Clinical characteristics: The phenotypic spectrum of SERAC1 deficiency comprises MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome), juvenile-onset complicated hereditary spastic paraplegia (in 1 consanguineous family), and adult-onset generalized dystonia (in 1 adult male). MEGD(H)EL syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent.
Diagnosis/testing: The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria) findings and biallelic pathogenic variants in SERAC1 identified by molecular genetic testing.
Management: Treatment of manifestations: Treatment of MEGD(H)EL syndrome is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible. Some individuals have experienced (temporary) improvement of spasticity with oral or intrathecal baclofen treatment. Respiratory problems resulting from excessive drooling improve with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or rerouting of glandular ducts. An age-appropriate diet given via nasogastric tube or gastrostomy can greatly improve overall clinical condition.
Surveillance: Neurologic and orthopedic evaluations as needed based on individual findings are appropriate.
Genetic counseling: SERAC1 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 SERAC1 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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