FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome

Excerpt

Clinical characteristics: FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.

Diagnosis/testing: The diagnosis of FBXL4-related mtDNA depletion syndrome is established in a proband by identification of biallelic pathogenic variants in FBXL4 on molecular genetic testing.

Management: Treatment of manifestations: Management is best provided by a multidisciplinary team including neurology, nutrition, clinical genetics/metabolism, and developmental pediatrics. Other specialties may be involved as needed. To date no definite treatment is available; thus, treatment is mainly supportive: assuring adequate nutrition and standard treatment of neurologic complications including developmental delay / intellectual disability, seizures, cardiac complications, eye involvement, and hearing loss. Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered.

Surveillance: No surveillance guidelines have been published. The treating physician should decide about the frequency of follow up of eyes, hearing, heart, feeding difficulties, liver, neurologic complications, and neutropenia based on the patient's findings.

Genetic counseling: FBXL4-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. When both parents are heterozygous carriers, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the FBXL4 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

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