SCA15 is a cerebellar ataxia characterized by postural tremor, hyperreflexia, dysarthria and scanning speech, as well as gait, limb and truncal ataxia. Ocular anomalies include dysmetric saccades, impaired smooth pursuits and horizontal, gaze-evoked nystagmus. Affected individuals exhibit cerebellar atrophy mainly affecting the vermis. The disease has a wide range of onset, affecting people between the ages of 10 and 50 years. It has a very slow progression and most patients remain ambulatory. Even though there have been only around 80 reported cases of SCA15 worldwide, the condition has been noted as the most common non-trinucleotide repeat spinocerebellar ataxia in Central Europe.
SCA15 is diagnosed based on clinical features, neuroimaging studies and molecular analysis of the ITPR1 gene. While there is currently no cure for the condition, patients usually benefit from physical and occupational therapy. Affected individuals may also require ambulatory aids and treatment for osteoporosis. Prenatal testing and genetic counselling is available for affected families.
The disorder follows an autosomal dominant pattern of inheritance and is caused by heterozygous mutations in the ITPR1 gene. The gene encodes an intracellular ion channel that mediates the release of calcium from the endoplasmic reticulum upon stimulation by its ligand, inositol 1,4,5-triphosphate. Mutations in the gene associated with SCA15 include missense variants and large deletions. Recent studies have also found homozygous ITPR1 mutations in SCA15 affected individuals.
Monies et al. (2017) reported the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 7-year-old female, presented with global developmental delay and brain atrophy. Using a multigene panel for neurological disorders, a homozygous mutation (c.6862C>T, p.R2288X) was identified in exon 50 of the patient’s ITPR1 gene. Hence this case presented an interesting finding of a recessive mutation in a gene normally associated with a dominant phenotype (SCA15). Further, the atypical presentation of the patient helped expand the phenotype of SCA15.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient harboring a deleterious variant of ITPR1 was diagnosed with spinocerebellar ataxia 15 (SCA15). The patient had presented with cerebellar atrophy and ataxia. A heterozygous variant in CHD7, a gene associated with autosomal dominant deafness, was additionally identified; however the patient had not presented with deafness.
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