome (CTS) was diagnosed in 155 cases giving a CPR = 3.1% with a significantly higher prevalence among females than males (5.3 vs. 0.9%) and in rural compared with urban populations (4.6 vs. 2.1%). Ulnar neuropathy at the elbow was the second common type of entrapment with a CPR = 0.1% followed by radial nerve palsy, tarsal tunnel syndrome and common peroneal nerve palsy. CONCLUSION: The overall crude prevalence rate of CTS is comparable with that in other countries.
Subject(s)
Arthrogryposis/epidemiology , Hereditary Sensory and Motor Neuropathy/epidemiology , Adult , Cross-Sectional Studies , Egypt/epidemiology , Female , Health Surveys , Humans , Male , Middle Aged , Prevalence , Rural Population , Urban Population , Young AdultABSTRACT
OBJECTIVES: CMT is a group of heterogeneous motor and sensory neuropathies divided into demyelinating (CMT1) and axonal forms (CMT2). Distal Hereditary Motor Neuropathy (dHMN) is a motor neuropathy/neuronopathy which resembles CMT. Final genetic diagnosis is poor in CMT2 and in dHMN when compared with CMT1. Our aim is to report clinical, neurophysiological and genetic findings in a cohort of patients with axonal inherited neuropathies. PATIENTS AND METHODS: We report clinical, neurophysiological and genetic findings from 45 patients with CMT2 or dHMN, coming from 39 unrelated families, observed in our Institute of Neurology over a 20-year period. RESULTS: Clinical and electrophysiological examinations showed that 38 patients had CMT2 and 7 patients presented dHMN. Extensive genetic evaluation showed 6 mutations in MFN2, 4 mutations in HSPB1, 2 mutations in BSCL2, 3 mutations in GJB1, 1 mutation in MPZ. CONCLUSION: Since next-generation sequencing will not be easily accessible, epidemiological data and clinical "phenotyping" remain the best strategy for clinicians to reach a correct genetic diagnosis in CMT2 and dHMN patients.
Subject(s)
Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/genetics , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Charcot-Marie-Tooth Disease/diagnosis , Child , Cohort Studies , Female , Hereditary Sensory and Motor Neuropathy/diagnosis , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
INTRODUCTION: Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. PATIENTS AND METHODS: Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. RESULTS: We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CONCLUSIONS: CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series.
TITLE: Experiencia en el diagnostico molecular de neuropatias hereditarias en un hospital pediatrico de tercer nivel.Introduccion. La enfermedad de Charcot-Marie-Tooth (CMT) es la neuropatia hereditaria sensitivomotora mas frecuente. Avances en el diagnostico molecular han incrementado las posibilidades diagnosticas de estos pacientes. Pacientes y metodos. Estudio retrospectivo de 36 casos pediatricos diagnosticados de CMT en un centro terciario en el periodo 2003-2015. Resultados. Se identificaron 16 pacientes con CMT1A por una duplicacion en PMP22; dos casos se diagnosticaron de neuropatia hereditaria con predisposicion a paralisis por presion, uno de ellos con una mutacion puntual en PMP22; un varon con un fenotipo leve desmielinizante se diagnostico de CMTX1 por mutacion en GJB1; un paciente con una hipotonia paralitica en el nacimiento y un patron axonal por mutacion en MFN2; un paciente de origen rumano se diagnostico de CMT4D por una mutacion en el gen NDRG1; una paciente con una atrofia muscular espinal congenita distal con neuropatia axonal leve asociada por mutacion en el gen TRPV4; tres niñas de una familia consanguinea de etnia gitana se diagnosticaron de CMT axonal con descargas neuromiotonicas por una mutacion en el gen HINT1; 12 pacientes no tienen diagnostico molecular actualmente, cuatro de ellos de etnia gitana. Conclusiones. CMT1A predomino en nuestra serie (44%), como corresponde a la bibliografia. Destacamos la descripcion de una paciente con una mutacion en TRPV4 recientemente descrita como causa de CMT2C y tres casos de una misma familia consanguinea gitana con la misma mutacion en el gen HINT1 recientemente publicada como causa de neuropatia axonal con neuromiotonia autosomica recesiva (AR-CMT2). El porcentaje de casos sin diagnostico molecular es similar al de grandes series europeas.
Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Molecular Diagnostic Techniques , Adolescent , Cell Cycle Proteins/genetics , Charcot-Marie-Tooth Disease/classification , Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/genetics , Child , Child, Preschool , Connexins/genetics , Consanguinity , Demyelinating Diseases/diagnosis , Demyelinating Diseases/epidemiology , Demyelinating Diseases/genetics , Female , GTP Phosphohydrolases/genetics , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Hospitals, Pediatric/statistics & numerical data , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mitochondrial Proteins/genetics , Myelin Proteins/genetics , Nerve Tissue Proteins/genetics , Retrospective Studies , Roma/genetics , Spain/epidemiology , TRPV Cation Channels/genetics , Tertiary Care Centers/statistics & numerical data , Gap Junction beta-1 ProteinABSTRACT
Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) represent the most common heritable neuromuscular disorders. Molecular diagnostics of CMT1A/HNPP diseases confirm clinical diagnosis, but their value is limited to the clinical course and prognosis. However, no biomarkers of CMT1A/HNPP have been identified. We decided to explore if the LITAF/SIMPLE gene shared a functional link to the PMP22 gene, whose duplication or deletion results in CMT1A and HNPP, respectively. By studying a large cohort of CMT1A/HNPP-affected patients, we found that the LITAF I92V sequence variant predisposes patients to an earlier age of onset of both the CMT1A and HNPP diseases. Using cell transfection experiments, we showed that the LITAF I92V sequence variant partially mislocalizes to the mitochondria in contrast to wild-type LITAF which localizes to the late endosome/lysosomes and is associated with a tendency for PMP22 to accumulate in the cells. Overall, this study shows that the I92V LITAF sequence variant would be a good candidate for a biomarker in the case of the CMT1A/HNPP disorders.
Subject(s)
Arthrogryposis/genetics , Charcot-Marie-Tooth Disease/genetics , Hereditary Sensory and Motor Neuropathy/genetics , Nuclear Proteins/genetics , Sequence Deletion , Transcription Factors/genetics , Age of Onset , Animals , Arthrogryposis/complications , Arthrogryposis/diagnosis , Arthrogryposis/epidemiology , Biomarkers , Cells, Cultured , Charcot-Marie-Tooth Disease/complications , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/epidemiology , Chlorocebus aethiops , Female , Genetic Predisposition to Disease , Hereditary Sensory and Motor Neuropathy/complications , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/epidemiology , Humans , Male , Mitochondria/metabolism , Myelin Proteins/metabolismABSTRACT
INTRODUCTION: This study characterizes the nature of pain in hereditary neuropathy with liability to pressure palsy (HNPP). METHODS: This retrospective study was performed to assess duration, nature, location, and intensity of pain on initial presentation of subjects with HNPP, including the degree and type of analgesic medication use and electrodiagnostic characteristics. Subjects who met the American College of Rheumatology criteria for fibromyalgia syndrome (FMS) were also identified. RESULTS: Of 32 HNPP subjects, 24 (75%) had symptoms of pain, and 4 (12%) had pain as an initial symptom. Of subjects who described pain, 9 (28%) reported only musculoskeletal pain, 10 (31%) only neuropathic pain, and 5 (16%) both musculoskeletal and neuropathic pain. All 9 subjects with only musculoskeletal pain met criteria for FMS. CONCLUSIONS: Neuropathic and musculoskeletal pain occur commonly in HNPP and may be a presenting symptom. Additionally, HNPP with predominantly musculoskeletal pain may meet criteria for FMS and potentially delay the diagnosis.
