FARS2 Deficiency

Clinical characteristics: The spectrum of FARS2 deficiency ranges from the infantile-onset phenotype, characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals), to the later-onset phenotype, characterized by spastic paraplegia, less severe neurologic manifestations, and longer survival (30% of affected individuals). To date FARS2 deficiency has been reported in 37 individuals from 25 families.

1. Infantile-onset phenotype. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus; some children have hypsarrhythmia on EEG. All have developmental delay; most are nonverbal and unable to walk. Feeding difficulties are common. More than half of affected children die in early childhood.

2. Later-onset phenotype. All affected individuals have spastic paraplegia manifested by weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties; some have developmental delay/intellectual disability; some have brief seizures that resolve over time.

Diagnosis/testing: The diagnosis of FARS2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in FARS2 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic and best provided by a multidisciplinary team comprising neurodevelopmental pediatricians, neurologists, physiatrists, occupational and physical therapists, feeding specialists, speech and language therapists, and social workers to assure adequate family support.

Surveillance: For those with infantile onset: routine monitoring of feeding and nutrition, seizure control, developmental progress, OT/PT needs, and family social support.

For those with later onset: routine monitoring of OT/PT needs (e.g., mobility and activities of daily living), orthopedic complications (contractures, scoliosis, foot deformities), seizure control, speech and language development, and educational and social needs.

Agents/circumstances to avoid: While valproic acid can induce liver failure in persons with mitochondrial diseases, some individuals with FARS2 deficiency received valproic acid with no evidence of liver dysfunction or worsening of existing liver disease. Given the limited number of affected individuals reported to date, no general recommendation can be made.

Genetic counseling: FARS2 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual 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. Once the FARS2 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.