Glutaric acidemia type 2

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Glutaric acidemia type 2
Other namesMultiple acyl-CoA dehydrogenase deficiency (MADD); [1] Glutaric academia/aceduria type II (GA-II)
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Glutaric acid
Specialty Medical genetics

Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis. It is a metabolic myopathy, categorized under fatty acid metabolism disorder as that is the bioenergetic system that it affects the most. It also affects choline metabolism. [2]

Contents

The phenotypic presentation has 3 forms: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). [3]

Individuals with glutaric acidemia type 2 frequently experience exercise-induced muscle fatigue, hypotonia, myalgia, and proximal muscle weakness. [4] The symptoms not only overlap with another type of metabolic myopathy, that of mitochondrial myopathy, but MADD also impairs the FAD-dependent respiratory chain in the mitochondria of muscle cells, as well as some muscle biopsies showing COX-negative fibres and deficiency of coenzyme Q10. [5] [2]

Genetics

Glutaric acidemia type 2 has an autosomal recessive pattern of inheritance. Autorecessive.svg
Glutaric acidemia type 2 has an autosomal recessive pattern of inheritance.

Mutations in the ETFA , ETFB , and ETFDH genes cause glutaric acidemia type II. Mutations in these genes result in a deficiency in one of two enzymes that normally work together in the mitochondria, which are the energy-producing centers of cells. The ETFA and ETFB genes encode two subunits of the enzyme electron transfer flavoprotein, while the ETFDH gene encodes the enzyme electron-transferring-flavoprotein dehydrogenase. When one of these enzymes is defective or missing, the mitochondria cannot function normally, partially broken-down proteins and fats accumulate in the cells and damage them; this damage leads to the signs and symptoms of glutaric acidemia type II. [1]

This condition is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – are needed to inherit the disorder. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the defective gene, but do not show signs and symptoms of the disorder themselves.[ citation needed ]

Diagnosis

Glutaric acidemia type 2 often appears in infancy as a sudden metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes, and vomiting. There may also be enlargement of the liver, heart failure, and a characteristic odor resembling that of sweaty feet. Some infants with glutaric acidemia type 2 have birth defects, including multiple fluid-filled growths in the kidneys (polycystic kidneys). Glutaric acidemia type 2 is a very rare disorder. Its precise incidence is unknown. It has been reported in several different ethnic groups.[ citation needed ]

Treatment

It is important for patients with MADD to strictly avoid fasting to prevent hypoglycemia and crises of metabolic acidosis; [6] [7] for this reason, infants and small children should eat frequent meals. [7] Patients with MADD can experience life-threatening metabolic crises precipitated by common childhood illnesses or other stresses on the body, [7] so avoidance of such stresses is critical. [6] Patients may be advised to follow a diet low in fat and protein and high in carbohydrates, particularly in severe cases. [6] [7] Depending on the subtype, riboflavin [7] (100-400 mg/day), [6] coenzyme Q10 (CoQ10), [6] L-carnitine, [7] or glycine [7] supplements may be used to help restore energy production. Some small, uncontrolled studies [8] [9] [10] have reported that racemic salts of beta-hydroxybutyrate (one of the ketone bodies) were helpful in patients with moderately severe disease; further research is needed. [6]

See also

Related Research Articles

MADD or Madd may refer to:

<span class="mw-page-title-main">Leigh syndrome</span> Mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products can accumulate and cause damage to the brain, but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may occur.

<span class="mw-page-title-main">Mitochondrial trifunctional protein deficiency</span> Medical condition

Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.

<span class="mw-page-title-main">Very long-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Very long-chain acyl-coenzyme A dehydrogenase deficiency is a fatty-acid metabolism disorder which prevents the body from converting certain fats to energy, particularly during periods without food.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">Short-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A of the disease appears to be much more common in some Algonkian Indian tribes in eastern Canada, while the type B disease is more present in European populations.

<span class="mw-page-title-main">Acyl-CoA</span> Group of coenzymes that metabolize fatty acids

Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.

