LCHAD/TFP Deficiency

Overview

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and trifunctional protein (TFP) deficiency are disorders of fatty acid oxidation. During times of fasting, the body uses fat as a major source of energy, catabolizing them through beta-oxidation. The overall reaction involves several different enzymes that break down very long-chain fats to long-chain fats, long-chain fats to medium-chain fats, eventually resulting in the production of ketone bodies and acetyl-CoA. Ketones are generated in the liver and provided to other organs (brain, muscle, heart) for energy production. Acetyl-CoA enters the Krebs cycle to generate ATP and reducing equivalents.

Long-chain fatty acids are broken down by very long-chain acyl CoA dehydrogenase (VLCAD) and then by the trifunctional protein (TFP). TFP catalyzes 3 reactions (hence its name) – hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase – in the beta-oxidation of fatty acids.

LCHAD and TFP deficiencies cause cellular damage from the accumulation of 3-OH-fatty acids and result in impaired energy production, leading to metabolic decompensation during prolonged fasting or increased energy demands, such as fever or other stress.

Treatment involves fasting avoidance, long-chain fat restriction, and supplemental medium-chain triglycerides or other appropriate supplements. Without effective treatment, consequences include:
  • Hepatic disease
  • Cardiomyopathy
  • Cardiac conduction defects (arrhythmia) with cardiac arrest
  • Peripheral neuropathy
  • Pigmentary retinopathy
  • Rhabdomyolysis/myopathy
Even with treatment, individuals with LCHAD and TFP deficiency may have symptoms that include episodes of hypoketotic hypoglycemia, rhabdomyolysis, pigmentary retinopathy, and axonal neuropathy.

Other Names & Coding

Long-chain acyl-CoA dehydrogenase deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Trifunctional protein (TFP) deficiency
ICD-10 coding

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

ICD-10 for Long-Chain/Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (icd10data.com) provides further coding details.

Prevalence

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

Genetics

LCHAD and TFP deficiencies are inherited in an autosomal recessive manner. The trifunctional protein is formed by 2 subunits (alpha and beta), encoded by 2 genes (HADA and HADB ), and located on chromosome (2p23). Mutations that completely abolish the function of the protein cause TFP deficiency. TFP deficiency can be caused either by mutations in the alpha (HADA gene) or beta subunit (HADB gene); LCHAD deficiency is caused by specific missense mutations in the alpha subunit that affect predominantly LCHAD activity.

Prognosis

Prognosis is based on classification of disorder (LCHAD/TFP deficiency), age of presentation, and severity. With proper treatment and prevention of hypoglycemia, neurological function should remain intact, even though there may be progression of peripheral neuropathy and pigmentary retinopathy. Without treatment, hypoglycemic episodes may lead to developmental delay, neurologic impairment, and death from cardiac failure or arrhythmia. Neuropathy is significant in patients with TFP deficiency. Even with treatment, most patients with LCHAD deficiency suffer episodic hypoketotic hypoglycemia and rhabdomyolysis.

Practice Guidelines

There are no published practice guidelines for the diagnosis or management of LCHAD or TFP deficiencies.

Roles of the Medical Home

Management of a child with LCHAD deficiency will include collaboration between medical genetics and the medical home clinician. The medical home clinician is crucial for early management of illnesses that may lead to decompensation. See LCHAD/TFP Deficiency for follow-up of a positive newborn screening test.

The main goal of treatment is to avoid progression of the disease and acute decompensation brought about by illness, fasting, and dehydration. IV glucose is necessary during times of illness and dehydration, and the medical home clinician should ensure that a plan is in place for such episodes. The usual treatment is the administration of glucose 10% with adequate salts (1/2 or normal saline - depending on age and weight - with 20 mEq/L of potassium chloride) at 1.5-twice maintenance, keeping in mind that this treatment does not provide all the calories that the child needs. The cause of acute decompensation should be identified and treated if possible. Oral feedings should be restarted as soon as possible.

