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

1.

Amendt, B. A., Rhead, W. J. The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria: mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts. J. Clin. Invest. 78: 205-213, 1986. [PubMed: 3722376]

Amendt, B. A., Rhead, W. J. The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria: mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts. J. Clin. Invest. 78: 205-213, 1986. [PubMed: 3722376]

2.

Angle, B., Burton, B. K. Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II. Molec. Genet. Metab. 93: 36-39, 2008. [PubMed: 17977044]

Angle, B., Burton, B. K. Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II. Molec. Genet. Metab. 93: 36-39, 2008. [PubMed: 17977044]

3.

Beard, S. E., Spector, E. B., Seltzer, W. K., Frerman, F. E., Goodman, S. I. Mutations in electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II (GA2). Clin. Res. 41: 271A, 1993.

Beard, S. E., Spector, E. B., Seltzer, W. K., Frerman, F. E., Goodman, S. I. Mutations in electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II (GA2). Clin. Res. 41: 271A, 1993. (Not available in PubMed)

4.

Bohm, N., Uy, J., Kiebling, M., Lehnert, W. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Europ. J. Pediat. 139: 60-65, 1982. [PubMed: 7173260]

Bohm, N., Uy, J., Kiebling, M., Lehnert, W. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Europ. J. Pediat. 139: 60-65, 1982. [PubMed: 7173260]

5.

Colevas, A. D., Edwards, J. L., Hruban, R. H., Mitchell, G. A., Valle, D., Hutchins, G. M. Glutaric acidemia type II: comparison of pathologic features in two infants. Arch. Path. Lab. Med. 112: 1133-1139, 1988. [PubMed: 3178428]

Colevas, A. D., Edwards, J. L., Hruban, R. H., Mitchell, G. A., Valle, D., Hutchins, G. M. Glutaric acidemia type II: comparison of pathologic features in two infants. Arch. Path. Lab. Med. 112: 1133-1139, 1988. [PubMed: 3178428]

6.

Colombo, I., Finocchiaro, G., Garavaglia, B., Garbuglio, N., Yamaguchi, S., Frerman, F. E., Berra, B., DiDonato, S. Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaricacidemia type II. Hum. Molec. Genet. 3: 429-435, 1994. [PubMed: 7912128]

Colombo, I., Finocchiaro, G., Garavaglia, B., Garbuglio, N., Yamaguchi, S., Frerman, F. E., Berra, B., DiDonato, S. Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaricacidemia type II. Hum. Molec. Genet. 3: 429-435, 1994. [PubMed: 7912128]

7.

Costa, C. G., Verhoeven, N. M., Kneepkens, C. M. F., Douwes, A. C., Wanders, R. J. A., Tavares De Almeida, I., Duran, M., Jakobs, C. Organic acid profiles resembling a beta-oxidation defect in two patients with coeliac disease. J. Inherit. Metab. Dis. 19: 177-180, 1996. [PubMed: 8739959]

Costa, C. G., Verhoeven, N. M., Kneepkens, C. M. F., Douwes, A. C., Wanders, R. J. A., Tavares De Almeida, I., Duran, M., Jakobs, C. Organic acid profiles resembling a beta-oxidation defect in two patients with coeliac disease. J. Inherit. Metab. Dis. 19: 177-180, 1996. [PubMed: 8739959]

8.

Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., Saudubray, J. M., Frezal, J. Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder. Hum. Genet. 59: 263-265, 1981. [PubMed: 7199025]

Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., Saudubray, J. M., Frezal, J. Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder. Hum. Genet. 59: 263-265, 1981. [PubMed: 7199025]

9.

Dubiel, B., Dabrowski, C., Wetts, R., Tanaka, K. Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts. J. Clin. Invest. 72: 1543-1552, 1983. [PubMed: 6630517]

Dubiel, B., Dabrowski, C., Wetts, R., Tanaka, K. Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts. J. Clin. Invest. 72: 1543-1552, 1983. [PubMed: 6630517]

10.

