LCHADD/TFP Deficiency

Other Names

Long chain 3 hydroxyacyl-CoA dehydrogenase deficiency

Trifunctional protein deficiency (TFP)

Diagnosis Coding

E71.310, long chain/very long chain acyl CoA dehydrogenase deficiency

Disorder Category

A fatty acid oxidation disorder

Screening

Finding

Elevated C16-OH +/- and C18:1-OH

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=100% [Schulze: 2003]

Overview

The trifunctional protein catalyzes 3 steps in the beta-oxidation of fatty acids, including the hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase. It is formed by 2 subunits encoded by 2 different genes (HADA and HADB) located on the same chromosome (2p23). In LCHAD deficiency, specific missense mutations within the alpha subunit (HADA) cause the disease. Mutations that completely abolish the function of the protein cause trifunctional protein (TFP) deficiency. TFP deficiency can be caused either by mutations in the alpha (HADA) or beta subunit (HADB); LCHAD is caused by specific missense mutations in the alpha subunit that allow the reaction to start, but not be completed. LCHAD and TFP deficiency cause cellular damage from accumulation of 3-OH-fatty acids, impaired energy production from longer chain fatty acids, and consequent hypoglycemic crises during prolonged fasting or increased energy demands, such as fever or other stress.

Prevalence

The incidence of LCHAD deficiency in the United States is approximately 1:363,738. [Therrell: 2014]

Inheritance

Autosomal recessive

Maternal & Family History

HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count), acute fatty liver of pregnancy (AFLP) syndrome, and increased incidence of pre-eclampsia and eclampsia can be seen in mothers carrying a child with LCHAD or TFP deficiency. These complications can be life-threatening in the mother and lead to premature birth.

Prenatal Testing

Prenatal testing involves DNA testing in cells obtained by amniocentesis or chorionic villous sampling (CVS).

Clinical Characteristics

With treatment prior to hypoglycemic crises, the child’s intelligence is likely to be normal, but progression of peripheral neuropathy and retinitis pigmentosa can occur. Without treatment, hypoglycemic episodes may lead to developmental delay and neurologic impairment. Cardiomyopathy and/or hepatic failure may result in death. Pigmentary retinopathy develops with time. Neuropathy is more frequent and usually occurs earlier in patients with trifunctional protein deficiency. Symptoms, whether mild or severe, may begin anytime between birth and 3 years of age. All patients have exercise intolerance and develop myoglobinuria and muscle pain with strenuous exercise.

Initial symptoms/signs may include:
  • Poor feeding
  • Vomiting
  • Lethargy
  • Hypotonia
  • Heptomegaly
  • Cardiac insufficiency
  • Cardiomyopathy
  • Lab findings:
    • Elevated liver function tests
    • Elevated CK
    • Metabolic acidosis
    • Lactic acidosis
    • Hypoglycemia

Without effective treatment, subsequent symptoms may include:
  • Hepatic disease
  • Cardiomyopathy
  • Cardiac conduction defects (arrhythmia)
  • Peripheral neuropathy
  • Pigmentary retinopathy
  • Rhabdomyolysis

Follow-up Testing after Positive Screen

Follow-up testing includes quantitative plasma acylcarnitine profile, urine organic acid analysis, free 3-OH-fatty acids, biochemical and molecular genetic testing in blood for differentiation between LCHADD and TFP.

Primary Care Management

Upon Notification of the + Screen

  • Contact the family and evaluate the infant for heptomegaly or cardiomyopathy. Ask about a family history of sudden death or a maternal history of pregnancy-related liver disease, such as hemolysis, elevated liver enzymes, low platelets (HELLP syndrome), or acute fatty liver of pregnancy (ALFP).
  • Provide emergency treatment and referral for symptoms of hypoglycemia, lethargy, or feeding problems.
  • To confirm diagnosis, work with the following service(s): we currently have no Newborn Screening Programs service providers listed, please search our Services database for related services.
  • Consult the following service(s): we currently have no Pediatric Genetics service providers listed, please search our Services database for related services for further advice or evaluation.

If the Diagnosis is Confirmed

  • Educate the family about signs and symptoms of hypoglycemia, and the need for urgent care if the infant becomes ill. See LCHADD/TFP Deficiency - Information for Parents (STAR-G) for additional information).
  • Support avoidance of fasting, and use of uncooked starch, medium chain triglycerides, and frequent, low fat and high carbohydrate meals and snacks.
  • Consider oral L-carnitine (at low doses) and docosahexanoic acid (DHA)/essential fatty acids supplements.
  • Assist in management of irreversible consequences as necessary, particularly with developmental and educational interventions.
  • See the Portal’s diagnosis and management module for LCHADD/TFP Deficiency.

Specialty Care Collaboration

Provide initial consultation and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management.

Resources

Information & Support

For Professionals

LCHADD - Information for Professionals (STAR-G)
Structured list of information about the condition and links to more information; Screening, Technology, and Research in Genetics.

LCHADD (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

For Parents and Patients

LCHADD/TFP Deficiency - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

LCHADD (Genetics Home Reference)
Excellent, detailed review of the condition for patients and families; sponsored by the U.S. National Library of Medicine.

Trifunctional Protein Deficiency (Genetics Home Reference)
Excellent, detailed review of the condition for patients and families; sponsored by the U.S. National Library of Medicine.

Fatty Oxidation Disorders (FOD) Family Support Group
Information for families about fatty acid oxidation disorders, support groups, coping, finances, and links to other sites.

Tools

ACT Sheet for LCHADD (ACMG) (PDF Document 333 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for LCHADD (ACMG) (PDF Document 69 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

LCHADD Acute Illness Protocol
A guideline for health care professionals treating the sick infant or child who has previously been diagnosed with LCHADD; developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs.

Services

Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Newborn Screening Programs

We currently have no Newborn Screening Programs service providers listed; search our Services database for related services.

Pediatric Genetics

We currently have no Pediatric Genetics service providers listed; search our Services database for related services.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search for LCHADD and neonatal screening, last 5 years.

De Biase I, Viau KS, Liu A, Yuzyuk T, Botto LD, Pasquali M, Longo N.
Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency.
JIMD Rep. 2017;31:63-71. PubMed abstract / Full Text

Gillingham MB, Purnell JQ, Jordan J, Stadler D, Haqq AM, Harding CO.
Effects of higher dietary protein intake on energy balance and metabolic control in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency.
Mol Genet Metab. 2007;90(1):64-9. PubMed abstract / Full Text

Authors

Author: Nicola Longo, MD, PhD - 2/2011
Reviewing Author: Nicola Longo, MD, PhD - 7/2017
Content Last Updated: 7/2017

Page Bibliography

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text