Aciduria Glutárica tipo II

Sinónimos:
Acidemia Glutárica, Tipo II

Descripción en lenguaje coloquial:
La aciduria glutárica tipo II es una enfermedad metabólica hereditaria rara.

El ácido glutárico es un producto intermediario del catabolismo de la lisina, la hidroxilisina y el triptófano (aminoácidos esenciales).

Hay dos formas de aciduria glutárica tipo II que ocurren durante diversas etapas de la vida, ambas se consideran acidemias orgánicas (grupo de enfermedades metabólicas caracterizadas por exceso de ácido en la sangre y orina).

A.- La primera es la aciduria glutárica tipo IIA (GA IIA), o forma neonatal, esta es una enfermedad hereditaria muy rara, caracterizada por grandes cantidades de ácido glutárico en sangre y orina. Algunos investigadores creen que la enfermedad se debe a un defecto en la ruptura de los compuestos de acil-CoA.

Se hereda como un rasgo genético autosómico recesivo. Habiéndose identificado el gen responsable de la enfermedad en el brazo largo del cromosoma 15 (15q23-q25).

B.- La segunda forma es la aciduria glutárica tipo IIB (GA IIB) o forma del adulto en la que los primeros síntomas pueden aparecer entre el año y medio y los 30 años de edad. Durante la infancia se observa sólo un leve retraso psicomotor (retraso en la adquisición de las habilidades que requieren la coordinación de la actividad muscular y mental), posteriormente ataxia (carencia de la coordinación de movimientos musculares) cerebral y deterioro mental progresivos. Pueden presentar convulsiones y macrocefalia (cabeza inusualmente grande); esta es la forma más leve de la enfermedad.

Se caracteriza por una marcada acidosis (estado metabólico en el que existen cantidades anormales de cuerpos cetónicos) metabólica en sangre y tejidos, y una hipoglucemia (niveles bajos de glucosa, azúcar, en sangre) sin cetosis (niveles elevados de acetona y otros cuerpos cetónicos en sangre).

Las grandes cantidades de ácido glutárico en la sangre y orina son debidas a la deficiencia de la enzima acil-CoA deshidrogenasa.

No existe tratamiento curativo de la enfermedad. La supervivencia es prolongada.

se hereda como un rasgo autosómico recesivo.

Fuente
Instituto de Investigación de Enfermedades Raras
http://iier.isciii.es/

acidemia glutarica tipo II

acidemia glutarica tipo II


Se presenta en 2 formas: La primera es la aciduria glutárica tipo IIA (GA IIA), o forma neonatal, caracterizada por grandes cantidades de ácido glutárico en sangre y orina, debido a un defecto en la ruptura de los compuestos de acil-CoA. La segunda es la aciduria glutárica tipo IIB (GA IIB) o forma del adulto en la que los primeros síntomas pueden aparecer entre el año y medio y los 30 años de edad. Durante la infancia se observa sólo un retraso en la adquisición de las habilidades que requieren la coordinación de la actividad muscular y mental, posteriormente ataxia cerebral y deterioro mental progresivos. Pueden presentar convulsiones y macrocefalia esta es la forma más leve de la enfermedad y se hereda como un rasgo genético autosómico recesivo. Se caracteriza por una marcada acidosis metabólica en sangre y tejidos y una hipoglucemia sin cetosis. Las grandes cantidades de ácido glutárico en la sangre y orina son debidas a la deficiencia de la enzima acil-CoA deshidrogenasa. La supervivencia es prolongada y no existe tratamiento.

