Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: Difficulties in the diagnosis

García‐Villoria, Judit; Navarro-Sastre, Aleix; Fons, Carme; Pérez‐Cerdá, Celia; Baldellou, A; Fuentes-Castelló, Miguel Ángel; González, Inmaculada; Hernández-Gonzalez, Arturo; Fernández, Cristina; Campistol, Jaume; Delpiccolo, Carina M. L.; Cortés, Nuria; Messeguer, Àngel; Briones, Paz; Ribes, Antònia

doi:10.1016/j.clinbiochem.2008.10.006

Cited by 37 publications

(45 citation statements)

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“…11 The female of family 1 (1IIF), like her brother (1IIM), presented a severe phenotype with psychomotor and speech delay, and a clear deficiency of HSD10 activity in fibroblasts. 11 When we sequenced her HSD17B10 cDNA, it seemed that only the Mut allele was identified (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…1,4-11 However, three patients were identified who presented symptoms in the first days of life. 1, 11 It has recently been shown that symptoms of these patients are unrelated to accumulation of metabolites in the isoleucine pathway and that the neurological handicap can be associated with an imbalance in neurosteroid metabolism 12 or to defects in general mitochondrial function. 13 In addition, the splice variant c.574C4A of HSD17B10 gene has been associated with a new syndromic form of X-linked mental retardation, choreoathetosis and abnormal behaviour.…”

Section: Introductionmentioning

confidence: 99%

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X-inactivation of HSD17B10 revealed by cDNA analysis in two female patients with 17β-hydroxysteroid dehydrogenase 10 deficiency

et al. 2010

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17b-Hydroxysteroid dehydrogenase 10 (HSD10) is a mitochondrial enzyme involved in the degradation pathway of isoleucine and branched-chain fatty acids. The gene encoding HSD10, HSD17B10, has been reported as one of the few genes that escapes X-inactivation. We previously studied two female patients with HSD10 deficiency, one of them was severely affected and the other presented a mild phenotype. To elucidate as to why these two carriers were so differently affected, cDNA analyses were performed. The HSD17B10 cDNA of eight control cell lines, two hemizygous patients and two carriers was obtained from cultured fibroblasts, amplified by PCR and sequenced by standard methods. All HSD17B10 cDNAs were quantified by real-time PCR. In the fibroblasts of the female patient who presented with the severe phenotype, only the mutant allele was identified in the cDNA sequence, which was further confirmed by relative quantification (RQ) of HSD17B10 cDNA. This is in agreement with an unfavourable X-inactivation. The other female patient, with slight clinical affectation, showed the presence of both mutant and wild-type alleles in the cDNA sequence, which was confirmed by RQ of HSD17B10 cDNA in fibroblasts. This is in line with normal X-inactivation and the expression of both alleles in different cells (functional mosaicism). RQ results of HSD17B10 cDNA did not differ significantly between male and female controls, which indicate that the genetic doses of mRNA of HSD17B10 was the same in both sexes. In conclusion, these results suggest that the HSD17B10 gene does not escape X-inactivation as has been reported previously. European Journal of Human Genetics (2010) 18, 1353-1355; doi:10.1038/ejhg.2010.118; published online 28 July 2010Keywords: HSD10 deficiency; HADH2; HSD17B10 INTRODUCTION 17b-Hydroxysteroid dehydrogenase 10 (HSD10) is a mitochondrial enzyme involved in the degradation pathway of isoleucine and branched-chain fatty acids. 1 This enzyme has also been found to be involved in the metabolism of sex steroid hormones, neuroactive steroids and in the detoxification of cytotoxic aldehydes. 2,3 HSD10 deficiency (OMIM 300256) is an X-linked defect caused by mutations in the HSD17B10 gene. Clinically, the great majority of male patients show normal early development followed by progressive loss of mental and motor skills. 1,4-11 However, three patients were identified who presented symptoms in the first days of life. 1,11 It has recently been shown that symptoms of these patients are unrelated to accumulation of metabolites in the isoleucine pathway and that the neurological handicap can be associated with an imbalance in neurosteroid metabolism 12 or to defects in general mitochondrial function. 13 In addition, the splice variant c.574C4A of HSD17B10 gene has been associated with a new syndromic form of X-linked mental retardation, choreoathetosis and abnormal behaviour. 14 The HSD17B10 gene has been mapped to chromosome Xp11.2 15 and has been reported as one of the few genes that escapes X-inactivation. 16 To date, 10 fema...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

