Glutaric acidemia type 2 is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...

that is characterised by defects in the ability of the body to use

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s and

fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers specif ...

s for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called

acidosis Acidosis is a biological process producing hydrogen ions and increasing their concentration in blood or body fluids. pH is the negative log of hydrogen ion concentration and so it is decreased by a process of acidosis. Acidemia The term ac ...

. It is a

metabolic myopathy Metabolic myopathies are myopathies that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects (inborn errors of metabolism) that interfere with the ability to create energy, causing a low A ...

, categorized under fatty acid metabolism disorder as that is the bioenergetic system that it affects the most. It also affects

choline Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...

metabolism. 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). Individuals with glutaric acidemia type 2 frequently experience exercise-induced

muscle fatigue Muscle fatigue is when muscles that were initially generating a normal amount of force, then experience a declining ability to generate force. It can be a result of vigorous exercise, but abnormal fatigue may be caused by barriers to or interfer ...

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...

myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...

, and proximal muscle weakness. The symptoms not only overlap with another type of metabolic myopathy, that of

mitochondrial myopathy Mitochondrial myopathies are types of myopathy, myopathies associated with mitochondrial disease. Adenosine triphosphate (Adenosine triphosphate, ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative ...

, but MADD also impairs the FAD-dependent respiratory chain in the mitochondria of muscle cells, as well as some muscle biopsies showing

COX Cox or COX may refer to: Companies * Cox Enterprises, a media and communications company ** Cox Communications, cable provider ** Cox Media Group, a company that owns television and radio stations ** Cox Automotive, an Atlanta-based busines ...

-negative fibres and deficiency of coenzyme Q₁₀.

Signs and symptoms

Genetics

Mutations in the '' ETFA'', '' ETFB'', and ''

ETFDH 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 tra ...

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s 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 A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

, 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 Electron-transferring-flavoprotein dehydrogenase (''ETF dehydrogenase'' or ''electron transfer flavoprotein-ubiquinone oxidoreductase'', ) is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, ...

. 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. This condition is inherited in an

pattern, which means the defective gene is located on an

autosome An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...

, 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.

Diagnosis

Glutaric acidemia type 2 often appears in infancy as a sudden metabolic crisis, in which acidosis and low blood sugar (

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

) cause weakness, behavior changes, and vomiting. There may also be enlargement of the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

, 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.

Treatment

It is important for patients with MADD to strictly avoid fasting to prevent

and crises of

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidn ...

; for this reason, infants and small children should eat frequent meals. Patients with MADD can experience life-threatening metabolic crises precipitated by common childhood illnesses or other stresses on the body, so avoidance of such stresses is critical. Patients may be advised to follow a diet low in fat and protein and high in carbohydrates, particularly in severe cases. Depending on the subtype,

riboflavin Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in ...

(100-400 mg/day),

coenzyme Q10 Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, seed oils, vegetables, ...

(CoQ10),

L-carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for fre ...

, or

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

supplements may be used to help restore energy production. Some small, uncontrolled studies have reported that racemic salts of beta-hydroxybutyrate (one of the

ketone bodies Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver ( ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acet ...

) were helpful in patients with moderately severe disease; further research is needed.

References

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

External links