Subject(s)
Fibromyalgia/diagnosis , Hereditary Sensory and Motor Neuropathy/diagnosis , Pain/diagnosis , Paralysis/diagnosis , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Fibromyalgia/epidemiology , Follow-Up Studies , Hereditary Sensory and Motor Neuropathy/epidemiology , Humans , Male , Middle Aged , Pain/epidemiology , Paralysis/epidemiology , Retrospective StudiesABSTRACT
OBJECTIVE: The sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) syndrome is a subgroup of mitochondrial chronic progressive external ophthalmoplegia (CPEO)-plus disorders associated with multiple mitochondrial DNA (mtDNA) deletions. There is no systematic survey on SANDO in patients with CPEO with either single or multiple large-scale mtDNA deletions. METHODS: In this retrospective analysis, we characterised the frequency, the genetic and clinical phenotype of 107 index patients with mitochondrial CPEO (n=66 patients with single and n=41 patients with multiple mtDNA deletions) and assessed these for clinical evidence of a SANDO phenotype. Patients with multiple mtDNA deletions were additionally screened for mutations in the nuclear-encoded POLG, SLC25A4, PEO1 and RRM2B genes. The clinical, histological and genetic data of 11 patients with SANDO were further analysed. RESULTS: None of the 66 patients with single, large-scale mtDNA deletions fulfilled the clinical criteria of SANDO syndrome. In contrast, 9 of 41 patients (22%) with multiple mtDNA deletions and two additional family members fulfilled the clinical criteria for SANDO. Within this subgroup, multiple mtDNA deletions were associated with the following nuclear mutations: POLG (n=6), PEO1 (n=2), unidentified (n=2). The combination of sensory ataxic neuropathy with ophthalmoparesis (SANO) was observed in 70% of patients with multiple mtDNA deletions but only in 4% with single deletions. The combination of CPEO and sensory ataxic neuropathy (SANO, incomplete SANDO) was found in 43% of patients with multiple mtDNA deletions but not in patients with single deletions. CONCLUSION: The SANDO syndrome seems to indicate a cluster of symptoms within the wide range of multisystemic symptoms associated with mitochondrial CPEO. SANO seems to be the most frequent phenotype associated with multiple mtDNA deletions in our cohort but not or is rarely associated with single, large-scale mtDNA deletions.
Subject(s)
DNA, Mitochondrial/genetics , Dysarthria/epidemiology , Dysarthria/genetics , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Ophthalmoplegia, Chronic Progressive External/epidemiology , Ophthalmoplegia, Chronic Progressive External/genetics , Ophthalmoplegia/epidemiology , Adolescent , Adult , Age of Onset , Aged , Biopsy , Child , Cohort Studies , DNA Helicases/genetics , DNA Polymerase gamma , DNA-Directed DNA Polymerase/genetics , Female , Gene Deletion , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Mitochondrial Proteins/genetics , Muscle, Skeletal/pathology , Ophthalmoplegia/genetics , Retrospective Studies , Syndrome , Young AdultABSTRACT
Hereditary neuropathies belong to the most common neurogenetic disorders. They appear mostly as sensory and motor neuropathies but there are also pure sensory, pure motor as well as sensory and autonomic hereditary neuropathies. In clinical practice, knowledge of hereditary neuropathies is important in order to recognize them among polyneuropathies and achieve a successful genetic diagnosis. The molecular genetics of hereditary neuropathies are very heterogeneous with currently more than 40 known disease-causing genes. The 4 most common genes account for almost 90% of the genetically diagnosed hereditary neuropathies. In this review article we provide an overview of the currently known genes and propose a rational genetic work-up protocol of the most common genes.
Subject(s)
Nervous System Diseases/genetics , Algorithms , Charcot-Marie-Tooth Disease/classification , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/genetics , Cross-Sectional Studies , Disability Evaluation , Genetic Testing , Hereditary Sensory and Autonomic Neuropathies/classification , Hereditary Sensory and Motor Neuropathy/classification , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Humans , Nervous System Diseases/classification , Nervous System Diseases/diagnosis , Nervous System Diseases/epidemiology , Neurologic Examination , Polyneuropathies/classification , Polyneuropathies/diagnosis , Polyneuropathies/epidemiology , Polyneuropathies/genetics , PrognosisABSTRACT
The infantile-onset axonal neuropathies and neuronopathies are an uncommon and heterogeneous group of conditions causing weakness, wasting, and developmental delay in early childhood. Many are associated with central nervous system or other systemic manifestations and cause early mortality. We review the axonal Charcot-Marie-Tooth subtypes with onset in infancy, spinal muscular atrophy, and related syndromes of early infancy, giant axonal neuropathy, infantile neuroaxonal dystrophy, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, early-onset neuropathies associated with mitochondrial disorders, and other less well-delineated clinical entities. Useful clinical and neuropathologic features in the diagnostic work-up of these conditions are also presented.