“Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2)

Abstract

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.

Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2

“…26 Sensorimotor axonopathy has been reported in AOA2 by a number of investigators. 3,4,6,11,12,15,22,27 However, as neither electromyographic (EMG) recordings of proximal muscles nor conduction studies of nerves of the proximal segments of the limbs were mentioned in those studies, and as somatosensory evoked potentials were documented only once, 4 it appears those studies did not aim to distinguish axonopathy from neuronopathy.…”

Sensory neuronopathy in ataxia with oculomotor apraxia type 2

“…AOA2 has been associated with various alterations that cause frameshift, nonsense, and missense mutations [15]. The missense mutation presented in this manuscript, c.7331GNA(p.Arg2444Hist), has been described previously [16,23] and consists of a homozygous substitution of guanine for adenine at position 7331, in exon 26 of the SETX gene.…”

“…Sensorimotor axonopathies [3,4,6,7,[13][14][15][16] and neuronopathies [17] have been reported in AOA2, although some authors have reported isolated sensory involvement in AOA2, on clinical grounds alone [2,16].…”

“…The SETX gene has an open reading frame of 8031 nucleotides [15]. AOA2 has been associated with various alterations that cause frameshift, nonsense, and missense mutations [15].…”

Ataxia oculomotor apraxia type 2: course over 27 years and a novel stop mutation in the senataxin gene

“…The disorder was first described in Japanese [11] and Pakistani [8] families, later reports included six families from different Mediterranean areas and the West Indies [5], ten French-Canadian families known as the Quebec cluster [3], four families from Italy [2], one German [10] and one Cypriot family [9]. Although included in the disease name, oculomotor apraxia is not obligatory for diagnosis of AOA2 and was absent in our patient [3][4][5].…”