An unusual case of familial ALS and cerebellar ataxia

Yasser, Sadia; Fecto, Faisal; Siddique, Teepu; Sheikh, Kazim A.; Athar, Parveen

doi:10.3109/17482961003636874

Cited by 14 publications

(6 citation statements)

References 12 publications

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“…We generally found slightly diminished vibration sensation in our ALS cases. It is already histopathologically proven that posterior columns can be involved in autopsy cases [13,14]. Meanwhile, urinary symptoms are unusual in ALS; ALS was the cause of urinary symptoms in only 0.1-0.3% of lower urinary tract symptoms in a community-based cohort of men [15].…”

Section: Discussionmentioning

confidence: 99%

Association of amyotrophic lateral sclerosis and Behcet’s disease: is there a relationship? A multi-national case series

et al. 2012

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Neurological involvement may be seen in 5-30% of the patients with Behcet's disease (BD). Occasionally, parenchymal neurological involvement in BD can present as a spinal cord syndrome. However, motor neuron disease-like presentation is extremely uncommon. Here we are reporting five patients (all male; median age, 38) fulfilling both International Study Group criteria for BD and El Escorial criteria for amyotrophic lateral sclerosis (ALS). These patients were identified by a questionnaire sent to the members of the Neuro-Behcet Study Group of the International Study Group for BD. Three out of five patients had only motor presentations. In two patients, sensory and urinary manifestations were present as well. Spinal cord MRIs were normal in all, and brain MRIs were normal in four patients; one patient had nonspecific white matter changes. Two patients passed away 1-3 years after diagnosis of ALS, and two patients were lost to follow-up 3 and 11 years after admission; one patient is still alive 3 years after onset. The patients that are presented here might represent a rare form of neurological involvement in BD as well as sole coincidence. Larger prospective series are needed to further answer this issue.

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Section: Discussionmentioning

confidence: 99%

Association of amyotrophic lateral sclerosis and Behcet’s disease: is there a relationship? A multi-national case series

et al. 2012

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“…Its negatively charged side-chain exists in multiple rotamers and forms no interactions with its surroundings. Glu100Lys, which reduces net charge to −4, is likely to have limited structural effects, does not reduce erythrocyte SOD1 activity, can lead to a complicated phenotype with very long progression and was shown not to co-segregate with disease in two ALS families (Felbecker et al ., 2010; Yasser et al ., 2010; Keskin et al ., 2017). Conversely, the Glu100Gly mutation, which reduces SOD1 net charge only to −5, leads to a typical ALS phenotype with high penetrance (Cudkowicz et al ., 1997; Aggarwal and Nicholson, 2005; Wang et al ., 2008).…”

Section: Cryptic Mutationsmentioning

confidence: 99%

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

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Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

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“…The most peculiar finding in this family was the clinical presentation of ataxia and cognitive deficits without overt signs of MND in the proband’s father. The ataxic gait with repeated falls has been reported in a patient with fALS and a p.Glu100Lys variant in SOD1 ( 43 ). Early cognitive dysfunction, together with bulbar involvement, has been recently described in two unrelated families harboring a p.N66Thr mutation in SOD1 ( 44 ) and has been considered an exceptional finding in SOD1 -ALS so far.…”

Section: Resultsmentioning

confidence: 94%

Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study

et al. 2023

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IntroductionSOD1 was the first gene associated with both familial and sporadic forms of amyotrophic lateral sclerosis (ALS) and is the second most mutated gene in Caucasian ALS patients. Given their high clinical and molecular heterogeneity, a detailed characterization of SOD1-ALS patients could improve knowledge about the natural history of this disease. Here, the authors aimed to provide a clinical and molecular description of a monocentric cohort of SOD1-ALS patients.MethodsAmyotrophic lateral sclerosis (ALS) patients referring to the neurology unit of our center between 2008 and 2021 were clinically assessed and underwent molecular testing for SOD1. Segregation studies in available family members and in silico analysis were performed to sustain the pathogenicity of the identified SOD1 variants.ResultsAmong the 576 patients in our cohort, we identified 19 individuals harboring a mutation in SOD1 (3.3%), including 15 (78.9%) with a familial and four (21.1%) with a sporadic form. The spinal onset of the disease was observed in all patients, and survival was extremely variable, ranging from 8 months to over 30 years. Twelve different SOD1 missense variants were identified in our cohort, including one novel mutation (p.Pro67Leu).DiscussionIn the present series, we provided the first description of an Italian monocentric cohort of SOD1-ALS patients, and we expanded the repertoire of SOD1 mutations. Our cohort presents several remarkable features, including variable expressivity in the same family, atypical presentation (ataxia, cognitive impairment, and other extra-motor symptoms), and different modes of inheritance of a given mutation in the same family. Given the recent authorization of SOD1-directed antisense oligonucleotide for use in SOD1-ALS patients, we recommend prompt screening for SOD1 mutations in novel ALS patients with familiar or sporadic presentations.

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An unusual case of familial ALS and cerebellar ataxia

Cited by 14 publications

References 12 publications

Association of amyotrophic lateral sclerosis and Behcet’s disease: is there a relationship? A multi-national case series

Association of amyotrophic lateral sclerosis and Behcet’s disease: is there a relationship? A multi-national case series

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study

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