Clinical Assessment

Overview

Individuals with LCHAD/TFP deficiency can be diagnosed by newborn screening. In both cases, 3-OH-long-chain acylcarnitines (C16-OH usually the most prominent) are elevated. The pattern is typically distinctive in LCHAD deficiency, whereas patients with TFP deficiency can have concomitant elevations in several other long-chain acylcarnitines (hydroxylated and non-hydroxylated) raising the possibility of other defects in long-chain fatty acid oxidation. When the screening test is positive, quantitative plasma acylcarnitine profile, urine organic acid analysis, free 3-OH-fatty acids, biochemical and molecular genetic testing in cultured fibroblasts derived from skin biopsy or in white blood cells will be performed to differentiate among LCHAD deficiency, TFP deficiency, and other defects of long-chain fatty acid oxidation. Alternatively, DNA testing for a panel of conditions, including all disorders of fatty acid oxidation, can identify the specific cause. In some patients, symptoms might occur before the results of newborn screening are back. These patients have a high mortality rate. [Sykut-Cegielska: 2010]

Screening

For the Condition

Positive newborn screen results are based on the elevation of C16-OH +/- and C18:1-OH as determined by tandem mass spectrometry (MS/MS) with a sensitivity of 100% and a specificity of 100%. [Schulze: 2003] However, elevations can be minimal in some forms of TFP deficiency. These milder biochemical variants still can cause sudden death and other morbidity characteristics of TFP deficiency.

Of Family Members

The DNA of parents of a child who died with suspected LCHAD or TFP deficiency can be sequenced to determine the presence or absence of mutations in the HADA or HADB genes to confirm or exclude the diagnosis if DNA from the deceased child is not available.

For Complications

Ongoing developmental screening enables early detection and intervention for developmental delays. Vision screening at all health maintenance visits may help detect early effects of pigmentary retinopathy. Periodic evaluation by pediatric ophthalmology is appropriate to begin in middle childhood or earlier if problems are identified through vision screening.

Presentations

LCHAD/TFP deficiency generally presents in 1 of 3 ways, along a spectrum of severity.
  1. Asymptomatic: Identified by newborn screening before symptoms develop
  2. Neonatal onset: Presenting shortly after birth, generally with a more severe form of the condition
  3. Late onset: Presenting at a few months or years of age; may show progressive pigmentary retinopathy and neuropathy although, generally, they have a milder form of TFP deficiency.
Initial symptoms/signs may include:
  • Poor feeding
  • Vomiting
  • Lethargy
  • Hypotonia
  • Hepatomegaly
  • Cardiac insufficiency
  • Cardiomyopathy
  • Lab findings: Elevated liver function tests, elevated CK, metabolic acidosis, lactic acidosis, hypoglycemia

Diagnostic Criteria

Following a positive newborn screen, the Confirmatory Algorithms for LCHAD and TFP Deficiency (ACMG) (PDF Document 69 KB) recommends obtaining plasma acylcarnitine profile and urine organic acids following abnormal screening results. The plasma acylcarnitine profile is usually abnormal, with elevation of C16-OH and other hydroxyacylcarnitine species. Other long-chain acylcarnitines are also usually increased. It is not possible to differentiate LCHAD from TFP deficiency with just the acylcarnitine profile, although levels of C16-OH-carnitine are usually higher in LCHAD deficiency. Urine organic acids are usually normal if the child is well-compensated.

Diagnosis requires the demonstration of an abnormal biochemical profile (increased hydroxylated long-chain acylcarnitines) and DNA sequencing that identifies bi-allelic variants in the HADA or HADB gene. If at least 1 copy of the common mutations causing LCHAD deficiency in the HADHA gene is identified, the patient likely has LCHAD deficiency. Diagnosis is confirmed if 2 known pathogenic variants are identified. If only 1 such variant is identified, functional studies in fibroblasts (enzyme assay, acylcarnitine profiling, fatty acid oxidation probe) can be obtained.

Differential Diagnosis

The neonatal form may be confused with other rare forms of cardiomyopathy or cardiac arrest, including glycogen storage disease type 2 (Pompe disease), VLCAD and multiple acyl-CoA dehydrogenase deficiency, and other carnitine disorders, such as carnitine-acylcarnitine translocase deficiency, carnitine palmitoyltransferase 2 (CPT2, neonatal form) deficiency, and carnitine uptake disorder. These would be distinguished by biochemical testing.

