SERAC1 Deficiency
SERAC1 Deficiency
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The study site has not been established. Author addresses may differ from where the research occurred.
Salzburg, AT · Author affiliation
Expertise Centre for Inborn Metabolic Disease, University Children's Hospital, Paracelsus Private Medical University, Salzburg, AustriaLocation evidence
Nijmegen, NL · Author affiliation
Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the NetherlandsLocation evidence
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Original abstract
Clinical characteristicsThe phenotypic spectrum of SERAC1 deficiency comprises infantile, severe MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome), juvenile-onset complicated hereditary spastic paraplegia (cHSP), and juvenile- or adult-onset generalized dystonia-parkinsonism. MEGD(H)EL syndrome is characterized by neonatal hypoglycemia, a sepsis-like clinical picture for which no infectious agent can be found, feeding problems, poor weight gain, muscular hypotonia, developmental delay, and liver involvement. By age two years, spasticity, dystonia, epilepsy, and progressive deafness 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. Individuals with SERAC1-related cHSP may have cognitive deficits that are generally mild, juvenile-onset spastic paraplegia, and dystonia. SERAC1-related juvenile- or adult-onset generalized dystonia is characterized by dystonia, cognitive issues, bradykinesia, and spasticity. In all forms the course is progressive over time.Diagnosis/testingThe 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.ManagementTreatment 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. Management of neonatal hypoglycemia; feeding therapy and gastrostomy tube as needed; 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. Supportive management of spasticity; some individuals have experienced (temporary) improvement of spasticity with oral or intrathecal baclofen treatment. Consideration of deep brain stimulation for dystonia and/or parkinsonism. Developmental and educational support; management of seizures per experienced neurologist; treatment of liver disease per hepatologist; treatment of hearing loss should be guided by expected benefit; treatment of scoliosis per orthopedist; management of vision issues per ophthalmologist; low vision services as needed; social work and family support. Treatment of SERAC1-related juvenile and adult phenotypes includes developmental and educational support as needed; supportive treatment of spasticity; baclofen may provide temporary improvement in spasticity; treatment of dystonia and movement disorder per neurologist; deep brain stimulation may be beneficial; feeding therapy and gastrostomy tube as needed. 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. Standard treatments of seizures and hearing loss; social work and family support. Surveillance: Monitor blood glucose in those with MEGD(H)EL syndrome. At each visit and at least annually assess growth, nutrition, safety of oral intake, neurologic manifestations, developmental progress, cognition, educational needs, hearing, musculoskeletal manifestations, ophthalmology evaluation, and family needs; laboratory assessment of liver dysfunction per hepatologist. Agents and circumstances to avoid: Medications known to impair mitochondrial function (e.g., valproic acid).Genetic counselingSERAC1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SERAC1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants and 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 and prenatal/preimplantation genetic testing are possible.