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Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients.
Pediatr Res. 2001 Mar; 49(3):326-31.PR

Abstract

Hereditary deficiency of mitochondrial HMG-CoA synthase (mHS, OMIM 600234) is a poorly defined, treatable, probably underdiagnosed condition that can cause episodes of severe hypoketotic hypoglycemia. We present clinical follow-up and molecular analysis of the two known mHS-deficient patients. The diagnosis of mHS deficiency is challenging because the symptoms and metabolite pattern are not specific. Moreover, enzyme analysis is technically difficult and requires sampling of an expressing organ such as liver. The patients, now aged 16 and 6 y, have normal development and have had no further decompensations since diagnosis. Patient 1 is homozygous for a phenylalanine-to-leucine substitution at codon 174 (F174L). Interestingly, although the F174 residue is conserved in vertebrate mHS and cytoplasmic HS isozymes, a Leu residue is predicted in the corresponding position of HS-like sequences from Caenorhabditis elegans, Arabidopsis thaliana, and Brassica juncea. Bacterial expression of human F174L-mHS produces a low level of mHS polypeptide with no detectable activity. Similarly, in purified cytoplasmic HS, which in contrast to purified human mHS is stable and can be studied in detail, the corresponding F-->L substitution causes a 10,000-fold decrease in V(max) and a 5-fold reduction in thermal stability. Patient 2 is a genetic compound of a premature termination mutation, R424X, and an as-yet uncharacterized mutant allele that is distinguishable by intragenic single nucleotide polymorphisms that we describe. Molecular studies of mHS are useful in patients with a suggestive clinical presentation.

Authors+Show Affiliations

Service de génétique médicale, Research Center, Ste-Justine Hospital, 3175 Côte Ste-Catherine, Montreal (Québec), Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11228257

Citation

Bouchard, L, et al. "Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency: Clinical Course and Description of Causal Mutations in Two Patients." Pediatric Research, vol. 49, no. 3, 2001, pp. 326-31.
Bouchard L, Robert MF, Vinarov D, et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients. Pediatr Res. 2001;49(3):326-31.
Bouchard, L., Robert, M. F., Vinarov, D., Stanley, C. A., Thompson, G. N., Morris, A., Leonard, J. V., Quant, P., Hsu, B. Y., Boneh, A., Boukaftane, Y., Ashmarina, L., Wang, S., Miziorko, H., & Mitchell, G. A. (2001). Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients. Pediatric Research, 49(3), 326-31.
Bouchard L, et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency: Clinical Course and Description of Causal Mutations in Two Patients. Pediatr Res. 2001;49(3):326-31. PubMed PMID: 11228257.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients. AU - Bouchard,L, AU - Robert,M F, AU - Vinarov,D, AU - Stanley,C A, AU - Thompson,G N, AU - Morris,A, AU - Leonard,J V, AU - Quant,P, AU - Hsu,B Y, AU - Boneh,A, AU - Boukaftane,Y, AU - Ashmarina,L, AU - Wang,S, AU - Miziorko,H, AU - Mitchell,G A, PY - 2001/3/3/pubmed PY - 2001/7/13/medline PY - 2001/3/3/entrez SP - 326 EP - 31 JF - Pediatric research JO - Pediatr Res VL - 49 IS - 3 N2 - Hereditary deficiency of mitochondrial HMG-CoA synthase (mHS, OMIM 600234) is a poorly defined, treatable, probably underdiagnosed condition that can cause episodes of severe hypoketotic hypoglycemia. We present clinical follow-up and molecular analysis of the two known mHS-deficient patients. The diagnosis of mHS deficiency is challenging because the symptoms and metabolite pattern are not specific. Moreover, enzyme analysis is technically difficult and requires sampling of an expressing organ such as liver. The patients, now aged 16 and 6 y, have normal development and have had no further decompensations since diagnosis. Patient 1 is homozygous for a phenylalanine-to-leucine substitution at codon 174 (F174L). Interestingly, although the F174 residue is conserved in vertebrate mHS and cytoplasmic HS isozymes, a Leu residue is predicted in the corresponding position of HS-like sequences from Caenorhabditis elegans, Arabidopsis thaliana, and Brassica juncea. Bacterial expression of human F174L-mHS produces a low level of mHS polypeptide with no detectable activity. Similarly, in purified cytoplasmic HS, which in contrast to purified human mHS is stable and can be studied in detail, the corresponding F-->L substitution causes a 10,000-fold decrease in V(max) and a 5-fold reduction in thermal stability. Patient 2 is a genetic compound of a premature termination mutation, R424X, and an as-yet uncharacterized mutant allele that is distinguishable by intragenic single nucleotide polymorphisms that we describe. Molecular studies of mHS are useful in patients with a suggestive clinical presentation. SN - 0031-3998 UR - https://www.unboundmedicine.com/medline/citation/11228257/Mitochondrial_3_hydroxy_3_methylglutaryl_CoA_synthase_deficiency:_clinical_course_and_description_of_causal_mutations_in_two_patients_ L2 - https://doi.org/10.1203/00006450-200103000-00005 DB - PRIME DP - Unbound Medicine ER -