Dusheiko, G., Kew, M. C., Joffe, B. I., Lewin, J. R., Mantagos, S., Tanaka, K. Recurrent hypoglycemia associated with glutaric aciduria type II in an adult. New Eng. J. Med. 301: 1405-1409, 1979. [PubMed: 514320]

Dusheiko, G., Kew, M. C., Joffe, B. I., Lewin, J. R., Mantagos, S., Tanaka, K. Recurrent hypoglycemia associated with glutaric aciduria type II in an adult. New Eng. J. Med. 301: 1405-1409, 1979. [PubMed: 514320]

11.

Freneaux, E., Sheffield, V. C., Molin, L., Shires, A., Rhead, W. J. Glutaric acidemia type II: heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha-subunit of electron transfer flavoprotein in eight patients. J. Clin. Invest. 90: 1679-1686, 1992. [PubMed: 1430199]

Freneaux, E., Sheffield, V. C., Molin, L., Shires, A., Rhead, W. J. Glutaric acidemia type II: heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha-subunit of electron transfer flavoprotein in eight patients. J. Clin. Invest. 90: 1679-1686, 1992. [PubMed: 1430199]

12.

Frerman, F. E., Goodman, S. I. Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (eds.) The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill (8th Ed.): 2357-2365, 2001.

Frerman, F. E., Goodman, S. I. Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (eds.) The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill (8th Ed.): 2357-2365, 2001. (Not available in PubMed)

13.

Goodman, S. I. Personal Communication. 1993. Denver, Colorado

Goodman, S. I. Personal Communication. 1993. Denver, Colorado (Not available in PubMed)

14.

Goodman, S. I., McCabe, E. R. B., Fennessey, P. V., Mace, J. W. Multiple acyl Co-A dehydrogenase deficiency (glutaric aciduria type II) with transient hypersarcosinemia and sarcosinuria; possible inherited deficiency of an electron transfer flavoprotein. Pediat. Res. 14: 12-17, 1980. [PubMed: 7360517]

Goodman, S. I., McCabe, E. R. B., Fennessey, P. V., Mace, J. W. Multiple acyl Co-A dehydrogenase deficiency (glutaric aciduria type II) with transient hypersarcosinemia and sarcosinuria; possible inherited deficiency of an electron transfer flavoprotein. Pediat. Res. 14: 12-17, 1980. [PubMed: 7360517]

15.

Gregersen, N. Acyl-CoA dehydrogenation disorders. Scand. J. Clin. Lab. Invest. 45 (suppl. 174): 1-60, 1985. [PubMed: 3892650]

Gregersen, N. Acyl-CoA dehydrogenation disorders. Scand. J. Clin. Lab. Invest. 45 (suppl. 174): 1-60, 1985. [PubMed: 3892650]

16.

Gregersen, N., Kolvraa, S., Rasmussen, K., Christensen, E., Brandt, N. J., Ebbesen, F., Hansen, F. H. Biochemical studies in a patient with defects in the metabolism of acyl-CoA and sarcosine: another possible case of glutaric aciduria type II. J. Inherit. Metab. Dis. 3: 67-72, 1980. [PubMed: 6158623]

Gregersen, N., Kolvraa, S., Rasmussen, K., Christensen, E., Brandt, N. J., Ebbesen, F., Hansen, F. H. Biochemical studies in a patient with defects in the metabolism of acyl-CoA and sarcosine: another possible case of glutaric aciduria type II. J. Inherit. Metab. Dis. 3: 67-72, 1980. [PubMed: 6158623]

17.