Hypoketotic hypoglycemia with hepatomegaly has a large differential diagnosis including:
  • Other fatty acid oxidation disorders (deficiency of medium-chain acyl-CoA dehydrogenase, very long-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I, carnitine-acylcarnitine translocase, and carnitine transporter) may appear similar. Important clinical features that might help differentiate LCHAD deficiency from the other fatty acid oxidation disorders include the presence of cardiomyopathy and/or rhabdomyolysis, seen in several, but not all of the other disorders, different metabolites in acylcarnitine, and urine organic acid profiles (abnormal only if collected during an acute crisis).

  • Ketogenesis defects often present within the first few days of life, although the pattern of presentation in later childhood may be very similar to that of LCHAD deficiency. Vomiting, decreased sensorium, and hepatomegaly are also presenting symptoms. Although hypoketotic hypoglycemia and sometimes hyperammonemia are biochemical features, severe ketoacidosis is the rule.

  • Organic acidurias can usually be diagnosed by urine organic acids and plasma acylcarnitine profile.

  • Respiratory chain defects are variable in their presentation. Biochemically, affected individuals have lactic acidosis and ketonemia (often paradoxical - increased ketones after eating). Diagnosis requires DNA testing for mtDNA and nuclear DNA, and, in some cases, muscle biopsy is necessary. Cardiomyopathy can be seen in these conditions, but hypoglycemia is not usually seen except as a result of liver involvement (mitochondrial DNA depletion syndromes).

  • Carbohydrate metabolism defects may present with hypoglycemia, significant lactic acidosis, +/- ketosis and hepatomegaly. Acylcarnitine profile and urine organic acid profile can help differentiate these disorders from LCHAD deficiency. Patients are usually diagnosed in childhood.

Comorbid & Secondary Conditions

Comorbid conditions include:
  • Pigmentary retinopathy: A genetic eye disorder in which progressive retinal damage occurs, usually affecting the rod cells of the retina, causing problems with night and peripheral vision, although the cone cells, affecting central vision, may also be affected. There is no treatment for this condition currently. Retinitis pigmentosa (MedlinePlus)

  • Neuropathy: The neuropathy affecting individuals with LCHAD/TFP deficiency has not been well characterized. In case reports, the neuropathy appears to affect the axons of both motor and sensory nerves. [Tein: 1999] Individuals with this condition might present with decreased patellar and ankle reflexes and decreased sensation in their feet. It is diagnosed by nerve conduction velocity/electromyography (NCV/EMG) if suspected.

  • Myopathy: The myopathy that may affect individuals with LCHAD/TFP deficiency is distinct from the neuropathy that may be associated with this condition. Individuals may present with proximal muscle weakness that may be due to bouts of rhabdomyolysis and myoglobinuria associated with this disorder. NCV/EMG testing may be ordered if suspected. Although myopathy has been described in individuals with LCHAD/TFP deficiency, the time course and prognosis are not well understood. [Spiekerkoetter: 2009]

History & Examination

As individuals with LCHAD/TFP deficiency are seen on an ongoing basis, it is important to keep in mind that either condition might progress despite treatment. Pigmentary retinopathy is one complication of these conditions and occurs over time in most individuals. Both conditions can cause episodic hypoketotic hypoglycemia and rhabdomyolysis. Mitochondrial TFP deficiency has a high early mortality rate, and progressive axonal neuropathy might occur. [Wilcken: 2010] Pigmentary retinopathy seems more frequent in LCHAD deficiency.

Current & Past Medical History

Ask about recent illnesses and episodes of hypoglycemia. Ask about vision abnormalities. Ask about episodes of muscle pain and brown urine due to rhabdomyolysis.

Family History

Ask about a family history of sudden death. Most patients are the first affected in the family with no previous history. Parental consanguinity increases the risk of LCHAD and TFP deficiencies and all other recessive conditions.

Pregnancy/Perinatal History

Ask about a maternal history of pregnancy-related liver disease (HELLP syndrome [hemolysis, elevated liver enzymes, low platelets] or ALFP [acute fatty liver of pregnancy]). These are very frequent in mothers of patients with LCHAD deficiency, although LCHAD deficiency is not a common cause of HELLP syndrome.

Developmental & Educational Progress

Patients with LCHAD/TFP deficiency can have completely normal development, although physical education or participation in intense activities might need to be restricted as they get older to prevent rhabdomyolysis.

Physical Exam

General

The physical examination of a well child with LCHAD or TFP deficiency is usually without abnormality unless sequelae are present from a previous acute episode.

