HMG-CoA Lyase Deficiency
Guidance for primary care clinicians receiving a positive newborn screen result for HMG-CoA lyase deficiency
Description
In HMG-CoA lyase deficiency, insufficient 3-hydroxy-3-methylglutaryl-CoA lyase enzyme activity (usually expressed at high levels in the liver) impairs the formation of ketone bodies from fat and the degradation of leucine. [Puisac: 2010] This leads to an increased reliance on glucose as an energy source, resulting in a risk for hypoglycemia and the accumulation of toxic metabolites. The resultant hypoketotic hypoglycemia and/or metabolic acidosis can lead to seizures and lethargy and, in some cases, long-term neurological sequelae from such episodes. Triggers for such episodes include metabolic stressors like prolonged fasting and intercurrent infectious illnesses, in particular those associated with vomiting and/or fever. Mutations in the HMGCL gene cause HMG-CoA lyase deficiency.
Clinical Characteristics
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.
- Poor feeding
- Vomiting
- Irritability
- Lethargy
- Lab findings:
- Metabolic acidosis
- Hypoketotic hypoglycemia
- Abnormal liver function tests
- Hyperammonemia
- Failure to thrive
- Hepatomegaly
- Seizures
- Apnea
- Developmental delay
- Intellectual disability
- Death
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
- To confirm the diagnosis, work with Newborn Screening Services (see NW providers [1]).
- Additional testing may include quantitative plasma acylcarnitine profile and urine organic acids.
If the Diagnosis is Confirmed
- For evaluation and ongoing collaborative management, consult Biochemical Genetics (Metabolics) (see NW providers [1]).
- 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).
- 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. Early Intervention for Children with Disabilities/Delays (see NW providers [3]).
Resources
Information & Support
Related Portal Content
Developmental Screening
Screening tools and follow-up for positive screens.
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
ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (
336 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive, along with resources
for consultation and patient education/support; from the American College of Genetics and Genomics
Confirmatory Algorithms for Elevated C5-OH (ACMG) ( 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 Nationwide (NW)
| Service Categories | # of providers* in: | NW | Partner states (4) (show) | | NM | NV | RI | UT | |
|---|---|---|---|---|---|---|---|---|---|
| Biochemical Genetics (Metabolics) | 1 | 1 | 2 | 3 | 2 | ||||
| Early Intervention for Children with Disabilities/Delays | 3 | 34 | 30 | 13 | 51 | ||||
| Medical Genetics | 1 | 2 | 5 | 4 | 7 | ||||
| Newborn Screening Services | 1 | 3 | 2 | 2 | 3 | ||||
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.
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 3/27/2023.