Paula and Bobby
Parents of Lillie
3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD
What is 3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD?
3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD is a rare disease. It is also known as Hl Deficiency HMG CoA lyase deficiency Hmg-coa Lyase Deficiency Hmgcl Deficiency Hydroxymethylglutaric Aciduria.
Patients with this condition present in the neonatal period with irritability, lethargy, vomiting and a decrease in the level of consciousness. They will be found to be hypoglycaemic and to have a metabolic acidosis without ketonuria. The diagnosis is made by the detection of a characteristic pattern of organic acids in the urine. Those that will be found are 3 hydroxy-3 methylglutaric acid, 3-methylglutatonic acid, 3 methylglutaric and 3 hydroxyisovaleric acids. Hyperammonaemia and enlarged liver might be additional features. The enzyme involved plays a role in leucine degradation and in ketogenesis. There is one case who developed retinitis pigmentosa and deafness (Jones et al., 1997).
The gene has now been mapped to 1p36. Mutations have been identified and this has been used in prenatal diagnosis (Mitchell et al., 1995). The condition is common in Saudi Arabia where there is a common mutation at R41Q (Mitchell et al., 1998).
Grünert et al. (2017) described 37 patients from 35 families with HMG-CoA lyase deficiency due to biallelic mutations in the HMGCL gene. Age of onset was between second day of life and four years. Most frequent clinical features during metabolic decompensations were seizures, recurring vomiting, refusal to eat, tachydyspnea, hepatomegaly, somnolence and lethargy. Number of decompensation episodes ranged between 1 to >20. Additional clinical characteristics included normal intelligence to severe cognitive impairment, failure to thrive, microcephaly, seizures, muscular hypotonia or spasticity, tremor, visual impairment including blindness, tetraplegia, hemiplegia, myoclonia, hydrocephalus, hyperkinesia and ataxia.
* This information is courtesy of the L M D.
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What gene changes cause 3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 246450 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
HMGCL - 1p36.11
What are the main symptoms of 3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD?
The typical symptoms of the syndrome are:
Hepatomegaly, Hypoglycemia, Glutaric aciduria, Hyperammonemia, Excessive daytime somnolence, Death in childhood, Autosomal recessive inheritance, 3-Methylglutaric aciduria, Ketonuria, Metabolic acidosis, Decreased plasma carnitine, Coma, Fever
How does someone get tested for 3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD?
The initial testing for 3-Hydroxy-3-Methylglutaryl-Coa Lyase Deficiency; HMGCLD can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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