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3-hydroxy-3-methylglutaryl-CoA synthase deficiency(HMGCS2D)

MedGen UID:
414399
Concept ID:
C2751532
Disease or Syndrome
Synonyms: 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 Deficiency; HMG-CoA synthase-2 deficiency; HMGCS2 DEFICIENCY; HMGCS2D; mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HMGCS2 (1p12)
 
Monarch Initiative: MONDO:0011614
OMIM®: 605911
Orphanet: ORPHA35701

Definition

Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (summary by Aledo et al., 2006). [from OMIM]

Clinical features

From HPO
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
Dicarboxylic aciduria
MedGen UID:
343550
Concept ID:
C1856432
Finding
An increased concentration of dicarboxylic acid in the urine.
Elevated urinary 3-hydroxybutyric acid
MedGen UID:
868023
Concept ID:
C4022414
Finding
An increased amount of 3-hydroxybutyric acid in the urine.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Steatorrhea
MedGen UID:
20948
Concept ID:
C0038238
Finding
Greater than normal amounts of fat in the feces. This is a result of malabsorption of lipids in the small intestine and results in frothy foul-smelling fecal matter that floats.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Coma induced by low blood sugar.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
An abnormally decreased phosphate concentration in the blood.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Increased circulating free fatty acid level
MedGen UID:
908805
Concept ID:
C4280773
Finding
A higher than normal levels of the fatty acids which can occur in plasma as a result of lipolysis in adipose tissue or when plasma triacyglycerols are taken into tissues.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGV3-hydroxy-3-methylglutaryl-CoA synthase deficiency
Follow this link to review classifications for 3-hydroxy-3-methylglutaryl-CoA synthase deficiency in Orphanet.

Professional guidelines

PubMed

Lanthaler B, Wieser S, Deutschmann A, Schossig A, Fauth C, Zschocke J, Witsch-Baumgartner M
Gene 2014 Oct 15;550(1):136-40. Epub 2014 Aug 8 doi: 10.1016/j.gene.2014.08.016. PMID: 25111118

Recent clinical studies

Prognosis

Liu H, Miao JK, Yu CW, Wan KX, Zhang J, Yuan ZJ, Yang J, Wang DJ, Zeng Y, Zou L
BMC Pediatr 2019 Oct 9;19(1):344. doi: 10.1186/s12887-019-1747-5. PMID: 31597564Free PMC Article
Pitt JJ, Peters H, Boneh A, Yaplito-Lee J, Wieser S, Hinderhofer K, Johnson D, Zschocke J
J Inherit Metab Dis 2015 May;38(3):459-66. Epub 2014 Dec 16 doi: 10.1007/s10545-014-9801-9. PMID: 25511235
Bouchard L, Robert MF, Vinarov D, Stanley CA, Thompson GN, Morris A, Leonard JV, Quant P, Hsu BY, Boneh A, Boukaftane Y, Ashmarina L, Wang S, Miziorko H, Mitchell GA
Pediatr Res 2001 Mar;49(3):326-31. doi: 10.1203/00006450-200103000-00005. PMID: 11228257

Clinical prediction guides

Pitt JJ, Peters H, Boneh A, Yaplito-Lee J, Wieser S, Hinderhofer K, Johnson D, Zschocke J
J Inherit Metab Dis 2015 May;38(3):459-66. Epub 2014 Dec 16 doi: 10.1007/s10545-014-9801-9. PMID: 25511235
Bouchard L, Robert MF, Vinarov D, Stanley CA, Thompson GN, Morris A, Leonard JV, Quant P, Hsu BY, Boneh A, Boukaftane Y, Ashmarina L, Wang S, Miziorko H, Mitchell GA
Pediatr Res 2001 Mar;49(3):326-31. doi: 10.1203/00006450-200103000-00005. PMID: 11228257

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