A number sign (#) is used with this entry because autosomal recessive spinocerebellar ataxia-16 (SCAR16) is caused by homozygous or compound heterozygous mutation in the STUB1 gene (607207) on chromosome 16p13.

Heterozygous mutation in the STUB1 gene causes an autosomal dominant complex neurodegenerative disorder, SCA48 (618093), which shows some overlapping features.

Autosomal recessive spinocerebellar ataxia-16 (SCAR16) is a progressive neurologic disorder characterized by truncal and limb ataxia, resulting in gait instability, associated with cerebellar atrophy on brain imaging. Most patients have onset in the teenage years, although earlier and later onset have been reported. Additional features may include dysarthria, nystagmus, hyperreflexia of the lower limbs, and mild peripheral sensory neuropathy. Some patients have gonadal dysfunction or hypogonadism and/or cognitive deficits. The phenotype represents a spectrum or continuum of neurodegenerative features that may overlap with those of SCA48 (summary by Shi et al., 2013 and Ravel et al., 2021).

Shi et al. (2013) reported a Chinese family in which 4 sibs developed progressive spinocerebellar ataxia between 14 and 19 years of age. All had dysarthria. Two patients had nystagmus, 2 had ophthalmoplegia, and 3 had increased tendon reflexes, including 2 with extensor plantar responses. Two patients developed mild cognitive impairment later in life. All had decreased position sense, and electrophysiologic studies showed subtle impairments in the peripheral nerves. Brain MRI of 3 patients showed severe cerebellar atrophy. Laboratory studies of all patients showed normal hormone levels, excluding hypogonadism. Two additional unrelated patients with a similar disorder were also reported. One had hyperreflexia.

Shi et al. (2014) reported 2 Chinese sisters with onset of spinocerebellar ataxia in the late teenage years and hypogonadotropic hypogonadism. Features of cerebellar ataxia included nystagmus, dysarthria, and gait disturbance. One sister developed hand and head tremor and showed hyperreflexia, suggestive of pyramidal tract involvement. Detailed cognitive testing suggested a mild defect in both patients. Brain MRI showed cerebellar atrophy. Both young women had poor sexual development and lack of menses in their early twenties. Laboratory studies showed decreased estradiol and progesterone as well as decreased follicle-stimulating hormone (FSH; see 136530) and luteinizing hormone (LH; see 152780), consistent with a pituitary or hypothalamic defect. Shi et al. (2014) noted that the phenotype in these sisters was consistent with a clinical diagnosis of Gordon Holmes syndrome (GDHS; 212840).

Synofzik et al. (2014) reported 4 Caucasian patients from 3 families with SCAR16. The families were from Germany, western Turkey, and Saudi Arabia, respectively. The age at onset of ataxia was highly variable, ranging from 2 to 48 years. All 4 patients also had evidence of pyramidal tract damage. Two had only electrophysiologic evidence, whereas 2 brothers showed clinical spasticity with hyperreflexia of the lower limbs. One patient had myoclonic jerks in the face and left arm; another had mildly reduced vibration sense in the legs, consistent with a sensory axonal neuropathy. None of the patients had evidence of gonadal dysfunction or cognitive impairment, although 1 had concentration difficulties. Brain MRI showed marked cerebellar atrophy in all patients.

Depondt et al. (2014) reported 2 Belgian brothers, born of unrelated parents, with spinocerebellar ataxia. They presented with progressive ataxia in their mid-twenties and cognitive deterioration in the following years. Features included gait instability, dysarthria, brisk tendon reflexes, and cerebellar atrophy on brain imaging. Cognitive testing indicated mental slowing, verbal and visuospatial memory deficits, executive dysfunction, and IQ in the 70s. Endocrine studies were normal. Whole-exome sequencing identified compound heterozygosity for 2 mutations in the STUB1 gene (607207.0013 and 607207.0015), confirming the diagnosis of SCAR16. No other family members were affected.

Heimdal et al. (2014) reported 3 sibs, born of consanguineous parents of Arab descent, with SCAR16. Two boys and their sister presented in early life (birth to 2 years) with impaired motor development and gait difficulties. The patients developed progressive cerebellar ataxia as well as variable additional neurologic features, including cognitive regression, dysarthria, dyspraxia, intermittent tremor, and increased muscle tone. Brain MRI showed cerebellar hypoplasia, thin pons, and thin corpus callosum. Puberty and sexual development were unremarkable, although the girl had slightly late menarche at age 15 years compared to other females in the family. All had an aged appearance as young adults, and 2 had slight presbycusis. Additional findings in this family included diabetes mellitus, alopecia, uveitis, and ulcerative colitis; it was unclear whether these features were related to SCAR16. An unrelated woman from Sri Lanka had a milder form of the disorder: she presented at age 25 years with oligomenorrhea and secondary infertility, developing gait ataxia and dysarthria in her thirties. Brain MRI showed cerebellar hypoplasia and 'empty sella,' consistent with pituitary dysfunction. Heimdal et al. (2014) concluded that mild to moderate cognitive impairment is common in this disorder, although hypogonadotropic hypogonadism is not an obligatory feature.