X-inactivation of HSD17B10 revealed by cDNA analysis in two female patients with 17β-hydroxysteroid dehydrogenase 10 deficiency

et al. 2010

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“…While other HSD10-disease associated mutations had decreased the enzyme's dehydrogenase activity, some of these mutations were analyzed in homogenates of patient fibroblasts, 7,33 where SDR5C1 levels among samples were not controlled. We chose to determine the mutational effect by comparing known quantities of purified wildtype and mutant enzyme, each expressed and purified from an E. coli over-expression strain.…”

Section: Structural Mapping Of the Pk212e Mutation In Sdr5c1 (Hsd17b10)mentioning

confidence: 99%

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

et al. 2016

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(2016) A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression, RNA Biology, 13:5, 477-485, DOI: 10.1080/15476286.2016 ABSTRACTWe report a Caucasian boy with intractable epilepsy and global developmental delay. Whole-exome sequencing identified the likely genetic etiology as a novel p.K212E mutation in the X-linked gene HSD17B10 for mitochondrial short-chain dehydrogenase/reductase SDR5C1. Mutations in HSD17B10 cause the HSD10 disease, traditionally classified as a metabolic disorder due to the role of SDR5C1 in fatty and amino acid metabolism. However, SDR5C1 is also an essential subunit of human mitochondrial RNase P, the enzyme responsible for 5 0 -processing and methylation of purine-9 of mitochondrial tRNAs. Here we show that the p.K212E mutation impairs the SDR5C1-dependent mitochondrial RNase P activities, and suggest that the pathogenicity of p.K212E is due to a general mitochondrial dysfunction caused by reduction in SDR5C1-dependent maturation of mitochondrial tRNAs.

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“…The younger sibling had several ketotic hypoglycemic events at 4 years of age, whereas the older brother showed no symptoms. The nonregressive Normal development in the first 6-18 months of life, followed by a progressive neurodegenerative course with retinopathy and cardiomyopathy, leading to death at the age of 2-4 years or older Zschocke et al (2000), Ensenauer et al (2002), Sutton et al (2003), Sass et al (2004), Perez-Cerda et al (2005), Cazorla et al (2007), Lenski et al (2006), García-Villoria et al (2009), Rauschenberger et al (2010 …”

Section: Resultsmentioning

confidence: 99%

Japanese Male Siblings with 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency (HSD10 Disease) Without Neurological Regression

et al. 2016

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2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) is a rare X-linked disorder caused by a mutation in the HSD17B10 gene. Fewer than 30 patients with this disorder have been reported worldwide. The classical infantile form of HSD10 disease is characterized by a progressive neurodegenerative course with retinopathy and cardiomyopathy, although HSD10 disease has broad clinical heterogeneity. However, several male patients have not shown neurological regression. Here, we describe two Japanese siblings with HSD10 disease without neurological regression. A 4-year-old boy presented with unconsciousness due to severe hypoglycemia. Laboratory testing on admission showed mild metabolic acidosis and mild hyperammonemia. Urinary organic acid analysis in the acute phase showed elevated excretion of 2-methyl-3-hydroxybutyric acid, tiglylglycine, and ketones. However, 2-methylacetoacetate was not elevated.

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Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: Difficulties in the diagnosis

Cited by 37 publications

References 17 publications

X-inactivation of HSD17B10 revealed by cDNA analysis in two female patients with 17β-hydroxysteroid dehydrogenase 10 deficiency

X-inactivation of HSD17B10 revealed by cDNA analysis in two female patients with 17β-hydroxysteroid dehydrogenase 10 deficiency

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

Japanese Male Siblings with 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency (HSD10 Disease) Without Neurological Regression

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