2025 Nov 20. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025.
ABSTRACT
CLINICAL CHARACTERISTICS: 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency can be categorized into three subtypes based on age of presentation. Neonatal onset, the least frequent phenotype, is characterized by hypotonia, seizures, and feeding difficulties at birth. There is a high risk of death in childhood, and individuals that survive typically have developmental delay, episodes of regression, seizures, poor weight gain, and growth deficiency and develop a movement disorder. Infantile onset is the most common phenotype, presenting in the first two years of life with feeding difficulties, vomiting, developmental delay with regression, hypotonia, seizures, movement disorder, microcephaly, vision impairment, and episodes of neurologic deterioration. Late onset is the second most common phenotype, presenting in childhood as a slowly progressive disease with significant movement disorder with or without paroxysmal dystonia, variable cognitive impairment, and high survivability.
DIAGNOSIS/TESTING: The diagnosis of HIBCH deficiency is established in a proband with characteristic clinical, laboratory, and brain imaging findings and biallelic pathogenic variants in HIBCH identified by molecular genetic testing.
MANAGEMENT: Targeted therapy: Valine-restricted diet. As seen in other metabolic disorders, treatment using special formulas (medical food) can be implemented successfully via oral route in individuals diagnosed within the first few months of life. Later on, if palatability or feeding intolerance becomes a problem, formula can be given by gastrostomy tube. A restriction in total protein intake without quantitation of valine may be necessary in individuals on an oral diet with poor adherence to medical food or formula.
Supportive care: Developmental and educational support; feeding therapy with gastrostomy tube as needed; standard treatments for spasticity and epilepsy; treatment of movement disorder per movement disorder specialist; management of ocular issues per ophthalmologist with low vision services as needed; early intervention for cerebral visual impairment; hearing aids per otolaryngologist and community hearing services as needed; transitional care support; social work and family support.
Surveillance: Evaluation with a metabolic specialist and metabolic dietitian including assessment of total protein and valine intake, fasting plasma amino acids, blood total and free carnitine and acylcarnitine profile, lactic acid in blood, and urine organic acids with frequency per metabolic specialist; measurement of growth parameters, evaluation of nutrition and oral intake, and assessment of developmental progress and educational needs at each visit; assessment for changes in tone, seizures, movement disorders, mobility, self-help skills, evidence of aspiration, respiratory insufficiency, and sleep apnea at each visit; ophthalmology evaluation at least annually; audiology evaluation as needed.
Agents/circumstances to avoid: Due to secondary mitochondrial abnormalities it may be beneficial to avoid sodium valproate if possible; consider anesthesia use carefully; avoid prolonged propofol use; prevent catabolism; avoid neuromuscular blocking agents in those with muscle disease; avoid lactate-containing agents, including dialysate containing lactate; ketogenic / modified Atkins diets should be avoided due to potential side effects; triheptanoin is contraindicated due to the potential increase in propionyl-CoA; dichloroacetate, as there is no published evidence to support its use in HIBCH deficiency.
Evaluation of relatives at risk: It is appropriate to evaluate at-risk newborns and older sibs of an affected individual to identify as early as possible those who would benefit from prompt initiation of targeted therapy.
GENETIC COUNSELING: HIBCH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HIBCH pathogenic variant, each sib of an affected individual has at conception 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 HIBCH pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.