RESUMEN
OBJECTIVES: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by the SACS gene variants. Main clinical features include early-onset and progressive cerebellar ataxia, spasticity, sensorimotor polyneuropathy. However, the phenotypic spectrum expanded with the increased availability of next-generation sequencing methods. MATERIALS AND METHODS: Herein, we describe the clinical features of nine patients from seven unrelated families with SACS variants from the cohort of the Neuromuscular Disorders Unit of the Neurology Department of the Istanbul University, Istanbul Faculty of Medicine. RESULTS: Seven patients were male. Seven patients in our cohort had disease onset in the first decade of life. Eight patients were born to consanguineous marriages. Distal weakness in the lower limbs was a prominent feature in all of our patients. Seven patients had ataxia, and six patients had spasticity. Interestingly, one patient showed an isolated Charcot-Marie-Tooth-like phenotype. Five patients showed sensorimotor demyelinating polyneuropathy in the nerve conduction studies. Linear pontine hypointensity was the most frequent cranial magnetic resonance imaging (MRI) abnormality. Two patients with a later disease onset had a homozygous c.11542_11544delATT (p.Ile3848del) variant. The rest of the identified variants were scattered throughout the SACS gene. CONCLUSIONS: Atypical clinical features in our patients highlight that the phenotypic spectrum of ARSACS can be observed in a wide range.
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Proteínas de Choque Térmico , Ataxias Espinocerebelosas , Proteínas de Choque Térmico/genética , Humanos , Masculino , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/genética , Mutación/genética , Ataxias Espinocerebelosas/congénito , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patologíaRESUMEN
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich's ataxia (FRDA). The identified missense mutation has been reported previously in two FRDA cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from our family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders.
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Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Proteínas de Unión a Hierro/genética , Mutación Missense , Adolescente , Adulto , Familia , Femenino , Homocigoto , Humanos , Masculino , Linaje , Fenotipo , Turquía , Adulto Joven , FrataxinaRESUMEN
OBJECTIVE: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B. METHODS: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score. RESULTS: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations. INTERPRETATION: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
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.
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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
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.
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Acetiltransferasas/genética , Enfermedad de Charcot-Marie-Tooth/genética , Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Acetiltransferasas/metabolismo , Adolescente , Adulto , Células Cultivadas , Enfermedad de Charcot-Marie-Tooth/complicaciones , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Humanos , Discapacidad Intelectual/complicaciones , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Mutación , Linaje , Adulto JovenRESUMEN
PURPOSE: Homozygosity mapping is an effective approach for detecting molecular defects in consanguineous families by delineating stretches of genomic DNA that are identical by descent. Constant developments in next-generation sequencing created possibilities to combine whole-exome sequencing (WES) and homozygosity mapping in a single step. METHODS: Basic optimization of homozygosity mapping parameters was performed in a group of families with autosomal-recessive (AR) mutations for which both single-nucleotide polymorphism (SNP) array and WES data were available. We varied the criteria for SNP extraction and PLINK thresholds to estimate their effect on the accuracy of homozygosity mapping based on WES. RESULTS: Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease. Filtering and mapping with optimized parameters was integrated into the HOMWES (homozygosity mapping based on WES analysis) tool in the GenomeComb package for genomic data analysis. CONCLUSION: We present recommendations for detection of homozygous regions based on WES data and a bioinformatics tool for their identification, which can be widely applied for studying AR disorders.Genet Med 18 6, 600-607.
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Proteínas Portadoras/genética , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas del Citoesqueleto/genética , Paraplejía Espástica Hereditaria/genética , beta-Glucosidasa/genética , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/patología , Mapeo Cromosómico , Consanguinidad , Femenino , Glucosilceramidasa , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Homocigoto , Humanos , Masculino , Mutación , Linaje , Polimorfismo de Nucleótido Simple/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/patología , Secuenciación del ExomaRESUMEN
Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2SH3TC2, histidine-triad nucleotide binding protein 1HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22% of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3% patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Mutación , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas del Tejido Nervioso/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Proteínas/genéticaRESUMEN
PURPOSE: Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot-Marie-Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive disease has not been associated with copy-number variation as a mutational mechanism. METHODS: We performed Agilent 8 × 60 K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation. RESULTS: We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6-8 that caused decreased mRNA expression of NDRG1. CONCLUSION: Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.