Multiple Acyl-CoA Dehydrogenase Deficiency

Multiple Acyl-CoA Dehydrogenase Deficiency

Background Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is also known as Glutaric Acidemia Type II (GA-II). It is associated with deficiency of several mitochondrial dehydrogenase enzymes that utilize Flavin Adenine Dinucleotide (FAD) as cofactor, at least 9 of which are known. These include the acyl-CoA dehydrogenases of fatty acid ß-oxidation, and enzymes that degrade glutaric acid, isovaleric acid, and sarcosine (a precursor to glycine). During these dehydrogenation reactions, reduced FAD contributes its electrons to the oxidized form of Electron Transfer Flavoprotein (ETF) and subsequently to the respiratory chain to produce ATP. The reduced form of ETF is recycled to oxidized ETF by action of ETF- ubiquinone oxidoreductase (ETF-QO, also known as ETF dehydrogenase). Deficiency of ETF or ETF-QO therefore results in decreased activity of many FAD-dependent dehydrogenases and the combined metabolic derangements seen in MADD. Some MADD patients have had normal ETF and ETF-QO, suggesting the existence of genetic defects in other unidentified proteins. Clinical Three clinical presentations are reported for MADD. Two newborn presentations are seen – one with congenital anomalies, and one without. Those with congenital anomalies are often premature, and develop symptoms in the first 24–48 hours consisting of hypotonia, hepatomegaly, severe nonketotic hypoglycemia, metabolic acidosis and variable body odor of sweaty feet. Dysmorphic facial features and dysplastic, cystic kidneys are present. Plasma carnitine levels are low. Those patients with no congenital anomalies have similar symptoms and metabolic abnormalities. With both neonatal presentations, most patients do not live past a few weeks, though some older survivors succumb at a few months of age from hypertrophic cardiomyopathy. Heart, liver and kidneys are infiltrated with fat. The third cohort of patients has a mild and/or later onset with variable symptoms including lipid storage myopathy. Testing Newborn screening using a dried blood spot has identified MADD patients by detecting elevated acylcarnitine (C4, C5, C8, C10, and C16). Severe hypoglycemia without ketosis is a cardinal finding. Analysis of the urine for abnormal organic acids in a suspected patient usually reveals elevated glutaric acid, and always shows elevated 2-hydroxyglutaric acid which is pathognomonic. Plasma and urine sarcosine levels are elevated in the milder patients, but not in the severe neonatal cases. Cultured fibroblasts and amniocytes have been used to measure dehydrogenase substrate oxidation. Mutations have been identified in the genes for ETF and ETF-QO. Prenatal diagnosis has been performed by finding elevated glutaric acid and elevated acylcarnitines in amniotic fluid. Prenatal diagnosis by DNA analysis is restricted to those families in which the mutation(s) is known. Treatment There is no effective treatment for the severe forms of MADD that present in the neonatal period. Patients with later onset less severe symptoms may respond to riboflavin (a precursor to FAD) and L-carnitine supplementation. Dietary restriction of fats and protein has had variable results. Because the diagnosis and therapy of MADD is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician. Inheritance This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder. As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care. References Frerman, F.E. and Goodman, S.I. Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 103, pg. 2357 - 2365. Goodman, S.I., Reale, M. and Berlow, S. Glutaric acidemia type II: A form with deleterious intrauterine effects. J Pediatrics 102:411, 1983. Goodman, S.I., Stene, D.O., McCabe, E.R.B, et al. Glutaric aciduria type II: Clinical, biochemical and morphologic considerations. J Pediatrics 100:946, 1982. Harpey, J.P., Charpentier, C., Goodman, S.I., et al. Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother. J Pediatrics 103:394, 1983. Mitchell, G., Saudubray, J.M., Gubler, M.C., et al. Congenital anomalies in Glutaric aciduria type 2. J Pediatrics 104:961, 1984. Stockler, S., Radner, H., Felizitas, K., et al. Symmetric hypoplasia of the temporal cerebral lobes in an infant with Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency). J Pediatrics 124:601, 1994. Sweetman, L., Nyhan, W.L., Trauner, D.A., et al. Glutaric aciduria type II. J Pediatrics 96:1020, 1980. Web Sites SaveBabies.org Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites. National Newborn Screening and Genetics Resource Center Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials. Disclaimers The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.

 

Glutaric acidemia type II

 

What is glutaric acidemia type II?

