Likely inborn error of metabolism

Gene: HMGCL

Comment on list classification: HMGCL is being demoted to Red on this panel on the recommendation of the GMS mitochondrial specialist test group, including by Carl Fratter (Oxford University Hospitals NHS Trust). It is associated with HMG-CoA lyase deficiency 246450, with microcephaly, seizures & metabolic disturbance. Although this is technically a mitochondrial disorder, the phenotype is quite different to other mitochondrial conditions.

Created: 1 Aug 2019, 1:35 p.m. | Last Modified: 1 Aug 2019, 1:35 p.m.

Panel Version: 1.416

Green List (high evidence)

Potential differential diagnosis for mitochondrial disorder, with elevated lactate, seizures, basal ganglia abnormalilty etc

Created: 19 Jun 2019, 12:26 p.m.

Phenotypes
HMG-CoA lyase deficiency, 246450

Red List (low evidence)

Red - fatty acid oxidation disorder, rather than a primary mitochondrial disorder

Created: 11 Jun 2019, 3:59 p.m.

Phenotypes
HMG-CoA lyase deficiency, 246450

Green List (high evidence)

Added from Intellectual disability panel update as this gene is also relevant to theMitochondrial disorders panel. This is a Confirmed disease gene in Developmental Disorders Genotype-Phenotype Database (DDG2P) for 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency. Grunert (2017) PMID: 28583327 reviewed the clinical presentation and outcome in a series of 37 patients with HMGCLD. 10 had no further metabolic decompensations after diagnosis, and 22 had at least one more metabolic crisis, most often associated with infections, especially gastroenteritis or respiratory tract infections. Half of the patients had normal cognitive development, and the remainder had psychomotor deficits of variable severity.

Created: 18 Dec 2017, 4:15 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
HMG-CoA lyase deficiency, 246450; 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency; HMGCLD; intellectual disability

Publications

• 28583327
• 8617516
• 9463337
• 11129331