VLCADD

Description

Other Names

ACADVL deficiency
Very long chain acyl-CoA dehydrogenase deficiency
VLCAD deficiency

Diagnosis Coding

ICD-10

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

Further coding details can be found at ICD-10 for LCHADD and VLCADD (icd10data.com).

Description

Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is a disorder of fatty acid oxidation. During periods of prolonged fasting or increased energy demands (e.g., fever, stress, or lack of sleep), energy production increasingly relies on fat metabolism. Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) impairs energy production from fats and causes metabolic crisis, cardiomyopathy, muscle pain, or myoglobinuria. Phenotypes of VLCAD deficiency include "early," "childhood," and "adult."

The early onset (infantile) form is associated with a nearly complete absence of the enzyme. It is characterized by dilated or hypertrophic cardiomyopathy, arrhythmia, hypotonia, hepatomegaly, hypoglycemia, and high morbidity and mortality occurring shortly after birth. The childhood form is milder and characterized by hypoketotic hypoglycemia, similar to MCAD deficiency with increased values of liver function tests and elevated creatine kinase. Stress usually triggers symptoms; cardiomyopathy is found rarely. The mildest form is the adult variant, with exercise or fasting-induced rhabdomyolysis. It resembles the muscle form of carnitine palmitoyl transferase 2 (CPT2) deficiency. Sudden death from cardiac conduction abnormalities is possible in any of the 3 types.

Prevalence

In the United States, the incidence is about 1:63,000. [Therrell: 2014]

Genetics

VLCADD is inherited in an autosomal recessive pattern. Gene testing should be performed if an individual is symptomatic or if a newborn screen is positive. VLCADD results from mutations in the ACADVL gene, which codes for very long chain acyl-CoA dehydrogenase, the first enzyme in the breakdown of long chain (14-20 carbons) fatty acids. Some mutations lead to a complete lack of activity of this enzyme, and these are associated with the early/infantile form. Other mutations allow for residual enzyme activity and are associated with childhood or adult forms. [Andresen: 1999] Prenatal DNA testing in cells obtained by amniocentesis or chorionic villus sampling (CVS) is available.

Prognosis

Except for infantile forms that are usually lethal, prognosis is excellent if the disease is identified before the first decompensation occurs.

Roles Of The Medical Home

The medical home clinician will need to help with ongoing management and:
  • Ensure that the family knows about the signs and symptoms of illness that would require urgent care.
  • Assist with implementation of a low-fat diet supplemented with medium chain triglycerides if necessary.
  • Consider oral L-carnitine and medium chain triglyceride (MCT) oil supplements.
  • Assist in management of irreversible consequences as necessary, particularly with developmental and educational interventions.
  • Coordinate care with a dietician and pediatric geneticist as necessary.

Practice Guidelines

There are no practice guidelines for the diagnosis and management of VLCADD.

Helpful Articles

PubMed search for VLCADD in children, last 5 years.

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.
Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.
J Inherit Metab Dis. 2009;32(4):498-505. PubMed abstract

Clinical Assessment

Pearls & Alerts

Upon notification of a positive screen

Upon notification of a positive newborn screen for VLCADD, the primary care clinician should contact the family; evaluate the infant for poor feeding, lethargy, hypotonia, hepatomegaly, or cardiac problems; provide emergency treatment and referral for symptoms of hypoglycemia, arrhythmia, or cardiac decompensation; and work with the local newborn screening program to confirm the diagnosis and begin management. VLCADD has further information about immediate management.

Exam is usually normal

Unless a decompensation has occurred, the exam is completely normal in most children with VLCADD.

Screening

For The Condition

Newborn screening by tandem mass spectrometry (MS/MS) identifies children with VLCADD who have elevated C14:1 +/- other long-chain acylcarnitines. The sensitivity of MS/MS is unknown, and the specificity is low; most infants with elevated C14:1 carnitine are carriers for VLCAD deficiency. [Ficicioglu: 2010]

If the newborn screen is positive, a metabolic geneticist will usually order additional testing, including quantitative plasma acylcarnitine profile, mutation analysis of the VLCAD gene, enzyme assay in fibroblasts, and additional biochemical genetic tests to confirm the diagnosis. Normal newborn screening results or plasma acylcarnitine profile do not exclude the diagnosis of VLCADD. An out-of-range screening result does not necessarily mean that the child has VLCADD; however, because the harmful effects of untreated VLCADD can occur soon after birth, follow-up testing must be completed as soon as possible.

For imformation about the immediate steps a primary care clinician can take upon notice of a positive newborn screen, please see the Portal's VLCADD.

Of Family Members

Siblings and parents of children identified with VLCADD can be screened by mutation analyses looking for the same mutation. Positive findings may help genetic counseling, preventive management of illnesses, and avoidance of fasting.

