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Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

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3-Hydroxyisobutyryl-CoA Hydrolase Deficiency

Synonym: HIBCH Deficiency

, MD and , MS, CGC.

Author Information and Affiliations

Initial Posting: ; Last Revision: February 12, 2026.

Estimated reading time: 34 minutes

Summary

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, 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.

Diagnosis

No consensus clinical diagnostic criteria for 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency have been published.

Suggestive Findings

HIBCH deficiency can be categorized into three subtypes based on age of presentation. Typically, earlier age of onset (e.g., neonatal onset) is associated with more severe disease. HIBCH deficiency should be suspected in probands with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

  • Neonatal onset (age <30 days)
    • Developmental delay
    • Feeding difficulties
    • Poor weight gain and growth deficiency
    • Microcephaly
    • Hypo- or hypertonia, including spasticity
    • Seizures
    • Ocular manifestations (visual impairment, nystagmus)
    • Metabolic decompensations (episodes of lethargy, emesis, hyperventilation, and/or poor perfusion usually triggered by intercurrent illness)
  • Infantile onset (age 1 month to 2 years)
    • Developmental delay with regression
    • Hypotonia
    • Movement disorder (chorea, athetosis, dystonia)
    • Hypertonia with spasticity in some infants
    • Ocular manifestations (optic nerve atrophy, strabismus, nystagmus)
    • Feeding difficulties, persistent vomiting
    • Poor weight gain and growth deficiency
    • Microcephaly
    • Seizures
    • Episodes of neurologic deterioration
  • Late onset (age >2 years)
    • Movement disorder (paroxysmal dystonia)
    • Hypertonia including spasticity
    • Hypotonia
    • Developmental delay with regression

Laboratory findings

  • Plasma acylcarnitine profile and/or newborn screening blood spot analysis shows elevated hydroxy-C4 carnitine (due to elevation of 3-hydroxyisobutyrylcarnitine). Note: Although the methodology allows for its detection, not all laboratories report this analyte.
  • Urine acylcarnitine profile shows presence of S-(2-carboxypropyl)cysteine carnitine. Note: Not all laboratories screen for this analyte.
  • Urine organic acid analysis shows elevated lactate and 2-methyl-2,3-dihydroxybutyric acid. Note: These analytes may only be increased during intercurrent illnesses. Detection of 2-methyl-2,3-dihydroxybutyric acid may require the use of selective ion monitoring techniques.
  • Urine liquid chromatography-tandem mass spectrometry analysis shows presence of methacrylyl-CoA metabolites (S-[2-carboxypropyl]cysteine and S-[2-carboxypropyl]cysteamine). Note: Testing of these analytes may not be performed by most laboratories.
  • Lactic and pyruvic acid are elevated in blood; lactic acid is elevated in cerebrospinal fluid (can be intermittent).
  • Multiple mitochondrial respiratory chain enzyme deficiencies are apparent in skeletal muscle and fibroblasts. Note: Muscle biopsy is not required to make a diagnosis of HIBCH deficiency.

Imaging findings

  • Brain MRI
    • Bilateral symmetric T2 hyperintensities within the basal ganglia, thalamus, and dentate nuclei (most frequently in the globus pallidus)
    • Variable T2 hyperintensities and atrophy of white matter
    • Progressive cerebellar atrophy or cerebellar hyperintensities
    • Brain stem abnormalities in the midbrain, pons, medulla, and cerebral peduncles
    • Brain atrophy
    • Congenital brain anomalies, most frequently agenesis/dysgenesis of the corpus callosum
  • Brain MR spectroscopy. Abnormal lactate peak

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HIBCH deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in HIBCH identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic HIBCH variants of uncertain significance (or of one known HIBCH pathogenic variant and one HIBCH variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic, laboratory, and imaging findings suggest the diagnosis of HIBCH deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of HIBCH is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes HIBCH and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by Leigh syndrome, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025]. To date, the majority of HIBCH pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
HIBCH Sequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 41 reported 5
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

5.

