HMG-CoA Lyase Deficiency

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

HL deficiency
HMG lyase deficiency
Hydroxymethylglutaric aciduria
3-hydroxy-3-methylglutaryl-CoA lyase deficiency

ICD-10 Coding

E71.118, Other branched-chain organic acidurias

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C5-OH (acylcarnitine)

Tested By

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

Description

In HMG-CoA lyase deficiency, 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 breakdown 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.

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/intellectual disability 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 and cornstarch and carnitine supplementation.

Incidence

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, vomiting, or lethargy.
  • Provide emergency treatment/referral for hypoglycemia, metabolic acidosis, or seizures.

Confirming the Diagnosis

If the Diagnosis is Confirmed

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

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.

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.

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

Tools

Confirmatory Algorithms for Elevated C5-OH (ACMG) (PDF Document 224 KB)
Basic steps involved in determining the final diagnosis of an infant with a positive newborn screen for this condition; American College of Medical Genetics.

HMG-CoA Lyase Deficiency Acute Illness Protocol (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.

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 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.

Screening, technology, and research in genetics.
3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
STAR-G; (2022) http://www.newbornscreening.info/Pro/organicaciddisorders/HMGCoA.html. Accessed on Feb 16, 2022.