A Novel Homozygous Variant of SETX Causes Ataxia with Oculomotor Apraxia Type 2

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.

Homozygosity mapping and mutation analysis of a consanguineous marriage family with autosomal recessive cerebellar ataxia / 中华神经科杂志

Objective To identify the pathogenic gene for a Chinese Han consanguineous marriage family with autosomal recessive cerebellar ataxia by homozygosity mapping and mutation analysis.Methods Six members of the family were enrolled in this study,including 3 patients,the unaffected sibling and their parents of first cousin marriage.After excluding GAA repeats mutation of FXN gene,whole-genome single nucleotide polymorphism (SNP) microarray scanning and homozygosity mapping were performed to localize the candidate gene.The coding regions and intronic flanking sequences of the candidate genes were analyzed.Results Four candidate regions were identified,including 2p25.3,9q22.2-34.3,13q12.3-14.3 and 17p13.The SETX gene localizing in 9q22.2-34.3 that is responsible for ataxia with oculomotor apraxia 2 was analyzed at first.There were 4 mutations in exon 10,including three missense mutations (c.3576T ＞ G,p.D1192E ; c.3754G ＞ A,p.G1252R; c.4156A ＞ G,p.I1386V) and a deletion mutation (c.5084_5087delAGTC,p.Q1695_S1696del).Three patients were homozygous of the 4 mutations,an unaffected sibling was normal,and their parents were heterozygous of 4 mutations.Conclusions The pathogenic haplotype comprising four mutations of the SETX gene was identified in the consanguinity family.c.5084_5087delAGTC (p.Q1695_S1696del) is a novel mutation.The affected individuals of this family were characterized by mild phenotype and slow progress without oculomotor apraxia,indicating the clinical variability of the disease.

Ocular Abnormality of Korean Patients with Molecular Genetically Confirmed Gaucher Disease

PURPOSE: To investigate the ophthalmologic manifestations of Korean patients with Gaucher disease. METHODS: Clinical records of 5 patients who were referred to the pediatric ophthalmology clinic of Seoul National University Bundang Hospital after diagnosis of Gaucher disease at the genetics clinic of Ajou University Hospital between 2007 and 2008 were retrospectively reviewed. RESULTS: Five patients with type 3 Gaucher disease had hepatosplenomegaly and oculomotor apraxia, and 4 patients had growth and developmental delay. The most commonly detected genetic mutation was L444P. In addition, P201H, F2131, R257Q, and D315E+Rec 1b were identified. Five patients had oculomotor apraxia and limitation of abduction, and 4 patients had esotropia. One of the 4 patients who showed combined limitation of abduction, oculomotor apraxia, and esotropia, yet did not have growth and developmental delay. CONCLUSIONS: Most of the patients who were referred for ocular motor abnormalities with Gaucher disease showed a limitation of abduction, oculomotor apraxia, and esotropia. In patients with a limitation of abduction, oculomotor apraxia, and esotropia, Gaucher disease should be considered. Ophthalmologic examination is essential for subtyping and prognosing Gaucher disease.

Sporadic Congenital Oculomotor Apraxia Associated with Ataxia

PURPOSE: To evaluate the natural clinical course of sporadic congenital oculomotor apraxia associated with ataxia. METHODS: In a retrospective study from June 1994 to March 2004, 3 patients with sporadic congenital oculomotor apraxia associated with ataxia were evaluated. Oculomotor apraxia and ataxia were checked. RESULTS: The three patients with sporadic congenital oculomotor apraxia associated with ataxia showed a decrease in head thrust which can be found specifically in oculomotor apraxia, and an improvement of oculomotor apraxia and ataxia over the 10-year observation period. CONCLUSIONS: A favorable natural clinical course can be expected in a case of sporadic congenital oculomotor apraxia associated with ataxia in the absence of any clinical evidence of inheritance or genetic abnormality.