SPAX4 is a neurodegenerative disorder characterized by cerebellar ataxia and spastic paraparesis. Other defining features of this condition include dysarthria and ocular anomalies such as optic atrophy and nystagmus. Patients also exhibit delayed walking, hyperreflexia of the lower limbs, brisk jaw jerk, extensor plantar responses, poor oromandibular coordination, learning difficulties, and in some cases, emotional lability. The disorder results in certain laboratory abnormalities such as defects in oxidative phosphorylation in fibroblasts and decreased amount and activity of mitochondrial complexes I and IV.
SPAX4 has an onset in early childhood. The disorder is slowly progressive and most affected patients are able to maintain independent ambulation. Treatment is mainly symptomatic and supportive. Patients may benefit from physical therapy, speech therapy and educational aids.
SPAX4 follows an autosomal recessive pattern of inheritance and is caused by homozygous mutations in the MTPAP gene. This gene encodes a polymerase responsible for the synthesis of poly(A) extensions on mitochondrial mRNA transcripts and for the catabolism of histone mRNAs. So far a 1432A-G transition in the gene, resulting in a N478D substitution, has been associated with the disorder.
Al-Shamsi et al. (2016) investigated a cohort of 85 patients seen at a metabolic center in Abu Dhabi. The patients could not be diagnosed using conventional methods, hence Whole Exome Sequencing (WES) was carried out. This helped definitively diagnose 50% of the cases in the cohort. One patient in the study suffered from developmental delay and regression starting at 8 months of age. Other symptoms included central hypotonia, short stature, failure to thrive, cerebellar atrophy, absence-like episodes, and hip dislocation. WES uncovered a homozygous variant of unknown significance (c.1468G > T, p.V490L) in the patient’s SPAX4 gene. The patient had an affected sibling carrying the same mutation and the consanguineous parents were found to be heterozygous for the variant.
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