Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.1
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: HADHA, HADHB
• Condition: Disorders of the trifunctional protein complex
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• HADHA ⇔ 0012172 (mitochondrial trifunctional protein deficiency): Moderate Actionability
• HADHA ⇔ 0012173 (long chain 3-hydroxyacyl-coa dehydrogenase deficiency): Moderate Actionability
• HADHB ⇔ 0012172 (mitochondrial trifunctional protein deficiency): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric. Although the scorers determined that it would be very appropriate to provide the described interventions to people identified with this condition, the fact that there were limitations to effectiveness prevented this topic from reaching strong actionability. Controlled trials are not expected to be forthcoming because although the treatment is not completely effective, it clearly leads to some improvement in outcomes.

Final Consensus Scores

Gene Condition Pairs: HADHA ⇔ 0012172 (OMIM:609015) HADHA ⇔ 0012173 (OMIM:609016) HADHB ⇔ 0012172 (OMIM:609015)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity associated with metabolic decompensation / Metabolic management (dietary management and illness protocols)	2	3C	2A	2	9CA
Morbidity associated with metabolic decompensation / Triheptanoin treatment	2	3C	2C	2	9CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

A systematic review to estimate birth prevalence of disorders of the trifunctional protein (TFP) complex including isolated long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD) reported on 13,421,143 individuals screened biochemically and 7,576,414 individuals screened clinically. Biochemically identified birth prevalence per 100,000 was 0.65 (95% confidence interval [CI]: 0.43, 0.91) in Western countries and 0.91 (95% CI: 0.47, 1.77) worldwide. Clinically identified birth prevalence per 100,000 was 0.41 (95% CI: 0.19, 0.90) in Western countries and 0.43 (95% CI: 0.22, 0.86) worldwide. However, around the Baltic Sea the frequency of LCHADD is higher; where clinically identified birth prevalence is predicted to be 0.83:100,000 in Poland and 5:100,000 in the Pomeranian district. [1, 2]

Clinical Features

The TFP-complex is comprised of four enzyme subunits encoded by HADHA and HADHB. HADHA contains the information for the long-chain enoyl-CoA hydratase (LCEH) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), whereas HADHB encodes long-chain ketoacyl-CoA thiolase (LCKT) activity. Compared to LCHADD, the molecular basis of MTPD is heterogeneous and different causative variants have been identified in both HADHA and HADHB. Since they are closely related to sometimes difficult to distinguish clinically, this report includes LCHADD and MTPD.
Disorders of the TFP-complex are characterized by a wide clinical spectrum, which may be classified into 3 main clinical phenotypes:
•A severe, neonatal-onset form with rapidly progressing severe cardiomyopathy, liver disease (steatosis, hepatic encephalopathy), Reye syndrome-like symptoms, skeletal myopathy, neuropathy, lethargy, and sudden unexplained infant death (SIDS).
•A moderate, infant-onset hepatic form (including hepatomegaly and cholestasis) with metabolic acidosis, neuropathy with or without cardiomyopathy, and recurrent hypoketotic hypoglycemia. It is often precipitated by prolonged fasting and/or intercurrent illness or infection.
•A mild, later adolescent-onset form associated with skeletal myopathy, hypotonia, decreased tendon reflexes, recurrent rhabdomyolysis (with subsequent respiratory failure), pigmentary retinopathy, and peripheral neuropathy. It is often induced by prolonged fasting, illness, exercise, or exposure to heat or cold.
Other features observed within the spectrum of disease include feeding difficulties, failure to thrive, seizures, developmental delay, hypoparathyroidism, and clotting defects. Long-term myopathic symptoms, and neuropathic complications (including chronic and/or irreversible peripheral neuropathy), are common. [1, 3, 4, 5, 6, 7, 8, 9, 10, 11]

