multiple acyl-CoA dehydrogenase deficiency

Definition: Autosomal recessive multiple acyl-CoA dehydrogenase deficiency (MADD) also known as glutaric aciduria II, can be caused by mutations in at least 3 different genes: ETFA (MIM.608053), ETFB (MIM.130410), and ETFDH (MIM.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.

Synopsis

 neonatal acidosis
 hypoglycemia
 sweaty feet odor
 stale breath odor
 neonatal death frequent
 nausea
 vomiting
 fatty infiltration of liver
 hepatomegaly
 hepatic periportal necrosis
 hypoglycemic coma
 muscle weakness
 muscular hypotonia
 facial dysmorphism
 macrocephaly
 cerebral pachygyria
 cerebral gliosis
 large anterior fontanel
 high forehead
 flat nasal bridge
 telecanthus
 congenital cataract
 malformed ears
 jaundice
 respiratory distress
 pulmonary hypoplasia
 selective proximal tubular damage
 bilareal non-obstructive renal dysplasia (BNORD)
 renal cortical cysts
 polycystic kidneys
 genital defects

Laboratory

 glutaric aciduria
 glutaric acidemia
 ethylmalonic aciduria
 glycosuria
 generalized aminoaciduria
 defective dehydrogenation of isovaleryl CoA and butyryl CoA
 electron transfer flavoprotein-ubiquinone oxidoreductase defect

Fatty acid oxidation disorders result from molecular defects in genes encoding mitochondrial enzymes required for the oxidation of fatty acids.

The absence or reduced expression of these enzymes leads to blockage of fatty acid degradation into acetyl-CoA. As a result, there is marked accumulation of free fatty acids, which in excess are oxidated into organic acids and acylglycines.

The excess fatty acids also accumulate as acyl-CoA esters, which associate with acylcarnitines, resulting in carnitine depletion.1 The best examples of fatty acid oxidation disorders are glutaric acidemia type II (GA-II), carnitine palmitoyltransferase II (CPT-II) deficiency and Zellweger syndrome.

Neonatal cases of GA-II are usually diagnosed soon after birth, when patients present with severe metabolic acidosis. Most patients die due to metabolic disturbances within the first few weeks of life.

In addition to the clinical picture described above, virtually all cases have renal multicystic dysplasia, presenting with abdominal distension and nephromegaly. Features of the oligohydramnios deformation sequence (Potter’s sequence) may be also present, although they may be subtle or undetectable in fetuses.

The most striking pathologic feature observed in neonatal GA-II is visceral steatosis, present in all cases (with or without malformations). The liver is the most affected organ, usually presenting with severe and diffuse steatosis; kidneys, thyroid, lung, myocardium and adrenal glands were less frequently described as sites of steatosis.

The diagnosis of GA-II can be established by biochemical studies.

Organic acid excretion can be quantified in urine and amniotic fluid and bile, with a characteristic profile of markedly increased glutaric acid, together with other organic acids and acylglycines.

A fatty acid and acylcarnitine profile can be obtained from autopsy tissue (blood, liver macerate or bile), and will characteristically show elevated long-chain species.

Western blot analysis for detection of ETF and ETF-QO antigens (encoded by the mutated genes in GA-II), or measurement of their enzymatic activities, can be performed in cultured fibroblasts from skin or chorionic villi, as well as in amniocytes.

The association of characteristic laboratory findings with the phenotypic features suggests the diagnosis of GA-II in this case. The differential diagnosis with CPT-II deficiency and Zellweger syndrome may be difficult.

In Zellweger syndrome, the renal lesion appears to be milder, and the liver disease is characterized by fibrosis and iron deposition; in contrast with GA-II, in Zellweger syndrome there is elevation of very-long-chain fatty acids.

CPT-II deficiency presents with a similar metabolic profile to GA-II, although glutaric acid is not increased, and is characterized by prominent myocardial steatosis leading to cardiomegaly, and malformations of the central nervous system (cysts, calcifications, ventriculomegaly and abnormalities of the corpus callosum).

Differential diagnosis

 other causes of multicystic kidney dysplasia

• urinary tract obstruction
• syndromic conditions
  • Meckel-Gruber syndrome
  • Bardet-Biedl syndrome
  • Joubert syndrome

The presence of visceral steatosis, a patent urinary system and the absence of other characteristic malformations should point towards the diagnosis of a disorder of lipid metabolism.

It is important to emphasize the need to store amniotic fluid, urine or even bile, as well as frozen liver and other tissues in fetal autopsies suspected of metabolic disorders, in order to confirm the chemical abnormalities.

Case studies

 Case #592

References

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 Sluvkin II, Salamat MS, Chandra S. Morphologic studies of the placenta and autopsy findings in neonatal-onset glutaric acidemia type II. Pediatr Dev Pathol 2002; 5: 315-321.

 Bohm N, Uy J, Kiebling M, Lehnert W. Multiple acyl-CoA dehydrogenation deficiency (glutaric acidemia type II) congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. Morphology and pathogenesis. Eur J Pediatr 1982; 139: 60-65.

 Boles RG, Buck EA, Blitzer MG, et al. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr 1998; 132: 924-933.

 Powers JM, Moser HW, Moser AB, et al. Fetal cerebrohepatorenal (Zellweger) syndrome: dysmorphic, radiologic, biochemical, and pathologic findings in four affected fetuses. Hum Pathol 1985; 16: 610-620.

 FitzPatrick DR. Zellweger syndrome and associated phenotypes. J Med Genet 1996; 33: 863-868.

 Elpeleg ON, Hammerman C, Saada A, et al. Antenatal presentation of carnitine palmitoyltransferase II deficiency. Am J Med Genet 2001; 102: 183-187.

 Sigauke E, Rakheja D, Kitson K, Bennett MJ. Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review. Lab Invest 2003; 83: 1543-1554.