3-Hydroxy-3-methylglutaryl-CoA lyase deficiency

Last updated
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
Other namesHMGCL deficiency, HMG-CoA lyase deficiency, HMGCLD, hydroxymethylglutaric aciduria.
HMG coenzyme A.svg
Skeletal formula of 3-hydroxy-3-methylglutaryl-coenzyme A
Specialty Pediatrics   OOjs UI icon edit-ltr-progressive.svg

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, (HMGCLD) also known as HMGCL deficiency, HMG-CoA lyase deficiency, or hydroxymethylglutaric aciduria, is an uncommon autosomal recessive inborn error in ketone body production and leucine breakdown caused by HMGCL gene mutations. [1] [2] HMGCL, located on chromosome 1p36.11's short arm, codes for HMG-CoA lyase, which aids in the metabolism of dietary proteins by converting HMG-CoA into acetyl-CoA and acetoacetate.

Contents

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency presents in various ways, from severe neonatal symptoms to adult symptoms. Symptoms include frequent vomiting, convulsions, and decreased alertness. Laboratory results include higher plasma/serum transaminase activity, hyperammonemia, acidosis, hypoglycemia, and an increased anion gap.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can be identified during newborn screening using tandem mass spectrometry, and is confirmed by enzyme activity testing in lymphocytes, immortalized lymphoblastoid cells, or fibroblasts, 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 or carnitine supplements. The main therapy is avoiding fasting, with L-carnitine supplementation potentially detoxifying and preventing secondary insufficiency.

Signs and symptoms

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 frequent vomiting, convulsions, and decreased alertness are displayed by patients. Typical laboratory results include higher plasma/serum transaminase activity, hyperammonemia, acidosis, hypoglycemia, and an increased anion gap. [1]

Causes

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is the result of HMGCL 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 converting HMG-CoA into acetyl-CoA and acetoacetate, which is the last stage of the breakdown of leucine and fat for energy. [6] As a result, the body is unable to produce ketone 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]

Mechanism

The pathophysiology of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, like that of many other inborn 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 with MRI 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 of acetyl-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]

Diagnosis

Since 3-hydroxy isovaleryl carnitine (C5-OH) is typically elevated in this condition, 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can be identified during newborn screening by testing it using tandem mass spectrometry methodology. [3] Enzyme activity testing in lymphocytes, immortalized lymphoblastoid cells, or fibroblasts, as well as HMGCL gene mutation studies, may confirm the diagnosis of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency. [1]

Treatment

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 or carnitine 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]

Outlook

The overall mortality rate of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is 16%. [1]

Epidemiology

The incidence of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is fewer than 1/100,000 live births. [15]

History

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 of hypoglycemia and acidosis. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">Inborn error of lipid metabolism</span> Medical condition

Numerous genetic disorders are caused by errors in fatty acid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">3-Methylcrotonyl-CoA carboxylase deficiency</span> Medical condition

3-Methylcrotonyl-CoA carboxylase deficiency also known as 3-Methylcrotonylglycinuria is an inborn error of leucine metabolism and is inherited through an autosomal recessive fashion. 3-Methylcrotonyl-CoA carboxylase deficiency is caused by mutations in the MCCC1 gene, formerly known as MMCA, or the MCCC2 gene, formerly known as MCCB. MCCC1 encodes the a-subunits of 3-methylcrotonyl-CoA carboxylase while MCCC2 encodes the b-subunits. The clinical presentation of 3-Methylcrotonyl-CoA carboxylase deficiency is varied, even within members of the same family.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase deficiency</span> Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

2-Methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive metabolic disorder. It causes the body to be unable to process the amino acid isoleucine properly. Initial case reports identified individuals with developmental delay and epilepsy, however most cases identified through newborn screening have been asymptomatic.

<span class="mw-page-title-main">HMG-CoA</span> Chemical compound

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.

Methylcrotonyl CoA carboxylase is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid.

<span class="mw-page-title-main">3-Hydroxy-3-methylglutaryl-CoA lyase</span> Class of enzymes

3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

<span class="mw-page-title-main">Acetoacetyl-CoA</span> Chemical compound

Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion pathway, it is no longer associated with having HMG-CoA as a product or as a reactant.

<span class="mw-page-title-main">Methylcrotonyl-CoA</span> Chemical compound

3-Methylcrotonyl-CoA is an intermediate in the metabolism of leucine.

