3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients

Grünert, Sarah C.; Schlatter, Sonja Marina; Schmitt, Robert Niklas; Gemperle-Britschgi, Corinne; Mrázová, Lenka; Balcı, Mehmet Cihan; Bischof, Felix; Çöker, Mahmut; Demirkol, Mübeccel; Vries, Maaike de; Gökçay, Gülden; Häberle, Johannes; Uçar, Sema Kalkan; Lotz-Havla, Amelie S.; Lücke, Thomas; Roland, Dominique; Rutsch, Frank; Santer, René; Schlune, Andrea; Staufner, Christian; Schwab, Karl Otfried; Mitchell, Grant A.; Sass, Jörn Oliver

doi:10.1016/j.ymgme.2017.05.014

Cited by 34 publications

(63 citation statements)

References 33 publications

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“…The outcome of severely sick patients with these disorders is dire in the published literature. There are several reports of deaths due to rapidly progressing encephalopathy occurring with decompensation in HMGCLD during adult life, sometimes unexpectedly in previously well individuals [7,8] [17]. Many cases in earlier series either died or had severe cognitive sequelae.…”

Section: Discussionmentioning

confidence: 99%

“…Many cases in earlier series either died or had severe cognitive sequelae. White matter abnormalities are common in this condition although the manifestation does not always correlate with disease course [7,18]. .Survival in early onset CACT deficiency is rare [4,19,20].…”

Section: Discussionmentioning

confidence: 99%

“…Failure to generate KB at times of physiological stress has catastrophic sequelae in MFAO and KB synthetic disorders [2]. In severe forms of these conditions, such as CACTD, HMGCL2 deficiency and CPT2D, life threatening encephalopathy, cardiomyopathy and arrythmias during metabolic decompensation are well recognised [3][4][5][6][7][8]. Chronic treatment generally utilises medium chain triglyceride (MCT) as an alternative energy source, but this would be ineffective in HMGCL2 deficiency [6,9].…”

Section: Introductionmentioning

confidence: 99%

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The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

Bhattacharya

Matar

Tolun³

et al. 2020

Orphanet J Rare Dis

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Background: Ketone bodies form a vital energy source for end organs in a variety of physiological circumstances. At different times, the heart, brain and skeletal muscle in particular can use ketones as a primary substrate. Failure to generate ketones in such circumstances leads to compromised energy delivery, critical end-organ dysfunction and potentially death. There are a range of inborn errors of metabolism (IEM) affecting ketone body production that can present in this way, including disorders of carnitine transport into the mitochondrion, mitochondrial fatty acid oxidation deficiencies (MFAOD) and ketone body synthesis. In situations of acute energy deficit, management of IEM typically entails circumventing the enzyme deficiency with replenishment of energy requirements. Due to profound multi-organ failure it is often difficult to provide optimal enteral therapy in such situations and rescue with sodium DL-3-hydroxybutyrate (S DL-3-OHB) has been attempted in these conditions as documented in this paper. Results: We present 3 cases of metabolic decompensation, one with carnitine-acyl-carnitine translocase deficiency (CACTD) another with 3-hydroxyl, 3-methyl, glutaryl CoA lyase deficiency (HMGCLD) and a third with carnitine palmitoyl transferase II deficiency (CPT2D). All of these disorders are frequently associated with death in circumstance where catastrophic acute metabolic deterioration occurs. Intensive therapy with adjunctive S DL-3OHB led to rapid and sustained recovery in all. Alternative therapies are scarce in these situations. Conclusion: S DL-3-OHB has been utilised in multiple acyl co A dehydrogenase deficiency (MADD) in cases with acute neurological and cardiac compromise with long-term data awaiting publication. The use of S DL-3-OHB is novel in non-MADD fat oxidation disorders and contribute to the argument for more widespread use.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

Bhattacharya

Matar

Tolun³

et al. 2020

Orphanet J Rare Dis

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“…In this respect, it should be emphasized that IEM pathophysiologies are generally not solely related to the primary genetic defects, but also to the subsequent adaptations by the patient's cells and organs. This is exemplified by the lack of genotype‐phenotype correlations in certain IEMs, illustrating the relevance of alternative mechanisms, such as epigenetics, to explain clinical heterogeneity between patients . Thus, the distinction between the primary genetic defect and the subsequent adaptations is important, as it may allow for different, yet complementary, effective therapeutic approaches that aim beyond the primary defect.…”

Section: Overview Of the Advantages And Disadvantages Of Different Gementioning

confidence: 99%

Exploiting epigenetics for the treatment of inborn errors of metabolism

Rutten

Rots

Oosterveer

2019

J of Inher Metab Disea

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Gene therapy is currently considered as the optimal treatment for inborn errors of metabolism (IEMs), as it aims to permanently compensate for the primary genetic defect. However, emerging gene editing approaches such as CRISPR‐Cas9, in which the DNA of the host organism is edited at a precise location, may have outperforming therapeutic potential. Gene editing strategies aim to correct the actual genetic mutation, while circumventing issues associated with conventional compensation gene therapy. Such strategies can also be repurposed to normalize gene expression changes that occur secondary to the genetic defect. Moreover, besides the genetic causes of IEMs, it is increasingly recognized that their clinical phenotypes are associated with epigenetic changes. Because epigenetic alterations are principally reversible, this may offer new opportunities for treatment of IEM patients. Here, we present an overview of the promises of epigenetics in eventually treating IEMs. We discuss the concepts of gene and epigenetic editing, and the advantages and disadvantages of current and upcoming gene‐based therapies for treatment of IEMs.

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“…Since the description of the deficiency in 1976, more than 150 patients have been reported in the literature [47,61]. It happens in all ethnic groups throughout the world, but with a greater incidence in countries of the Mediterranean area, Spain and Portugal [47] and in Saudi Arabia [62].…”

Section: Hmg-coa Lyase Related Diseasesmentioning

confidence: 99%

More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones

Arnedo

Latorre‐Pellicer

Lucia-Campos

et al. 2019

IJMS

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There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.

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3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients

Cited by 34 publications

References 33 publications

The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

Exploiting epigenetics for the treatment of inborn errors of metabolism

More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones

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