Also known as: 3-HMG-CoA synthase-2 deficiency, mitochondrial HMG-CoA synthase, HMGCS2D
(OMIM#2605911)
1. The disease
3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMG-CoA synthase deficiency) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. There are only around 20 patients reported to date in the world.
2. The symptoms
As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Characterized clinically by episodes of decompensation (often associated with gastroenteritis or fasting), which present with vomiting, lethargy, hepatomegaly (fatty liver), non-ketotic hypoglycemia and, in rare cases, coma. Infants are initially asymptomatic at birth and during the neonatal period. Symptoms develop within the first year of life, often between 6 months and 1 year of age. If untreated, HMGCS2 can cause seizures, brain atrophy and developmental delay. Patients are mostly asymptomatic between acute episodes. HMG-CoA synthase deficiency requires an early diagnosis in order to avoid hypoglycemic crises that can lead to permanent brain damage or death. Lack of early signs or symptoms does not exclude the diagnosis.
3. Actions to take in case of early diagnosis
- Infants with a positive genetic test should continue breastfeeding and AVOID FASTING. Early treatment, with frequent fractional meals/ frequent breastfeeding, is essential in preventing chronic symptoms.
- Biochemical correlation is essential for confirming diagnosis with venous gasometry, lipid profile, liver ultrasound and urinary organic acids. Hypertriglyceridemia, or low HDL cholesterol levels with acidosis are seen, mild ketosis, and mental status changes after illness or prolonged fasting.
- HMGCS2D is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and a multidisciplinary approach to care.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Orphanet:
https://www.orpha.net/consor/cgibin/Disease_Search.php?lng=EN&data_id=10391&Disease_Disease_Search_diseaseGroup=HMGCS2&Disease_Disease_Search_diseaseType=Gen&Disease(s)/group%20of%20diseases=3-hydroxy-3-methylglutaryl-CoA-déficit en synthase&title=3-hydroxy-3-méthylglutarylCoA%20synthase%20deficiency&search=Disease_Search_Simple
Biblio :
- Rojnueangnit K, Maneechai P, Thaweekul P, et al. Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. Eur J Med Genet. 2020;63(12):104086. doi:10.1016/j.ejmg.2020.104086. PMID: 3304540
- Conboy E, Vairo F, Schultz M, et al. Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features. JIMD Rep. 2018;40:63-69. doi:10.1007/8904_2017_59. PMID: 29030856
- Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis. 2014;37(4):541-551. doi:10.1007/s10545-014-9704-9. PMID: 24706027.