Presentations

Symptoms of the early form of VLCADD may begin between birth and 4 months of age. Symptoms are usually associated with cardiomyopathy and multi-organ system involvement. The early/infantile form responds poorly to treatment. The childhood form may begin in later infancy or early childhood, particularly during fasting or illness. Cardiomyopathy is generally absent, but can sometimes be observed.

Initial signs/symptoms in the early and childhood forms of VLCADD may include:
  • Poor feeding
  • Vomiting
  • Diarrhea
  • Irritability
  • Behavior changes
  • Extreme sleepiness
  • Muscle weakness
  • Lethargy
If not treated promptly, patients may experience:
  • Hepatomegaly
  • Difficulty breathing
  • Muscle weakness with exertion
  • Arrhythmia
  • Cardiomyopathy
  • Seizures
  • Brain damage
  • Death
The adult form of VLCADD, which presents with myopathy, may begin in adolescence or adulthood and may be triggered by prolonged exercise. Symptoms may be mild or severe. Adult type symptoms include:
  • Muscle breakdown with exercise or prolonged fasting
  • Muscle aches
  • Weakness
  • Cramps
  • Reddish-brown urine
  • Kidney failure
For those identified after irreversible consequences, global developmental delays and/or abnormalities in the neurological exam may be evident. Sudden death has been reported even in patients with milder forms of the disease. [Coughlin: 2010]

Diagnostic Criteria

Diagnosis is generally based on positive newborn screening and subsequent genetic testing or genetic testing in individuals who present with symptoms. Additional biochemical testing, guided by a metabolic geneticist, may be involve these features:. [Roe: 1999] [Hale: 1990]
  • Elevation of C14:1 acylcarnitines (may not be present when the child is well)
  • Mutations in the ACADVL gene with biochemical testing in fibroblasts if variations of unknown significance are identified

Clinical Classification

VLCADD is clinically heterogeneous, with 3 major phenotypes based on varying degrees of enzyme deficiency.
  • The early onset/infantile form, associated with nearly complete absence of the enzyme, is characterized by dilated or hypertrophic cardiomyopathy, arrhythmia, hypotonia, hepatomegaly, hypoglycemia, and high morbidity and mortality usually shortly after birth.
  • The childhood form is milder and associated with hypoketotic hypoglycemia, similar to MCAD deficiency with increased values of liver function tests and elevated creatine kinase. Symptoms are usually triggered by stress. Cardiomyopathy can be found in a few cases.
  • The mildest form is the adult variant, with exercise or fasting-induced rhabdomyolysis, resembling the muscle form of carnitine palmitoyl transferase 2 (CPT2) deficiency.

Differential Diagnosis

Early onset VLCADD may be confused with other rare forms of cardiomyopathy, including glycogen storage disease type 2, Pompe disease, and carnitine disorders, such as carnitine palmitoyltransferase II (CPT II, neonatal variety only) or carnitine acylcarnitine translocase deficiency and carnitine uptake disorder. These are distinguished by biochemical testing.

Other differential diagnoses include:

Other fatty acid oxidation disorders (medium chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, carnitine transporter defect, multiple acyl CoA dehydrogenase, carnitine palmitoyltransferase I, and carnitine-acylcarnitine translocase deficiency): Clinical features that may help differentiate VLCADD from the other fatty acid oxidation disorders include cardiomyopathy and/or rhabdomyolysis (seen in several but not all of the other disorders) and different metabolites in acylcarnitine and urine organic acid profiles.

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 VLCADD. Vomiting, decreased sensorium, and hepatomegaly are also presenting symptoms. Although hypoketotic hypoglycemia and sometimes hyperammonemia are biochemical features, severe ketoacidosis is the rule. Cardiomyopathy is not seen in defects of ketogenesis.

Organic acidurias: Urine organic acids and a plasma acylcarnitine profile usually differentiate these from VLCADD.

Respiratory chain defects: These are variable in their presentation. 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 depletion syndromes).

Carbohydrate metabolism defects. Carbohydrate metabolism defects 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 VLCADD because specific abnormalities are seen only in VLCADD and in none of the disorders of the carbohydrate metabolism.

The adolescent/adult form may resemble the classic form of carnitine palmitoyltransferase II (CPT II) deficiency, mild forms of multiple acyl CoA dehydrogenase deficiency, McArdle's disease and other rarer muscle glycogen storage disorders, and lipin-1 deficiency. A plasma acylcarnitine profile and other tests can differentiate among these possibilities.

History & Examination

Family History

VLCAD is a recessive condition for which consanguinity might be a factor. There may be a history of sudden infant death syndrome (SIDS) in siblings.

Pregnancy Or Perinatal History

No pregnancy-related abnormalities are associated with carrying a child with VLCADD.