<span class="mw-page-title-main">Methylglutaconyl-CoA hydratase</span> Protein-coding gene in the species Homo sapiens

3-Methylglutaconyl-CoA hydratase, also known as MG-CoA hydratase and AUH, is an enzyme encoded by the AUH gene on chromosome 19. It is a member of the enoyl-CoA hydratase/isomerase superfamily, but it is the only member of that family that is able to bind to RNA. Not only does it bind to RNA, AUH has also been observed to be involved in the metabolic enzymatic activity, making it a dual-role protein. Mutations of this gene have been found to cause a disease called 3-Methylglutaconic Acuduria Type 1.

<span class="mw-page-title-main">Hydroxymethylglutaryl-CoA synthase</span> Class of enzymes

In biochemistry, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.

<span class="mw-page-title-main">ETFDH</span> Protein-coding gene in humans

Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.

<span class="mw-page-title-main">Fatty-acid metabolism disorder</span> Medical condition

A broad classification for genetic disorders that result from an inability of the body to produce or utilize an enzyme or transport protein that is required to oxidize fatty acids. They are an inborn error of lipid metabolism, and when it affects the muscles also a metabolic myopathy.

<span class="mw-page-title-main">HMGCS2</span> Protein-coding gene in the species Homo sapiens

3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an enzyme in humans that is encoded by the HMGCS2 gene.

β-Hydroxy β-methylbutyryl-CoA Chemical compound

β-Hydroxy β-methylbutyryl-coenzyme A (HMB-CoA), also known as 3-hydroxyisovaleryl-CoA, is a metabolite of L-leucine that is produced in the human body. Its immediate precursors are β-hydroxy β-methylbutyric acid (HMB) and β-methylcrotonoyl-CoA (MC-CoA). It can be metabolized into HMB, MC-CoA, and HMG-CoA in humans.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. However, the methylmalonic acid levels exceed those of malonic acid. CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII). Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