HEENT/Oral

Pigmentary retinopathy can be evident in children after a few years of age. Dark spots may be noted on retinal examination.

Neurologic Exam

Check deep tendon reflexes and sensory exam. Neuropathy can develop in older children and adolescents with TFP deficiency. Check muscle strength and Gower's maneuver for evidence of myopathy.

Testing

Sensory Testing

Because of the potential for pigmentary retinopathy, visual acuity should be tested regularly.

Laboratory Testing

Monitor CK, CMP (liver function tests, glucose), carnitine free and total, plasma acylcarnitine profile.

Imaging

Cardiac ECHO should be obtained and monitored over time to exclude cardiomyopathy.

Genetic Testing

Sequencing of HADA and HAB and DB genes is necessary to establish the diagnosis. Carrier status within individual families can be ascertained by DNA testing once the mutations in the proband are known.

Prenatal testing can be performed by DNA testing in cells obtained by amniocentesis or chorionic villous sampling (CVS). See Genetic Testing Laboratories for LCHAD/TFP Deficiency (Genetic Testing Registry).

Other Testing

Nerve conduction velocity testing/electromyography (NCV/EMG) testing may be ordered if neuropathy is suspected. ECG and Holter monitoring should be obtained during cardiac evaluations for the risk of arrhythmia.

Specialty Collaborations & Other Services

Newborn Screening Services (see Services below for local providers)

Most individuals with LCHAD deficiency will be diagnosed through newborn screening.

Pediatric Metabolic Genetics (see Services below for local providers)

Refer for initial consultation and ongoing collaboration if the child is affected. Periodic visits will be needed to review the condition, assess the diet, and determine if metabolic testing is needed.

Nutrition, Metabolic (see Services below for local providers)

A dietician may work with the family to devise an optimal approach to dietary management.

Pediatric Cardiology (see Services below for local providers)

Children should have a baseline evaluation and periodic assessments to detect cardiomypoathy.

Pediatric Ophthalmology (see Services below for local providers)

Children should be followed to detect and manage pigmentary retinopathy.

Treatment & Management

Overview

The primary goal of management is to avoid fasting and limit the intake of long-chain fatty acids.

Pearls & Alerts for Treatment & Management

Fasting, dehydration, and illness may lead to metabolic decompensation

Children with LCHAD deficiency are not able to break down fats for energy and can develop acute decompensation (with or without hypoglycemia) in times of fasting or stress. Instruct parents to bring the child to the ER if unable to eat for any reason (fever, gastroenteritis, other illness preventing food consumption) to receive IV glucose.

How should common problems be managed differently in children with LCHAD/TFP Deficiency?

Viral Infections

For viral and bacterial infections, use aggressive therapy with ibuprofen to keep temperature as close to normal as possible while looking for possible bacterial causes.

Over the Counter Medications

Ibuprofen is preferred to acetaminophen to control fever due to risk of hepatic damage with the latter.

Common Complaints

Muscle pain is frequently experienced by older children. Use Gatorade with added sugar (1 tablespoon in 240 ml (8 oz)) or medium-chain triglycerides just before and during exercise.

Systems

Nutrition/Growth/Bone

The mainstay of management is the avoidance of fasting, although the disease may progress despite treatment. Fasting precautions should be directed by the metabolic clinic with a general rule of 1-hour fasting per 1kg bodyweight. The metabolic geneticist and nutritionist will work with the family to develop a plan for feeding both on a regular basis and in case of an intervening illness. Children who are ill and not eating sufficient carbohydrates and drinking enough water may need IV fluids with glucose to prevent acute decompensation. A care plan that addresses this possibility may be helpful for the family in case they need to seek treatment while traveling or in an emergency room unfamiliar with LCHAD deficiency.

A diet that is low in long-chain fats and balanced in carbohydrates and lean proteins will be recommended for most individuals. Medium-chain triglyceride (MCT) supplements do not require the LCHAD enzyme for breakdown and are typically necessary to provide sufficient amounts of calories. The metabolic geneticist also may prescribe L-carnitine supplementation at low doses (25 mg/kg per day) in case of carnitine deficiency. Docosahexanoic acid (DHA)/essential fatty acids supplements may also be prescribed. Cornstarch supplements are sometimes required in children with hypoglycemia.