Natural History

The severe neonatal-onset severe form presents at or within a few days of birth and is usually lethal. The moderate, infant-onset form presents from the neonatal period to 24 months of age and can be fatal. The mild, later adolescent-onset form can merge with the moderate, infant-onset form and can present from a few months of age until adolescence or adulthood. Rarely, adults presenting for the first time with a previously unrecognized disease are described. Some patients present with slow, insidious disease and dilated cardiomyopathy has the potential to develop across the lifespan. There is a high mortality rate in disorders of the TFP-complex in the first days and weeks of life, with the rate among children reported to be 38-90% even with treatment. [1, 3, 4, 5, 6, 7, 9, 10]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making for LCHAD or TFP deficiencies following newborn screening: https://www.acmg.net/PDFLibrary/LCHADD-ACT-Sheet.pdf

Disorders of the TFP-complex require a strict fat-reduced (long chain triglyceride [LCT] intake as low as possible) and fat-modified (medium-chain triglyceride [MCT]-supplemented) diet starting immediately upon diagnosis, even if asymptomatic, for prevention of long-term neuropathic symptoms. A special formula for neonates that is low in LCT and high in MCT is recommended, and reliance on breast milk or regular infant formula alone should be avoided. After 4 months of age and with the start of solid food, LCT intake should remain as low as possible (25-30% of total energy). Additional essential fatty acids are supplemented to cover the daily requirements. Despite adequate treatment many patients still suffer acute life-threatening events or long-term neuropathic symptoms. (Tier 2) [3]

A systematic review investigated whether early dietary management provides better outcomes than late treatment for a total of 204 pediatric patients with genetically confirmed disorders of the TFP-complex. Outcomes for patients diagnosed earlier (through newborn screening, cascade testing, or incidental detection) compared to those diagnosed later (following symptomatic presentation) indicated fewer problems with the heart (16% vs. 63%, respectively) and liver (17% vs. 50%, respectively). However, it is unclear whether there was reduced mortality in the early treatment group. Additional outcomes (vision, neurologic, and motor/muscular problems) did not yield consistently significant differences between groups, partly due to the small sample sizes. (Tier 1) [5]

In disorders of the TFP-complex, supplementation of docosahexanoic acid (DHA) is recommended. In a perspective cohort study of 14 genetically confirmed pediatric patients with LCHADD, optimal dietary therapy, as indicated by low plasma 3-hydroxyacylcarnitine and high plasma DHA concentrations, was associated with retention of retinal function and visual acuity (p=0.051 after 2 years of supplementation). (Tier 2) [3]

We did not identify a recommendation for triheptanoin treatment in LCHADD or MTPD.

However, in June 2020, the FDA approved DOJOLVI (triheptanoin) for the treatment of pediatric and adult patients with molecularly confirmed long-chain FAO disorders. One study described clinical response to treatment with triheptanoin in 12 pediatric patients, including 5 with LCHADD and 2 with MTPD. Treatment duration was for an average of 22 months (range of 9 to 228 months). Ten (83%) patients reported reduction in fatigue and weakness, 8 (67%) experienced reduced intensity of myalgia, and 8 (67%) had decreased episodes of rhabdomyolysis. Of 3 patients who had severe hypoglycemic events in the year prior to starting triheptanoin, none had these events in the year following initiation of therapy. Average emergency hospital care visits and days of emergency home care were also reduced. (Tier 3) [6, 12]

The family should be taught to recognize the symptoms and signs of acute decompensation so that treatment may start at the earliest possible stage, considering that early signs may be subtle. In all individuals with long-chain FAO disorders, regardless of ever having clinical symptoms or not, catabolic states must be managed by emergency regimens. Emergency treatment aims to intervene while blood glucose is normal and to reduce mobilization of fat by providing ample glucose. Early intervention is important and may prevent complications. Oral or nasogastric feeding may be sufficient, though a patient’s clinical status and previous decompensation history may warrant intravenous treatment. A cardiology assessment is necessary to evaluate a child with acute symptomatic LCHADD. Many children take days to weeks to improve clinically from an acute decompensation, even once biochemical parameters have normalized. Improvements in mental status, hypotonia, hepatomegaly and cardiomyopathy can be problematic. Despite emergency therapy, children with LCHADD have died or been left with chronic neurologic, cardiac, and hepatic problems. (Tier 2) [3, 7, 11, 13, 14]