References

  1. 1 2 3 4 5 6 Grünert, 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. ISSN   1096-7192. PMID   28583327.
  2. 1 2 Gibson, 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. ISSN   0340-6199. PMID   3063529.
  3. 1 2 Alfadhel, Majid; Abadel, Basma; Almaghthawi, Hind; Umair, Muhammad; Rahbeeni, Zuhair; Faqeih, Eissa; Almannai, Mohammed; Alasmari, Ali; Saleh, Mohammed; Eyaid, Wafaa; Alfares, Ahmed; Al Mutairi, Fuad (2022-05-13). "HMG-CoA Lyase Deficiency: A Retrospective Study of 62 Saudi Patients". Frontiers in Genetics. 13. doi: 10.3389/fgene.2022.880464 . ISSN   1664-8021. PMC   9136170 . PMID   35646072.
  4. ↑ Pié, Juan; López-Viñas, Eduardo; Puisac, Beatriz; Menao, Sebastián; Pié, Angeles; Casale, Cesar; Ramos, Feliciano J.; Hegardt, Fausto G.; Gómez-Puertas, Paulino; Casals, Núria (2007). "Molecular genetics of HMG-CoA lyase deficiency". Molecular Genetics and Metabolism. 92 (3). Elsevier BV: 198–209. doi:10.1016/j.ymgme.2007.06.020. ISSN   1096-7192.
  5. ↑ Menao, Sebastián; López-Viñas, Eduardo; Mir, Cecilia; Puisac, Beatriz; Gratacós, Esther; Arnedo, María; Carrasco, Patricia; Moreno, Susana; Ramos, Mónica; Gil, María Concepción; Pié, Ángeles; Ribes, Antonia; Pérez-Cerda, Celia; Ugarte, Magdalena; Clayton, Peter T.; Korman, Stanley H.; Serra, Dolors; Asins, Guillermina; Ramos, Feliciano J.; Gómez-Puertas, Paulino; Hegardt, Fausto G.; Casals, Nuria; Pié, Juan (2009-01-28). "Ten novelHMGCLmutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria". Human Mutation. 30 (3). Hindawi Limited: E520–E529. doi:10.1002/humu.20966. ISSN   1059-7794. PMID   19177531.
  6. ↑ Puisac, Beatriz; Arnedo, María; Casale, Cesar H.; Ribate, María Pilar; Castiella, Tomás; Ramos, Feliciano J.; Ribes, Antonia; Pérez-Cerdá, Celia; Casals, Nuria; Hegardt, Fausto G.; Pié, Juan (2010-06-08). "Differential HMG-CoA lyase expression in human tissues provides clues about 3-hydroxy-3-methylglutaric aciduria". Journal of Inherited Metabolic Disease. 33 (4). Wiley: 405–410. doi:10.1007/s10545-010-9097-3. ISSN   0141-8955. PMC   2903694 . PMID   20532825.
  7. ↑ Václavík, Jan; Mádrová, Lucie; Kouřil, Štěpán; de Sousa, Julie; Brumarová, Radana; Janečková, Hana; Jáčová, Jaroslava; Friedecký, David; Knapková, Mária; Kluijtmans, Leo A. J.; Grünert, Sarah C.; Vaz, Frédéric M.; Janzen, Nils; Wanders, Ronald J. A.; Wevers, Ron A.; Adam, Tomáš (2020). "A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency". JIMD Reports. 54 (1): 79–86. doi:10.1002/jmd2.12118. ISSN   2192-8312. PMC   7358667 . PMID   32685354.
  8. 1 2 3 Thompson, Susan; Hertzog, Ashley; Selvanathan, Arthavan; Batten, Kiera; Lewis, Katherine; Nisbet, Janelle; Mitchell, Ashleigh; Dalkeith, Troy; Billmore, Kate; Moore, Francesca; Tolun, Adviye Ayper; Devanapalli, Beena; Bratkovic, Drago; Hilditch, Cathie; Rahman, Yusof; Tchan, Michel; Bhattacharya, Kaustuv (2023-01-19). "Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases". Nutrients. 15 (3). MDPI AG: 531. doi: 10.3390/nu15030531 . ISSN   2072-6643. PMC   9920477 . PMID   36771238.
  9. ↑ Wortmann, Saskia B.; Kluijtmans, Leo A.; Engelke, Udo F. H.; Wevers, Ron A.; Morava, Eva (2010-09-30). "The 3-methylglutaconic acidurias: what's new?". Journal of Inherited Metabolic Disease. 35 (1). Wiley: 13–22. doi:10.1007/s10545-010-9210-7. ISSN   0141-8955. PMC   3249181 . PMID   20882351.
  10. ↑ Morris, A. A. M. (2004-08-13). "Cerebral ketone body metabolism". Journal of Inherited Metabolic Disease. 28 (2). Wiley: 109–121. doi:10.1007/s10545-005-5518-0. ISSN   0141-8955.
  11. ↑ Jones, Dylan E.; Perez, Leanne; Ryan, Robert O. (2020). "3-Methylglutaric acid in energy metabolism". Clinica Chimica Acta. 502. Elsevier BV: 233–239. doi:10.1016/j.cca.2019.11.006. ISSN   0009-8981. PMC   6994337 . PMID   31730811.
  12. ↑ 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. ISSN   1096-7192. PMID   28396157.
  13. ↑ 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. ISSN   1096-7192. PMID   18337138.
  14. ↑ Grünert, Sarah C.; Sass, Jörn Oliver (2020-02-14). "3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease — many faces". Orphanet Journal of Rare Diseases. 15 (1). Springer Science and Business Media LLC: 48. doi: 10.1186/s13023-020-1319-7 . ISSN   1750-1172. PMC   7023732 . PMID   32059735.
  15. ↑ Santarelli, Francesca; Cassanello, Michela; Enea, Ausilia; Poma, Francesca; D'Onofrio, Valentina; Guala, Giovanna; Garrone, Giangiacomo; Puccinelli, Paola; Caruso, Ubaldo; Porta, Francesco; Spada, Marco (2013). "A neonatal case of 3-hydroxy-3-methylglutaric-coenzyme A lyase deficiency". Italian Journal of Pediatrics. 39 (1). Springer Science and Business Media LLC: 33. doi: 10.1186/1824-7288-39-33 . ISSN   1824-7288. PMC   3685558 . PMID   23705938.
  16. 1 2 "Patient with Defect in Leucine Metabolism". New England Journal of Medicine. 294 (18). Massachusetts Medical Society: 1013. 1976-04-29. doi:10.1056/nejm197604292941823. ISSN   0028-4793.
  17. ↑ Mitchell, G. A.; Robert, M. F.; Hruz, P. W.; Wang, S.; Fontaine, G.; Behnke, C. E.; Mende-Mueller, L. M.; Schappert, K.; Lee, C.; Gibson, K. M.; Miziorko, H. M. (1993-02-25). "3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency". The Journal of Biological Chemistry. 268 (6): 4376–4381. doi: 10.1016/S0021-9258(18)53620-6 . ISSN   0021-9258. PMID   8440722.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.