Glutaric acidemia type II is an inherited disorder that interferes with the body's ability to break down proteins and fats to produce energy. Incompletely processed proteins and fats can build up in the body and cause the blood and tissues to become too acidic (metabolic acidosis).
Glutaric acidemia type II usually appears in infancy or early childhood as a sudden episode called a metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes such as poor feeding and decreased activity, and vomiting. These metabolic crises, which can be life-threatening, may be triggered by common childhood illnesses or other stresses.
In the most severe cases of glutaric acidemia type II, affected individuals may also be born with physical abnormalities. These may include brain malformations, an enlarged liver (hepatomegaly), a weakened and enlarged heart (dilated cardiomyopathy), fluid-filled cysts and other malformations of the kidneys, unusual facial features, and genital abnormalities. Glutaric acidemia type II may also cause a characteristic odor resembling that of sweaty feet.
Some affected individuals have less severe symptoms that begin later in childhood or in adulthood. In the mildest forms of glutaric acidemia type II, muscle weakness developing in adulthood may be the first sign of the disorder.

How common is glutaric acidemia type II?

Glutaric acidemia type II is a very rare disorder; its precise incidence is unknown. It has been reported in several different ethnic groups.

What genes are related to glutaric acidemia type II?

Mutations in any of three genes, ETFA, ETFB, and ETFDH, can result in glutaric acidemia type II. The ETFA and ETFB genes provide instructions for producing two protein segments, or subunits, that come together to make an enzyme called electron transfer flavoprotein. The ETFDH gene provides instructions for making another enzyme called electron transfer flavoprotein dehydrogenase.
Glutaric acidemia type II is caused by a deficiency in either of these two enzymes. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are normally active in the mitochondria, which are the energy-producing centers of cells. These enzymes help break down proteins and fats to provide energy for the body. When one of the enzymes is defective or missing, partially broken down nutrients accumulate in the cells and damage them, causing the signs and symptoms of glutaric acidemia type II.
People with mutations that result in a complete loss of either enzyme produced from the ETFA, ETFB or ETFDH genes are likely to experience the most severe symptoms of glutaric acidemia type II. Mutations that allow the enzyme to retain some activity may result in milder forms of the disorder.
Read more about the ETFA, ETFB, and ETFDH genes.

How do people inherit glutaric acidemia type II?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis, management, or treatment of glutaric acidemia type II?

These resources address the diagnosis or management of glutaric acidemia type II and may include treatment providers.

• Gene Tests: Multiple Acyl-CoA Dehydrogenase Deficiency

You might also find information on the diagnosis or management of glutaric acidemia type II in Educational resources and Patient support.
To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about glutaric acidemia type II?

You may find the following resources about glutaric acidemia type II helpful. These materials are written for the general public.

• MedlinePlus - Health information (2 links)
• Educational resources - Information pages (2 links)
• Patient support - For patients and families (4 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

• Gene Tests - DNA tests ordered by healthcare professionals
• PubMed - Recent literature
• OMIM - Genetic disorder catalog

What other names do people use for glutaric acidemia type II?

• Electron transfer flavoprotein deficiency
• EMA
• ETFA deficiency
• ETFB deficiency
• ETFDH deficiency
• Ethylmalonic-adipicaciduria
• GA II
• Glutaric acidemia, type 2
• Glutaric aciduria, type 2
• MAD
• MADD
• Multiple acyl-CoA dehydrogenase deficiency
• multiple FAD dehydrogenase deficiency

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about glutaric acidemia type II?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

• What does it mean if a disorder seems to run in my family?
• What are the different ways in which a genetic condition can be inherited?
• If a genetic disorder runs in my family, what are the chances that my children will have the condition?
• Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

• Genetics and health
• Resources for Patients and Families
• Resources for Health Professionals

What glossary definitions help with understanding glutaric acidemia type II?