<span class="mw-page-title-main">Glutaryl-CoA dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Glutaryl-CoA dehydrogenase (GCDH) is an enzyme encoded by the GCDH gene on chromosome 19. The protein belongs to the acyl-CoA dehydrogenase family (ACD). It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants.

<span class="mw-page-title-main">3-Hydroxy-3-methylglutaryl-CoA lyase</span> Class of enzymes

3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

<span class="mw-page-title-main">Electron-transferring-flavoprotein dehydrogenase</span> Protein family

Electron-transferring-flavoprotein dehydrogenase is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane. It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the ETFDH gene. Deficiency in ETF dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.

Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

<span class="mw-page-title-main">ETFA</span> Protein-coding gene in humans

The human ETFA gene encodes the Electron-transfer-flavoprotein, alpha subunit, also known as ETF-α. Together with Electron-transfer-flavoprotein, beta subunit, encoded by the 'ETFB' gene, it forms the heterodimeric electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ETFB</span> Protein-coding gene in humans

The human ETFB gene encodes the Electron-transfer-flavoprotein, beta subunit, also known as ETF-β. Together with Electron-transfer-flavoprotein, alpha subunit, encoded by the 'ETFA' gene, it forms the heterodimeric Electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ETFDH</span> Protein-coding gene in humans

Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.

<span class="mw-page-title-main">Fatty-acid metabolism disorder</span> Medical condition

A broad classification for genetic disorders that result from an inability of the body to produce or utilize an enzyme or transport protein that is required to oxidize fatty acids. They are an inborn error of lipid metabolism, and when it affects the muscles also a metabolic myopathy.

References

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  2. 1 2 Henriques, Bárbara J.; Katrine Jentoft Olsen, Rikke; Gomes, Cláudio M.; Bross, Peter (2021-04-15). "Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease". Gene. 776: 145407. doi:10.1016/j.gene.2021.145407. ISSN   1879-0038. PMC   7949704 . PMID   33450351.
  3. "#231680 - MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD". www.omim.org. Retrieved 2023-12-06.
  4. "Glutaric acidemia type II". Genetic and Rare Diseases Information Center. Retrieved 23 February 2023.
  5. Béhin, A.; Acquaviva-Bourdain, C.; Souvannanorath, S.; Streichenberger, N.; Attarian, S.; Bassez, G.; Brivet, M.; Fouilhoux, A.; Labarre-Villa, A.; Laquerrière, A.; Pérard, L.; Kaminsky, P.; Pouget, J.; Rigal, O.; Vanhulle, C. (March 2016). "Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease". Revue Neurologique. 172 (3): 231–241. doi:10.1016/j.neurol.2015.11.008. ISSN   0035-3787. PMID   27038534.
  6. 1 2 3 4 5 6 "Multiple acyl-CoA dehydrogenase deficiency". Orphanet . INSERM and the European Commission . Retrieved 30 August 2018.
  7. 1 2 3 4 5 6 7 "Glutaric acidemia type II". Genetic and Rare Diseases Information Center (GARD). National Institutes of Health National Center for Advancing Translational Sciences . Retrieved 30 August 2018.
  8. Gautschi M, Weisstanner C, Slotboom J, Nava E, Zürcher T, Nuoffer JM (January 2015). "Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy". Pediatr Res. 77 (1): 91–8. doi: 10.1038/pr.2014.154 . PMID   25289702.
  9. Van Rijt WJ, Heiner-Fokkema MR, du Marchie Sarvaas GJ, Waterham HR, Blokpoel RG, van Spronsen FJ, Derks TG (October 2014). "Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD". Pediatrics. 134 (4): e1224-8. doi:10.1542/peds.2013-4254. PMID   25246622. S2CID   16829114 . Retrieved 30 August 2018.
  10. Van Hove JL, Grünewald S, Jaeken J, Demaerel P, Declercq PE, Bourdoux P, Niezen-Koning K, Deanfeld JE, Leonard JV (26 April 2003). "D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD)". The Lancet . 361 (9367): 1433–5. doi:10.1016/S0140-6736(03)13105-4. PMID   12727399. S2CID   25397192.

This article incorporates public domain text from The U.S. National Library of Medicine