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LCHAD & TFP Deficiency

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Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Long chain 3 hydroxyacyl-CoA dehydrogenase deficiency
Trifunctional protein deficiency (TFP)

ICD-10 Coding

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

Disorder Category

Fatty acid oxidation disorder

Screening

Abnormal Finding

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

Tested By

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

Description

In LCHADD/TFP deficiency, 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 (HADHA and HADHB) located on the same chromosome (2p23).

Isolated LCHAD deficiency is caused by specific types of variants that only affect the alpha subunit (HADHA). Alternatively, variants typically involving the beta subunit (HADHB), and certain types of alpha subunit variants, result in dysfunction of the entire enzyme complex, causing the similar though generally more severe condition trifunctional protein (TFP) deficiency.

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 metabolic stress such as fever and other infectious processes.

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.

Clinical Characteristics

With treatment, the effects of crises can be avoided or minimized if treated in a timely manner. This may require adherence to strict dietary changes and supplementation with medium chain fats. The child’s intelligence is likely to be normal, but progression of peripheral neuropathy and retinitis pigmentosa can occur. In the most severe cases, available therapies may not be able to sufficiently control the progressive cardiomyopathy, skeletal myopathy, and hypoketotic hypoglycemia. [García: 2021]
Without treatment, recurrent hypoketotic hypoglycemic episodes may lead to developmental delays and neurologic impairment. Additionally, metabolic crises can result in severe acute life-threatening decompensation. Progressive cardiomyopathy, liver disease, and pigmentary retinopathy are likely to occur over time and may result in significant morbidity/mortality. 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
  • Liver disease
  • Cardiomyopathy
  • Lab findings:
    • Elevated liver function tests
    • Elevated CK
    • Metabolic acidosis
    • Hypoketotic hypoglycemia
Without effective treatment, subsequent symptoms may include:
  • Hepatic disease
  • Cardiomyopathy
  • Cardiac conduction defects (arrhythmia)
  • Peripheral neuropathy
  • Pigmentary retinopathy
  • Rhabdomyolysis

Incidence

The incidence in the United States is approximately 1:363,738 for LCHAD deficiency and 1:1,822,568 for TFP deficiency. [Therrell: 2014]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for hepatomegaly 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.

Confirming the Diagnosis

  • To confirm diagnosis, work with Newborn Screening Services (see NW providers [1]).
  • Follow-up testing includes quantitative plasma acylcarnitine profile, urine organic acid analysis, and genetic testing to differentiate between LCHAD and TFP deficiency.

If the Diagnosis is Confirmed

  • Consult Medical Genetics (see NW providers [1]) for further advice or evaluation.
  • Educate the family about the signs and symptoms of hypoglycemia, and the need for urgent care if the infant becomes ill. See LCHAD Deficiency - Information for Parents (STAR-G) for additional information).
  • Support avoidance of fasting, strict dietary adherence, and compliance with dietary supplements as prescribed by the metabolic geneticist and dietitian.
  • Assist in management of irreversible consequences as necessary, particularly with developmental and educational interventions.
  • See Portal’s diagnosis and management module for LCHAD/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. See: below for providers:

Resources

Information & Support

Related Portal Content
LCHAD/TFP Deficiency
Assessment and management information for the primary care clinician caring for the child with LCHAD/TFP deficiency.
Fatty Acid Oxidation Disorders (FAQ)
Answers to questions frequently asked by families with a child diagnosed with LCHAD/TFP deficiency.
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

LCHAD Deficiency (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

For Parents and Patients

LCHAD 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.

Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Mitochondrial Trifunctional Protein Deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the 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 LCHAD and TFP Deficiency (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 Algorithms for LCHAD and TFP Deficiency (ACMG) (PDF Document 69 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Long Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (LCHADD) (NECMP)
A guideline for health care professionals treating the sick infant or child who has been diagnosed with LCHADD.

Services for Patients & Families Nationwide (NW)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Studies

LCHAD/TFP Deficiency in Children (birth-17 years) (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Helpful Articles

PubMed search for LCHAD/TFP deficiency and neonatal screening, last 10 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

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(1):258. PubMed abstract / Full Text

Vockley J, Burton B, Berry G, Longo N, Phillips J, Sanchez-Valle A, Chapman K, Tanpaiboon P, Grunewald S, Murphy E, Lu X, Cataldo J.
Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.
J Inherit Metab Dis. 2021;44(1):253-263. PubMed abstract / Full Text

Williams-Hall R, Tinsley K, Kruger E, Johnson C, Bowden A, Cimms T, Gater A.
Qualitative evaluation of the symptoms and quality of life impacts of long-chain fatty acid oxidation disorders.
Ther Adv Endocrinol Metab. 2022;13:20420188211065655. PubMed abstract / Full Text

Authors & Reviewers

Initial publication: March 2007; last update/revision: June 2022
Current Authors and Reviewers:
Authors: Hannah Holik, MD
Kimberly Stowers, MD
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2017: update: Nicola Longo, MD, Ph.D.A
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

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

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(1):258. PubMed abstract / Full Text

García García LC, Zamorano Martín F, Rocha de Lossada C, García Lorente M, Luque Aranda G, Escudero Gómez J.
Retinitis pigmentosa as a clinical presentation of LCHAD deficiency: A clinical case and review of the literature.
Arch Soc Esp Oftalmol (Engl Ed). 2021;96(9):496-499. PubMed abstract

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

Vockley J, Burton B, Berry G, Longo N, Phillips J, Sanchez-Valle A, Chapman K, Tanpaiboon P, Grunewald S, Murphy E, Lu X, Cataldo J.
Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.
J Inherit Metab Dis. 2021;44(1):253-263. PubMed abstract / Full Text

Williams-Hall R, Tinsley K, Kruger E, Johnson C, Bowden A, Cimms T, Gater A.
Qualitative evaluation of the symptoms and quality of life impacts of long-chain fatty acid oxidation disorders.
Ther Adv Endocrinol Metab. 2022;13:20420188211065655. PubMed abstract / Full Text