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SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 13; SCAR13

SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 13; SCAR13

Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning i...

Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning in infancy. Affected individuals show mildly to profoundly impaired intellectual development with poor or absent speech as well as gait and stance ataxia and hyperreflexia. Most individuals also have eye movement abnormalities. Brain MRI shows cerebellar atrophy and ventriculomegaly (Guergueltcheva et al., 2012).

▼ Clinical Features
Guergueltcheva et al. (2012) reported 10 patients from 5 families with spinocerebellar ataxia. All families belonged to the Roma Bowlmaker ethnic group in Bulgaria, a young Gypsy population subisolate with low genetic diversity. The patients ranged in age from 6 to 57 years, but all had infantile onset of delayed psychomotor development. Three never walked and 5 never learned to talk; mental retardation ranged from mild to profound. All patients had moderate to severe gait and stance ataxia, with variable mild dysarthria, dysmetria, tremor, and dysdiadochokinesia. Only a few patients had mild pyramidal signs in the lower limbs. Two patients had seizures. About half of patients had variable ophthalmologic abnormalities, including horizontal nystagmus, hypometric saccades, abduction deficits, esotropia, and ptosis. Other features included short stature in adults, pes planus, and hypotonia. Brain MRI showed generalized cerebellar atrophy with a small inferior vermis. Five patients had a small brain overall. Most patients had mildly enlarged ventricles and retrocerebellar cysts. The disorder appeared to be slowly progressive.

Davarniya et al. (2015) reported 3 Iranian sibs (family 9000105), aged 28, 37, and 40 years, with moderately to severely impaired intellectual development, nystagmus, ataxia, short stature, and aggressive behavior. All had seizures starting within the first 2 years of life. Brain MRI in the youngest sib showed cerebellar atrophy and an increased number of cerebellar cisterns.

Cabet et al. (2019) reported a 6-year-old boy who had psychomotor delay and axial hypotonia noted at 6 months of age. He had dysmetria at age 1 year, and head nodding was seen at age 3 years. He also had dystonic and choreiform movements. Ophthalmologic examination at age 10 months showed strabismus and vertical gaze-evoked nystagmus. He had profoundly impaired intellectual development. Brain MRI at age 1 year was normal, but cerebellar atrophy was seen on repeat MRI at age 5 years.

▼ Inheritance
The transmission pattern of spinocerebellar ataxia in the Roma Bowlmaker families reported by Guergueltcheva et al. (2012) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In 10 affected individuals from 5 Bulgarian families of Roma Bowlmaker Gypsy origin with autosomal recessive spinocerebellar ataxia, Guergueltcheva et al. (2012) identified a homozygous mutation in the GRM1 gene (604473.0001) that generated various aberrant transcripts lacking important functional domains. This founder mutation was identified by linkage analysis and exome sequencing. The GRM1 gene encodes a metabotropic glutamate receptor that is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. Guergueltcheva et al. (2012) noted that several animal models deficient in GluR1 showed similar neurologic abnormalities (see ANIMAL MODEL).

Davarniya et al. (2015) identified a homozygous missense mutation (L454F; 604473.0005) in the GRM1 gene in 3 Iranian sibs, born to consanguineous parents, with SCAR13. The mutation was identified by autozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in 100 ethnically matched controls.

Cabet et al. (2019) identified a homozygous nonsense mutation (R297X; 604473.0005) in the GRM1 gene in a 6-year-old Tunisian boy, born to consanguineous parents, with SCAR13. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were heterozygous for the mutation.

▼ Animal Model
Sachs et al. (2007) stated that the recoil wobbler (rcw) series of ataxic mouse mutants arose spontaneously and are characterized by an early-onset, nonprogressive ataxic gait noticeable by postnatal day 16. Mutant animals have a normal life span and show no gross histologic abnormalities. Using complementation tests, Sachs et al. (2007) showed that the rcw mutations and another N-ethyl-N-nitrosourea (ENU)-induced mutant with a similar phenotype were allelic to a knockout mutant of Grm1. They identified a duplication of exon 4 and 3 missense mutations in the Grm1 gene of these mutant mice. All mutations occurred within the ligand-binding region of Grm1 and changed conserved amino acids. In the original rcw mutant, Grm1 was expressed and the protein was properly localized to the molecular layer of the cerebellar cortex. See also Aiba et al. (1994) and Conquet et al. (1994).

Tags: 6q24.3