acidosis ; acids ; aciduria ; autosomal ; autosomal recessive ; cardiomyopathy ; cell ; CoA ; cysts ; deficiency ; dehydrogenase ; dilated ; electron ; enzyme ; fatty acids ; gene ; hypoglycemia ; incidence ; kidney ; malformation ; mitochondria ; mutation ; newborn screening ; oxidation ; protein ; recessive ; screening ; sign ; stress ; subunit ; symptom ; tissue

Multiple acyl-CoA dehydrogenase deficiency, in OMIM

MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD

Alternative titles; symbols

• GLUTARIC ACIDURIA II
• GA II
• ETHYLMALONIC-ADIPICACIDURIA; EMA

Other entities represented by this entry

• GLUTARIC ACIDURIA IIA, INCLUDED
• ETFA DEFICIENCY, INCLUDED
• GLUTARIC ACIDURIA IIB, INCLUDED
• ETFB DEFICIENCY, INCLUDED
• GLUTARIC ACIDURIA IIC, INCLUDED
• ETFDH DEFICIENCY, INCLUDED

Gene map locus: 15q23-q25, 4q32-qter, etc.

Clinical Synopsis

TextBack to Top

A number sign (#) is used with this entry because MADD, also known as glutaric aciduria II, can be caused by mutations in at least 3 different genes: ETFA (608053), ETFB (130410), and ETFDH (231675). The disorders resulting from defects in these 3 genes are referred to as glutaric aciduria IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotypes.

DescriptionBack to Top

Glutaric aciduria II (GA II) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be nondistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). Clearly, there is much heterogeneity in the group of multiple acyl-CoA dehydrogenation disorders (Amendt and Rhead, 1986).
Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).

Clinical FeaturesBack to Top

Neonatal Onset

In the son of healthy parents from the same small town in Turkey, Przyrembel et al. (1976) described fatal neonatal acidosis and hypoglycemia with a strong 'sweaty feet' odor. Large amounts of glutaric acid were found in the blood and urine. The defect was tentatively located to the metabolism of a range of acyl-CoA compounds. A possibly identically affected child died earlier.
Lehnert et al. (1982), Bohm et al. (1982), and others described malformations with multiple acyl-CoA dehydrogenation deficiency: congenital polycystic kidneys, characteristic facies, etc.
Typical clinical features of the disorder are respiratory distress, muscular hypotonia, sweaty feet odor, hepatomegaly, and death often in the neonatal period. Of the 12 previously reported cases reviewed by Niederwieser et al. (1983), 7 died in the first 5 days of life and only 2 patients survived to ages 5 and 19 years. Niederwieser et al. (1983) reported the case of the son of consanguineous Jewish parents who died at age 7 months. In a note added in proof, they described the prenatal diagnosis of an affected female of the same parentage, indicating autosomal recessive inheritance.
Harkin et al. (1986) described apparently characteristic and perhaps pathognomonic, cytoplasmic, homogeneous, and moderately electron-dense membrane-limited bodies in the central nervous system and renal tissues of a female patient who died at age 5 days. The kidneys were enlarged with numerous cortical cysts. Selective proximal tubular damage leads to glycosuria and generalized amino aciduria. The patient came from an inbred Louisiana Cajun community and had a sib who also died in the newborn period.
Patients with severe deficiency of the ETF dehydrogenase type have distinctive congenital malformations, whereas those with ETF deficiency do not; the severity of the metabolic block, rather than its location, and the resulting profound acidosis in utero may disturb normal morphogenesis. Colevas et al. (1988) described the pathologic findings in 2 cases. The pattern of lesions, in particular the striking localization of renal dysplasia to the medulla, suggested that the malformations may be the consequence of an accumulation of toxic metabolites that is not corrected by placental transfer. Other malformations included cerebral pachygyria, pulmonary hypoplasia, and facial dysmorphism. Lipid accumulation was demonstrated in the liver, heart, and renal tubular epithelium, all tissues that use fatty acids as a primary source of energy.
Wilson et al. (1989) found reports of malformations in 8 of 16 cases. The anomalies included macrocephaly, large anterior fontanel, high forehead, flat nasal bridge, telecanthus, and malformed ears. Abnormalities such as hypotonia, cerebral gliosis, heterotopias, hepatomegaly, hepatic periportal necrosis, polycystic kidneys, and genital defects were considered reminiscent of the anomalies in Zellweger syndrome, but elevations of glutaric, ethylmalonic, adipic, and isovaleric acids were considered distinctive for glutaric aciduria type II. Wilson et al. (1989) described a unique ultrastructural change in the glomerular basement membrane which they suggested may represent an early stage in renal cyst formation and provide a diagnostic criterion for glutaric aciduria II when enzyme studies are unavailable.
Poplawski et al. (1999) reported a family in which an unexplained neonatal death had occurred. Twelve years after the death, they retrospectively diagnosed multiple acyl-CoA-dehydrogenase deficiency by demonstrating an abnormal acyl-carnitine profile in the child's archived neonatal screening card, using tandem mass spectrometry.
Angle and Burton (2008) reported 3 unrelated infants with genetically confirmed MADD who experienced sudden acute life-threatening events in the first year of life, resulting in death in 2 infants. All had been correctly diagnosed via a newborn screening protocol. Each developed cardiopulmonary arrest concurrent with metabolic stress or limited caloric intake, including vomiting, upper respiratory infection, and rotaviral diarrhea. Although only 1 patient had a documented arrhythmia, Angle and Burton (2008) suggested that an intrinsic abnormality of myocardial function due to altered energy production may have played a role. The authors emphasized the importance of aggressive nutritional management in infants with MADD.