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Proteínas de Ciclo Celular/genética , Enfermedad de Charcot-Marie-Tooth/genética , Variaciones en el Número de Copia de ADN/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedad de Refsum/genética , Adulto , Secuencia de Bases , Hibridación Genómica Comparativa , Femenino , Duplicación de Gen , Expresión Génica , Genes Recesivos , Humanos , Masculino , Mutación , Análisis de Secuencia de ADN , Turquía , Adulto JovenRESUMEN
Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.
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Edad de Inicio , Neuropatía Hereditaria Motora y Sensorial/genética , Adolescente , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Neuropatía Hereditaria Motora y Sensorial/patología , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Lactante , Persona de Mediana Edad , Mutación , Fenotipo , Adulto JovenRESUMEN
Inherited peripheral neuropathies (IPNs) are a heterogeneous group of disorders of the peripheral nervous system. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease, which constitutes an interesting research focus for neurologists and human geneticists alike. Most cases with CMT manifest with a slowly progressive symmetric distal weakness in the lower limbs that usually begin in the first to the third decade that causes atrophy and foot drop. Deep tendon reflexes are usually absent or reduced. A proven and efficient CMT therapy is yet available and may require different molecules and approaches due to its high clinical and genetic heterogeneity. Several ongoing clinical trials are promising and are mostly focused on the most frequent form, namely CMT Type 1A (CMT1A). Approximately, 60% of patients with CMT can be genetically diagnosed using the most advanced mutation screening techniques that cover approximately 100 IPN genes. Turkey has a 25% consanguineous marriage rate, and nearly 60% genetic diagnosis rate can still be reached when SH3 Domain and Tetratricopeptide Repeat Domain 2, Ganglioside-induced Differentiation-Associated Protein 1, and Histidine Triad Nucleotide Binding Protein 1 genes are also screened along with Myelin Protein Zero and Gap Junction Protein Beta-1 after exclusion of CMT1A duplication in families with probable recessive inheritance. The genetic diagnosis rates in different regions worldwide implicate that the most recent sequencing techniques should be more commonly used for both diagnosis and identification of further CMT genes. Herein, presented our 30 years of experience on genetic diagnosis and management strategies in CMT neuropathy in Turkey and review clinical and genetic features of this group of disorders.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Consanguinidad , Humanos , Mutación , TurquíaRESUMEN
INTRODUCTION: In the demyelinating form of Charcot-Marie-Tooth disease, median motor conduction velocity (MCV) was noted to be around 20 m/s in peripheral myelin protein 22 (PMP22) duplications, in contrast to higher MCVs in connexin 32 gene (Cx32) mutations and lower MCVs in the demyelinating form of myelin protein zero gene (MPZ) mutations. METHODS: Nerve conduction studies were performed in 64 families with both common and rare mutations. RESULTS: Mean MCV of the median nerve was 20 ± 5 m/s in PMP22 duplications, 34 ± 6 m/s in Cx32 mutations, 20 ± 9 m/s in KIAA1985 (SH3TC2) mutations, and 11 ± 8 m/s in MPZ mutations. Conduction was generally uniform; however, conduction blocks were present in 1 patient each with the MPZ mutation and PMP22 duplication, both with unusual phenotypes. CONCLUSION: Our results confirm those of the other investigators. Electrophysiological results of the rare KIAA1985 (SH3TC2) mutation reveal that their MCVs span a broad range and that conduction is uniform.
