Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Clinical Course and Description of Causal Mutations in Two Patients

Bouchard, Luigi; Robert, Mathieu; Vinarov, Dmitriy A.; Stanley, Charles A.; Thompson, Greg; Morris, Andrew A. M.; Leonard, James V.; Quant, Patti A.; Hsu, Betty Y.L.; Boneh, Avihu; Boukaftane, Youssef; Ashmarina, L.I.; Wang, Shupei; Miziorko, Henry M.; Mitchell, Grant A.

doi:10.1203/00006450-200103000-00005

Cited by 40 publications

(38 citation statements)

References 18 publications

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“…Variations in the genes encoding ketogenic mediators, including HMGCS2, HMG-CoA lyase, and βOHB dehydrogenase, have not yet emerged as independent predictors of liver pathology or diabetes. While HMGCS2 deficiency is very rare in humans, total HMGCS2 enzymatic deficiency is associated with pediatric hypoketonemic hypoglycemia and hepatic steatosis (66)(67)(68)(69)(70)(71). Importantly, our studies of neonatal mice revealed that partial loss of HMGCS2 activity caused marked hepatic steatosis vastly out of proportion to the diminution in neonatal ketosis, but did not result in neonatal hypoglycemia or failure to thrive.…”

Section: Discussionmentioning

confidence: 72%

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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R e s e a R c h a R t i c l e5 1Ketogenic insufficiency causes hepatic inflammation, injury, and altered glucose metabolism in the setting of carbohydrate-replete overnutrition. To determine the effects of ketogenic insufficiency in the context of overnutrition, mice previously receiving ASOs for 2 weeks while on a standard low-fat chow diet were then maintained for 8 weeks on a 60% high-fat diet (HFD) commonly used to induce hyperglycemia, hepatic steatosis, and inflammation in WT mice. HMGCS2 immunoblots indicated that hepatic HMGCS2 mice (Supplemental Figure 2, A-C). HMGCS2 ASO-treated mice also exhibited normal serum free fatty acid (FFA) and TAG concentrations and a normal physiologic distribution of residual βOHB and AcAc (Supplemental Figure 2, D-F). Interestingly, HMGCS2 ASO-treated mice displayed mild, but very consistently elevated, blood glucose concentrations (160.9 ± 3.2 mg/dl vs. 145.0 ± 3.4 mg/dl in controls, n = 28-36/group, P = 0.0013), without changes in serum insulin concentrations (Supplemental Figure 2, G and H). C]pyruvate, quantified by NMR profiling of perfused liver extracts from ASO-treated mice fed a 60% HFD for 8 weeks. n = 4-5/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student's t test.

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Section: Discussionmentioning

confidence: 72%

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

et al. 2014

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“…HMGCS2 encodes mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (HMG-CoA synthase-2), an enzyme integral to ketogenesis. Mutations of HMGC2 lead to hypoketotic hypoglycemia due to HMG-CoA synthase-2 deficiency 60 .…”

Section: Locus 1p12mentioning

confidence: 99%

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

et al. 2017

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Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genomewide association study (GWAS) with 476 cases and 1733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10 -8 ) were identified at 3 independent loci (rs73171800 at 5q14.3, P = 7.74 × 10 -17 ; rs715 at 2q34, P = 9.97 × 10 -14 ; rs477992 at 1p12, P = 2.60 × 10 -12 ) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences of blood serum levels of glycine (P = 4.04 × 10 -6 ) and serine (P = 2.48 × 10 -4 ) between MacTel cases and controls.MacTel cases typically present at 40-60 years with abnormal right-angled juxtafoveolar capillaries and parafoveal telangiectasias. It is an uncommon disease with a 0.0045-0.1% population prevalence and no obvious sex bias [1][2][3] . Retinal lesions typically co-present with MacTel, including retinal transparency, outer retinal and choroidal neovascularization, lamellar holes or foveal cysts, photoreceptor dysfunction, minimal exudation, yellow-white parafoveal crystals, and retinal pigment epithelial (RPE) pigmentation abnormalities and atrophy. Central vision impairment and decreased visual acuity are the usual clinical outcomes. MacTel is a bilateral disease, but asymmetry of the eyes for disease severity and presence of lesions is possible. The lesions also occur in 0.06-1.18% of the general population 2 .Risk factors for MacTel are largely unknown, however associations have been observed with smoking 2,4 , diabetes 5,6 , high BMI 6 , hypertension 6 and obesity 6 .Observations of MacTel affected monozygotic twins 4,[7][8][9] , and multiplex families with vertical transmissions of MacTel 1,5,[9][10][11][12] , suggest a genetic etiology for the disease. The late-age of onset, low penetrance and variable phenotype as exemplified by asymptomatic affected relatives 9 , and positive and negative misdiagnoses, complicate the discovery of genetic variants predisposing to MacTel. We previously screened 27 candidate genes in 8 unrelated MacTel cases but found no causative mutations 13 . Linkage analysis of 17 families with MacTel individuals identified a 15.3Mb locus on chromosome 1q41-42.2 (LOD=3.45), however sequencing of the underlying genes revealed no causative mutations 14 . Results Discovery GWAS stageThe GWAS discovery stage included genotype data for 6,312,048 single nucleotide polymorphisms (SNPs) after quality control and imputation (including 1,093,805 SNPs genotyped on the Illumina Omni SNP chips) in 476 MacTel cases and 1,733 controls (see Table 1 and Online Methods). This sample size was large enough to achieve power of at least 0.90 for risk variants with allele frequencies of 0.10-...

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“…Liver biopsy showed a decrease in the activity of mHS. Molecular study of the gene confirmed the diagnosis (Bouchard et al, 2001). Generally, the disease shows unspecific clinical symptoms and metabolites excretion profile, sometimes attributed to a fatty acid β-oxidation enzyme defect and that makes it to be underdiagnosed.…”

Section: Mhs Deficiencymentioning

confidence: 86%

“…In general, this type of mutations produces the deletion of the affected exon (exon 5 in this case), although in this disease the mechanism has not been confirmed (Zschocke et al, 2002). In order to prove the effect of the mutation in the enzyme activity, protein over-expression has been tried with recombinant DNA techniques although with no success (Bouchard et al, 2001). Table 2.…”

Section: Mutation Updatementioning

confidence: 99%

“…One of these variants, the Y167C, affects to a closed Cys 166 amino acid, which is considered the catabolic site of the enzyme (Hegard, 1999). The nonsense variant R424X (Bouchard et al, 2001;Morris et al, 1998), produced a truncated protein of 424 amino acids that probably cannot be incorporated into the active protein dimer. The intronic mutation is located in the first nucleotide of the intron 5 (c.1016+1G>A).…”

Section: Mutation Updatementioning

confidence: 99%

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