Later Onset

Hypoglycemia caused by inborn errors of metabolism, including disturbances of organic-acid metabolism, usually appear during infancy or childhood. Thus, the case reported by Dusheiko et al. (1979) was unusual. A 19-year-old woman had episodic vomiting, severe hypoglycemia, and fatty infiltration of the liver. The parents were not related. One of her sisters, at age 7, developed nausea, vomiting, and a 'stale' odor to the breath, and died after 3 days in hypoglycemic coma. At age 10, a second sister was found to have jaundice, hepatomegaly, and hypoglycemia after an acute febrile illness. She recovered from that illness but died 'in her sleep' 2 years later. Excess amounts of glutaric and ethylmalonic acids were found in the urine, consistent with defective dehydrogenation of isovaleryl CoA and butyryl CoA, respectively. These organic acids plus others are excreted in the urine in excess in Jamaican vomiting sickness, caused by the ingestion of unripe akee. Unripe akee contains the toxin hypoglycin, which inhibits several acyl CoA dehydrogenases. Cultured fibroblasts in the patient of Dusheiko et al. (1979) showed reduced ability to oxidize radiolabeled butyrate and lysine.
Mongini et al. (1992) reported a 25-year-old woman who complained of episodes of muscle weakness, nausea and vomiting since the age of 10 years. She had been born with bilateral cataracts and strabismus. Muscle biopsy showed free fatty acid accumulation. Low-fat diet reduced the episodes of muscle weakness.
Liang et al. (2009) reported 4 Taiwanese patients from 3 unrelated families with MADD due to mutations in the ETFDH gene (231675.0003-231675.0005). There was marked phenotypic variability, even between 2 affected sibs with the same genotype. The first patient was a 27-year-old woman who had exercise intolerance since early childhood. In her teens, she developed several episodes of acute pancreatitis. At age 19, she developed dysphagia with progressive weakness of neck and proximal limb muscles, and later had a more severe episode of muscle weakness with acute respiratory failure, but no metabolic acidosis and hypoketotic hypoglycemia. Serum creatine kinase was elevated, and muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. Urinary profile was consistent with MADD. Her older sister had a milder phenotype, with 2 bouts of muscle weakness and difficulty climbing stairs and combing her hair. She never had metabolic crisis, hypoketotic hypoglycemia, or respiratory failure. Laboratory studies showed low serum carnitine, increased serum acylcarnitine levels, and elevated glutaric, ethylmalonic, 2-hydroxylglutaric, 3-methylglutaconic, and lactic acids in urine. Both patients responded well to riboflavin and carnitine treatment. The third patient developed exercise intolerance, dysphagia, poor head control, and limb weakness at age 14 years, and was wheelchair-bound by age 16. He had neck and proximal muscle weakness with wasting, lordosis, winged scapula, and absent tendon reflexes. He did not have metabolic acidosis or hypoketotic hypoglycemia. Pulmonary function tests demonstrated a severe restrictive ventilatory defect. Muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. He also responded well to riboflavin and carnitine treatment. The last patient was a 10-year-old girl who was a slow runner since childhood. She had an upper respiratory tract infection followed by progressive proximal muscle weakness. A few days after discharge from the hospital, her condition rapidly deteriorated and she developed fatal cardiopulmonary failure associated with marked metabolic acidosis, hyperammonemia, and hypoglycemia.

