SPAX1 is a neurodegenerative disorder that results in gait disturbances, spastic paraplegia, dysarthria, hyperreflexia, dystonia, pes cavus, head jerks and memory loss. Affected individuals also suffer from ocular anomalies such as slow saccades, supranuclear gaze palsy and ptosis. The disorder has an onset between 10 and 20 years of age. It is slowly progressive and patients may become wheelchair-bound later in life. However, the condition does not affect life span or cognition. The disease varies in severity, even within affected members of the same family. While the global rate of incidence of the condition is unknown, it is found to be highly prevalent in the Canadian region of Newfoundland.
Diagnosis of SPAX1 is made based on clinical features and molecular analysis of the Vesicle-Associated Membrane Protein 1 (VAMP1) gene. There is currently no cure for SPAX1. However, several therapies are available that provide symptomatic support, such as baclofen, tizanidine, diazepam and clonazepam. Patients also benefit from physical and occupational therapy.
Monies et al. (2017) analyzed the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, an 8-month-old male, suffered from an atrial septal defect, fine/gross motor delay, hypotonia, muscle weakness, contractures, pneumonia and congenital myopathy. A muscle biopsy of his left thigh helped diagnose congenital muscular dystrophy. WES was used to identify a homozygous mutation (c.128_129del, p.E43fs) in exon 2 of the patient’s VAMP1 gene. Another patient, a 2-year-old female presented with congenital hypotonia, rigid spine, myopathic facies and normal CK levels. Her parents were not related and her family history was negative for this phenotype. WES helped uncover a homozygous c.129+1G>A mutation in exon 2 of the patient’s VAMP1 gene. As VAMP1 is generally implicated in autosomal dominant SPAX1, these recessive mutations were a unique finding. They were attributed to enhanced autozygosity and were noted to help our understanding of the molecular pathogenesis of the dominant counterpart.