Current And Past Medical History

The medical history may be uninformative; however, recurrent episodes of nausea, vomiting, or listlessness associated with periods of fasting or illness suggest inadequate management. In the adolescent/adult form, there may be a history of muscle cramps and myoglobulinuria, particularly with physical stress.

Developmental And Educational Progress

Developmental milestones and school performance may be affected by severe episodes of decompensation. Progress should be monitored closely.

Social And Family Functioning

The family's ability to identify and manage episodes of illness and avoid fasting are important to good outcomes.

Physical Exam

General

The physical examination of a well child with VLCADD is usually normal unless sequelae are present from a previous acute episode. During acute episodes, vomiting, decreased level of consciousness, and somnolence may be noted.

Heart

Signs of heart failure may be present in a patient with the early/infant onset.

Abdomen

Hepatomegaly may be present during an acute decompensation.

Testing

After a positive newborn screening test, the American College of Medical Genetics recommends measuring a repeat acylcarnitine profile in plasma and obtaining DNA testing.

The plasma acylcarnitine profile can be completely normal if the child is well compensated. With DNA testing, if 2 mutations are identified, parental testing should be considered to determine if the 2 mutations are on 2 different chromosomes (each parent is a carrier of 1 mutation).

Diagnosis is confirmed if 2 known pathogenic variants are identified. If only 1 pathogenic variant is identified, functional studies in fibroblasts (acylcarnitine profiling, fatty acid oxidation probe) can be obtained. DNA testing fails to identify about 10% of mutations and functional studies might be considered if the diagnosis is still uncertain after DNA testing.

See Confirmatory Algorithm for VLCADD (ACMG) (PDF Document 45 KB).

Laboratory Testing

Obtain baseline liver function tests and creatine kinase. If a patient is ill, obtain a basic metabolic panel, including a glucose level, ammonia, and liver function tests. At tertiary care facilities, acylcarnitine profiles and urine organic acid profiles are often obtained. Initial lab findings in the early and childhood types may include metabolic acidosis and hypoglycemia.

Genetic Testing

A DNA sequence analysis looking for mutations in the ACADVL gene is performed. Genetic Testing Registry: VLCADD provides a list of labs.

Other Testing

Obtain a baseline cardiac echocardiography and EKG.

If the diagnosis remains in question, an analysis of fatty acid beta-oxidation in cultured fibroblasts or VLCADD enzyme activity in leukocytes, fibroblasts, liver, heart, or skeletal muscle can be used to confirm the diagnosis. [Roe: 1999] [Hale: 1990] This testing is usually ordered by a metabolic geneticist.

Elevated fatty acid levels may be present with hypoglycemia and can help in distinguishing VLCADD and other fatty acid oxidation defects from hyperinsulinemia. Essential fatty acids can become low with a low-fat diet and need periodic monitoring and supplementation.

Subspecialist Collaborations & Other Resources

Newborn Screening Programs (see Services below for relevant providers)

Many children with VLCADD will be diagnosed by newborn screening. The primary care clinician should collaborate with the newborn screening program to coordinate initial diagnosis.

Pediatric Metabolic Genetics (see Services below for relevant providers)

Refer for collaboration and counseling for parents.

Nutrition, Metabolic (see Services below for relevant providers)

Refer for formulation of an appropriate low-fat diet and guidance on the intake of necessary fats, carbohydrates, proteins, vitamins, minerals, and cofactors to support growth and development.

Developmental Pediatrics (see Services below for relevant providers)

Refer if there is any concern related to sequelae following a decompensation or developmental deficits.

Treatment & Management

Overview

The goal of treatment is to avoid decompensation brought about by physical stressors, such as illness, dehydration, fasting, and in some cases, high-fat foods.

Pearls & Alerts

Avoid factors causing physical stress

Physical stress caused by illness, dehydration, fatigue, and, in some cases, high-fat diets can lead to acute decompensation.

Avoid low-carbohydrate, high-fat, calorie-restricted diets

Avoid these diets. If weight loss is necessary, the metabolic nutritionist should be consulted.

Avoid fasting

Although fasting tolerance improves with age, prolonged fasting in an affected individual can lead to coma and death at any age.

How should common problems be managed differently in children with VLCADD?

Other

Patients with VLCADD need early evaluation and treatment for illness, There should be a low threshold for providing interventions, such as IV glucose.

Systems

Endocrine/Metabolism

The medical home clinician should ensure that a plan is in place during times of acute illness. The usual treatment is 10% glucose with adequate salts (quarter or half normal saline - depending on age and weight - with 20 mEq/L of potassium chloride) at 1.5-2 times maintenance, keeping in mind that this treatment does not provide all the needed calories.

