A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-49 (SCA49) is caused by heterozygous mutation in the SAMD9L gene (611170) on chromosome 7q21. One such family has been reported.

Spinocerebellar ataxia-49 (SCA49) is an autosomal dominant neurologic disorder characterized initially by gait abnormalities, gaze-evoked nystagmus, and hyperreflexia. The age at onset is highly variable, ranging from the second to seventh decades, even within the same family. The disorder is slowly progressive, and later features may include dysarthria, dysmetria, diplopia, pyramidal signs, and axonal peripheral neuropathy. Brain imaging shows cerebellar atrophy and myelination defects (Corral-Juan et al., 2022).

Corral-Juan et al. (2022) reported a large 5-generation Spanish family (M-SCA) from Menorca in which 11 individuals had spinocerebellar ataxia. Detailed clinical information was provided for 9 patients who were all adults at the time of report. The age at symptom onset was highly variable, ranging from 12 to 60 years. The presenting signs were unsteady gait, vertical and horizontal gaze-evoked nystagmus, and hyperreflexia. The disorder was slowly progressive with later onset of gait ataxia between 30 and 60 years of age. More variable features that developed as the disease progressed included dysarthria, dysmetria, diplopia, oscillopsia, and strabismus. Some patients showed dysdiadochokinesis and extensor plantar responses with pyramidal signs. One younger patient had ankle clonus and pes cavus. Five patients had a moderate axonal sensory polyneuropathy of the lower limbs which progressed to the upper limbs at later stages. Two patients became wheelchair-bound in their seventies. All 5 patients who underwent brain imaging studies showed cerebellar atrophy and diffuse cerebral demyelination. None of the patients had seizures, cognitive impairment, extrapyramidal signs, or hematologic abnormalities.

The transmission pattern of SCA49 in the family reported by Corral-Juan et al. (2022) was consistent with autosomal dominant inheritance.

In 9 affected individuals from a multigenerational Spanish family (M-SCA) with SCA49, Corral-Juan et al. (2022) identified a heterozygous missense mutation in the SAMD9L gene (S626L; 611170.0007). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased levels of SAMD9L compared to controls. Further analysis of patient fibroblasts showed increased mitochondrial replication and increased ATP levels compared to controls, suggesting mitochondrial stress, although there were no mtDNA alterations. There was also evidence of dysregulation of the lysosomal/autophagy pathway with diffuse mitochondrial crests and mitophagy; fibroblasts had a dilated endoplasmic reticulum and increased numbers of lysosomes. The authors postulated that the mutation prevented proper protein folding, leading to abnormal mitochondrial clearance by mitophagy and compensatory mitochondrial biogenesis. The mechanism could be haploinsufficiency or a dominant-negative effect.

Corral-Juan et al. (2022) found that zebrafish expressing the human SAMD9L S262L mutation (611170.0007) had impaired locomotor activity and decreased head turning, indicating vestibular and sensory dysfunction, compared to controls. The protein showed mitochondrial localization in neurons of zebrafish larvae, including in the spinal cord, peripheral nerves, and hindbrain, where it located with ATP5B (102910). Mutant fish showed increased levels of the mitochondrial fusion protein DRP1 (603850) compared to controls, suggesting mitochondrial biogenesis.