LCHADD/TFP Deficiency

Description

Diagnosis Coding

ICD-10

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

ICD-10 for LCHADD and VLCADD (icd10data.com) provides further coding details.

Description

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a disorder of fatty acid oxidation. During times of fasting, the body uses fat as a major source of energy. Fats are catabolized through a process called beta-oxidation. The overall reaction involves several different enzymes which break down very-long chain fats to long-chain fats, long-chain fats to medium-chain fats, eventually resulting in ketone bodies and acetyl-CoA. The former are used directly for energy and the latter enter the Kreb cycle to generate ATP and reducing equivalents.

Long-chain fatty acids are broken down by the trifunctional protein (TFP) after initial metabolism by very-long chain acyl CoA dehydrogenase. This protein catalyzes 3 steps (for which it got its name) in the beta-oxidation of fatty acids, including the hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase activity. Mutations that completely abolish the function of the protein cause TFP deficiency. LCHADD is caused by mutations that allow the reaction to start but not to be completed.

LCHADD 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. Treatment mainly involves avoiding fasting, following strict dietary recommendations, and using supplements as needed.

Prevalence

A German study indicates a prevalence of 1:250,000 for LCHADD. [Schulze: 2003] The incidence of LCHADD in the United States is approximately 1:363,738. [Therrell: 2014]

Genetics

LCHADD and TFP deficiency are inherited in an autosomal recessive manner. TFP is formed by 2 subunits (alpha and beta) encoded by 2 different genes (HADA and HADB) located on the same chromosome (2p23). TFP deficiency can be caused either by mutations in the alpha (HADA gene) or beta subunit (HADB gene). LCHADD is caused by specific missense mutations in the alpha subunit that allow the reaction to start but not to be completed.

Prognosis

Prognosis varies depending on whether there is LCHADD alone or TFP deficiency. Symptoms (mild to severe) may begin at birth or take a few years to present. If LCHADD is treated prior to hypoglycemic crises, the child’s intelligence is likely to be normal; 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 TFP 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.

Roles Of The Medical Home

The goal of treatment is to avoid progression of the disease and acute decompensations brought about by illness, fasting, and dehydration. Although management of the child with LCHADD will be a collaboration with metabolic genetics, the medical home clinician is crucial for early management of illnesses that may lead to decompensation. In the event of acute decompensation, the cause should be identified and treated if possible. Oral feedings should be restarted as soon as possible.

IV glucose is necessary during 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 (one quarter or one half 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.

LCHADD/TFP Deficiency has information for medical home clinicians about the response to a positive newborn screen. The LCHADD Acute Illness Protocol (New England Consortium of Metabolic Programs) is a helpful guideline for health care professionals treating the sick infant or child who has previously been diagnosed with LCHADD.

Practice Guidelines

There are no published practice guidelines for LCHADD or TFP deficiency.

Helpful Articles

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

Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Humphrey R, Mayhew J, Bowden A, Zhang L, Cataldo J, Marsden DL, Kakkis E.
UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.
Mol Genet Metab. 2017;120(4):370-377. PubMed abstract

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

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

Clinical Assessment

Overview

Individuals with LCHADD or TFP deficiency can be diagnosed by newborn screening. In both cases, 3-OH-long-chain acylcarnitines (C16-OH being usually the most prominent) are elevated. The pattern is usually distinctive in LCHAD deficiency, whereas patients with TFP deficiency can have concomitant elevation of 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 white blood cells will be performed to differentiate between LCHADD, TFP, and other defects of long-chain fatty acid oxidation. 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

Prenatal testing can be performed by DNA testing in cells obtained by amniocentesis or chorionic villous sampling (CVS). The newborn screening finding is elevated 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]

The American College of Medical Genetics endorses Confirmatory Algorithms for LCHAD and TFP Deficiency (ACMG) (PDF Document 69 KB), which 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 and other long-chain acylcarnitines are usually increased. It is not possible to differentiate LCHADD from TFP deficiency based solely on the acylcarnitine profile, although levels of C16-OH-carnitine are usually higher in LCHADD. Urine organic acids are usually normal if the child is well compensated. LCHADD/TFP Deficiency has further information about the response to a positive newborn screen.

