3-Hydroxy-3-Methylglutaryl CoA Lyase (HMG) Deficiency: HMGCL Gene Deletion/Duplication

Condition Description

3-Hydroxy-3-methylglutaryl-CoA lyase (HMG) deficiency is an autosomal recessive disorder that affects ketogenesis and L-leucine catabolism[1]. Patients with HMG deficiency have a reduced capacity to synthesize ketone bodies (acetoacetate and 3-hydroxybutyrate) which are primary energy sources for the brain when metabolic needs are not met by glucose[2].

Affected individuals usually present in the first year of life with severe vomiting and diarrhea, hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, and hepatomegaly. Acute pancreatitis and dilated cardiomyopathy can be some of the clinical complications. Patients may also have macrocephaly, hypotonia, and developmental delay. Untreated, this may progress rapidly to coma and death or may result in permanent neurological damage.

With dietary and pharmacologic treatment, the disease can be controlled, although recurrent metabolic decompensation can occur, especially with prolonged fasting and inter-current infections. Rapid biochemical diagnosis by plasma acylcarnitine analysis using tandem mass spectrometry reveals elevation of 3-methylglutarylcarnitine and 3-hydroxyisovalerylcarnitine[3]. Urine analysis by gas chromatography mass spectrometry reveals the presence of 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids. HMG can also be measured in various tissues including lymphocytes and fibroblasts[4]. HMG-CoA human mitochondrial lyase is encoded by the HMGCL gene located at the 1p36.1-p35 chromosomal locus. To date, 31 variant alleles in the HMGCLgene (29 mutations and 2 SNPs) in 93 patients have been reported[5]. In the coding region, missensed mutations are the most frequent (14), followed by nonsense mutations (4), frameshift deletions (4) or insertions (1), and 3 large deletions. Three mutations have been found in intron sequences that cause abnormal splicing. The mutational spectrum is population specific with higher frequency in Saudi Arabia and Portugal and lower frequency in Europe and Japan [6-10]. Genotype-phenotype correlations have been difficult to establish [5]. Sequencing of the HMGCL gene is recommended after a biochemical analysis consistent with HMG deficiency, and provides a complementary method to confirm the presence of mutations in a proband, identify carriers among the proband's relatives, and provide prenatal diagnosis in families with known mutations.

Please click here for the OMIM summary on this condition.

1. Barash et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations. J Inherit Metab Dis 1990, 13: 156-164.
2. Kayer M.A. Disorders of ketone production and utilization. Mol Genet Metab 2006, 87:281283.
3. Rashed et al. Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res 1995, 38(3):324-331.
4. Wanders and Zoeters. 3-Hydroxy-3-methylglutaryl-CoA lyase in human skin fibroblasts: study of its properties and deficient activity in 3-hydroxy-3-methylglutaric aciduria patients using a simple spectrophotometric method. Clin Chim Acta 1988, 171(1):95-101.
5. Pie et al. Molecular genetics of HMG-CoA lyase deficiency. Mol Genet Metab 2007, in press.
6. Al-Sayed et al. Mutations underlying 3-Hydroxy-3-Methylglutaryl CoA Lyase deficiency in the Saudi population. BMC Med Genet 2006, 7:86-91.
7. Muroi et al. Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl- CoA lyase (HL) deficiency. J Inherit Metab Dis 2000, 23:636637.
8. Ozand and Gascon. Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 1992, 7 Suppl:S4-11.
9. Cardoso et al. The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. Mol Genet Metab 2004, 82(4):334-338.
10. Pospisilova et al. Biochemical and molecular analyses in three patients with 3-hydroxy- 3-methylglutaric aciduria. J Inherit Metab Dis 2003, 26:433441.

Genes (1)


This test is indicated for:

  • Individuals with a clinical and biochemical diagnosis consistent with HMG deficiency.
  • Carrier testing in individuals with a family history of HMG deficiency.


DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.


Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Prevalence of HMG deficiency is rare with incidence estimates of 1:100,000 live births.

Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Please submit copies of diagnostic biochemical test results along with the sample. Contact the laboratory if further information is needed. Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
  • Acylcarnitine Profile (AR)
  • Organic Acids Analysis (OA) - Urine
  • Known Mutation Analysis (KM) is available to family members if mutations are identified by sequencing.
  • Prenatal Custom Diagnostics is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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