We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.
"No mutation was found in patient ZM. Our findings confirm the hypothesis that variants of ANG gene may influence clinical manifestations in patients bearing SOD1 mutation (Penco et al., 2011). ANG mutations were recently reported in 2 patients harboring FUS mutations , but the possible effect on phenotypic variability was not investigated (Millecamps et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: SOD1 G93D mutation has been described in amyotrophic lateral sclerosis (ALS) patients with slowly progressive disease. We describe an Italian patient affected by sporadic ALS with the SOD1 G93D mutation that disclosed an unusual rapid progression with death occurring after 30 months from the symptom onset. Considering the atypical clinical course further genes associated with ALS or known to be causative were studied including ANG, PGRN, TARDBP, FUS, VCP, CHRNA3, CHRNA4, and CHRNB4. A novel heterozygous ANG missense variant (c.433 C>T, p.R145C) was identified which is neither reported in controls nor in 1000 genomes and single nucleotide polymorphism (SNP) databases. This report confirms that clinical course of SOD1-related ALS may be modulated by other causative or associated genes, including ANG and suggests that extensive screening of ALS-associated genes in patients with an already identified mutation may be helpful for better knowledge of genetic architecture of ALS.
Neurobiology of aging 05/2011; 32(10):1924.e15-8. DOI:10.1016/j.neurobiolaging.2011.04.004 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Scleroderma is a rare systemic autoimmune disease with multiple organ manifestations, including skin fibrosis. The groups of disorders classified as scleroderma mimics share the common thread of skin thickening but are otherwise quite incongruous in terms of underlying disease process and other organ involvement. This article reviews the clinical presentation, etiology, and treatment options available for scleroderma mimics, including morphea, scleredema, diabetic cheiroarthropathy, scleromyxedema, nephrogenic systemic fibrosis, and eosinophilic fasciitis. Through greater understanding of these diseases and the associated extradermal implications, we hope to facilitate recognition of scleroderma and its mimics.
Current Rheumatology Reports 12/2011; 14(1):39-46. DOI:10.1007/s11926-011-0220-8 · 2.87 Impact Factor
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