A single‐residue mutation, G203E, causes 3‐hydroxy‐3‐methylglutaric aciduria by occluding the substrate channel in the 3D structural model of HMG‐CoA lyase

Mir, Cecilia; López-Viñas, Eduardo; Aledo, Rosa; Puisac, Beatriz; Rizzo, Cristiano; Dionisi‐Vici, Carlo; Deodato, Federica; Pié, Juan; Gómez‐Puertas, Paulino; Hegardt, Fausto G.; Casals, Núria

doi:10.1007/s10545-006-0138-x

Cited by 5 publications

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References 28 publications

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“…The altered gene is the HMGCL, located on chromosome 1p36.1 and 48 mutations have been identified [5, 6]. The most common in Mediterranean countries and the second most common in the world is the E37X [7, 8]. …”

Section: Introductionmentioning

confidence: 99%

Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency

2017

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Background3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare inborn error of metabolism characterized by recurrent metabolic crises caused by fasting, intercurrent illness and excessive physical exercise. Non ketotic hypoglycemia is normally the cause of primary symptoms but without an immediate treatment the illness can evolve into a worsening metabolic state resembling the Reye’s syndrome that may cause the patient’s death. We report a case with some clinical and therapeutic features not previously described.Case presentationPatient with HMG-CoA lyase deficiency whom after diagnosis at 2 years of age was re-admitted 12 years later, after severe metabolic decompensation following consumption of alcohol. Despite a quick correction of hypoglycemia, within the following few hours, the patient fell into a coma. Suspecting intracranial hypertension (ICH), the patient required mechanical ventilation. Although liver cytolysis was minimal, hyperamoniemia reached 1394 μmol/L, returning to normal, a few hours after administering sodium phenylacetate and sodium benzoate, whose use has not been reported in these patients. Brain edema was evidenced in the computed tomography and by the magnetic resonance imaging that determined that the edema was cytotoxic, as quantified with the restriction of diffusion in the apparent diffusion coefficient map. During the recovery of the ICH, we belatedly, detected vasospasm moderate-severe that was treated with nimodipine. Currently, the patient maintains clinical normality.ConclusionsThe alcohol consumption must be avoided in patients with HMG-CoA lyase deficiency. In our patient hyperamoniemia was effectively treated with sodium phenylacetate and sodium benzoate. Magnetic resonance imaging showed and quantified the cytotoxic brain edema. Belatedly, a cerebral vasospasm was an additional mechanism of cerebral injury. None of these observations has been previously reported.

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Section: Introductionmentioning

confidence: 99%

Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency

2017

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ThePAH gene, phenylketonuria, and a paradigm shift

2007

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“Inborn errors of metabolism,” first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbjörn Fölling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L‐phenylalanine, and in nature, where mutations (>500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L‐phenylalanine hydroxylase enzyme (EC 1.14.16.1). The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus‐specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus‐specific mutation database (http://www.pahdb.mcgill.ca; last accessed 20 March 2007). The individual Mendelian PKU phenotype has no “simple” or single explanation; every patient has her/his own complex PKU phenotype and will be treated accordingly. Knowledge about PKU reveals genomic components of both disease and health. Hum Mutat 28(9), 831–845, 2007. Published 2007 Wiley‐Liss, Inc.

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