RESUMEN
Charcot-Marie-Tooth (CMT) is a commonly inherited, non-fatal neurodegenerative disorder that affects sensory and motor neurons in patients. More than 90 genes are known to cause axonal and demyelinating forms of CMT. The p.R158H mutation in the pyruvate dehydrogenase kinase 3 (PDK3) gene is the genetic cause for an X linked form of axonal CMT (CMTX6). In vitro studies using patient fibroblasts and iPSC-derived motor neurons have shown that this mutation causes deficits in energy metabolism and mitochondrial function. Animal models that recapitulate pathogenic in vivo events in patients are crucial for investigating mechanisms of axonal degeneration and developing therapies for CMT. We have developed a C. elegans model of CMTX6 by knocking-in the p.R158H mutation in pdhk-2, the ortholog of PDK3. In addition, we have developed animal models overexpressing the wild type and mutant form of human PDK3 specifically in the GABAergic motor neurons of C. elegans. CMTX6 mutants generated in this study exhibit synaptic transmission deficits, locomotion defects and show signs of progressive neurodegeneration. Furthermore, the CMTX6 in vivo models display energy deficits that recapitulate the phenotype observed in patient fibroblasts and iPSC-derived motor neurons. Our CMTX6 animals represent the first in vivo model for this form of CMT and have provided novel insights into the cellular function and metabolic pathways perturbed by the p.R158H mutation, all the while closely replicating the clinical presentation observed in CMTX6 patients.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Adenosina Trifosfato/metabolismo , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Humanos , Mutación , Fenotipo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Transmisión Sináptica/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally. METHODS: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations. RESULTS: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research. CONCLUSIONS: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Adolescente , Adulto , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/terapia , Niño , Consenso , Humanos , Calambre Muscular , Debilidad Muscular , Guías de Práctica Clínica como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
Biallelic mutations in sorbitol dehydrogenase (SORD) have been recently identified as a common cause of recessive axonal Charcot-Marie-Tooth neuropathy (CMT2). We aimed to assess a novel long-read sequencing approach to overcome current limitations in SORD neuropathy diagnostics due to the SORD2P pseudogene and the phasing of biallelic mutations in recessive disease. We conducted a screen of our Australian whole exome sequencing (WES) CMT cohort to identify individuals with homozygous or compound heterozygous SORD variants. Individuals detected with SORD mutations then underwent long-read sequencing, clinical assessment, and serum sorbitol analysis. An individual was detected with compound heterozygous truncating mutations in SORD exon 7, NM_003104.5:c.625C>T (p.Arg209Ter) and NM_003104.5:c.757del (p.Ala253GlnfsTer27). Subsequent Oxford Nanopore Tech (ONT) long-read sequencing was used to successfully differentiate SORD from the highly homologous non-functional SORD2P pseudogene and confirmed that the mutations were biallelic through haplotype-resolved analysis. The patient presented with axonal sensorimotor polyneuropathy (CMT2) and ulnar neuropathy without compression at the elbow. Burning neuropathic pain in the forearms and feet was also reported and was exacerbated by alcohol consumption and improved with alcohol cessation. UPLC-tandem mass spectrometry confirmed that the patient had elevated serum sorbitol levels (12.0 mg/L) consistent with levels previously observed in patients with biallelic SORD mutations. This represents a novel clinical presentation and expands the phenotype associated with biallelic SORD mutations causing CMT2. Our study is the first report of long-read sequencing for an individual with CMT and demonstrates the utility of this approach for clinical genomics.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , L-Iditol 2-Deshidrogenasa , Australia , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Humanos , L-Iditol 2-Deshidrogenasa/genética , Mutación , Linaje , Fenotipo , Sorbitol , Secuenciación del ExomaRESUMEN