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Enfermedad de Charcot-Marie-Tooth/epidemiología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Conducción Nerviosa/fisiología , Adolescente , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/genética , Niño , Estudios de Cohortes , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Turquía/epidemiología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: To report the findings in 12 members over 3 generations of a family with dominantly inherited Charcot-Marie-Tooth disease (CMT1B) due to a novel MPZ mutation, who all had moderately severe selective impairment of vestibular function with normal hearing. Methods used were video head impulse testing of the function of all 6 semicircular canals, Romberg test on foam, nerve conduction studies, and whole exome and Sanger sequencing. RECENT FINDINGS: All affected patients had a demyelinating neuropathy and a novel MPZ mutation: c.362A>G (chr1: 161276584, p.D121G). All also had normal hearing for age but a moderately severe impairment of semicircular canal function and a positive Romberg test on foam. SUMMARY: Some CMT mutations can impair vestibular function, presumably because of a vestibular nerve involvement but spare hearing. In such patients, impairment of vestibular function and impairment of proprioception contribute to imbalance.
RESUMEN
BACKGROUND AND OBJECTIVES: Inherited peripheral neuropathies (IPNs) are a group of genetic disorders of the peripheral nervous system in which neuropathy is the only or the most predominant clinical feature. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease. Autosomal recessive CMT (ARCMT) is generally more severe than dominant CMT and its genetic basis is poorly understood due to high clinical and genetic diversity. Here, we report clinical and genetic findings from 56 consanguineous Turkish families initially diagnosed with CMT disease. METHODS: We initially screened the GDAP1 gene in our cohort as it is the most commonly mutated ARCMT gene. Next, whole-exome sequencing and homozygosity mapping based on whole-exome sequencing (HOMWES) analysis was performed. To understand the molecular impact of candidate causative genes, functional analyses were performed in patient primary fibroblasts. RESULTS: Biallelic recurrent mutations in the GDAP1 gene have been identified in 6 patients. Whole-exome sequencing and HOMWES analysis revealed 16 recurrent and 13 novel disease-causing alleles in known IPN-related genes and 2 novel candidate genes: 1 for a CMT-like disease and 1 for autosomal recessive cerebellar ataxia with axonal neuropathy. We have achieved a potential genetic diagnosis rate of 62.5% (35/56 families) in our cohort. Considering only the variants that meet the American College for Medical Genetics and Genomics (ACMG) classification as pathogenic or likely pathogenic, the definitive diagnosis rate was 55.35% (31/56 families). DISCUSSION: This study paints a genetic landscape of the Turkish ARCMT population and reports additional candidate genes that might help enlighten the mechanism of pathogenesis of the disease.
RESUMEN
Chemotherapeutic drugs are the most common toxic agents for peripheral nerves. Vincristine is a vinca alkaloid drug that is used for the treatment of several malignancies in combination with other chemotherapeutic agents. Treatment with intravenous (IV) vincristine at doses above 5 mg leads to a dose-dependent neuropathy with sensory symptoms but higher cumulative doses at around 30 to 50 mg are needed for the development of motor symptoms. The standard maximum adult IV vincristine dose is 2 mg IV per dose given at weekly intervals. However, administration of a single 2-mg dose IV vincristine may rarely result in the development of peripheral neuropathy. Few case reports have been presented on vincristine-associated severe paralysis in patients with preexisting hereditary neuropathy like Charcot-Marie Tooth (CMT) disease, who received doses even lower than 2 mg. Herein, we reported a Hodgkin lymphoma patient who developed severe polyneuropathy after receiving 2 mg vincristine treatment and was subsequently found to carry the CMT1A duplication responsible for CMT disease.