Clinical Characteristics

Clinical Description

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency presents with a wide spectrum of clinical features. 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, 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. To date, 62 individuals have been identified with HIBCH deficiency [Loupatty et al 2007, Ferdinandusse et al 2013, Reuter et al 2014, Yamada et al 2014, Peters et al 2015, Soler-Alfonso et al 2015, Stiles et al 2015, Zhu et al 2015, Charng et al 2016, Schottmann et al 2016, Tan et al 2018, Yang et al 2018, Candelo et al 2019, Karimzadeh et al 2019, Xu et al 2019, Abdenur et al 2020, D'Gama et al 2020, Hu et al 2020, Wirth et al 2020, Çakar & Görükmez 2021, Casano et al 2021, Kose et al 2021, Marti-Sanchez et al 2021, Spitz et al 2021, Wang et al 2021, François-Heude et al 2022, Taura et al 2023, Gana et al 2024, Puvabanditsin et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Frequency of Select Features

FeatureAge of OnsetAll Ages of Onset 4, 5
(n=62)		Comment
Neonatal
(age <30 days)
(n=7) 1		Infantile
(age 1 mo-2 yrs)
(n=43) 2		Late
(age >2 yrs)
(n=10) 3
Developmental delay4/437/394/845/51Regression in >50%
Feeding difficulties5/517/271/223/34
Poor weight gain & growth deficiency3/39/150/212/20
Microcephaly4/49/200/213/26
Regression0/1 628/385/733/46
Hypotonia6/631/365/742/49
Hypertonia2/219/247/828/34Incl spasticity
Seizures3/410/331/214/39
Movement disorder1/327/338/836/44Dystonia, chorea
Paroxysmal dystonia0/15/254/59/31Triggered by exercise / physical activity
Ocular manifestations3/324/340/427/41Vison loss, nystagmus, strabismus
1.
2.
3.
4.

Two individuals did not have age of onset reported.

5.

François-Heude et al [2022] did not indicate which individual had prematurity and which individual had IUGR within their cohort with infantile onset and late onset HIBCH deficiency. These individuals are included in all presentations column but not within age of onset columns.

6.

Data is limited due to high mortality rate.

Neonatal Onset

Global developmental delay was reported in all infants with neonatal onset. Most individuals exhibit profound global delays, failing to acquire any motor developmental milestones. Long-term data is limited due to the high mortality rate [Brown et al 1982, Zhu et al 2015, Tan et al 2018, Marti-Sanchez et al 2021].

Acute metabolic decompensations. Episodes of poor feeding, lethargy, emesis, hyperventilation, and poor perfusion can occur and are usually triggered by intercurrent illness.

Feeding difficulties. Most infants had frequent vomiting, reflux, and/or required nasogastric tube feedings [Brown et al 1982, Ferdinandusse et al 2013, Tan et al 2018, D'Gama et al 2020, Marti-Sanchez et al 2021].

Poor weight gain and growth deficiency were reported in all neonates when this information was provided. A history of intrauterine growth deficiency was reported in one of three infants.

Microcephaly was detected in all reported individuals at birth or upon initial exam.

Abnormal muscle tone. Significant hypotonia, mainly axial, was universally present. Spasticity developed in the extremities in survivors over time [Tan et al 2018, Marti-Sanchez et al 2021]. Two infants were reported to have hypertonia.

Seizures. Infantile spams with hypsarrhythmia and multifocal seizures have been described [Ferdinandusse et al 2013, D'Gama et al 2020].

Movement disorder. Limited information is reported likely due to early death. One individual who survived until age two years and eight months had progressive dystonia [Ferdinandusse et al 2013].

Ocular manifestations. Nystagmus and visual impairment have been described [Ferdinandusse et al 2013, D'Gama et al 2020, Marti-Sanchez et al 2021]. It is possible that not all individuals had formal ophthalmologic evaluations.

Respiratory issues. Due to hypotonia, decreased mobility, and gastrointestinal reflux, individuals are at risk for respiratory infections, including aspiration pneumonia. Central apneas have been documented.

Hearing impairment. One individual was reported to have bilateral hearing loss on newborn hearing screen [D'Gama et al 2020].

