ISCA2-Related Mitochondrial Disorder

Excerpt

Clinical characteristics: Infants with ISCA2-related mitochondrial disorder (IRMD) typically attain normal development in the first months of life. At age three to seven months, affected individuals usually present with a triad of neurodevelopmental regression, nystagmus with optic atrophy, and diffuse white matter disease. As the disease progresses, global psychomotor regression continues at a variable pace and seizures may develop. Affected children become vegetative within one to two years. During their vegetative state, which may persist for years, affected individuals are prone to recurrent chest infections that may require ventilator support. Most affected individuals die during early childhood.

Diagnosis/testing: The diagnosis of ISCA2-related mitochondrial disorder is established in a proband by the identification of biallelic pathogenic variants in ISCA2 on molecular genetic testing.

Management: Treatment of manifestations: Treatment is primarily supportive and may require input from a geneticist, neurologist, dietician, and developmental specialist. A feeding tube (nasogastric or gastrostomy) is typically required. Standard treatment for epilepsy. Recurrent chest infections may require ventilator support in addition to antimicrobial therapy. Referral to early intervention services is recommended. For muscle tone abnormalities including hypertonia, baclofen and/or Botox^® may be considered.

Prevention of secondary complications: Constipation may become problematic and may require ensuring adequate hydration and/or treatment with stool softeners or laxatives.

Surveillance: Periodic evaluation of swallowing function is suggested.

Genetic counseling: ISCA2-related mitochondrial disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual with IRMD 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 ISCA2 pathogenic variants in the family are known.