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3-Hydroxy-3-methylglutaryl-CoA lyase deficiency

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.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
Other namesHMGCL deficiency, HMG-CoA lyase deficiency, HMGCLD, hydroxymethylglutaric aciduria.
Skeletal formula of 3-hydroxy-3-methylglutaryl-coenzyme A
SpecialtyPediatrics Edit this on Wikidata

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

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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

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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

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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

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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

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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

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

Epidemiology

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

History

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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

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References

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  1. ^ a b c d e f 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. ^ a b 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. ^ a b 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. ^ a b c 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. ^ a b "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

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