Dysmorphic features. Reports of dysmorphic features have not been consistent or specific for this disorder. One individual was reported to have low-set ears, high-arched palate, bilateral syndactyly of second and third toes, and single transverse palmar creases [Tan et al 2018]. Nonspecific dysmorphic features have been described in other individuals [Brown et al 1982, Puvabanditsin et al 2024].

Prognosis. Mortality rate is high. Four of six individuals died before age three years. Cause of death ranged from an acute metabolic decompensation with acidosis and hyperammonemia within the first 48 hours of life to progression of the neurologic disease [Brown et al 1982, Ferdinandusse et al 2013, D'Gama et al 2020, Puvabanditsin et al 2024].

Infantile Onset

Developmental delay and intellectual disability. Global developmental delays are reported in most individuals. There is a wide range in the severity of delays and recovery of skills after regression. Development ranges from severe impairment with no independent ambulation, head control, or speech to normal motor and speech development. Some individuals could not walk unassisted but could speak in short sentences, while others gained no speech but were mildly delayed in motor attainment. Support and therapies were not consistently reported in available publications. Intellect also varied from presumed normal intelligence to significant impairment.

Abnormal muscle tone. Profound truncal hypotonia was reported in almost all individuals; spasticity and/or appendicular hypertonicity developed over time.

Movement disorder. Reported movement disorders include chorea, athetosis, and dystonia. Paroxysmal dystonia can present at any age with variable frequency and duration of episodes. Common triggers are prolonged exercise or physical activity; however, episodes may have no apparent trigger [Wirth et al 2020, Spitz et al 2021, Wang et al 2021, François-Heude et al 2022].

Ophthalmologic involvement. Most individuals have ocular manifestations; these include optic atrophy, ophthalmoplegia, strabismus, nystagmus, and other abnormal eye movements and visual dysfunction not otherwise specified.

Feeding difficulties. Poor feeding and/or frequent vomiting is common, leading to gastronomy tube placement in some individuals.

Growth deficiency. Poor weight gain with growth deficiency was reported in more than half of individuals. Microcephaly was reported in 45%. Four individuals had growth deficiency and microcephaly.

Seizures. About one third of individuals were reported to have seizures or abnormalities on EEG. Tonic, focal (frontal and temporal regions), multifocal, absence, refractory, generalized, myoclonus, and status epilepticus (with or without fever) with variable response to anti-seizure medications have been reported [Loupatty et al 2007, Ferdinandusse et al 2013, Reuter et al 2014, Candelo et al 2019, Marti-Sanchez et al 2021, Wang et al 2021].

Hearing impairment. Sensorineural hearing loss detected at age 17 months was reported in one individual, and nonspecific hearing loss was reported in two others [Ferdinandusse et al 2013, Yamada et al 2014, Marti-Sanchez et al 2021].

Neuroimaging. Almost all individuals have T2 hyperintensities in the basal ganglia (40/42), most frequently in the globus pallidus with variable involvement in the thalamus, dentate nuclei, or brain stem. White matter or cerebellar hyperintensities have been described, as well as cerebellar or brain atrophy and agenesis/dysgenesis of the corpus callosum.

Prognosis. Individuals with infantile onset have higher survivability than those with neonatal onset, with ~15% mortality during childhood. Cause of death ranges from acute metabolic crisis with or without heart failure to disease progression without specified terminal event [Ferdinandusse et al 2013, Yamada et al 2014, Peters et al 2015, Kose et al 2021, François-Heude et al 2022].

Late Onset

Movement disorder, which may include chorea, athetosis, and/or dystonia, is frequent [Schottmann et al 2016, Xu et al 2019, Spitz et al 2021, François-Heude et al 2022]; paroxysmal dystonia appears to be a prominent feature in individuals with late onset. It may present at any age with variable frequency and duration of episodes. Common triggers are prolonged exercise or physical activity; however, episodes may have no apparent trigger [Xu et al 2019, Spitz et al 2021, François-Heude et al 2022].

Abnormal muscle tone. Hypotonia was reported in most individuals. Static or progressive spasticity is also reported [Schottmann et al 2016, Xu et al 2019, Çakar & Görükmez 2021, François-Heude et al 2022].

