ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome

Clinical characteristics: ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.

Diagnosis/testing: The diagnosis of ISCA1-MMDS is established in a proband with suggestive findings and/or biallelic pathogenic variants in ISCA1 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is primarily supportive. A feeding tube (nasogastric or gastrostomy) may be required. Standard treatment for spasticity, seizures, abnormal vision, and hearing loss.

Prevention of secondary complications: Adequate hydration, stool softeners, and laxatives may help to prevent severe constipation.

Surveillance: Assessment for new neurologic manifestations, safety of oral intake, adequate nutrition, and evidence of respiratory insufficiency and aspiration at each visit. Monitor constipation, developmental progress, growth parameters, and family needs at each visit. Ophthalmologic and audiologic evaluations annually or based on clinical suspicion.

Genetic counseling: ISCA1-related multiple mitochondrial dysfunctions syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual with ISCA1-MMDS has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic ISCA1 variants in the family are known.