The second most common form of Charcot-Marie-Tooth neuropathy (CMT), X-linked CMT type X1 (CMTX1), is caused by coding and non-coding mutations in the gap junction beta 1 (GJB1) gene. The non-coding GJB1 c.-103C > T mutation (NM_000166.5) has been reported to cause CMTX1 in multiple families. This study assessed the internal ribosomal entry site (IRES) activity previously reported for the rat Gjb1 P2 5' untranslated region (UTR). Using a bicistronic assay and transfecting RT4 Schwann cells, IRES activity of the human GJB1 P2 5' UTR was compared to the GJB1 P2 5' UTR containing either the c.-103C > T mutation or the non-pathogenic c.-102G > A variant. No differences in GJB1 P2 5' UTR IRES activity were observed between the negative control, the wild-type P2 5' UTR, the c.-103C > T 5' UTR or the c.-102G > A 5' UTR, irrespective of the GJB1 intron being present (p = .429 with intron, and p = .865 without). A theoretical c.-131A > G variant was predicted to result in the same RNA secondary structure as the GJB1 c.-103C > T P2 5' UTR. However, no significant difference was observed between expression from the wild-type GJB1 P2 5' UTR and the GJB1 c.-131A > G variant (p = .688). Deletion of the conserved region surrounding the c.-103C > T mutation (c.-108_-103del) resulted in significantly higher expression than the c.-103C > T mutation alone (p = .019), suggesting that the conserved c.-108_-103 region was not essential for translation. The reporter assays in this study do not recapitulate the previously reported GJB1 IRES activity and suggest an alternate pathogenic mechanism for the c.-103C > T CMTX1 non-coding mutation.
Asunto(s)
Regiones no Traducidas 5'/efectos de los fármacos , Enfermedad de Charcot-Marie-Tooth/genética , Genes Ligados a X/genética , Animales , Enfermedad de Charcot-Marie-Tooth/etiología , Conexinas/genética , Uniones Comunicantes/genética , Uniones Comunicantes/patología , Mutación/genética , RatasRESUMEN
Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas del Citoesqueleto/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Adolescente , Alelos , Biopsia , Mapeo Cromosómico , Consanguinidad , Salud de la Familia , Femenino , Fibroblastos/metabolismo , Genes Recesivos , Ligamiento Genético , Marcadores Genéticos , Haplotipos , Humanos , Escala de Lod , Pérdida de Heterocigocidad , Malasia , Masculino , Mutación Missense , Neuronas/metabolismo , Linaje , Secuenciación del ExomaRESUMEN
With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Cromosomas Humanos Par 8 , Mutagénesis Insercional , Mapeo Cromosómico , Cromosomas/ultraestructura , Cromosomas Humanos X/genética , Biología Computacional , Análisis Mutacional de ADN , Exoma , Regulación de la Expresión Génica , Genoma Humano , Genotipo , Haplotipos , Humanos , Masculino , MutaciónRESUMEN
OBJECTIVE: To use linkage analysis and whole exome sequencing to identify the genetic mutation in a multigenerational Australian family with Charcot-Marie-Tooth disease type 2 (CMT2) and pyramidal signs. METHODS: Genome-wide linkage analysis was performed to map the locus. Whole exome sequencing was undertaken on selected individuals (3 affected, 1 normal), and segregation analysis and mutation screening were carried out using high-resolution melt analysis. The GEM.app database was queried to identify additional families with mutations. RESULTS: Significant linkage (2-point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6Mb interval on chromosome 22q12.1-q12.3. Whole exome sequencing identified a novel mutation (p.R252W) in the microrchidia CW-type zinc finger 2 (MORC2) gene mapping within the linkage region. The mutation fully segregated with the disease phenotype in the family. Screening additional families and querying unsolved CMT2 exomes, we identified the p.R252W mutation in 2 unrelated early onset CMT2 families and a second mutation p.E236G in 2 unrelated CMT2 families. Both the mutations occurred at highly conserved amino acid residues and were absent in the normal population. INTERPRETATION: We have identified a new locus in which MORC2 mutations are the likely pathogenic cause of CMT2 and pyramidal signs in these families. MORC2 encodes the human CW-type zinc finger 2 protein, which is a chromatin modifier involved in the regulation of DNA repair as well as gene transcription.
Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Predisposición Genética a la Enfermedad/genética , Tractos Piramidales/patología , Factores de Transcripción/genética , Adulto , Femenino , Humanos , Masculino , Mutación/genéticaRESUMEN
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle. We have previously shown the R158H mutation confers PDK3 enzyme hyperactivity. In this study we demonstrate that the increased PDK3 activity in patient fibroblasts (PDK3(R158H)) leads to the attenuation of PDC through hyper-phosphorylation of E1 at selected serine residues. This hyper-phosphorylation can be reversed by treating the PDK3(R158H) fibroblasts with the PDK inhibitor dichloroacetate (DCA). In the patient cells, down-regulation of PDC leads to increased lactate, decreased ATP and alteration of the mitochondrial network. Our findings highlight the potential to develop specific drug targeting of the mutant PDK3 as a therapeutic approach to treating CMTX6.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/metabolismo , Mitocondrias/metabolismo , Mutación , Proteínas Serina-Treonina Quinasas/genética , Adenosina Trifosfato/metabolismo , Humanos , Isoenzimas/metabolismo , Mutación/genética , Fosforilación , Piruvato Deshidrogenasa Quinasa Acetil-TransferidoraRESUMEN
Hereditary motor and sensory disorders of the peripheral nerve form one of the most common groups of human genetic diseases collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis in a three generation kindred, we have mapped a new locus for X-linked dominant CMT to chromosome Xp22.11. A microsatellite scan of the X chromosome established significant linkage to several markers including DXS993 (Zmax = 3.16; θ = 0.05). Extended haplotype analysis refined the linkage region to a 1.43-Mb interval flanked by markers DXS7110 and DXS8027. Whole exome sequencing identified a missense mutation c.G473A (p.R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. The change localized within the 1.43-Mb linkage interval, segregated with the affected phenotype and was excluded in ethnically matched control chromosomes. PDK3 is one of the four isoenzymes regulating the pyruvate dehydrogenase complex (PDC), by reversible phosphorylation, and is a nuclear-coded protein located in the mitochondrial matrix. PDC catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA and is a key enzyme linking glycolysis to the energy-producing Krebs cycle and lipogenic pathways. We found that the R158H mutation confers enzyme hyperactivity and binds with stronger affinity than the wild-type to the inner-lipoyl (L2) domain of the E2p chain of PDC. Our findings suggest a reduced pyruvate flux due to R158H mutant PDK3-mediated hyper-phosphorylation of the PDC as the underlying pathogenic cause of peripheral neuropathy. The results highlight an important causative link between peripheral nerve degeneration and an essential bioenergetic or biosynthetic pathway required for the maintenance of peripheral nerves.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación Missense , Proteínas Serina-Treonina Quinasas/genética , Adenosina Trifosfato/química , Adolescente , Adulto , Secuencia de Bases , Enfermedad de Charcot-Marie-Tooth/enzimología , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genes Dominantes , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/enzimología , Sitios Genéticos , Heterocigoto , Humanos , Isoenzimas/genética , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Unión Proteica , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Adulto JovenRESUMEN
The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor-activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort.
Asunto(s)
Dineínas Citoplasmáticas/genética , Enfermedades del Sistema Nervioso Periférico/genética , Proteínas de Unión al ADN , Femenino , Pruebas Genéticas , Humanos , Masculino , MutaciónRESUMEN
EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.
Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Predisposición Genética a la Enfermedad , Neuropatía Hereditaria Motora y Sensorial/genética , Mutación/genética , Adolescente , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Simulación por Computador , Proteína 2 de la Respuesta de Crecimiento Precoz/química , Femenino , Neuropatía Hereditaria Motora y Sensorial/diagnóstico por imagen , Neuropatía Hereditaria Motora y Sensorial/patología , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Linaje , Dominios Proteicos , Células de Schwann/metabolismo , Transcripción Genética , Activación Transcripcional/genética , Secuenciación del ExomaRESUMEN
Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next-generation sequencing with over 80 causative genes available for testing. Despite this success, up to 50% of cases remain genetically unsolved. In the absence of protein coding mutations, noncoding DNA or structural variation (SV) mutations are a possible explanation. The most common IPN, Charcot-Marie-Tooth neuropathy type 1A (CMT1A), is caused by a 1.5 Mb duplication causing trisomy of the dosage sensitive gene PMP22. Using genome sequencing, we recently identified two large genomic rearrangements causing IPN subtypes X-linked CMT (CMTX3) and distal hereditary motor neuropathy (DHMN1), thereby expanding the spectrum of SV mutations causing IPN. Understanding how newly discovered SVs can cause IPN may serve as a useful paradigm to examine the role of topologically associated domains (TADs), chromatin interactions, and gene dysregulation in disease. This review will describe the growing role of SV in the pathogenesis of IPN and the importance of considering this type of mutation in Mendelian diseases where protein coding mutations cannot be identified.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Enfermedad de Charcot-Marie-Tooth/genética , Cromatina , Mapeo Cromosómico , Dosificación de Gen/genética , Genoma , Variación Estructural del Genoma/genética , Genómica , Neuropatía Hereditaria Motora y Sensorial/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación PuntualRESUMEN
OBJECTIVE: To describe in detail the clinical profile of Charcot-Marie-Tooth disease subtype 3 (CMTX3) to aid appropriate genetic testing and rehabilitative therapy. METHODS: We reviewed the clinical and neurophysiologic profile and CMT Pediatric Scale (CMTPedS) assessments of 11 children with CMTX3. RESULTS: Compared with the more common forms of CMT, CMT1A and CMTX, CMTX3 was characterized by early onset with early and progressive hand weakness. Most affected children were symptomatic within the first 2 years of life. The most common presentation was foot deformity in the first year of life. CMTPedS analysis in these children revealed that CMTX3 progressed more rapidly (4.3 ± 4.1 points over 2 years, n = 7) than CMT1A and CMTX1. Grip strength in affected boys was 2 SDs below age- and sex-matched normative reference values (z score -2.05 ± 1.32) in the second decade of life. The most severely affected individual was wheelchair bound at 14 years of age, and 2 individuals had no movement in the small muscles of the hand in the second decade of life. Nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor conduction velocity ≤23 m/s. CONCLUSIONS: CMTX3 had an earlier onset, severe hand weakness, and more rapidly progressive disability compared to the more common forms of CMT. Understanding the unique phenotype of CMTX3 is essential for directing genetic testing because the CMTX3 insertion will not be seen on a routine microarray or neuromuscular gene panel. Early diagnosis will enable rehabilitation to be started early in this rapidly progressive neuropathy.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Conexinas/genética , Mutación/genética , Adolescente , Australia , Estudios de Casos y Controles , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Enfermedad de Charcot-Marie-Tooth/rehabilitación , Niño , Preescolar , Estudios de Cohortes , Salud de la Familia , Femenino , Pruebas Genéticas , Fuerza de la Mano/fisiología , Humanos , Lactante , Masculino , Conducción Nerviosa/fisiología , Adulto JovenRESUMEN
We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.
Asunto(s)
Glicina-ARNt Ligasa/genética , Enfermedades Musculares/genética , Adolescente , Adulto , Brazo , Biopsia/métodos , Enfermedad de Charcot-Marie-Tooth/etnología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Electromiografía/métodos , Salud de la Familia , Femenino , Humanos , Pierna , Masculino , Persona de Mediana Edad , Debilidad Muscular/etnología , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/etnología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Enfermedades Musculares/etnología , Enfermedades Musculares/fisiopatología , Mutación , Conducción Nerviosa/fisiología , Fenotipo , Nervio Sural/patologíaRESUMEN
Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.