Developmental delay. Global or isolated motor or language delays have been reported, ranging in severity from mild to severe. Normal psychomotor development is also reported [Schottmann et al 2016, Xu et al 2019, Çakar & Görükmez 2021, François-Heude et al 2022]. Regression, associated with intercurrent illness, may occur after normal initial development or early delays. While stable, individuals can improve or recover to their previous baseline with supportive therapies [Schottmann et al 2016, Çakar & Görükmez 2021, François-Heude et al 2022].

Neuroimaging. All individuals have T2 hyperintensities in the basal ganglia, with the globus pallidus most frequently affected. Cerebellar atrophy or hypotrophy was reported in two individuals, confirmed to be progressive in one [Schottmann et al 2016, Xu et al 2019, Hu et al 2020, Çakar & Görükmez 2021, Spitz et al 2021, François-Heude et al 2022].

Prognosis. All reported individuals were alive at the time of publication; the oldest individual was age 43 years [Schottmann et al 2016].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Prevalence

HIBCH deficiency is rare, and the exact prevalence is unknown. To date, 62 individuals from 48 families have been reported [Stiles et al 2015].

Differential Diagnosis

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency can result in a Leigh-like presentation due to secondary inhibition of the pyruvate dehydrogenase complex and electron transport chain (see Molecular Pathogenesis). Due to this, many individuals with HIBCH deficiency are misdiagnosed with mitochondrial disease or primary pyruvate dehydrogenase complex deficiency.

Genetic disorders of interest in the differential diagnosis of HIBCH deficiency are listed in Table 3.

Note: While biochemical findings characteristic of HIBCH deficiency can be useful in distinguishing the disorder from other possible diagnoses, in some affected individuals (particularly individuals with late-onset HIBCH deficiency) biochemical abnormalities may be subtle or absent.

Table 3.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Differential Diagnosis

Gene(s)Disorder 1MOIFeatures of Disorder
Overlapping w/HIBCH deficiencyDistinguishing from HIBCH deficiency 2
>120 nuclear genes;
15 mtDNA genes		Leigh syndrome spectrum (See Mitochondrial DNA-Associated Leigh Syndrome Spectrum & Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.)AD
AR
MT
XL
  • Developmental regression
  • Dystonia
  • Spasticity
  • Lactic acidosis
  • T2 hyperintensities in basal ganglia on brain MRI
Absence of biochemical findings characteristic of HIBCH deficiency 2
DLAT
DLD
PDHA1
PDHB
PDHX
PDP1
PDK3 		Primary pyruvate dehydrogenase complex deficiency (PDCD)AR
XL
  • PDCD may be clinically indistinguishable from HIBCH deficiency at all ages of presentation, w/developmental delay, movement disorder, & paroxysmal dystonia.
  • ↑ blood lactate w/proportional ↑ of pyruvate (normal lactate-to-pyruvate ratio)
  • MRI abnormalities: dysgenesis or agenesis of corpus callosum, basal ganglia hyperintensities
LIPT1 Lipoyltransferase 1 deficiency (OMIM 616299)AR
  • Dystonia
  • Spasticity
  • Lactic acidosis
  • T2 hyperintensities in basal ganglia on brain MRI
SLC19A3 Biotin-thiamine-responsive basal ganglia disease (BTBGD)AR
  • Dystonia
  • Spasticity
  • Lactic acidosis (most notable in early-infantile BTBGD)
  • T2 hyperintensities in basal ganglia on brain MRI
  • Absence of biochemical findings characteristic of HIBCH deficiency 2
  • Prompt administration of biotin & thiamine early in disease course results in partial or complete improvement w/in days in classic & adult BTBGD; however, most infants w/early-infantile BTBGD have a poor outcome.
ECHS1 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1 deficiency)AR
  • May be clinically indistinguishable from HIBCH deficiency at all ages of presentation
  • ↑ 2-methyl-2,3-dihydroxybutyrate on urine organic acids 3
  • Lactic acidosis
  • T2 hyperintensities in basal ganglia on brain MRI
  • Clinical benefit of valine-restricted diet has been reported. 4
  • Hydroxy-C4 carnitine [C4-OH] due to ↑ 3-hydroxyisobutyryl carnitine is absent in ECHS1 deficiency.
  • However, ↑ hydroxy-C4 carnitine [C4-OH] due to ↑ 3-hydroxybutyryl carnitine can be seen in those who are ketotic. 3
PC Pyruvate carboxylase deficiency AR
  • May present w/hypoglycemia, hyperammonemia, ketosis, & abnormal plasma amino acids
  • ↑ lactate & pyruvate concentration in blood
Absence of biochemical findings characteristic of HIBCH deficiency 2
SLC2A1 Glucose transporter type 1 deficiency syndrome (Glut1DS)AD
(AR)		Paroxysmal exercise-induced dystonia & epilepsy in late-diagnosed Glut1DS
  • Normal brain MRI
  • Absence of biochemical findings characteristic of HIBCH deficiency 2
PRRT2 PRRT2-related paroxysmal kinesigenic dyskinesia (See PRRT2-Related Disorder.)AD
(AR)		Paroxysmal attacks are often characterized by dystonia (may be exercise induced).
PNKD Familial paroxysmal nonkinesigenic dyskinesia ADParoxysmal attacks of dystonia (rarely triggered by exercise)

