3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, (HMGCLD) also known asHMGCL deficiency,HMG-CoA lyase deficiency, orhydroxymethylglutaric aciduria, is an uncommon autosomal recessive inborn error inketone body production andleucine breakdown caused byHMGCL gene mutations.[1][2] HMGCL, located on chromosome 1p36.11's short arm, codes forHMG-CoA lyase, which aids in the metabolism of dietary proteins by convertingHMG-CoA intoacetyl-CoA andacetoacetate.
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency presents in various ways, from severe neonatal symptoms to adult symptoms. Symptoms include frequentvomiting,convulsions, and decreased alertness. Laboratory results include higher plasma/serumtransaminase activity,hyperammonemia,acidosis,hypoglycemia, and an increasedanion gap.
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can be identified duringnewborn screening usingtandem mass spectrometry, and is confirmed by enzyme activity testing inlymphocytes, immortalized lymphoblastoid cells, orfibroblasts, as well as HMGCL gene mutation studies.
There are no controlled treatment studies for 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, making it difficult to determine the need for specific diet orcarnitine supplements. The main therapy is avoiding fasting, withL-carnitine supplementation potentially detoxifying and preventing secondary insufficiency.
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can appear in a variety of ways in terms of clinical presentation, from a severe neonatal onset with potentially fatal consequences to an adult presentation.[1] Clinical signs of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency appear either early in the neonatal stage or later in the first year of life.[3] Typically, nonspecific symptoms such as frequentvomiting,convulsions, and decreased alertness are displayed by patients. Typical laboratory results include higher plasma/serumtransaminase activity,hyperammonemia,acidosis,hypoglycemia, and an increasedanion gap.[1]
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is the result ofHMGCL gene mutations.[1] HMGCL is found on chromosome 1p36.11's short arm and codes for the enzyme 3-hydroxymethyl-3-methylglutaryl-coenzyme A lyase (HMG-CoA lyase).[4][5] This mitochondrial enzyme contributes to the metabolism of dietary proteins by convertingHMG-CoA intoacetyl-CoA andacetoacetate, which is the last stage of the breakdown of leucine and fat for energy.[6] As a result, the body is unable to produceketone bodies, which are necessary for generating energy during fasting.[7] 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is passed down as an autosomal recessive trait.[2]
The pathophysiology of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, like that of many otherinborn errors of metabolism, can be explained by the accumulation of potentially harmful metabolites (leucine) and a lack of products (ketone bodies).[8]Hypoglycemia severely impairs counterregulatory compensation because it affects leucine catabolism as well as fat oxidation, which results in secondary metabolic dysfunction.[9][10][11]Metabolite levels in the leucine oxidation pathway may be significantly raised, including 3-MGL and 3-HIVA.[8] Additionally, patients withMRI spectroscopy have shown 3-HIVA and 3-HMG, suggesting that these proximal metabolites may play a role in pathogenesis.[12] Depletion of Coenzyme A recycling for other activities can also result from intramitochondrial buildup ofacetyl-coA.[13] The relationship between 3-MGC accumulation as a measure of mitochondrial malfunction and leucine oxidation in terms of symptomatology is still unknown.[8]
Since 3-hydroxy isovaleryl carnitine (C5-OH) is typically elevated in this condition, 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can be identified duringnewborn screening by testing it usingtandem mass spectrometry methodology.[3] Enzyme activity testing inlymphocytes, immortalized lymphoblastoid cells, orfibroblasts, as well asHMGCL gene mutation studies, may confirm the diagnosis of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency.[1]
As with other uncommon inherited metabolic illnesses, there are no controlled treatment studies for 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency. Consequently, it is impossible to make any judgments about whether a particular diet orcarnitine supplements are required. Clinical reports and pathobiochemical considerations suggest that the mainstay of therapy is avoiding fasting.L-carnitine supplementation may have detoxifying properties, prevent intracellular loss of free coenzyme A, and prevent secondary L-carnitine insufficiency.[14]
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency was initially reported in 1976,[16] and the gene was discovered and cloned in 1993.[17] The first case in the literature was published in Western Australia in 1976, with usual findings ofhypoglycemia andacidosis.[16]
^abcdefGrünert, Sarah Catharina; Schlatter, Sonja Marina; Schmitt, Robert Niklas; Gemperle-Britschgi, Corinne; Mrázová, Lenka; Balcı, Mehmet Cihan; Bischof, Felix; Çoker, Mahmut; Das, Anibh M.; Demirkol, Mübeccel; de Vries, Maaike; Gökçay, Gülden; Häberle, Johannes; Uçar, Sema Kalkan; Lotz-Havla, Amelie Sophia; Lücke, Thomas; Roland, Dominique; Rutsch, Frank; Santer, René; Schlune, Andrea; Staufner, Christian; Schwab, Karl Otfried; Mitchell, Grant A.; Sass, Jörn Oliver (2017). "3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients".Molecular Genetics and Metabolism.121 (3). Elsevier BV:206–215.doi:10.1016/j.ymgme.2017.05.014.ISSN1096-7192.PMID28583327.
^abGibson, K. M.; Breuer, J.; Nyhan, W. L. (1988). "3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients".European Journal of Pediatrics.148 (3):180–186.doi:10.1007/BF00441397.ISSN0340-6199.PMID3063529.
^Roland, Dominique; Jissendi-Tchofo, Patrice; Briand, Gilbert; Vamecq, Joseph; Fontaine, Monique; Ultré, Vincent; Acquaviva-Bourdain, Cécile; Mention, Karine; Dobbelaere, Dries (2017). "Coupled brain and urine spectroscopy — in vivo metabolomic characterization of HMG-CoA lyase deficiency in 5 patients".Molecular Genetics and Metabolism.121 (2). Elsevier BV:111–118.doi:10.1016/j.ymgme.2017.03.006.ISSN1096-7192.PMID28396157.
^Mitchell, Grant A; Gauthier, Nicolas; Lesimple, Alain; Wang, Shu Pei; Mamer, Orval; Qureshi, Ijaz (2008). "Hereditary and acquired diseases of acyl-coenzyme A metabolism".Molecular Genetics and Metabolism.94 (1). Elsevier BV:4–15.doi:10.1016/j.ymgme.2007.12.005.ISSN1096-7192.PMID18337138.
Bischof, Felix; Nägele, Thomas; Wanders, Ronald J. A.; Trefz, Friedrich K.; Melms, Arthur (2004). "3-hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy".Annals of Neurology.56 (5):727–730.doi:10.1002/ana.20280.ISSN0364-5134.PMID15505778.
