RESUMO
Neurofilaments are neuron-specific intermediate filaments essential for the radial growth of axons during development and the maintenance of axonal diameter. Pathogenic variants of Neurofilament Light (NEFL) are associated with CMT1F, CMT2E, and CMTDIG and have been observed in less than 1% of Charcot-Marie-Tooth (CMT) cases, resulting in the reporting of 35 variants in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing. No genotype-phenotype correlations have yet been established. Here, we report an additional case: a 69-year-old female, who originally presented with axonal sensory and motor neuropathy at the age of 45, associated with moderate sensorineural hearing loss, with a slight slope at high frequencies. Next-generation sequencing identified a novel pathogenic variant: c.269A > G, p.(Glu90Gly). Hearing impairment is often linked to CMT due to pathogenic variants of NEFL, especially p.(Glu90Lys) and p.(Asn98Ser), and in our case p.(Glu90Gly). These pathogenic variants are all located at hot spots, in the head domain and the two ends of the rod domain of the protein.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Neurofilamentos/genética , Idoso , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Literatura de Revisão como AssuntoRESUMO
PHARC syndrome (MIM612674) is an autosomal recessive neurodegenerative pathology that leads to demyelinating Polyneuropathy, Hearing loss, cerebellar Ataxia, Retinitis pigmentosa, and early-onset Cataracts (PHARC). These various symptoms can appear at different ages. PHARC syndrome is caused by mutations in ABHD12 (α-ß hydrolase domain 12), of which several have been described. We report here a new complex homozygous mutation c.379_385delAACTACTinsGATTCCTTATATACCATTGTAGTCTTACTGCTTTTGGTGAACACA (p.Asn127Aspfs*23). This mutation was detected in a 36-year-old man, who presented neuropathic symptoms from the age of 15, using a next-generation sequencing panel. This result suggests that the involvement of ABHD12 in polyneuropathies is possibly underestimated. We then performed a comparative study of other patients presenting ABHD12 mutations and searched for genotype-phenotype correlations and functional explanations in this heterogeneous population.
Assuntos
Ataxia/genética , Catarata/genética , Análise Mutacional de DNA , Monoacilglicerol Lipases/genética , Mutação/genética , Polineuropatias/genética , Retinose Pigmentar/genética , Adulto , Animais , Ataxia/fisiopatologia , Catarata/fisiopatologia , Homozigoto , Humanos , Masculino , Modelos Moleculares , Polineuropatias/fisiopatologia , Retinose Pigmentar/fisiopatologiaRESUMO
We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4-c.122T>C patients suffering from Charcot-Marie-Tooth disease type 4J (AR-CMT-FIG4). This syndrome usually involves compound heterozygosity associating FIG4-c.122T>C, a hypomorphic allele coding an unstable FIG4-p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progression, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients' observations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR-CMT-FIG4-patients might be efficient.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Doenças Desmielinizantes/genética , Flavoproteínas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Adulto , Alelos , Doenças Desmielinizantes/fisiopatologia , Testes Genéticos , Genótipo , Homozigoto , Humanos , Padrões de Herança , Masculino , Mutação , FenótipoRESUMO
BACKGROUND: CMTX5 is characterized by peripheral neuropathy, early-onset sensorineural hearing impairment, and optic neuropathy. Only seven variants have been reported and no genotype-phenotype correlations have yet been established. PRPS1 has a crystallographic structure, as it is composed of three dimers that constitute a hexamer. METHODS: Next-generation sequencing (NGS) was performed using a custom 92-gene panel designed for the diagnosis of Charcot-Marie-Tooth (CMT) and associated neuropathies. RESULTS: We report the case of a 35-year-old male, who had presented CMT and hearing loss since childhood associated to bilateral optic neuropathy without any sign of retinitis pigmentosa. A new hemizygous variant on chromosomic position X:106,882,604, in the PRPS1 gene, c.202A > T, p.(Met68Leu) was found. This change is predicted to lead to an altered affinity between the different subunits in the dimer, thereby may prevent the hexamer formation. CONCLUSION: CMTX5 is probably under-diagnosed, as an overlap among the different features due to PRPS1 exists. Patients who developed polyneuropathy associated to sensorineural deafness and optic atrophy during childhood should be assessed for PRPS1.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Dimerização , Perda Auditiva Central/genética , Perda Auditiva Neurossensorial/genética , Transtornos Musculares Atróficos/genética , Atrofias Ópticas Hereditárias/genética , Polineuropatias/genética , Ribose-Fosfato Pirofosfoquinase/genética , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico , Surdez/genética , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Polineuropatias/diagnóstico , Conformação Proteica , Retinose Pigmentar , Ribose-Fosfato Pirofosfoquinase/químicaRESUMO
BACKGROUND: The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known. METHODS: The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype-genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed. RESULTS: Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype-phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4. CONCLUSION: Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.