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Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic l…
ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion
Abstract There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS ca…
Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis
Key Points Question What genetic variants are associated with juvenile amyotrophic lateral sclerosis (ALS)? Findings In this family-based genetic study, exome sequencing was performed in 3 patients diagnosed with juvenile ALS and failure to thrive; this identified de novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient). Variants in SPTLC1 are a known cause of hereditary sensory and autonomic neuropathy, type 1A, and these data extend the phenotype associated with this gene. Meaning De novo variants in the SPTLC1 gene are associated with juvenile ALS, a fatal neurological disorder.
Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation
Recently, fused in sarcoma/translated in liposarcoma (FUS/TLS) gene, located on chromosome 16p11.2, has been identified as a disease gene in familial amyotrophic lateral sclerosis (FALS). We have analyzed FUS/TLS in a cohort of 52 index cases from seven Italian regions with non-SOD1 and non-TARDBP FALS. We identified a heterozygous c.G1542C missense mutation in a family of northern Italian origin, and a heterozygous c.C1574T missense mutation in a family of Sicilian origin. Both variants are located in exon 15 encoding the RNA-recognition motif, and result in a substitution of an arginine with a serine in position 514 (p.R514S) and substitution of a proline with a leucine at position 525 (p…
CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients
Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n= 64) and apparently sporadic ALS (n= 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHC…
Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register
Abstract Background Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. Methods This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000–2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing–remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers’ characteristics, geographic macro-ar…