Patients with FAO disorders (including LCHADD and others) are at risk of metabolic decompensation during surgery, particularly if catabolism is precipitated by fasting and surgery. Elective surgery is usually best done at the hospital with the regional metabolic unit. It is important to minimize catabolism by providing adequate amounts of carbohydrate (orally or intravenously) prior to and during surgery. Operations should be postponed, if possible, in children who are unwell. (Tier 2) [13]

Surveillance

In all patients with long-chain FAO disorders, careful follow-up in should be performed in metabolic centers. Monitoring of pediatric patients should include quarterly clinical evaluations. Information gathered at each visit should include details regarding growth and development, eye and muscle symptoms, pain, and a formal dietary record. The provider should update the patient’s acute regimen and provide advice concerning physical exercise. Yearly assessments may include eye examination, echocardiography, liver ultrasound, and nerve conduction velocity testing. Electrocardiography and/or abdominal ultrasonography may be needed in some patients. Plasma free carnitine, acylcarnitine, erythrocyte fatty acid profile, and creatine kinase should be measured regularly. (Tier 2) [3, 15]

Circumstances to Avoid

The role of carnitine in both the standard and emergency treatment of FAOs is controversial with guidelines suggesting it should be avoided, especially intravenous carnitine, which may be arrhythmogenic. Instances of sudden death have been reported. (Tier 2) [3, 7, 11, 16]

Fasting should be avoided, including overnight fasting. (Tier 2) [3, 7]

Certain medications should be used with caution, including intravenous epinephrine, which stimulates lipolysis and can exacerbate an FAO disorder. Valproic acid inhibits FAO and is relatively contraindicated. (Tier 3) [8]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 6, 9, 10]

Prevalence of Genetic Variants

No information on the prevalence of pathogenic variants associated with disorders of the TFP-complex was identified.

Penetrance

A study reviewing the clinical presentation and follow-up of 50 pediatric patients with LCHADD (49 genetically confirmed, mean age at presentation of 5.8 months) reported that 39 patients (78%) presented with acute hypoketotic hypoglycemia. The other 11 patients (22%) presented with a more chronic disorder consisting of cholestatic liver disease, failure to thrive, feeding difficulties, and/or hypotonia. Mortality was high (38%), with patients all dying before or within 3 months after diagnosis. Of the 31 surviving LCHADD patients, the following signs and symptoms were reported:
•Recurrent metabolic derangement: 8/31 (26%)
•Recurrent muscular pains: 10/31 (32%)
•Cardiomyopathy: 0/31 (0%)
•Failure to thrive: 7/31 (23%)
•Feeding difficulties: 8/31 (26%)
•Hypotonia: 4/31 (13%)
•Motor delay: 6/31 (19%)
•Peripheral neuropathy: 3/31 (10%)
•Retinopathy with progressive visual impairment: 9/31 (29%) (Tier 3) [6, 9]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Heterogeneity of clinical phenotypes has been reported in patients with disorders of the TFP-complex. Clinical presentations of LCHADD/MTPD are variable, even in cases with the same underlying pathogenic variant. (Tier 3) [3, 5, 9]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified for disorders of the TFP-complex include dietary modifications, avoidance of fasting and other triggers, extra precautions before and during surgical procedures, and regular monitoring. These interventions may be burdensome, particularly in pediatric patients.

