Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency

Clinical characteristics: Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described:

1. The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia.

2. A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay.

3. A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion.

Across all three groups, T₂ hyperintensity in the basal ganglia is very common, and may affect any part of the basal ganglia.

Diagnosis/testing: The diagnosis of ECHS1D is established in a proband by the identification of biallelic pathogenic variants in ECHS1 on molecular genetic testing or low short-chain enoyl-CoA hydratase (SCEH) activity using cultured skin fibroblasts.

Management: Treatment of manifestations: Treatment of severe metabolic acidosis with bicarbonate therapy; hyperammonemia (which may be related to severe acidosis or low ATP from impaired aerobic oxidation) may be addressed by treatment of the metabolic acidosis and/or consideration of hemodialysis. Inadequate nutrition may require feeding therapy; placement of a feeding tube may be considered. Paroxysmal dystonia may respond to benzodiazepines, whereas chronic dystonia may require botulinum toxin injections. Treatment of dystonia with levodopa may also be considered. Standard treatment for seizures, cardiomyopathy, pulmonary hypertension, optic atrophy, sensorineural hearing loss, and developmental delay.

Surveillance: At least annual echocardiogram, dilated eye examination, and audiologic evaluation. Routine monitoring for neurologic symptoms and developmental issues. Assessment of acid/base status and blood lactate level with all illnesses or metabolic stressors.

Agents/circumstances to avoid: Mitochondrial toxins (i.e., valproic acid, prolonged propofol infusions); ketogenic diet.

Genetic counseling: ECHS1 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% change of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the ECHS1 pathogenic variants in the family are known.