AD = autosomal dominant; AR = autosomal recessive; HIBCH = 3-hydroxyisobutyryl-CoA hydrolase; MT = mitochondrial; MOI = mode of inheritance; mtDNA = mitochondrial DNA; XL = X-linked

1.

Disorders are listed in order of relevance to the differential diagnosis of HIBCH deficiency.

2.

Individuals with HIBCH deficiency have elevated hydroxy-C4 carnitine on plasma acylcarnitine profile and elevated 2-methyl-2,3-dihydroxybutyric acid on urine organic acids (elevated 2-methyl-2,3-dihydroxybutyric acid can be intermittent).

3.
4.

Management

No clinical practice guidelines for 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HIBCH deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Metabolic/
Nutrition/
Feeding
  • Serum amino acids
  • Blood total & free carnitine & acylcarnitine profile
  • Lactic acid in blood or CSF
  • Urine organic acids
  • Gastroenterology / nutrition / feeding team eval
  • Assess baseline total protein & valine intake.
  • Assess weight, length, & head circumference.
  • To incl eval of aspiration risk & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, &/or aspiration risk.
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Neurologic
  • Neurologic exam
  • Brain MRI
Consider EEG if seizures are a concern.
  • Eval w/movement disorder specialist
  • Consider referral to PT, OT, & ST
To incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
Eyes Ophthalmologic evalTo assess for reduced vision, abnormal ocular movement, strabismus, & retinal exam that may require referral for subspecialty care &/or low vision services
Respiratory Pulmonology / sleep medicine evalConsider early eval for sleep apnea &/or microaspiration.
Hearing Audiologic evalAssess for hearing loss.
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of HIBCH deficiency to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADL = activities of daily living; CSF = cerebrospinal fluid; HIBCH = 3-hydroxyisobutyryl-CoA hydrolase; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; ST = speech therapy

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Table 5.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Targeted Therapy

TypeTreatmentDosageConsideration
Medical nutrition therapy Valine-restricted diet 1
  • A valine-restricted diet appears to be beneficial for patients w/HIBCH and ECHS1 deficiencies, improving biochemical and clinical manifestations of these disorders.
  • There is still limited information about recommended valine intake for different ages. It has been suggested that intake of valine should be restricted to a level that is lower than what is recommended for propionic & methylmalonic acidurias, & greater than recommended for MSUD. 2 Meeting protein DRIs is unlikely to be sufficient.
  • The valine content of the diet can be ↓ safely by limiting intact protein intake & using an appropriate amount of valine-free medical food to meet protein requirements.
  • A valine-only restricted formula is not available; an MSUD formula (restricted in valine, leucine, & isoleucine) is the best alternative.
  • Other protein-free medical foods should be added as needed to meet energy & micronutrient needs.
  • Plasma amino acid levels should be followed periodically to titrate valine & protein intake to maintain fasting plasma valine w/in lower quartile of normal values for age.
  • Leucine & isoleucine levels should also be monitored & supplemented if needed.
  • Diet should be implemented & followed in consultation w/metabolic dietitian.
  • In those fed by gastrostomy tube, use of medical food or formula allows for accurate titration of valine intake.
  • In those on oral diet, adherence to medical food or formula may be difficult due to palatability. Therefore, consider restricting total protein w/o quantitation of valine intake.
  • It is possible that dietary treatment will have a greater impact on persons w/early diagnosis &/or mild clinical presentations.