MCT supplements are administered in multiple doses throughout the day (every 6-8 hours) and can cause diarrhea and gastrointestinal (GI) upset. [8]

The fat-reduced and fat-modified diet required for patients with disorders of the TFP-complex are the strictest of all FAO disorders. [4]

Minor adverse effects reported from triheptanoin treatment primarily consisted of GI upset such as abdominal pain (60%), diarrhea (44%), and vomiting (44%). In the 2 clinical trials (N=108 patients) used to assess safety for FDA approval, median time to onset of a GI adverse reaction was 7.3 weeks. GI adverse reactions led to dose reductions in 12-35% of patients. [12]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Most of the time patients are healthy but intercurrent infections, prolonged fasting, alcohol excess, excessive exercise, vomiting or diarrhea can lead to serious complications with rhabdomyolysis, encephalopathy, and sudden death. Children or their sibs affected with FAO disorders have often been misdiagnosed as having Reye syndrome or idiopathic cardiomyopathy; some who have died have also been labeled as SIDS deaths. (Tier 4) [1, 7, 16]

Date of Search: 05.19.2021

Reference List

1. Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=5

2. Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. (2014) 37(6):889-98.

3. Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, Das A, Haase C, Hennermann JB, Karall D, de Klerk H, Knerr I, Koch HG, Plecko B, Roschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U. Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. (2009) 32(4):498-505.

4. Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, Das A, Haase C, Hennermann JB, Karall D, de Klerk H, Knerr I, Koch HG, Plecko B, Röschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis. (2009) 32(1573-2665):488-97.

5. Fraser H, Geppert J, Johnson R, Johnson S, Connock M, Clarke A, Taylor-Phillips S, Stinton C. Evaluation of earlier versus later dietary management in long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency: a systematic review. Orphanet J Rare Dis. (2019) 14(1750-1172):258.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. LONG-CHAIN 3-HYDROXYACYL-CoA DEHYDROGENASE DEFICIENCY. MIM: 609016: 2021 Jun 14. World Wide Web URL: http://omim.org.

7. New England Consortium of Metabolic Programs. Long Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (LCHADD). LCHADD ACUTE ILLNESS MATERIALS.. (2000) Accessed: 2021-05-25. Website: https://www.newenglandconsortium.org/lchadd

8. Aldubayan SH, Rodan LH, Berry GT, Levy HL. Acute Illness Protocol for Fatty Acid Oxidation and Carnitine Disorders. Pediatr Emerg Care. (2017) 33(1535-1815):296-301.

9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY; MTPD. MIM: 609015: 2021 Jun 14. World Wide Web URL: http://omim.org.

10. Mitochondrial trifunctional protein deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=746

11. British Inherited Metabolic Diseases Group. Long chain fat oxidation disorders - acute decompensation. (2017) Accessed: 2021-05-19. Website: https://bimdg.org.uk/store/guidelines/ER-LCFAO-v5_700028_05042017.pdf

12. US Food and Drug Administration. DOJOLVI (triheptanoin) [label]. (2020) Accessed: 2021-05-26. Website: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213687s000lbl.pdf

13. British Inherited Metabolic Diseases Group. Management of surgery in children with disorders of fatty acid oxidation. (2017) Accessed: 2021-05-20. Website: https://bimdg.org.uk/store/guidelines/Management_of_surgery_in_children_with_fat_oxidation_disorde_846764_09092016.pdf

14. British Inherited Metabolic Diseases Group. General Dietary Information for Emergency Regimens. (2016) Accessed: 2021-05-20. Website: https://bimdg.org.uk/store/guidelines/General_dietary_information_for_ER_2016_441245_09092016.pdf

15. Lund AM, Skovby F, Vestergaard H, Christensen M, Christensen E. Clinical and biochemical monitoring of patients with fatty acid oxidation disorders. J Inherit Metab Dis. (2010) 33(1573-2665):495-500.

16. British Inherited Metabolic Diseases Group. Adult emergency management; Long chain fatty acid oxidation defects. (2018) Accessed: 2021-05-19. Website: https://bimdg.org.uk/store/guidelines/ADULT_FAOD-rev_2015_428281_09012016.pdf