Identify and treat the cause for acute decompensation if possible. Oral feedings should be restarted as soon as possible. Further emergency treatment details are in the VLCADD Acute Illness Protocol (NECMP).

Ongoing treatment to prevent complications may include:
  • Fasting avoidance
  • A low fat-diet supplemented with essential fatty acids
  • Medium chain triglycerides, which do not require the VLCAD enzyme for break-down
  • Cornstarch supplements, sometimes required in children with the childhood form of the disease
  • Low-dose (25 mg/kg per day) carnitine, used when individuals are carnitine deficient

Subspecialist Collaborations & Other Resources

Nutrition, Metabolic (see Services below for relevant providers)

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

Genetics

Ongoing management, particularly for the child with recurrent decompensations, should involve periodic collaboration with a metabolic geneticist who can offer new research findings and experience, as well as genetic counseling for the family and the patient as he/she nears puberty.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Periodic visits are important to monitor for problems, support families, and provide needed education.

Nutrition/Growth/Bone

Depending on the severity of the enzyme deficiency, children may need restriction of dietary fat and supplementation by medium chain triglycerides (MCT oil). This will be determined by the metabolic nutritionist who will monitor growth and supplement as necessary.

Subspecialist Collaborations & Other Resources

Nutrition, Metabolic (see Services below for relevant providers)

If a child needs to be on a special diet, periodic visits with the metabolic nutritionist may be helpful.

Development (general)

In children who have experienced decompensation, developmental delay, and/or neurologic symptoms may be present. The medical home clinician should monitor development and educational progress, and if impaired, make referrals as necessary.

Subspecialist Collaborations & Other Resources

Developmental Assessment (see Services below for relevant providers)

May be performed by a child psychologist or, often, with a team-based approach.

Developmental Pediatrics (see Services below for relevant providers)

May be helpful, particularly as part of an evaluation team.

Questions from Clinicians

What are the goals of therapy?

After diagnosis, the main goal of treatment is to avoid progression of the disease and acute decompensations brought about by illness, fasting, and dehydration. IV glucose may be necessary during illness and dehydration. The usual treatment is 10% glucose with adequate salts (quarter or half normal saline - depending on age and weight - with 20 mEq/L of potassium chloride) at 1.5-2 times maintenance, keeping in mind that this treatment does not provide all the needed calories.

Issues Related to VLCADD

Funding & Access to Care

Writing Letters of Medical Necessity

Resources

Information for Clinicians

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

ACT Sheet for VLCADD (ACMG) (PDF Document 347 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

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

VLCADD (OMIM)
Extensive literature review organized by description, clinical features, genetics, diagnosis, differential diagnosis, management, nomenclature, history, and animal models; Online Mendelian Inheritance in Man.

VLCADD Acute Illness Protocol (NECMP)
A guideline for health care professionals treating the sick infant or child with VLCADD; 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.

VLCADD (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information for the condition; U.S. National Library of Medicine.

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

PubMed search for VLCADD in children, last 5 years.

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.
Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.
J Inherit Metab Dis. 2009;32(4):498-505. PubMed abstract

Clinical Tools

Information & Support for Families

Family Diagnosis Page

Information on the Web

The Portal's page Health Insurance/Financial Aids and Financing Your Child's Healthcare may be helpful for some families.

VLCADD - 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 a newborn disorder; Screening, Technology and Research in Genetics.

VLCADD (Genetics Home Reference)
Excellent, detailed review of 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 Nevada

Select services for a different state: ID, MT, NM, RI, UT
Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Developmental Assessment

See all Developmental Assessment services providers (1) in our database.

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 Genetics

See all Pediatric Genetics 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.

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

Authors & Reviewers

Initial Publication: September 2014; Last Update: May 2016
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

Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N.
Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.
Am J Hum Genet. 1999;64(2):479-94. PubMed abstract / Full Text

Coughlin CR 2nd, Ficicioglu C.
Genotype-phenotype correlations: sudden death in an infant with very-long-chain acyl-CoA dehydrogenase deficiency.
J Inherit Metab Dis. 2010. PubMed abstract

Ficicioglu C, Coughlin CR 2nd, Bennett MJ, Yudkoff M.
Very long-chain acyl-CoA dehydrogenase deficiency in a patient with normal newborn screening by tandem mass spectrometry.
J Pediatr. 2010;156(3):492-4. PubMed abstract

Hale DE, Stanley CA, Coates PM.
Genetic defects of acyl-CoA dehydrogenases: studies using an electron transfer flavoprotein reduction assay.
Prog Clin Biol Res. 1990;321:333-48. PubMed abstract

Roe CR, Roe DS.
Recent developments in the investigation of inherited metabolic disorders using cultured human cells.
Mol Genet Metab. 1999;68(2):243-57. 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.
Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.
J Inherit Metab Dis. 2009;32(4):498-505. 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