DRI = dietary reference intake; MSUD = maple syrup urine disease

1.
2.

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay / Intellectual disability / Neurobehavioral issues See Developmental Delay / Intellectual Disability Management Issues.
Poor weight gain / Vomiting
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Spasticity
  • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
  • Botox, serial casting, or surgical interventions as indicated
Consider need for positioning & mobility devices & disability parking placard.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Movement disorder Treatment to be determined by experienced movement disorder specialist
  • Specific medication depending on type of symptoms & severity
  • Efficacy of deep brain stimulation in HIBCH deficiency-related movement disorder has not been established.
Eyes Treatment of refractive errors & strabismus per ophthalmologist
Referral to ophthalmic subspecialist as needed for more complex findings
Low vision services
  • Children: through early intervention programs &/or school district
  • Adults: low vision clinic &/or community vision services / OT / mobility services
Cerebral visual impairment Early intervention program to stimulate visual development
Hearing
  • Hearing aids may be helpful per otolaryngologist.
  • Community hearing services through early intervention or school district
Transition to adult care Develop realistic plans for adult life (see American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care).Starting by age ~10 yrs
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; HIBCH = 3-hydroxyisobutyryl-CoA hydrolase; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Recommended Surveillance

System/ConcernEvaluationFrequency
Metabolic/
Nutrition/
Feeding
  • Eval w/metabolic specialist & metabolic dietician
  • Assessment of total protein & valine intake
As recommended by metabolic specialist
  • Fasting plasma amino acids
  • Blood total & free carnitine & acylcarnitine profile
  • Lactic acid in blood
  • Urine organic acids
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Development Monitor developmental progress & educational needs.
Neurologic
  • Assess for new manifestations such as changes in tone, seizures, & movement disorders.
  • Monitor those w/seizures as clinically indicated.
Musculoskeletal Physical medicine & OT/PT assessment of mobility & self-help skills
Ophthalmologic involvement Evaluate ability to track or follow & assess for abnormal eye movements.
Ophthalmology evalAt least annually
Respiratory Monitor for evidence of aspiration, respiratory insufficiency, & sleep apnea.At each visit
Hearing Audiologic evalAs needed

CSF = cerebrospinal fluid; OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

HIBCH deficiency has secondary mitochondrial abnormalities. Pyruvate dehydrogenase and enzymes involved in the electron transport chain may be inhibited, secondary to accumulation of metabolites. As a cautionary approach, it may be beneficial to follow the same recommendations as proposed in the Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.

A Delphi review has examined drug safety in mitochondrial disorders [De Vries et al 2020]. However, it is important to tailor medication recommendations to each individual.

  • Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes [De Vries et al 2020].
  • Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use [Shear & Tobias 2004, Niezgoda & Morgan 2013, Hsieh et al 2017].
  • Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis.
  • Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia.
  • Neuromuscular blocking drugs should be avoided in individuals with muscle disease or, if necessary, used under strict monitoring.
  • Avoid lactate-containing agents (e.g., Ringer's lactate) [Parikh et al 2017, De Vries et al 2020] including dialysate containing lactate.

Ketogenic / modified Atkins diets have not been formally studied in HIBCH deficiency and should be avoided due to potential side effects.

Triheptanoin (odd-carbon [C7] medium chain triglyceride) is contraindicated due to the potential increase in propionyl-CoA, which can be converted to acrylyl-CoA, a homologous compound to methacrylyl-CoA [Peters et al 2015].

Dichloroacetate (DCA) has been used in the treatment of pyruvate dehydrogenase complex (PDC) deficiency and is being investigated for other mitochondrial diseases. Individuals with HIBCH deficiency may have secondary inhibition of PDC. To date, there is no published evidence to support the use of dichloroacetate in HIBCH deficiency.

