LCHADD/TFP Deficiency
Other Names
Long chain 3 hydroxyacyl-CoA dehydrogenase deficiency
Trifunctional protein deficiency (TFP)
Screening
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.Incidence
The incidence of LCHAD deficiency in the United States is approximately 1:363,738. [Therrell: 2014]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): see all Newborn Screening Programs services providers (2) in our database.
- Consult the following service(s): see all Pediatric Genetics services providers (4) in our database 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 (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.
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (Genetics Home Reference)
Excellent, detailed review of the condition for patients and families; sponsored by the U.S. National Library of Medicine.
Mitochondrial 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) (
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) ( 69 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.
LCHADD Acute Illness Protocol (New England Consortium of Metabolic Programs)
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
Newborn Screening Programs
See all Newborn Screening Programs services providers (2) in our database.
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, Ph.D. - 2/2011 |
| Reviewing Author: | Nicola Longo, MD, Ph.D. - 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