Ravel et al. (2021) reported 4 patients from 2 unrelated French families (families 1 and 2) with SCAR16. The mean age at symptom onset was 30 years (range 14 to 45), and the patients presented with features of a cerebellar syndrome, including slowly progressive gait ataxia or dysarthria. Variable additional features included eye movement abnormalities, such as nystagmus or saccadic pursuit, tremor, dystonia, dysphagia, urinary incontinence, hyperreflexia, and extensor plantar responses. All patients had cerebellar atrophy on brain imaging. One patient in family 1 had an unusually severe phenotype with symptom onset at age 14. She had profound hypotonia, amyotrophy, generalized dystonia, dyskinetic movements, joint contractures, limb areflexia, severely impaired intellectual development with no verbal communication, and behavioral and psychiatric features, including depression, aggression, and mutism. Her sister, who had a more typical disease course, had word-finding difficulties, suggesting that cognitive dysfunction may occur in SCAR16.

The transmission pattern of SCAR16 in the families reported by Shi et al. (2014) and Synofzik et al. (2014) and in family 1 reported by Shi et al. (2013) was consistent with autosomal recessive inheritance.

In affected members of 3 unrelated Chinese families with SCAR16, Shi et al. (2013) identified homozygous or compound heterozygous mutations in the STUB1 gene (see, e.g., 607207.0001-607207.0003). The mutation in the first family was found by linkage analysis and whole-exome sequencing. The 2 additional families were ascertained by direct sequencing of the STUB1 gene in a larger cohort of 36 families with spinocerebellar ataxia and 196 patients with sporadic disease in whom mutations in common ataxia genes had been excluded. In vitro functional expression studies in HEK293 cells showed that none of the mutations identified by Shi et al. (2014) effectively promoted the degradation of GRIN2A (138253), indicating a loss of ubiquitinase activity. Shi et al. (2014) hypothesized that the inability to degrade NMDA receptors in neurons may contribute to the pathogenesis of ataxia.

In 2 Chinese sisters with SCAR16 and hypogonadotropic hypogonadism, Shi et al. (2014) identified a homozygous missense mutation in the STUB1 gene (T246M; 607207.0004). The mutation was found by whole-exome sequencing and homozygosity mapping. In vitro functional expression studies showed that the mutation caused a loss of ubiquitin ligase activity, but chaperone function was not disturbed. Shi et al. (2014) concluded that the disorder resulted from loss of STUB1 function.

In 3 (1.8%) of 167 patients with autosomal recessive cerebellar ataxia, Synofzik et al. (2014) identified 4 novel homozygous or compound heterozygous missense mutations in the STUB1 gene (607207.0005-607207.0008). One of the mutations affected the ubiquitin ligase domain, whereas the others affected the TPR (tetratricopeptide repeat) domain. No STUB1 mutations were found in 133 patients with spastic paraplegia.

In 3 sibs, born of consanguineous parents of Arab descent, with SCAR16, Heimdal et al. (2014) identified a homozygous missense mutation in the STUB1 gene (N65S; 607207.0009). In vitro functional expression studies showed that N65S-mutant STUB1 had significantly impaired ability to ubiquitinate HSC70 (HSPA8; 600816) compared to wildtype, most likely due to low substrate affinity. The findings were consistent with a loss of function. An unrelated woman with onset of cerebellar ataxia and hypogonadotropic hypogonadism as a young adult was found to be compound heterozygous for a nonsense and a missense mutation in the STUB1 gene.

In 2 Belgian sibs with SCAR16, Depondt et al. (2014) identified compound heterozygous mutations in the STUB1 gene (607207.0013 and 607207.0015). Functional studies of the variants and studies of patient cells were not performed.

In 4 patients from 2 unrelated French families (families 1 and 2) with SCAR16, Ravel et al. (2021) identified compound heterozygous mutations in the STUB1 gene. There were 3 missense variants and an in-frame deletion. The mutations were found by targeted next-generation sequencing. The mutations occurred throughout the gene and often affected functional domains; functional studies of the variants and studies of patient cells were not performed.

Shi et al. (2014) found that Stub1-null mice had severe motor impairment due to cerebellar dysfunction. They also showed mild defects in learning and memory, suggesting hippocampal compromise. Neuropathologic examination showed loss of Purkinje cells in the cerebellum of mutant mice. In addition, mutant mice showed evidence of gonadal dysfunction, with decreased testicular weight and decreased levels of FSH.