De Novo Deletion of AFG3L2 Causing Spinocerebellar Ataxia Type 28 in the Context of Multiple Genomic Anomalies (P6.046)

OBJECTIVE: Present a case of spinocerebellar ataxia 28 (SCA28) secondary to de novo deletion of AFG3L2. BACKGROUND: SCA28 is one of the less common autosomal dominant progressive spinocerebellar ataxias. The clinical phenotype is juvenile-onset, slowly progressive ataxia with associated ophthalmoplegia and gaze-evoked nystagmus. The causative gene is AFG3L2, located at 18p11. Missense mutations of this gene have been the identified genetic abnormality in all individuals described thus far. DESIGN/METHODS: Comparative genomic hybridization microarray was used, along with standard genetic analysis techniques. RESULTS: 23 year old man with global developmental delay had continued to slowly acquire motor and language milestones until 13 years of age, when the onset of progressive neurologic deterioration, including ataxia and abnormal eye movements, was noted. MRI of the brain at 16 years of age showed mild cerebellar atrophy. Cytogenetic investigations demonstrated one full additional copy of the X chromosome with a full complement of the Y chromosome (Klinefelter syndrome) as a Y;18 translocation. In addition, a 5.3 MB deletion in the region 18p11.23-p11.21 including 33 RefSeq genes (including AFG3L2) and a 6.72 MB mosaic deletion in the region 18p11.32-p11.31 including 38 RefSeq genes were identified and were shown to reside on the translocated chromosome 18. In addition a 39 CAG repeat expansion in the HD gene at 4p16.3 (reduced penetrance Huntington disease) was identified. CONCLUSIONS: The neurologic deterioration is clinically consistent with the few previously described cases of SCA28 and, in this case, is presumed to be secondary to the heterozygous deletion of AFG3L2. This appears to be a de novo change, as there is no family history of ataxia, chromosome testing of both parents was normal, and the deletion likely happened in concert with the Y;18 translocation. This demonstrates a novel genetic mechanism for generation of the SCA28 phenotype.

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