Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia

Abstract

BACKGROUND Sporadic-onset ataxia is common in a tertiary care setting but a significant percentage remains unidentified despite extensive evaluation. Rare genetic ataxias, reported only in specific populations or families, may contribute to a percentage of sporadic ataxia. METHODS Patients with adult-onset sporadic ataxia, who tested negative for common genetic ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia), were evaluated using a stratified screening approach for variants in seven rare ataxia genes. RESULTS We screened patients for published mutations in SYNE1 (n=80) and TGM6 (n=118), copy number variations in LMNB1 (n=40) and SETX (n=11), sequence variants in SACS (n=39) and PDYN (n=119), and the pentanucleotide insertion of spinocerebellar ataxia type 31 (n=101). Overall, we identified one patient with a LMNB1 duplication, one patient with a PDYN variant, and one compound SACS heterozygote, including a novel variant. CONCLUSIONS The rare genetic ataxias examined here do not significantly contribute to sporadic cerebellar ataxia in our tertiary care population.

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

“…The classic phenotype associated with this gene is an autosomal recessive adult-onset pure cerebellar ataxia, 3,4,32 a presentation commonly seen in sporadic cases presenting to an ataxia clinic. 10 Because of the large size of this gene with 146 exons in the canonical transcript (ENST00000423061; Ensembl database; http://www.ensembl.org/), next-generation sequencing is the only cost-effective means for routine clinical screening. 10 Previously only reported in the French-Canadian population, more widespread sequencing efforts have identified additional cases from France (1 case), Brazil (1 case), and Japan (3 cases), 32–34 consistent with the observation of multiple cases in this cohort and suggesting this to be a worldwide disorder with higher prevalence than previously known.…”

“…8,9 This is a potentially useful addition to the physician’s armamentarium because, given the number of rare genes related to ataxia, overuse of low-yield single-gene and genetic panel testing represents a significant cost to patient health care. 7,10 The anticipated widespread benefits of CES have already prompted recommendations for its inclusion as part of routine clinical algorithms. 4,5,9,11,12 Although CES is much less expensive than sequentially examining multiple single genes, there are limited data to support the widespread use of this testing as part of the standard evaluation of patients with cerebellar ataxia especially those without a family history.…”

Hereditary ataxias: overview

“…If no acquired cause of the ataxia is identified, the probability is ~13% that the affected individual has SCA1, SCA2, SCA3, SCA6, SCA8, SCA17, or FRDA, 74 and mutations in rare ataxia genes are even less common. 75 Other possibilities to consider are a de novo mutation in a different autosomal dominant ataxia, decreased penetrance, alternative paternity, or a single occurrence of an autosomal recessive or X-linked disorder in a family such as fragile X-associated tremor/ataxia syndrome. Although the probability of a positive result from molecular genetic testing is low in an individual with ataxia who has no family history of ataxia, such testing is usually justified to establish a specific diagnosis for the individual's medical evaluation and for genetic counseling.…”

1H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms

“…The genetic basis of the disease is a duplication of the lamin B1 gene (LMNB1) [4]. Since the first description, ADLD with LMNB1 duplications has been reported in 12 families [4][5][6][7][8][9]. The patients usually present in the fourth to sixth decade with autonomic symptoms such as trouble with bowel and bladder regulation and orthostatic hypotension, later progressing to show symptoms from cerebellar and corticospinal tracts.…”