Adolescents and adults with LCHAD deficiency may experience symptoms with exercise, particularly if they have not had sufficient carbohydrates. These may include muscle aches, cramps, and rhabdomyolysis, which may manifest as brown or reddish urine. Teens should avoid heavy exercise and drink plenty of sugar-containing beverages even with normal exercise. If they have symptoms, they should seek treatment immediately that includes IV rehydration with glucose-containing fluids to prevent kidney damage from rhabdomyolysis.

When surgeries or dental procedures are needed, the child will need specific IV fluids containing glucose (see emergency management) to be started when the child is unable to eat before the procedure and continued until the child is able to eat again.

Specialty Collaborations & Other Services

Pediatric Metabolic Genetics (see Services below for local providers)

Periodic visits are needed for dietary management and to update families about new findings.

Nutrition, Metabolic (see Services below for local providers)

Consider referral to help review growth parameters and diet.

Eyes/Vision

Pigmentary retinopathy occurs over time and is usually apparent in older children. There is no treatment to prevent this.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see Services below for local providers)

Refer for periodic evaluation to detect and manage pigmentary retinopathy.

Development (general)

In children who have delayed development due to metabolic crises, management should include developmental therapies for cognitive and motor issues. See Intellectual Disability, Treatment & Management and Cerebral Palsy.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see Services below for local providers)

Referral may be helpful to clarify developmental delays and coordinate detailed evaluation and management.

Issues Related to LCHAD/TFP Deficiency

Funding & Access to Care

Writing Letters of Medical Necessity

Ask the Specialist

Should I screen other children in the family for the disorder?

Although LCHAD deficiency usually causes noticeable symptoms, it is possible that older siblings, who were born before newborn screening tested for LCHAD deficiency, could have the condition. Ask about other children in the family who have, or have had, symptoms similar to those reported for LCHAD deficiency.

Resources for Clinicians

On the Web

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

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

LCHAD Deficiency (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)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American Academy of Pediatrics.

Helpful Articles

PubMed search for articles published in the last 3 years about LCHAD/TFP deficiency in children or adolescents

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

Wilcken B.
Fatty acid oxidation disorders: outcome and long-term prognosis.
J Inherit Metab Dis. 2010. PubMed abstract

Clinical Tools

Care Processes & Protocols

ACT Sheet for LCHAD and TFP Deficiencies (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 LCHAD and TFP Deficiencies (ACMG) (PDF Document 69 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

LCHAD Deficiency Acute Illness Protocol (New England Consortium of Metabolic Programs)
A guideline for health care professionals treating the sick infant or child who has been diagnosed with LCHADD.

Letters of Medical Necessity

Letter of Medical Necessity for Medical Food/LCHAD Deficiency (Word Document 5.4 MB)
A 1-page, adaptable letter requesting coverage of the costs for Enfaport (medical food) for an individual with long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.

Other

Sample Emergency Letter for LCHAD/TFP Deficiency (Word Document 18 KB)
A sample letter with emergency treatment details that can be provided to families who have a child with LCHAD/TFP deficiency.

Resources for Patients & Families

Information on the Web

LCHAD/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.

National & Local Support

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

Services for Patients & Families in Idaho (ID)

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.

Authors & Reviewers

Initial publication: March 2011; last update/revision: August 2019
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Contributing Author: Chelsea Norman, BS, RDN, CD
Authoring history
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

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

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

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

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(4):488-97. PubMed abstract

Sykut-Cegielska J, Gradowska W, Piekutowska-Abramczuk D, Andresen BS, Olsen RK, Ołtarzewski M, Pronicki M, Pajdowska M, Bogdańska A, Jabłońska E, Radomyska B, Kuśmierska K, Krajewska-Walasek M, Gregersen N, Pronicka E.
Urgent metabolic service improves survival in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency detected by symptomatic identification and pilot newborn screening.
J Inherit Metab Dis. 2010. PubMed abstract

Tein I, Vajsar J, MacMillan L, Sherwood WG.
Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency neuropathy: response to cod liver oil.
Neurology. 1999;52(3):640-3. 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

Wilcken B.
Fatty acid oxidation disorders: outcome and long-term prognosis.
J Inherit Metab Dis. 2010. PubMed abstract