Co‐occurrence of <i>ATXN3</i> and <i>ATXN2 </i>repeat expansions in Chinese ataxia patients with slow saccades

Wu, Chao; Cai, Quan; You, Huajing; Zhou, Xin; Chen, Dingbang; Mo, Guiling; Li, Xunhua

doi:10.1002/mgg3.663

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…In our Family B, both the proband and her father were heterozygous for a 41-repeat expansion in TBP . Repeat expansions of 41–45 in TBP have been described as intermediate penetrant alleles associated with SCA17 [ 23 , 24 ]; however, the pathogenicity of the 41-repeat expansion allele has been questioned since it is present at a minor allele frequency of 0.5–0.7% in control populations [ 25 , 26 ] and has been found in many asymptomatic individuals [ 27 ]. Since no SCA17 families with a heterozygous 41-repeat allele and dominant inheritance have been published, it is highly unlikely that this alone can cause the severe phenotype in patient II-1, and milder effects on I-2 in family B.…”

Section: Discussionmentioning

confidence: 99%

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16

Pakdaman

Berland

Bustad

et al. 2021

IJMS

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Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.

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Section: Discussionmentioning

confidence: 99%

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16

Pakdaman

Berland

Bustad

et al. 2021

IJMS

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“…[1,2] The co-existence of TNRe in two different SCA genes in a single patient is seldom reported. The evidence from literature illustrates co-existence of SCA2 with SCA12, [3] SCA8 with SCA1, SCA3 and SCA6, [4][5][6] SCA2 with SCA10, [7] SCA3 with SCA2 and SCA17 [8,9] in a single patient. To the best of our knowledge, co-occurrence of SCA1 and SCA2 in a single individual has not been reported so far.…”

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confidence: 99%

A Novel Co‐existence of Spinocerebellar Ataxia 1 and Spinocerebellar Ataxia 2 Mutations in Indian Patients

Sharma

Sonakar

Goel

et al. 2022

Movement Disord Clin Pract

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BackgroundBackground: Spinocerebellar ataxia 1 (SCA1) and SCA2 are dominantly inherited ataxias caused due to CAG expansion mutation in ATXN1 (CAG≥39) and ATXN2 (CAG≥32) genes located at 6p22.3 and 12q24.12 loci, respectively, with key manifestations of progressive limb and gait ataxia and with or without brain stem and pyramidal tract involvement. Both SCA1 and SCA2 are quite prevalent subtypes among the SCAs. There are very few reports that describe a combinatorial SCA subtype mutation in a single patient. Cases Cases: Here, we report a novel co-occurrence of SCA1 and SCA2 mutations in two unrelated patients. Case-1 was observed to carry ATXN1-CAG (30/40) and ATXN2-CAG (23/45), while case-2 harbored ATXN1-CAG (29/42) and ATXN2-CAG (23/41). Overall, the clinical outcome was complex with probable early onset than expected in Case-1 and in Case-2, we observed a significant delayed onset of the disease than expected. Conclusion Conclusion:These cases highlight the probabilistic interactive outcome of two unrelated genetic events towards a converging phenotype. Case Series Case 1A 25 year old male (Fig. 1A: III:3) presented in our clinic with a history of gait ataxia for the past 10 years (AO: 15 years). The patient reported no history of alcohol, smoking, or any other substance abuse. The patient gradually developed slurred speech and upper limb in-coordination within the next 5 years of disease progression (AO: 20 years). There were no signs of visual, sensory, hearing impairment or psychogenic symptoms experienced by the patient. Cerebellar signs like gait ataxia, impaired finger to nose test, impaired heel to shin test, dysarthria, dysdiadochokinesia and slow saccades were assessed during clinical assessment of the patient. The patient did not show any symptoms of fasciculation, broken pursuits, nystagmus, dysphasia, tremor and dementia but had complaints of excessive sleep. His mini mental state examination (MMSE) score was 30.

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Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

Sharma

Sonakar²,

Tyagi

et al. 2022

Advanced Genetics

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Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30–40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients’ referrals (Pan‐India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co‐occurrence of SCA‐subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA‐FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.

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Co‐occurrence of ATXN3 and ATXN2 repeat expansions in Chinese ataxia patients with slow saccades

Cited by 4 publications

References 18 publications

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16

A Novel Co‐existence of Spinocerebellar Ataxia 1 and Spinocerebellar Ataxia 2 Mutations in Indian Patients

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

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