Biochemical FeaturesBack to Top

By fusion of isovaleric acidemia (243500) cells with those of GA II, Dubiel et al. (1983) showed that these disorders are genetically distinct, since complementation was observed. In both disorders, isovaleryl-CoA dehydrogenation is blocked. The defect in GA II is in one of the proteins involved in the transfer of electrons from acyl-CoA dehydrogenases to coenzyme Q of the mitochondrial electron transport chain. Sarcosinemia and sarcosinuria are also observed in this disorder (Goodman et al., 1980; Gregersen et al., 1980).
Ikeda et al. (1985) concluded that defective synthesis of ETFA was the fundamental defect in 3 cell lines from patients with severe MADD.
Moon and Rhead (1987) detected 2 complementation groups in cell lines from patients with severe multiple acyl-CoA dehydrogenation disorder. This was consistent with the different defects in glutaric aciduria IIA and glutaric aciduria IIB. The metabolic block in the cell lines from the latter disorder was 3 times more severe than the former, as assayed by oxidation of radiolabelled palmitate. No intragenic complementation was observed within either group. Complementation was started after polyethylene glycol fusion.
Onkenhout et al. (2001) determined the fatty acid composition of liver, skeletal muscle, and heart obtained postmortem from patients with deficiency of 1 of 3 types of acyl-CoA dehydrogenase: medium-chain (MCAD; 607008), multiple (MADD), and very long-chain (VLCADD; 201475). Increased amounts of multiple unsaturated fatty acids were found exclusively in the triglyceride fraction. They could not be detected in the free fatty acid or phospholipid fractions. Onkenhout et al. (2001) concluded that intermediates of unsaturated fatty acid oxidation that accumulate as a consequence of MCADD, MADD, and VLCADD are transported to the endoplasmic reticulum for esterification into neutral glycerolipids. The pattern of accumulation is characteristic for each disease, which makes fatty acid analysis of total lipid of postmortem tissues a useful tool in the detection of mitochondrial fatty acid oxidation defects in patients who have died unexpectedly.
Riboflavin-responsive multiple acylcoenzyme A dehydrogenase deficiency is characterized by, among other features, a decrease in fatty acid beta-oxidation capacity. Muscle uncoupling protein-3 (UCP3; 602044) is upregulated under conditions that either increase the levels of circulating free fatty acid and/or decrease fatty acid beta-oxidation. Using a relatively large cohort of 7 MADD patients, Russell et al. (2003) studied the metabolic disturbances of this disease and determined if they might increase UCP3 expression. Biochemical and molecular tests demonstrated decreases in fatty acid beta-oxidation and in the activities of respiratory chain complexes I (see 157655) and II (see 600857). These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acid/acylCoA. The authors considered MADD an optimal model to study the hypothesis that UCP3 is involved in the outward translocation of an excess of fatty acid from the mitochondria and to show that, in humans, the effects of fatty acid on UCP3 expression are direct and independent of fatty acid beta-oxidation.

InheritanceBack to Top

Mantagos et al. (1979) proved autosomal recessive inheritance of MADD by demonstration of partial enzyme deficiency in each parent of a female patient.

