A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-43 (SCA43) is caused by heterozygous mutation in the MME gene (120520) on chromosome 3q25. One such family has been reported.

Spinocerebellar ataxia-43 is an autosomal dominant, slowly progressive neurologic disorder characterized by adult-onset gait and limb ataxia and often associated with peripheral neuropathy mainly affecting the motor system, although some patients may have distal sensory impairment (summary by Depondt et al., 2016).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Depondt et al. (2016) reported a large 5-generation Belgian family in which 7 living members had adult-onset spinocerebellar ataxia and peripheral neuropathy. The 69-year-old proband presented around age 58 with gait and balance problems and pain in the distal lower limbs. She had pes cavus, mild distal lower limb atrophy, hyporeflexia with absent Achilles reflexes, and mild upper and lower limb ataxia. She also had mild upper limb cogwheel rigidity, positive palmomental reflex, hypometric saccades, and dysarthria. Sensory examination was normal. EMG showed a severe motor neuropathy with preserved sensory responses; nerve conduction velocities were normal. Brain imaging showed moderate cerebellar vermis atrophy. The 6 additional living affected family members had similar features, including balance problems, ataxia, unsteady gait, tremor, and hyporeflexia. More variable features included dysarthria, nystagmus, and distal sensory impairment consistent with a peripheral polyneuropathy. Two patients had an MRI that showed cerebellar atrophy, and 1 patient had a sural nerve biopsy that showed axonal neuropathy. Many of the patients also had pectus carinatum. None of the individuals reported cognitive problems.

The transmission pattern of SCA43 in the family reported by Depondt et al. (2016) was consistent with autosomal dominant inheritance.

In 7 affected members of a large Belgian family with SCA43, Depondt et al. (2016) identified a heterozygous missense mutation in the MME gene (C143Y; 120520.0006). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Sequencing of the MME gene in 96 additional patients with dominant ataxia did not identify any more mutations.