2019 Jun 20 [updated 2026 Mar 12]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026.
ABSTRACT
CLINICAL CHARACTERISTICS: Mitochondrial short-chain enoyl-CoA hydratase deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described. Individuals with ECHS1D can present as neonates with hypotonia, dilated cardiomyopathy, severe developmental delay, seizures, sensorineural hearing loss, and severe lactic acidosis. More commonly, individuals present in infancy with developmental delay or regression, dystonia, hypotonia, ophthalmologic manifestations, sensorineural hearing loss, epilepsy, and feeding difficulties. In the late-onset form, individuals primarily present with paroxysmal dystonia that may be exacerbated by illness or exertion, subtle axial hypotonia, sensorineural hearing loss, and learning differences or normal development. T2 hyperintensity in the basal ganglia is very common in all individuals with ECHS1D and may affect any part of the basal ganglia. Prognosis is dependent on age of onset. In the neonatal form, clinical manifestations typically progress quickly, and infants succumb to central apnea or arrhythmia often consequent to overwhelming metabolic acidosis.
DIAGNOSIS/TESTING: The diagnosis of ECHS1D is established in a proband with characteristic findings and biallelic pathogenic variants in ECHS1 identified by molecular genetic testing.
MANAGEMENT: Targeted therapies: Valine-restricted diet; N-acetylcysteine
Supportive care: Treatment of severe metabolic acidosis with bicarbonate therapy; hyperammonemia may be addressed by treatment of metabolic acidosis and/or consideration of hemodialysis. Standard treatment for developmental delay, seizures, spasticity, cardiomyopathy, pulmonary hypertension, sensorineural hearing loss, and optic atrophy. Paroxysmal dystonia may respond to benzodiazepines, whereas chronic dystonia may require botulinum toxin injections. Treatment of dystonia with levodopa may also be considered. Inadequate nutrition may require feeding therapy; placement of a feeding tube may be considered. Management of respiratory issues and apnea per intensivist and/or pulmonologist. Transition to adult care starting by approximately age 12 years; social work and family support.
Surveillance: Evaluation with metabolic specialist and biochemical dietician, including assessment of total protein and valine intake, fasting plasma amino acids, blood total and free carnitine, acylcarnitine profile, blood lactate, and urine organic acids with frequency per metabolic specialist; measure sodium bicarbonate and blood lactate concentration with all viral illnesses or metabolic stressors. Measurement of growth parameters and assessment of nutritional status, safety of oral intake, developmental and educational needs, changes in neurologic manifestations, evidence of aspiration, respiratory insufficiency, sleep apnea, and family needs at each visit. Physical medicine and occupational and physical therapy assessment of mobility and self-help skills at each visit. Brain MRI and EEG as needed in those with new neurologic manifestations. At least annual echocardiogram and audiologic evaluation. Assess eye movements at each visit; dilated ophthalmology examination at ages six and 12 months and then annually.
Agents/circumstances to avoid: Mitochondrial toxins (e.g., sodium valproate, prolonged propofol infusions); anesthesia should be used with caution; prevent catabolism; avoid lactate-containing agents; ketogenic diet may be poorly tolerated.
Evaluation of relatives at risk: It is appropriate to evaluate at-risk newborns and apparently asymptomatic sibs of an affected individual to identify as early as possible those who would benefit from prompt institution of treatment. In an at-risk newborn, it is crucial to ensure metabolic stability by evaluating lactic acid concentration and blood gas. Urine organic acids and acylcarnitine profile may also be used as biochemical screening testing while waiting for ECHS1 molecular genetic testing results.
GENETIC COUNSELING: ECHS1D is inherited in an autosomal recessive manner. In most instances, both parents of an affected child are heterozygous for an ECHS1 pathogenic variant. If the proband is compound heterozygous for an ECHS1 pathogenic variant and the ECHS1 c.489G>A variant, a parent may be homozygous for the c.489G>A variant (the c.489G>A variant does not cause disease when homozygous). If the proband has a chromosome 10q26 deletion involving ECHS1, a parent may carry a balanced rearrangement involving the 10q26 region. Rarely, a proband has one de novo pathogenic variant and one pathogenic variant inherited from a carrier parent. If both parents of an affected individual are known to be heterozygous for an ECHS1 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. If one parent is known to be heterozygous for an ECHS1 pathogenic variant and the other parent is known to be homozygous for the c.489G>A variant, each sib of an affected individual has at conception a 50% chance of inheriting biallelic variants and being affected and a 50% chance of inheriting only the c.489G>A variant and being an asymptomatic carrier. Once the ECHS1 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk and prenatal/preimplantation genetic testing are possible.