Clinical Guidance

HADHA. Homozygous variants are associated with LCHAD deficiency. Most individuals with LCHAD deficiency have at least one allele with this variant . In the largest cohort of individuals with LCHAD deficiency, was present in 84 of 98 alleles. Only one individual was homozygous for another variant . However, a few individuals who were compound heterozygous for this variant and another pathogenic variant in HADHA were reported to have TFP deficiency . Enzymatic studies were not provided for those individuals. In the absence of homozygosity for this variant, enzyme assay is needed to distinguish between these conditions. HADHB. In general, individuals with HADHB missense pathogenic variants present with milder phenotypes than those with premature termination or frameshift variants.

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Diagnostic Criteria

No consensus clinical diagnostic criteria for long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency or trifunctional protein (TFP) deficiency have been published.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for LCHAD/TFP deficiency is primarily based on quantification of the analytes 3-hydroxypalmitoyl carnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH) on dried blood spots. C16-OH and C18:1-OH values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing including plasma acylcarnitine and urine organic acid profiles. If the follow-up biochemical testing supports the likelihood of LCHAD/TFP deficiency, additional testing is required to establish the diagnosis .

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Differential Diagnosis

Table 3. Genetic Disorders of Interest in the Differential Diagnosis of LCHAD/TFP Deficiency

Management Guidelines

A brief outline of treatment recommendations for long-chain fatty acid oxidation defects including long-chain hydroxyacyl-CoA dehydrogenase (LCHAD)/ trifunctional protein (TFP) deficiency has been published . Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with LCHAD/TFP deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with LCHAD/TFP Deficiency

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Clinical Guidance

Avoid the following:

• Fasting, including periods of preparation and recovery from planned surgery or anesthesia

• Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

• Inadequate calories following vaccination

Note: Vaccination is safe.

• Dehydration (risk for rhabdomyolysis and acute renal failure)

• High-fat diet including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet

• Administration of intravenous intralipids during an acute metabolic crisis

Anesthetics that contain high doses of long-chain fatty acids (e.g., propofol, etomidate) are avoided in long-chain fatty acid oxidation defects. However, a retrospective analysis revealed no adverse events with propofol for short-duration procedures in individuals with LCHAD/TFP deficiency . A combination of midazolam, thiopental, fentanyl, and remifentanil was used successfully in an individual with LCHAD deficiency .

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Therapies Under Investigation

Cardiac transplantation. Favorable outcome after cardiac transplantation in individuals with TFP deficiency has been reported . However, it is expected that with timely diagnosis, strict dietary therapy, and MCT or triheptanoin supplementation, cardiac transplantation may not be required. Bezafibrate is a hypolipidemic drug and an agonist of peroxisome proliferator-activated receptor (PPAR). It increases expression of several enzymes involved in mitochondrial fatty acid oxidation, including TFP . Bezafibrate was reported to have a favorable outcome in two individuals with TFP deficiency . Bezafibrate is not available in the United States. REN001 (Reneo Pharmaceuticals®) is a selective PPAR- agonist that increases transcription of genes involved in mitochondrial fatty acid oxidation.

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Surveillance Guidelines

There are no current published guidelines for surveillance. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in are recommended.

Table 9.

Recommended Surveillance for Individuals with LCHAD/TFP Deficiency

Manifestation | Evaluation | Frequency/Comment

Metabolism

| Nutritional mgmt | At each visit. Frequency of visits is determined by clinical severity. Follow-up interval can be adjusted based on metabolic control. A rough guideline (by age):

• 1 yr: weekly to monthly

• 1-7 yrs: every 1-6 mos

• 7 yrs: every 6-12 mos

Comprehensive fatty acid profile to assess for essential fatty acid deficiency1 | Annually

Plasma free total carnitine, acylcarnitine profile, CK, AST, ALT | Recommended frequency (by age):

• 1 yr: every 3 mos

• 1-7 yrs: every 3-6 mos

• 7 yrs: every 6-12 mos

Growth

| Measurement of head circumference growth | At each visit throughout childhood

Development

| Monitoring of developmental milestones

• Neuropsychological testing using age-appropriate standardized assessment batteries

• Standardized quality of life assessment tools for affected persons parents/caregivers

| As needed

Cardiomyopathy

| EKG echocardiography | Annually or more frequently for severe presentation

Peripheral neuropathy

| Neurology eval | Annually

NCV EMG | As needed

Retinopathy

| Ophthalmology eval | Annually

ERG | Every 2-3 yrs

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"