Gregersen, N., Wintzensen, H., Christensen, S. K. E., Christensen, M. F., Brandt, N. J., Rasmussen, K. C(6)-C(10)-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects. Pediat. Res. 16: 861-868, 1982. [PubMed: 7145508]

Gregersen, N., Wintzensen, H., Christensen, S. K. E., Christensen, M. F., Brandt, N. J., Rasmussen, K. C(6)-C(10)-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects. Pediat. Res. 16: 861-868, 1982. [PubMed: 7145508]

18.

Harkin, J. C., Gill, W. L., Shapira, E. Glutaric acidemia type II: phenotypic findings and ultrastructural studies of brain and kidney. Arch. Path. Lab. Med. 110: 399-401, 1986. [PubMed: 3754423]

Harkin, J. C., Gill, W. L., Shapira, E. Glutaric acidemia type II: phenotypic findings and ultrastructural studies of brain and kidney. Arch. Path. Lab. Med. 110: 399-401, 1986. [PubMed: 3754423]

19.

Ikeda, Y., Keese, S., Tanaka, K. Molecular heterogeneity of electron transfer flavoprotein (ETF) in glutaric acidemia type II due to an ETF deficiency. Pediat. Res. 19: 249A, 1985.

Ikeda, Y., Keese, S., Tanaka, K. Molecular heterogeneity of electron transfer flavoprotein (ETF) in glutaric acidemia type II due to an ETF deficiency. Pediat. Res. 19: 249A, 1985. (Not available in PubMed)

20.

Indo, Y., Glassberg, R., Yokota, I., Tanaka, K. Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient. Am. J. Hum. Genet. 49: 575-580, 1991. [PubMed: 1882842]

Indo, Y., Glassberg, R., Yokota, I., Tanaka, K. Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient. Am. J. Hum. Genet. 49: 575-580, 1991. [PubMed: 1882842]

21.

Jakobs, C., Sweetman, L., Wadman, S. K., Duran, M., Saudubray, J.-M., Nyhan, W. L. Prenatal diagnosis of glutaric aciduria type II by direct chemical analysis of dicarboxylic acids in amniotic fluid. Europ. J. Pediat. 141: 153-157, 1984. [PubMed: 6698061]

Jakobs, C., Sweetman, L., Wadman, S. K., Duran, M., Saudubray, J.-M., Nyhan, W. L. Prenatal diagnosis of glutaric aciduria type II by direct chemical analysis of dicarboxylic acids in amniotic fluid. Europ. J. Pediat. 141: 153-157, 1984. [PubMed: 6698061]

22.

Lehnert, W., Wendel, U., Lindenmaier, S., Bohm, N. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Europ. J. Pediat. 139: 56-59, 1982. [PubMed: 7173260]

Lehnert, W., Wendel, U., Lindenmaier, S., Bohm, N. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Europ. J. Pediat. 139: 56-59, 1982. [PubMed: 7173260]

23.

Liang, W.-C., Ohkuma, A., Hayashi, Y. K., Lopez, L. C., Hirano, M., Nonaka, I., Noguchi, S., Chen, L.-H., Jong, Y.-J., Nishino, I. ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromusc. Disord. 19: 212-216, 2009. [PubMed: 19249206]

Liang, W.-C., Ohkuma, A., Hayashi, Y. K., Lopez, L. C., Hirano, M., Nonaka, I., Noguchi, S., Chen, L.-H., Jong, Y.-J., Nishino, I. ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromusc. Disord. 19: 212-216, 2009. [PubMed: 19249206]

24.

Mantagos, S., Genel, M., Tanaka, K. Ethylmalonic-adipic aciduria: in vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases. J. Clin. Invest. 64: 1580-1589, 1979. [PubMed: 500826]

Mantagos, S., Genel, M., Tanaka, K. Ethylmalonic-adipic aciduria: in vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases. J. Clin. Invest. 64: 1580-1589, 1979. [PubMed: 500826]

25.

