Autosomal Recessive Cerebellar Ataxia with Oculomotor Apraxia (Ataxia-Telangiectasia–Like Syndrome) Is Linked to Chromosome 9q34

Abstract

Ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome [AOA]; MIM 208920) is an autosomal recessive disorder characterized by ataxia, oculomotor apraxia, and choreoathetosis. These neurological features resemble those of ataxia-telangiectasia (AT), but in AOA there are none of the extraneurological features of AT, such as immunodeficiency, neoplasia, chromosomal instability, or sensitivity to ionizing radiation. It is unclear whether these patients have a true disorder of chromosomal instability or a primary neurodegenerative syndrome, and it has not been possible to identify the defective gene in AOA, since the families have been too small for linkage analysis. We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia. We have localized the disease gene, by linkage analysis and homozygosity mapping, to a 15.9-cM interval on chromosome 9q34. This work will ultimately allow the disease gene to be identified and its relevance to other types of autosomal recessive cerebellar ataxias to be determined.

Autosomal recessive spinocerebellar ataxia and peripheral neuropathy with raised ?-fetoprotein

“…The clinical and biochemical phenotype of our cases most closely resembles that described in AOA2 and shares some overlapping features with ATL [7]. In AOA2 and ATL, affected individuals have juvenile onset of ataxia and axonal neuropathy.…”

“…In addition other AT variant syndromes, ATLD [4], SCAN1 [5], AOA1 [8,9], and ATL [7] share overlapping clinical and laboratory characteristics with AT. Our patients developed ataxia and a sensory neuropathy, but had no evidence of oculomotor apraxia, telangiectasia, retinopathy, brainstem symptoms, choreoathetosis, myoclonus, pes cavus, intellectual impairment, deafness, diabetes, cardiomyopathy, gonadal dysfunction, somatic growth impairment, premature ageing, or cancer susceptibility.…”

“…Critical recombinations between D9S1861, D9S179 and D9S1830 in affected and unaffected sibs in family one, places the disease gene distal to D9S1830 and in family two, a critical recombination suggests the gene may lie proximal to D9S1818 at 9q34. This distance is estimated to be ~6.3cM [7]. …”

“…Laboratory tests showed borderline hypoalbuminaemia and hypercholesterolaemia and mutations in TDP1, at 14q31-q32 segregate with disease [5]. Ataxia with oculomotor apraxia (AOA1) [6], and ataxia-telangiectasia-like syndrome (ATL) [7] present with ataxia, oculomotor apraxia, choreoathetosis and peripheral neuropathy, but lack telangiectasia and the laboratory features of AT. Symptoms start in early childhood in AOA1, with hypoalbuminaemia, hypercholesterolaemia and pes cavus developing as the disease progresses.Most AOA1 families come from Portugal and Japan and mutations in aprataxin, APTX, at 9p13, are responsible for AOA1 [8,9].…”

“…Symptoms start in early childhood in AOA1, with hypoalbuminaemia, hypercholesterolaemia and pes cavus developing as the disease progresses.Most AOA1 families come from Portugal and Japan and mutations in aprataxin, APTX, at 9p13, are responsible for AOA1 [8,9]. ATL was described in five individuals from a single consanguineous Pakistani family, with an onset in late childhood, normal albumin, cholesterol, CK and AT laboratory investigations, and homozygosity mapping identified a locus at 9q34 [7]. Four individuals from a consanguineous Japanese family developed juvenile onset spinocerebellar ataxia and peripheral neuropathy (AOA2), with elevated levels of creatine kinase (CK), γ-globulin and AFP [10].…”