Presentations

There are 3 main ways that LCHAD/TFP deficiency may present, although clinical presentations occur in a spectrum of severity.
  1. Infants may be identified by newborn screening before they show symptoms.
  2. Infants may present near birth and generally have a more severe form of the condition. Symptoms may begin anytime between birth and 3 years, and may be mild or severe. 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
  3. Some individuals may not present until they are a few years of age. These individuals may show progressive retinitis pigmentosa and neuropathy although generally they have a milder form of LCHAD/TFP deficiency.
4. Without effective treatment, subsequent symptoms may include:
  • Hepatic disease
  • Cardiomyopathy
  • Cardiac conduction defects (arrhythmia)
  • Peripheral neuropathy
  • Pigmentary retinopathy
  • Rhabdomyolysis/myopathy
Even with treatment, individuals with LCHADD and TFP deficiency may have episodes of hypoketotic hypoglycemia, rhabdomyolysis, retinitis pigmentosa, and axonal neuropathy.

Diagnostic Criteria

DNA testing usually targets the common mutations causing LCHADD in the HADHA gene. If at least 1 copy of this mutation is identified, the patient likely has LCHADD. If this mutation is not present, both the HADHA and HADHB gene should be sequenced. Diagnosis is confirmed if 2 known pathogenic variants are identified. If only one such variant is identified, functional studies in fibroblasts (enzyme assay, acylcarnitine profiling, fatty acid oxidation probe) can be obtained.

Differential Diagnosis

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

Nonketotic hypoglycemia with hepatomegaly has a large differential diagnosis including:
  • Other fatty acid oxidation disorders: These include deficiency of medium chain acyl-CoA dehydrogenase, very long-chain acyl-CoA dehydrogenase, carnitine palmitoyl transferase I, carnitine-acylcarnitine translocase, and carnitine transporter. Important clinical features that might help differentiate LCHADD 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) and different metabolites in acylcarnitine and urine organic acid profiles (this latter is abnormal only if collected during an acute crisis).
  • Ketogenesis defects: The 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 LCHADD. 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: These can usually be diagnosed by urine organic acids and plasma acylcarnitine profile.
  • Respiratory chain defects: These are variable in their presentation with a variety of symptoms. Biochemically, affected individuals have lactic acidosis and ketonemia (often paradoxical - increased ketones after eating). Diagnosis is difficult and muscle biopsy is often necessary. Cardiomyopathy can be seen in these conditions, but hypoglycemia is not usually seen except as a result of liver involvement (mitochondrial DNA depletions syndromes).
  • Carbohydrate metabolism defects: These may present with hypoglycemia, significant lactic acidosis, +/- ketosis, and hepatomegaly. Acylcarnitine profile and urine organic acid profile will be helpful in differentiating these disorders from LCHADD. Patients are usually diagnosed in childhood.

Comorbid Conditions

Comorbid conditions include:
  • Retinitis pigmentosa (RP): This is a genetic eye disorder. In this condition, 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) has information about symptoms, exams, and tests.
  • 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 myoglobulinuria 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 is 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. Retinitis pigmentosa is a complication of these conditions and occurs over time in most individuals. Isolated LCHADD can cause episodic hypoketotic hypoglycemia and rhabdomyolysis. Mitochondrial TFP has a high early mortality rate and progressive axonal neuropathy might occur. [Wilcken: 2010]

Family History

Ask about a family history of sudden death.

Pregnancy Or Perinatal 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.

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.

Physical Exam

General

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

HEENT

Retinitis pigmentosa 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 retinitis pigmentosa, visual acuity should be tested regularly.

Laboratory Testing

Relevant laboratories can be found at Genetic Testing Resources for LCHADD (GeneTests).

Other Testing

Nerve conduction velocity testing/electromyography (NCV/EMG) testing may be ordered if neuropathy is suspected.

Subspecialist Collaborations & Other Resources

Newborn Screening Programs (see Services below for relevant providers)

Most individuals with LCHADD will be diagnosed through newborn screening.

Pediatric Metabolic Genetics (see Services below for relevant 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 evaluate if any metabolic testing is needed.

Nutrition, Metabolic (see Services below for relevant providers)

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

Pediatric Cardiology (see Services below for relevant providers)

Children should have a baseline evaluation for cardiomypoathy and then periodic evaluation to detect cardiomyopathy.

