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1.
Cerebellum ; 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39287920

RESUMO

Spinocerebellar ataxias (SCAs) are characterized by substantial phenotypic variability. Among them, SCA42 is a rare non-expansion entity presenting with slowly progressive cerebellar syndrome but whose clinical spectrum may be also wider. A 53-year-old male presented with progressive myoclonus-ataxia and intellectual disability. Genetic screening revealed a novel c.3835G > A (p. Asp1279Asn) variant in the CACNA1G gene. SCA42 is a rare non-expansion SCA caused by mutations in CACNA1G on chromosome 17q21, encoding the Ca(V)3.1, a low-threshold voltage-gated T-type calcium channel. The novel variant we identified is potentially involved in channel activity. This case expands the knowledge regarding CACNA1G-associated phenotype and highlights the importance of genetic screening in myoclonus-ataxia disorders.

2.
Neurol Sci ; 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39223423

RESUMO

BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT) is a heterogeneous group of genetic neuropathies and is typically characterized by distal muscle weakness, sensory loss, pes cavus and areflexia. Herein we describe a case of CMT2CC presenting with proximal muscle weakness and equivocal electrophysiological features, that was misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). CASE REPORT: A 30-year-old woman complained of proximal muscle weakness with difficulty climbing stairs. Neurological examination showed weakness in lower limb (LL) muscles, that was marked proximally and mild distally, and absence of deep tendon reflexes in the ankles. Nerve conduction studies (NCS) showed sensory-motor neuropathy with non-uniform NC velocity and a partial conduction block (CBs) in peroneal nerve and tibial nerves. Thus, a diagnosis of CIDP was entertained and the patient underwent ineffective treatment with intravenous immunoglobulins. At electrophysiological revaluation CB in peroneal nerve was undetectable as also distal CMAP had decreased whereas the CBs persisted in tibial nerves. Hypothesizing a hereditary neuropathy, we examined the proband's son, who presented mild weakness of distal and proximal muscles at lower limbs. Neurophysiological investigation showed findings consistent with an intermediate-axonal electrophysiological pattern. A targeted-NGS including 136 CMT genes showed the heterozygous frameshift mutation (c.3057dupG; p.K1020fs*43) in the NEFH gene, coding for the neurofilament heavy chain and causing CMT2CC. INTERPRETATION: Diagnosis of a genetic neuropathy may be challenging when clinical features are atypical and/or electrophysiological features are misleading. The most common misdiagnosis is CIDP. Our report suggests that also CMT2CC patients with proximal muscle weakness and equivocal electrophysiological features might be misdiagnosed as CIDP.

3.
Neurogenetics ; 24(3): 147-160, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37131039

RESUMO

Hereditary spastic paraplegia (HSP) refers to a group of heterogeneous neurological disorders mainly characterized by corticospinal degeneration (pure forms), but sometimes associated with additional neurological and extrapyramidal features (complex HSP). The advent of next-generation sequencing (NGS) has led to huge improvements in knowledge of HSP genetics and made it possible to clarify the genetic etiology of hundreds of "cold cases," accelerating the process of reaching a molecular diagnosis. The different NGS-based strategies currently employed as first-tier approaches most commonly involve the use of targeted resequencing panels and exome sequencing, whereas genome sequencing remains a second-tier approach because of its high costs. The question of which approach is the best is still widely debated, and many factors affect the choice. Here, we aim to analyze the diagnostic power of different NGS techniques applied in HSP, by reviewing 38 selected studies in which different strategies were applied in different-sized cohorts of patients with genetically uncharacterized HSP.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Paraplegia Espástica Hereditária , Humanos , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Testes Genéticos , Loci Gênicos
4.
Neurol Sci ; 43(2): 1071-1077, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34296356

RESUMO

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a "pure" cerebellar phenotype, and one a "pure" spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14-18. Interestingly, this patient had the most "complex" presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.


Assuntos
Atrofia Óptica , Paraparesia Espástica , Paraplegia Espástica Hereditária , Ataxias Espinocerebelares , Ataxia/diagnóstico por imagem , Ataxia/genética , Criança , Humanos , Mutação , Fenótipo , RNA Polimerase III/genética , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genética
5.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445196

RESUMO

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Degenerações Espinocerebelares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento do Exoma , Adulto Jovem
6.
J Neurol ; 269(10): 5431-5435, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35633373

RESUMO

We screened 62 late-onset ataxia patients for the AAGGG pathological expansion in the RFC-1 gene that, when biallelic, causes Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS). Nine patients tested positive. Six had a previous diagnosis of sporadic adult-onset ataxia (SAOA) and three of multisystem atrophy type C (MSA-C). Further six patients were heterozygous for the pathological RFC-1 expansion, four with an initial diagnosis of MSA-C and two of SAOA. In comparison with CANVAS, MSA-C patients had faster progression and shorter disease duration to walking with aids. An abnormal DaTscan does not seem to contribute to differential diagnosis between CANVAS and MSA-C.


Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Atrofia de Múltiplos Sistemas , Doenças do Sistema Nervoso Periférico , Doenças Vestibulares , Adulto , Ataxia/diagnóstico , Ataxia/genética , Vestibulopatia Bilateral/diagnóstico , Ataxia Cerebelar/genética , Diagnóstico Diferencial , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Reflexo Anormal , Síndrome , Doenças Vestibulares/diagnóstico
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