Clinical and Molecular Characterization of Ataxia with Oculomotor Apraxia Patients In Saudi Arabia

Abstract

BackgroundAutosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia.MethodsThis study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11).ResultsA novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia.ConclusionMutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene.

MRE11A Gene Mutations Responsible for the Rare Ataxia Telangiectasia-Like Disorder

“…Therefore, the diagnosis of MRE11A ATLD should be in the mind of physicians whenever they encounter an A-T like disorder and genetic study should be carried out to confirm the diagnosis. This is how the 5 patients reported by Bohlega and colleagues were diagnosed (Bohlega et al, 2011). The fact that the 10 previously described Saudi ATLD patients (Fernet et al, 2005) are from the central region of Saudi Arabia could suggest higher frequency of this mutation in geographically isolated families www.intechopen.com with high level of consanguineous marriages.…”

“…Age at onset is almost similar to that of AT, but disease progression is slower with the absence of telangiectasia. Pedigrees and further details on these families were described previously (Fernet et al, 2005;Bohlega et al, 2011). Clinical features include progressive ataxia that was noted as early as two years old in some patients.…”

“…Taylor et al, 2004;Fernet et al, 2005;Uchisaka et al, 2009;Bohlega et al, 2011;Matsumoto et al, 2011). The 4 British patients belonged to 2 unrelated families.…”

“…The 15 Saudi Arabian patients were related to 5 independent families and represent the largest ATLD cohort (Fernet et al, 2005;Khan et al, 2008;Bohlega et al, 2011). Genetic studies have identified in all patients the same G to C transversion at position 630 (c.630G>C) located in exon 7, which results in the missense change of Trp to Cys (W210C).…”

DNA Repair Defects

“…ATLD is a disease that develops slowly until around 14 years of age and then stabilizes. 115,116 Two cases in Japan had clinical features similar to Nijmegen Breakage syndrome, comprising severe microcephaly, bird-like facies, compromised growth, and mental retardation. In younger children, delayed speech and writing difficulties have been described.…”