Mitchell, G., Saudubray, J. M., Benoit, Y., Rocchiccioli, F., Charpentier, C., Ogier, H., Boue, J. Antenatal diagnosis of glutaricaciduria type II. Lancet 321: 1099-only, 1983. (Note: Originally Volume I.) [PubMed: 6133123]

Mitchell, G., Saudubray, J. M., Benoit, Y., Rocchiccioli, F., Charpentier, C., Ogier, H., Boue, J. Antenatal diagnosis of glutaricaciduria type II. Lancet 321: 1099-only, 1983. (Note: Originally Volume I.) [PubMed: 6133123]

26.

Mongini, T., Doriguzzi, C., Palmucci, L., De Francesco, A., Bet, L., Manfredi, L., Ponzetto, C., Bresolin, N. Lipid storage myopathy in multiple acyl-CoA dehydrogenase deficiency: an adult case. Europ. Neurol. 32: 170-176, 1992. [PubMed: 1592075]

Mongini, T., Doriguzzi, C., Palmucci, L., De Francesco, A., Bet, L., Manfredi, L., Ponzetto, C., Bresolin, N. Lipid storage myopathy in multiple acyl-CoA dehydrogenase deficiency: an adult case. Europ. Neurol. 32: 170-176, 1992. [PubMed: 1592075]

27.

Moon, A., Rhead, W. J. Complementation analysis of fatty acid oxidation disorders. J. Clin. Invest. 79: 59-64, 1987. [PubMed: 3793932]

Moon, A., Rhead, W. J. Complementation analysis of fatty acid oxidation disorders. J. Clin. Invest. 79: 59-64, 1987. [PubMed: 3793932]

28.

Niederwieser, A., Steinmann, B., Exner, U., Neuheiser, F., Redweik, U., Wang, M., Rampini, S., Wendel, U. Multiple acyl-CoA dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy: detection of N-isovalerylglutamic acid and its monoamide. Helv. Paediat. Acta 38: 9-26, 1983. [PubMed: 6862997]

Niederwieser, A., Steinmann, B., Exner, U., Neuheiser, F., Redweik, U., Wang, M., Rampini, S., Wendel, U. Multiple acyl-CoA dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy: detection of N-isovalerylglutamic acid and its monoamide. Helv. Paediat. Acta 38: 9-26, 1983. [PubMed: 6862997]

29.

Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum. Mutat. 22: 12-23, 2003. [PubMed: 12815589]

Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum. Mutat. 22: 12-23, 2003. [PubMed: 12815589]

30.

Onkenhout, W., Venizelos, V., Scholte, H. R., De Klerk, J. B. C., Poorthuis, B. J. H. M. Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects. J. Inherit. Metab. Dis. 24: 337-344, 2001. [PubMed: 11486898]

Onkenhout, W., Venizelos, V., Scholte, H. R., De Klerk, J. B. C., Poorthuis, B. J. H. M. Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects. J. Inherit. Metab. Dis. 24: 337-344, 2001. [PubMed: 11486898]

31.

Poplawski, N. K., Ranieri, E., Harrison, J. R., Fletcher, J. M. Multiple acyl-coenzyme A dehydrogenase deficiency: diagnosis by acyl-carnitine analysis of a 12-year-old newborn screening card. J. Pediat. 134: 764-766, 1999. [PubMed: 10356148]

Poplawski, N. K., Ranieri, E., Harrison, J. R., Fletcher, J. M. Multiple acyl-coenzyme A dehydrogenase deficiency: diagnosis by acyl-carnitine analysis of a 12-year-old newborn screening card. J. Pediat. 134: 764-766, 1999. [PubMed: 10356148]

32.

Przyrembel, H., Wendel, U., Becker, K., Bremer, H. J., Bruinvis, L., Ketting, D., Wadman, S. K. Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clin. Chim. Acta 66: 227-239, 1976. [PubMed: 1245071]

Przyrembel, H., Wendel, U., Becker, K., Bremer, H. J., Bruinvis, L., Ketting, D., Wadman, S. K. Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clin. Chim. Acta 66: 227-239, 1976. [PubMed: 1245071]

33.

