A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-4 (SCAR4) is caused by compound heterozygous mutation in the VPS13D gene (608877) on chromosome 1p36.

Autosomal recessive spinocerebellar ataxia-4 (SCAR4) is a neurologic disorder characterized by abnormal movements. Most patients have ataxic gait with spasticity and hyperreflexia of the lower limbs resulting in difficulty walking. The age at onset is highly variable: some have onset in early childhood with delayed walking, whereas others have onset of gait difficulties in adulthood. Additional features may include dysarthria, oculomotor abnormalities, distal sensory impairment, dystonia, chorea, hypotonia, pyramidal signs, and cerebellar atrophy on brain imaging. The disorder is slowly progressive. Some patients with onset in childhood may have global developmental delay with mildly impaired intellectual development (summary by Seong et al., 2018).

Swartz et al. (2002) reported a family of Slovenian descent in which 5 of 14 sibs presented with progressive ataxia beginning in the third decade with gait unsteadiness and difficulty reading. All patients eventually showed gait, trunk, and limb ataxia, as well as pyramidal tract signs with increased reflexes and extensor plantar responses. Also present were myoclonic jerks, fasciculations, impaired joint position sense, cerebellar dysarthria, and mild pes cavus. There was also striking disturbance of eye movements, with horizontal macrosaccadic oscillations of a high velocity that were induced with each gaze shift. The pattern of inheritance appeared to be autosomal recessive.

On follow-up of the same family, Swartz et al. (2003) reported that all sensory modalities, including vibration, joint position, thermal, and pain, were impaired over the feet and calves of affected individuals. Limb ataxia and dysarthria were progressive, with all affected members requiring walking aids by age 49 to 56 years. Nerve conduction studies showed mild to moderate axonal sensorineural peripheral neuropathy in all 5 affected individuals. MRI showed mild cerebellar atrophy with involvement of the dorsal vermis. Affected individuals showed overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades; other eye movements were normal. Swartz et al. (2003) postulated that slowed conduction in axons could explain both the sensorimotor neuropathy and the saccadic disorder, which would be caused by delayed feedback control due to slowed conduction in cerebellar parallel fibers.

Seong et al. (2018) reported follow-up of the family reported by Swartz et al. (2002, 2003) (family UM1) and reported 2 sisters from an unrelated German family (family LUB1) with the disorder. They also reported 5 additional unrelated patients with SCAR4 who were identified from international collaboration studies. Most of the patients were adults, although 2 of the 5 sporadic cases were 2 and 6 years of age. Affected members in the 2 families and 1 of the sporadic cases had onset of gait ataxia or spasticity between 20 and 40 years of age, whereas 4 of the sporadic cases had onset of delayed walking and gait difficulties before the age of 5. All patients had gait difficulties, either ataxic gait or spasticity of the lower limbs, and many of the adults were wheelchair-bound. Additional common features included pyramidal signs, weakness and/or atrophy of the lower limbs, hyperreflexia, extensor plantar responses, dysarthria, and oculomotor dysfunction with saccadic pursuit or saccadic oscillations, hypermetric saccades, and nystagmus. About half of patients had cerebellar atrophy on brain imaging, and about half had distal sensory impairment, including 2 patients who had electrophysiologic evidence of an axonal peripheral neuropathy. All had normal cognition except for 2 unrelated children who had global developmental delay with delayed or absent walking, mild intellectual disability, and speech delay.

Gauthier et al. (2018) reported 7 patients from 5 unrelated families with a slowly progressive neurologic disorder with onset before 12 years of age. Four patients were adults and 3 were children at the time of the report. The patients were of various origins, including French Canadian, Egyptian, European, and Italian. Common features at presentation included axial hypotonia, gait instability, frequent falls, developmental delay, and mild intellectual disability. Progressive spastic ataxia and dystonia became apparent in adulthood. Two sibs in 1 family (family 4) had a slightly different phenotype with normal motor and cognitive development and resting and action tremor, with later onset of pyramidal signs, dystonia, hyperreflexia, and variable spasticity. Brain imaging of 4 patients from 3 families showed T2-weighted signal abnormalities in the basal ganglia. Brain imaging in family 4 showed more diffuse white matter abnormalities. The 2 most severely affected individuals (families 3 and 5), who were children, had symptom onset soon after birth and showed global developmental delay with microcephaly, hypotonia, dystonia, chorea, and seizures. One of these patients was unable to walk at age 3.

The transmission pattern of SCAR4 in the family reported by Swartz et al. (2002) was consistent with autosomal recessive inheritance.

By genomewide linkage analysis of a Slovenian family with spinocerebellar ataxia with saccadic intrusions, Burmeister et al. (2002) identified a candidate locus on chromosome 1p36 (maximum lod score of 3.03). The 30-cM (13-Mb) nonrecombinant region was flanked by markers D1S468 and D1S507.

In affected members of 2 unrelated families (UM1 and LUB1) with SCAR4, Seong et al. (2018) identified compound heterozygous mutations in the VPS13D gene (608877.0001-608877.0004). The mutations in the first family (UM1) were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing; this family had previously been reported by Swartz et al. (2002). Mutations in the second family were also found by whole-exome sequencing. International collaboration studies sharing whole-exome data identified 5 additional patients with sporadic occurrence of the disorder who had biallelic mutations in the VPS13D gene. All mutations were confirmed by Sanger sequencing. All but 2 patients were compound heterozygous for a missense and a loss-of-function mutation; the 2 patients who had biallelic mutations that presumably resulted in a loss of function had a more severe disorder with earlier onset. Fibroblasts derived from family UM1 showed abnormal mitochondrial morphology, with high amounts of perinuclear spherical or donut-shaped objects and decreased mitochondrial branching compared to controls, whereas fibroblasts derived from family LUB1 showed decreased mitochondrial branching and reduced ATP production compared to controls. Functional studies of the variants were not performed.

In 7 patients from 5 unrelated families of various ethnic descent with SCAR4, Gauthier et al. (2018) identified homozygous or compound heterozygous mutations in the VPS13D gene (see, e.g., 608877.0005-608877.0007). The families were collected using the GeneMatcher collaborative project. All mutations were found by exome sequencing and confirmed by Sanger sequencing to segregate with the disorder in the families. Affected members of 3 families were compound heterozygous for a loss-of-function and a missense mutation, whereas affected members of 2 families were homozygous or compound heterozygous for 2 missense mutations. Functional studies of the variants and studies of patient cells were not performed, but muscle biopsy of 1 patient showed mitochondrial abnormalities. Gauthier et al. (2018) postulated a loss-of-function pathogenetic mechanism.

Seong et al. (2018) noted that complete knockdown of the homolog of the Vps13d gene in Drosophila and mouse is embryonic lethal. Vps13d-null flies had abnormal mitochondrial morphology. Specific knockdown of the gene in Drosophila motoneurons resulted in enlarged spherical mitochondria with loss of complexity of the mitochondrial network within neurons, as well as impairment of the distribution of mitochondria in the peripheral axons of segmental nerves and neuromuscular junction synapses. The authors noted that these findings could represent defects in mitochondrial fission and fusion.