Diagnostic Criteria

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)

Source: GeneReviews — "3-Hydroxyisobutyryl-CoA Hydrolase Deficiency"

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 . 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 . 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

Source: GeneReviews — "3-Hydroxyisobutyryl-CoA Hydrolase Deficiency"

Management Guidelines

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 (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/Concern | Evaluation | Comment

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

Source: GeneReviews — "3-Hydroxyisobutyryl-CoA Hydrolase Deficiency"

Clinical Guidance

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 . 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 .

• 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 .

• 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) including dialysate containing lactate.

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

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.

Source: GeneReviews — "3-Hydroxyisobutyryl-CoA Hydrolase Deficiency"

Surveillance Guidelines

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

Table 7.

3-Hydroxyisobutyryl-CoA Hydrolase Deficiency: Recommended Surveillance

System/Concern | Evaluation | Frequency

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 eval | At least annually

Respiratory

| Monitor for evidence of aspiration, respiratory insufficiency, sleep apnea. | At each visit

Hearing

| Audiologic eval | As needed

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

Source: GeneReviews — "3-Hydroxyisobutyryl-CoA Hydrolase Deficiency"