ResearchPad - 298 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[<i>TGM6</i> L517W is not a pathogenic variant for spinocerebellar ataxia type 35]]> https://www.researchpad.co/article/elastic_article_7785 To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6.MethodsNeurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype.ResultsThe proband, presenting with myoclonic epilepsy, cognitive decline, and ataxia, harbored both the TGM6 p.L517W variant and expanded CAG repeats in gene ATN1. Further analysis of the other living family members in this pedigree revealed that the CAG repeat number was expanded in all the patients and within normal range in all the unaffected family members. However, the TGM6 p.L517W variant was absent in 2 affected family members, but present in 3 healthy individuals.ConclusionsThe nonsegregation of the TGM6 variant with phenotype does not support this variant as the disease-causing gene in this pedigree, questioning the pathogenicity of TGM6 in SCA35. ]]> <![CDATA[Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia]]> https://www.researchpad.co/article/N4b558b06-8845-4208-b423-3e434f803484

Objective

To determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.

Methods

Homozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.

Results

We identified a homozygous mutation as causative of middle age–onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.

Conclusions

This is the report of middle age–onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.

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<![CDATA[Psychometric properties of the Friedreich Ataxia Rating Scale]]> https://www.researchpad.co/article/Nd7fbac11-63bd-4c2f-a9a2-3b4c14e6afbb

Objective

To investigate the psychometric properties of the Friedreich Ataxia Rating Scale neurologic examination (FARSn) and its subscores, as well as the influence of the modifications resulting in the now widely used modified FARS (mFARS) examination.

Methods

Based on cross-sectional FARS data from the FA–Clinical Outcome Measures cohort, we conducted correlation-based psychometric analyses to investigate the interplay of items and subscores within the FARSn/mFARS constructs.

Results

The results provide support for both the FARSn and the mFARS constructs, as well as individually for their upper limb and lower limb coordination components. The omission of the peripheral nervous system subscore (D) and 2 items of the bulbar subscore (A) in the mFARS strengthens the overall construct compared with the complete FARS.

Conclusions

A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.

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<![CDATA[The complex structure of ATXN2 genetic variation]]> https://www.researchpad.co/article/5c2d4200d5eed0c484e01ca1 ]]> <![CDATA[Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations]]> https://www.researchpad.co/article/5c16ccdad5eed0c4845238c7

Objective

To clinically, genetically, and radiologically characterize a large cohort of SPG7 patients.

Methods

We used data from next-generation sequencing panels for ataxias and hereditary spastic paraplegia to identify a characteristic phenotype that helped direct genetic testing for variations in SPG7. We analyzed MRI. We reviewed all published SPG7 mutations for correlations.

Results

We identified 42 cases with biallelic SPG7 mutations, including 7 novel mutations, including a large multi-exon deletion, representing one of the largest cohorts so far described. We identified a characteristic phenotype comprising cerebellar ataxia with prominent cerebellar dysarthria, mild lower limb spasticity, and a waddling gait, predominantly from a cohort of idiopathic ataxia. We report a rare brain MRI finding of dentate nucleus hyperintensity on T2 sequences with SPG7 mutations. We confirm that the c.1529C>T allele is frequently present in patients with long-standing British ancestry. Based on the findings of the present study and existing literature, we confirm that patients with homozygous mutations involving the M41 peptidase domain of SPG7 have a younger age at onset compared to individuals with mutations elsewhere in the gene (14 years difference, p < 0.034), whereas c.1529C>T compound heterozygous mutations are associated with a younger age at onset compared to homozygous cases (5.4 years difference, p < 0.022).

Conclusions

Mutant SPG7 is common in sporadic ataxia. In patients with British ancestry, c.1529C>T allele represents the most frequent mutation. SPG7 mutations can be clinically predicted by the characteristic hybrid spastic-ataxic phenotype described above, along with T2 hyperintensity of the dentate nucleus on MRI.

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<![CDATA[Homozygous 31 trinucleotide repeats in the SCA2 allele are pathogenic for cerebellar ataxia]]> https://www.researchpad.co/article/5c16ccd1d5eed0c48452370e ]]>