HMG-CoA Lyase Deficiency

Other Names

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

HMG lyase deficiency

Hydroxymethylglutaric aciduria

HL deficiency

Diagnosis Coding

E71.118, other branched-chain organic acidurias

Disorder Category

An organic acidemia



Elevated C5-OH (acylcarnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity: NA; specificity: NA


The lack of the enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (usually expressed at high levels in the liver) impairs the formation of ketone bodies from fat and the break down of leucine [Puisac: 2010]. This results in increased utilization of glucose with hypoglycemia and accumulation of toxic metabolites. The lack of energy causes seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycemia. Mutations in the HMGCL gene cause HMG-CoA lyase deficiency.


Autosomal recessive

Prenatal Testing

DNA testing by amniocentesis or chorionic villus sampling (CVS) if both disease causing mutations of an affected family member have been identified; enzyme testing by maternal urine analysis possible at >23 weeks gestational age.

Clinical Characteristics

With treatment, normal development and IQ are possible. However, severe episodes of hypoglycemia may still result in seizures and/or mental retardation. Without treatment, recurring metabolic crises, associated with illness or fasting, will likely result in developmental delay/mental retardation or death. Symptoms generally begin from infancy up to 3 years of age. Affected children may be healthy between metabolic crises.

Initial signs/symptoms may include:
  • Poor feeding
  • Vomiting
  • Irritability
  • Lethargy
  • Lab findings:
    • Metabolic acidosis
    • Non-ketotic hypoglycemia
If not treated promptly and consistently, patients may experience:
  • Failure to thrive
  • Hepatomegaly
  • Seizures
  • Apnea
  • Developmental delay/mental retardation
  • Death
Treatment consists of limiting fasting time, prompt treatment of infections/fever/gastroenteritis, use of corn-starch, and carnitine supplementation.

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile and urine organic acids.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Education for the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see HMG-CoA Lyase Deficiency - Information for Parents (STAR-G) for additional information)
  • Frequent, low protein, low fat, and high carbohydrate meals - avoidance of fasting
  • Oral L-carnitine and cornstarch supplementation
  • Bicarbonate and glucose during metabolic crisis episodes
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

Initial consultation with the following service(s):Pediatric Genetics (see ID providers [3]); and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.


Information & Support

For Professionals

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

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

For Parents and Patients

HMG-CoA Lyase 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.

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.


3-hydroxymethylglutaryl-CoA (3-HMG CoA) Lyase Deficiency (NECMP)
A guideline for health care professionals treating the sick infant/child who has previously been diagnosed with HMG-CoA lyase deficiency; 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.

ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (PDF Document 400 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Services for Patients & Families in Idaho (ID)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

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 2007; last update/revision: July 2012
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Reviewer: Kimberly Hart, MS, LCGC

Page Bibliography

Puisac B, Arnedo M, Casale CH, Ribate MP, Castiella T, Ramos FJ, Ribes A, Pérez-Cerdá C, Casals N, Hegardt FG, Pié J.
Differential HMG-CoA lyase expression in human tissues provides clues about 3-hydroxy-3-methylglutaric aciduria.
J Inherit Metab Dis. 2010;33(4):405-10. PubMed abstract / Full Text
The pathophysiology of 3-Hydroxy-3-methylglutaric aciduria, caused by HMG-CoA lyase deficiency, is only partially understood. Findings from this study help the understanding of the enzyme function and consequences of its deficiency and suggest the need for pancreatic damage assessment.