Final Diagnosis -- Fatty acid oxidation disorder


Fatty acid oxidation disorder, most likely glutaric acidemia type II


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. 2-7 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. 4, 7, 8 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 2, 6 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. 2, 6, 9, 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. 10, 11 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). 12, 13

Other causes of multicystic kidney dysplasia should also be included in the differential diagnosis, such as urinary tract obstruction and other syndromic conditions (including Meckel-Gruber syndrome, Ivemark syndrome, Bardet-Biedl syndrome and Joubert syndrome); however, 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.


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  9. 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.
  10. 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.
  11. FitzPatrick DR. Zellweger syndrome and associated phenotypes. J Med Genet 1996; 33: 863-868.
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  13. Sigauke E, Rakheja D, Kitson K, Bennett MJ. Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review. Lab Invest 2003; 83: 1543-1554.

Contributed by Mariana Cajaiba, MD

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