"Pseudodominant inheritance" of ataxia with ocular apraxia type 2 (AOA2).

Ataxia with ocular apraxia type 2 (AOA2) is an autosomal recessive, early onset ataxia caused by mutations in the senataxin (SETX) gene. Ocular apraxia and increased levels of alpha-fetoprotein are characteristic but not obligate markers of the disease. AOA2 is allelic with ALS4, a motor neuron disorder of early onset and autosomal dominant inheritance. We observed a two generation family with ataxia which started at age 14 and 17 in two sibs and at age 23 in their paternal uncle.Oculomotor disturbances included strabismus, saccadic pursuit and gaze evoked nystagmus. MRI revealed severe cerebellar atrophy. All patients presented pronounced peripheral neuropathy with wasting of hand and leg muscles resembling distal motor neuronopathy. Increased alphafetoprotein levels triggered genetic analyses of SETX. We found the sib pair to be compound heterozygous for a single base deletion c.2835delC, resulting in a frameshift mutation and causing nonsense related mRNA decay, and a base exchange c.6106G > A, resulting in abnormal splicing and skipping of exon 15. The similarly affected uncle was homozygous for the c.6106G > A mutation probably due to distant consanguinity in the paternal branch of the family. Pseudodominant occurrence in two generations has not been described before in AOA2 and led, in this family, to false categorization as dominant ataxia before SETX mutations were detected. Clinically this family presented with a phenotype combining typical features of AOA2 and ALS4; thus extending the phenotypic spectrum of SETX mutations.