Asunto(s)
Enfermedad de Hodgkin/complicaciones , Polineuropatías/inducido químicamente , Vincristina/efectos adversos , Adolescente , Antineoplásicos Fitogénicos , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Proteínas/genéticaAsunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Cinesinas/genética , Proteínas de la Membrana/genética , Mitocondrias/enzimología , Proteínas Mitocondriales/genética , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Exones , Femenino , GTP Fosfohidrolasas , Humanos , Intrones , Escala de Lod , Masculino , Persona de Mediana Edad , Mitocondrias/genética , LinajeRESUMEN
Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Adolescente , Adulto , Edad de Inicio , Secuencia de Bases , Biopsia , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Humanos , Masculino , Proteínas de la Membrana/análisis , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Linaje , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas no Receptoras , Nervio Sural/química , Nervio Sural/ultraestructuraRESUMEN
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in â¼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.
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Enfermedad de Charcot-Marie-Tooth/genética , Exoma , Carga Genética , Enfermedades del Sistema Nervioso Periférico/genética , Fenotipo , Animales , Femenino , Variación Genética , Proteínas del Choque Térmico HSP40/genética , Humanos , Masculino , Mutación , Proteína P2 de Mielina/genética , Linaje , Penetrancia , Serina C-Palmitoiltransferasa/genética , Supresión Genética , Pez CebraRESUMEN
Myotonic Dystrophy Type 1 (DM1) in combination with demyelinating neuropathy is very rare in literature. In this study, DM1 and demyelinating neuropathy were demonstrated clinically and electromyographically in a 43-year-old female patient from Turkey. In the patient an expanded CTG repeat in the Myotonic Dystrophy Protein Kinase (DMPK) gene was confirmed in combination with a duplication in the Charcot-Marie-Tooth Disease (CMT1A) gene. DM1 was also determined in her 25-year-old son.
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Neuropatía Hereditaria Motora y Sensorial/complicaciones , Distrofia Miotónica/complicaciones , Adulto , ADN/genética , Electrofisiología , Femenino , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Masculino , Debilidad Muscular/etiología , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/genética , Conducción Nerviosa , Examen Neurológico , Parestesia/etiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
GTPases of the Rho subfamily are widely involved in the myelination of the vertebrate nervous system. Rho GTPase activity is temporally and spatially regulated by a set of specific guanine nucleotide exchange factors (GEFs). Here, we report that disruption of frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42 (Cdc42), causes peripheral nerve demyelination in patients with autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. These data, together with the ability of frabin to induce Cdc42-mediated cell-shape changes in transfected Schwann cells, suggest that Rho GTPase signaling is essential for proper myelination of the peripheral nervous system.
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Enfermedad de Charcot-Marie-Tooth/genética , Enfermedades Desmielinizantes/genética , Proteínas de Microfilamentos/genética , Vaina de Mielina/enzimología , Nervios Periféricos/enzimología , Proteínas de Unión al GTP rho/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Enfermedades Desmielinizantes/patología , Femenino , Humanos , Masculino , Proteínas de Microfilamentos/análisis , Datos de Secuencia Molecular , Mutación , Vaina de Mielina/patología , Nervios Periféricos/patología , Células de Schwann/enzimología , Células de Schwann/patología , Proteínas de Unión al GTP rho/análisisRESUMEN
Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating peripheral neuropathy, and CMT Type 1A is the most common form. In most cases, CMT1A is usually caused by duplication at chromosome 17p11.2-12. Type 2 diabetes mellitus (Type 2 DM) is a common metabolic disorder, characterized by chronic hyperglycemia that can be associated with micro- and/or macrovascular complications. Only a few studies reported CMT1A duplication in association with Type 2 DM. This article explores the characteristics of a large family of 69 members with respect to CMT1A and Type 2 DM. CMT1A was detected in 28 of them. Molecular genetic study was performed in 22, and duplication was detected in all of them. Six of the 22 members with CMT1A also had Type 2 DM based on the American Diabetes Association diagnostic criteria. Association of these two conditions may be coincidental; however, the occurrence of these two diseases in this large family may also suggest a genetic basis. More extensive reports and further investigations of such families having this combination will certainly provide a better understanding of this link.