Pediatric Ophthalmology (see Services below for relevant providers)

Children should be followed to detect and manage retinitis pigmentosa.

Treatment & Management

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

Other

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.

Pearls & Alerts

Fasting, dehydration, and illness

Fasting, dehydration, and illness may lead to hypoglycemia. Children with LCHADD aren't able to break down fats for energy and low glucose due to these conditions may lead to an acute decompensation.

IV glucose is necessary during illness and dehydration

The medical home clinician should ensure that a plan is in place for times of illness or dehydration. The usual treatment is the administration of glucose 10% with adequate salts (one quarter or one half 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.

Systems

Nutrition/Growth/Bone

The mainstay of management is the avoidance of fasting, although the disease may progress despite treatment. Infants shouldn't go longer than 4 hours without eating; this interval will gradually increase as the child gets older. 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 hypoglycemic crises. 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 LCHADD.

A diet that is low in fat and high in carbohydrates may be recommended for some individuals. Foods high in long-chain fatty acids may need to be avoided. Medium chain triglyceride (MCT) oil supplements, as they don't require the LCHAD enzyme for breakdown, are necessary at least in the first year of life to provide sufficient amounts of calories. The metabolic geneticist may prescribe docosahexanoic acid (DHA)/essential fatty acids supplements and L-carnitine supplementation at low doses (25 mg/kg per day) for carnitine deficiency. Cornstarch supplements are sometimes required in children with the childhood form of the disease.

Adolescents and adults with LCHADD may experience symptoms with exercise, particularly if they haven't had sufficient carbohydrates. Symptoms 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 that should be continued until the child is able to eat again.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Periodic visits will be needed to help with dietary management and updates on new findings.

Nutrition, Metabolic (see Services below for relevant providers)

Refer to help review growth parameters and diet.

Eyes/Vision

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

Subspecialist Collaborations & Other Resources

Pediatric Ophthalmology (see Services below for relevant providers)

Periodic evaluation to detect and manage retinitis pigmentosa.

Development (general)

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

Subspecialist Collaborations & Other Resources

Developmental Pediatrics (see Services below for relevant providers)

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

Frequently Asked Questions

How will my patient's family be affected?

Your patient's family will need to follow strict guidelines with regard to illness and dehydration, and may need medications, depending on the enzyme deficiency. Support groups may be helpful.

Issues Related to LCHADD/TFP Deficiency

Funding & Access to Care

Writing Letters of Medical Necessity

Resources

Information for Clinicians

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (GeneReviews)
Excellent review by Nancy D Leslie, MD including information about the clinical description, differential diagnoses, management, genetic counseling, and molecular genetics.

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.

Helpful Articles

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

Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Humphrey R, Mayhew J, Bowden A, Zhang L, Cataldo J, Marsden DL, Kakkis E.
UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.
Mol Genet Metab. 2017;120(4):370-377. PubMed abstract

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

Clinical Tools

Algorithms/Care Processes

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 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.

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.

Other

Emergency Protocol Information & Letter Samples (FOD)
Links to emergency care sample letters for MCADD, VLCADD, LCHADD, and unclassified FOD; International Fatty Oxidation Disorders Support Group.

Information & Support for Families

Family Diagnosis Page

Information on the Web

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.

Resources for LCHAD Deficiency (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Support National & Local

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 Nevada

Select services for a different state: ID, MT, NM, RI, UT

Developmental Pediatrics

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

Newborn Screening Programs

See all Newborn Screening Programs services providers (1) in our database.

Nutrition, Metabolic

We currently have no Nutrition, Metabolic service providers listed; search our Services database for related services.

Pediatric Cardiology

See all Pediatric Cardiology services providers (2) in our database.

Pediatric Metabolic Genetics

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

Pediatric Ophthalmology

See all Pediatric Ophthalmology services providers (5) in our database.

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

Authors & Reviewers

Initial Publication: January 2018;
Current Authors and Reviewers (click on name for bio):
Author: Nicola Longo, MD, Ph.D.
Authoring history
(Limited detail is available on authoring dates before 2014.)
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

Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Humphrey R, Mayhew J, Bowden A, Zhang L, Cataldo J, Marsden DL, Kakkis E.
UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.
Mol Genet Metab. 2017;120(4):370-377. PubMed abstract

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