RESUMEN
Hereditary sensory neuropathies (HSNs) are rare disorders characterized by progressive distal sensory loss, predominantly affecting the lower limbs. Foot ulcers, severe skin and bone infections, arthropathy, and amputations are frequent and feared complications. Occasionally, patients complain of spontaneous shooting or lancinating pain. Autonomic fibers can be affected to a variable degree. Patients with HSN can also have severe distal weakness, and some HSN variants have therefore been classified among the hereditary motor and sensory neuropathies (HMSNs). Molecular genetic studies of autosomal dominant inherited neuropathies with prominent sensory loss and ulceromutilating features have assigned the genetic loci for HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1 to chromosomes 3q13-22 and 9q22.1-22.3, respectively. However, some families with HSN have been excluded for linkage to these loci, suggesting further genetic heterogeneity. Recently, disease-causing mutations in the SPTLC1 gene have been identified in patients with HSN type 1. In this review, we discuss the hallmark features associated with the distinct genetic subtypes of autosomal dominant inherited HSN and provide genotype-phenotype correlations.
Asunto(s)
Neuropatías Hereditarias Sensoriales y Autónomas/complicaciones , Neuropatías Hereditarias Sensoriales y Autónomas/fisiopatología , Automutilación/etiología , Automutilación/fisiopatología , Genes Dominantes , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Humanos , Automutilación/genética , Trastornos Somatosensoriales/etiología , Trastornos Somatosensoriales/genética , Trastornos Somatosensoriales/fisiopatologíaRESUMEN
OBJECTIVE: We investigated peripheral nerve function in X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), and considered the functional consequences of mutant connexin-32. METHODS: Twelve subjects (9 female, 3 male) were assessed clinically, by nerve conduction and excitability studies. A model of myelinated axon was used to clarify the contributing changes. RESULTS: All subjects had abnormal nerve conduction. Excitability studies on median nerve axons showed greater threshold changes to hyperpolarising currents, with "fanning out" in threshold electrotonus, and modest changes in the recovery cycle. Modelling suggested shortening of internodal length, increase in nodal fast potassium currents, shift of the voltage activation hyperpolarisation-activated cyclic-nucleotide-gated channels, and axonal hyperpolarisation. Plotting threshold versus extent of hyperpolarising threshold change in threshold electrotonus distinguished the CMTX1 patients from other chronic demyelinating neuropathies reported in the literature except hereditary neuropathy with pressure palsies (HNPP). CONCLUSIONS: Some measures of axonal excitability are similar in CMTX1 and HNPP (though not the recovery cycle), but they differ from those in other chronic demyelinating neuropathies. The findings in CMTX1 are consistent with known pathology, but are not correlated to neuropathy severity. SIGNIFICANCE: The findings in CMTX1 could be largely the result of morphological alterations, rather than plasticity in channel expression or distribution.
Asunto(s)
Axones/fisiología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Nervio Mediano/fisiopatología , Modelos Neurológicos , Nervios Periféricos/fisiopatología , Adulto , Anciano , Conexinas/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Adulto Joven , Proteína beta1 de Unión ComunicanteRESUMEN
MRI shows areas where muscle has been replaced by fat, a process which occurs in neuropathies. The purpose of this study was to investigate the usefulness of MRI in assessing disease severity in Charcot-Marie-Tooth (CMT) and hereditary motor neuropathy (HMN) compared to manual muscle testing (MMT). MRI and MMT correlated well (Spearman's rank correlation coefficient 0.910, 0.789-1.0). MRI was useful to document the extent and pattern of muscle atrophy and fat replacement and to determine the level of denervation. In addition, nerve length dependent denervation was confirmed in both CMT and HMN. MRI will be useful to confirm MMT findings and may be helpful for diagnosis of early or subclinical disease, as well as to further investigate the mechanisms of hereditary neuropathies.