Evaluation of Relatives at Risk

Newborn sibs. It is appropriate to evaluate at-risk newborn sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted therapy. Evaluations include:

  • Molecular genetic testing for the HIBCH pathogenic variants identified in the proband;
  • Biochemical testing (blood gas, blood lactic acid and acylcarnitine, and urine organic acids).

Older sibs. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted therapy.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for an HIBCH pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HIBCH pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has HIBCH deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in HIBCH.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HIBCH pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the HIBCH pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

Prenatal Testing and Preimplantation Genetic Testing

Once the HIBCH pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Metabolic Support UK
    United Kingdom
    Phone: 0845 241 2173
  • United Mitochondrial Disease Foundation
    Phone: 888-317-UMDF (8633)
    Email: info@umdf.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
HIBCH2q32​.23-hydroxyisobutyryl-CoA hydrolase, mitochondrialHIBCH databaseHIBCHHIBCH

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency (View All in OMIM)

2506203-HYDROXYISOBUTYRYL-CoA HYDROLASE DEFICIENCY; HIBCHD
6106903-@HYDROXYISOBUTYRYL-CoA HYDROLASE; HIBCH

Molecular Pathogenesis

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine catabolism. HIBCH is responsible for the conversion of 3-OH-isobutyryl-CoA to 3-OH-isobutyric acid. HIBCH deficiency results in the buildup of 3-OH-isobutyryl-CoA, which conjugates with free carnitine to yield 3-OH-isobutyryl carnitine (C4-OH). The accumulation of 3-OH-isobutyryl-CoA leads to increased methacrylyl-CoA, a highly reactive compound, which conjugates with thiol groups and results in the accumulation of several toxic intermediates, including S-(2-carboxypropyl)cysteamine, S-(2-carboxypropyl)cysteine, and S-(2-carboxypropyl)cysteine's carnitine ester [Loupatty et al 2007, Abdenur et al 2020]. Methacrylyl-CoA metabolites result in secondary inhibition of the pyruvate dehydrogenase complex and electron transport chain, leading to a Leigh-like presentation [Ferdinandusse et al 2013, Abdenur et al 2020]. Thus, many individuals are misdiagnosed with mitochondrial disease or pyruvate dehydrogenase complex deficiency.

The majority of pathogenic variants reported are missense. A variety of other loss-of-function variants have also been reported, including splice site [Loupatty et al 2007, Soler-Alfonso et al 2015, Zhu et al 2015, Tan et al 2018, Yang et al 2018] and frameshift [Reuter et al 2014, Peters et al 2015, D'Gama et al 2020, Puvabanditsin et al 2024] variants and an 868-kb deletion including HIBCH [Wang et al 2021]. Most pathogenic variants are private; however, recurrent variants have been reported (see Table 8).

Mechanism of disease causation. Loss of function

Table 8.

HIBCH Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_014362​.4
NP_055177​.2 		c.913A>Gp.Thr305AlaRecurrent variant identified in 15 persons from 9 families of Turkish, Iranian, Greek, Middle Eastern. & other unspecified ancestry [Schottmann et al 2016, Karimzadeh et al 2019, Wirth et al 2020, Marti-Sanchez et al 2021, Spitz et al 2021, François-Heude et al 2022]
c.1027C>Gp.His343AspRecurrent variant identified in 6 persons from 6 families of Chinese ancestry [Zhu et al 2015, Xu et al 2019, Wang et al 2021]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Jose Abdenur is the director of the metabolic laboratory at the Children's Hospital of Orange County (CHOC) and has a special interest in undiagnosed rare disorders and translational research of defects of energy metabolism.
Web pages: choc.org/research/metabolic-rare-disease-research and choc.org/programs-services/metabolic-disorders/metabolic-lab

Rebekah Barrick is a metabolic genetic counselor at CHOC and has a special interest in mitochondrial, neurometabolic, and undiagnosed rare disorders.
Web page: choc.org/programs-services/metabolic-disorders

Revision History

  • 12 February 2026 (aa) Revision: Table 2 corrected; no regression in neonatal-onset phenotype
  • 20 November 2025 (sw) Review posted live
  • 16 May 2025 (ja) Original submission

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