DiagnosisBack to Top

Costa et al. (1996) noted that a number of subclinical deficiencies caused by malabsorption could be misdiagnosed as inherited mitochondrial fatty acid oxidation defects. They suggested that in the presence of organic acid profiles reminiscent of a defect in the beta-oxidation pathway or a profile reminiscent of glutaric aciduria type II, a possible digestive disorder should be ruled out.
<Suhead> Prenatal Diagnosis
Yamaguchi et al. (1990, 1991) described type II glutaric aciduria due to deficiency of ETFB. The patient had a neonatal onset of intermittent illness without congenital anomalies. The diagnosis was made at the age of 10 months. Subsequently, the parents of the patient of Yamaguchi et al. (1991) had another pregnancy and Yamaguchi et al. (1991) performed prenatal diagnosis by immunochemical procedures on cultured amniocytes and by organic acid analysis of amniotic fluid, using a stable isotope dilution method. They also described the monitoring of the clinical course and metabolite excretion in early infancy when the patient had no symptoms. Glutarate concentration was increased in the cell-free supernatant of the amniotic fluid.

Clinical ManagementBack to Top

Gregersen et al. (1982) reported successful treatment of a 5 year old with riboflavin.
Riboflavin-responsive glutaric aciduria type II was reported by Uziel et al. (1995) in a boy who developed gradually progressive spastic ataxia and a leukodystrophy without ever having experienced episodic metabolic crises.

Molecular GeneticsBack to Top

Glutaric aciduria IIA

Indo et al. (1991), Rhead et al. (1992), and Freneaux et al. (1992) identified mutations in the ETFA gene in patients with GA IIA (e.g., 608053.0001).

Glutaric aciduria IIB

Colombo et al. (1994) identified mutations in the ETFB gene in patients with GA IIB (e.g., 130410.0001).

Glutaric aciduria IIC

Beard et al. (1993) identified 5 mutations in the ETFDH gene (e.g., 231675.0001) in 4 patients with GA IIC. All 5 mutations were rare and caused total lack of enzyme activity and antigen.
In 4 Taiwanese patients from 3 unrelated families with relatively late-onset MADD, Liang et al. (2009) identified homozygous or compound heterozygous mutations in the ETFDH gene (231675.0003-231675.0005). The A84T mutation (231675.0003) was present in all 4 patients.

Genotype/Phenotype CorrelationsBack to Top

The heterogeneous clinical features of patients with MADD fall into 3 classes (Frerman and Goodman, 2001): 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). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress.
To examine whether the different clinical forms of MADD can be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, Olsen et al. (2003) investigated the molecular genetic basis for disease development in 9 patients representing the phenotypic spectrum of MADD. They identified and characterized 7 novel and 3 previously reported disease-causing mutations. Studies of these 9 patients yielded results consistent with 3 clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of the disease. Homozygosity for 2 null mutations caused fetal development of congenital anomalies, resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seemed to be sufficient to prevent embryonic development of congenital anomalies, giving rise to type II disease. Studies of an asp128-to-asn mutation of the ETFB gene (D128N; 130410.0003), identified in a patient with type III disease, showed that the residual activity of the enzyme could be rescued up to 59% of that of wildtype activity when ETFB(D128N)-transformed E. coli cells were grown at low temperature. This suggested that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors such as cellular temperature.

HistoryBack to Top

A neonatal lethal form, called 'GA IIA' by Coude et al. (1981), was thought possibly to be X-linked. Coude et al. (1981) reported a pedigree supportive of X-linked inheritance because of the occurrence of a total of 5 proved or presumed cases in 3 sibships related through 5 presumptive carrier females. ('GA IIB' was the designation used by Coude et al. (1981) for a mild form that presented as recurrent hypoglycemia without ketosis and showed a less severe evolution with survival to adulthood.)

See AlsoBack to Top

Gregersen (1985); Jakobs et al. (1984); Mitchell et al. (1983)

ReferencesBack to Top

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