Rhead, W. J., Freneaux, E., Sheffield, V. C., Molin, L., Shires, A. Glutaric acidemia type II (GAII): heterogeneity in beta-oxidation flux, polypeptide synthesis and cDNA mutations in the alpha-subunit of electron transfer flavoprotein in 8 patients. Am. J. Hum. Genet. 51 (suppl.): A175, 1992. [PubMed: 1430199]

Rhead, W. J., Freneaux, E., Sheffield, V. C., Molin, L., Shires, A. Glutaric acidemia type II (GAII): heterogeneity in beta-oxidation flux, polypeptide synthesis and cDNA mutations in the alpha-subunit of electron transfer flavoprotein in 8 patients. Am. J. Hum. Genet. 51 (suppl.): A175, 1992. [PubMed: 1430199]

34.

Russell, A. P., Schrauwen, P., Somm, E., Gastaldi, G., Hesselink, M. K. C., Schaart, G., Kornips, E., Lo, S. K., Bufano, D., Giacobino, J.-P., Muzzin, P., Ceccon, M., Angelini, C., Vergani, L. Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3. J. Clin. Endocr. Metab. 88: 5921-5926, 2003. [PubMed: 14671191]

Russell, A. P., Schrauwen, P., Somm, E., Gastaldi, G., Hesselink, M. K. C., Schaart, G., Kornips, E., Lo, S. K., Bufano, D., Giacobino, J.-P., Muzzin, P., Ceccon, M., Angelini, C., Vergani, L. Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3. J. Clin. Endocr. Metab. 88: 5921-5926, 2003. [PubMed: 14671191]

35.

Uziel, G., Garavaglia, B., Ciceri, E., Moroni, I., Rimoldi, M. Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy. Pediat. Neurol. 13: 333-335, 1995. [PubMed: 8771170]

Uziel, G., Garavaglia, B., Ciceri, E., Moroni, I., Rimoldi, M. Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy. Pediat. Neurol. 13: 333-335, 1995. [PubMed: 8771170]

36.

Wilson, G. N., de Chadarevian, J.-P., Kaplan, P., Loehr, J. P., Frerman, F. E., Goodman, S. I. Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am. J. Med. Genet. 32: 395-401, 1989. [PubMed: 2658591]

Wilson, G. N., de Chadarevian, J.-P., Kaplan, P., Loehr, J. P., Frerman, F. E., Goodman, S. I. Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am. J. Med. Genet. 32: 395-401, 1989. [PubMed: 2658591]

37.

Yamaguchi, S., Orii, T., Maeda, K., Oshima, M., Hashimoto, T. A new variant of glutaric aciduria type II: deficiency of beta-subunit of electron transfer flavoprotein. J. Inherit. Metab. Dis. 13: 783-786, 1990. [PubMed: 2246866]

Yamaguchi, S., Orii, T., Maeda, K., Oshima, M., Hashimoto, T. A new variant of glutaric aciduria type II: deficiency of beta-subunit of electron transfer flavoprotein. J. Inherit. Metab. Dis. 13: 783-786, 1990. [PubMed: 2246866]

38.

Yamaguchi, S., Orii, T., Suzuki, Y., Maeda, K., Oshima, M., Hashimoto, T. Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II. Pediat. Res. 29: 60-63, 1991. [PubMed: 2000260]

Yamaguchi, S., Orii, T., Suzuki, Y., Maeda, K., Oshima, M., Hashimoto, T. Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II. Pediat. Res. 29: 60-63, 1991. [PubMed: 2000260]

39.

Yamaguchi, S., Shimizu, N., Orii, T., Fukao, T., Suzuki, Y., Maeda, K., Hashimoto, T., Previs, S. F., Rinaldo, P. Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency. Pediat. Res. 30: 439-443, 1991. [PubMed: 1754299]