Fatty acids catabolism disorders

Fatty Acid Catabolism Disorders and Knockout Models... 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

In humans, several genetic disorders of fatty acid catabolism, such as the most common MCAD-deficiency, have been reported but their description falls beyond the scope of this review. Several recent reviews have described many of these diseases and their symptoms in more detail (Longo et al., 2006 Rinaldo et ah, 2002 Wanders and Waterham, 2006 Yang et ah, 2005). For mitochondrial fatty acid oxidation disorders the symptoms often develop at infancy during an episode of increased energy demand such as fasting, exercise or illness. Peroxisomal fatty acid oxidation enzyme deficiencies often involve neuropathy and retinopathy. 

Defects of fatty acid catabolism, with the exception of SCAD deficiency, generally have elevation of more than one characteristic metabolite. MCAD deficiency is characterized by accumulation of C6, C8 (mainly) and C10 l species. LCAD and VLCAD are characterized by accumulation of C14 l, C14 2 and (usually) C16 and C18 l species. LCHADD and TFP deficiencies are characterized by the accumulation of OH-C16, 0H-C18 1 and usually at least one of the other long-chain species C14 1, C16 and C18 l. The CPT-II and CAT (carnitine/acylcarnitine translocase) deficiencies are characterized by marked elevation of both C16 and C18 1, but not C14 1. Multiple acyl-CoA deficiency (MAD) has several different etiologies, including electron transferring protein (ETF) deficiency, ETF-dehydrogenase deficiency and riboflavin deficiency. Disease patterns vary considerably. In severe forms of the disorder, a generalized marked elevation of mxiltiple intermediates is observed. CPT-I should be suspected when both C16 and Cl8 1 are very low in whole blood, especially if free carnitine is normal or elevated. 

During more acute episodes the excretion of 3-hydroxyisovaleric acid increases. This metabolite is also observed in urine from patients with 3-methyl-crotonylglycinuria and tends to characterize that disorder (Section 10.3.2), but its occurrence is due to different mechanisms in the different diseases. In isovaleric acidaemia, the supply of glycine is exceeded by the accumulation of isovaleryl-CoA during periods of increased leucine catabolism (for example, high protein intake, infections) the isovaleryl-CoA is hydrolysed to free isovaleric acid which accumulates in turn in the tissues and body fluids. The free isovaleric acid is then oxidized to 3-hydroxyisovaleric acid and is excreted into the urine. The accumulation of isovaleric acid during these periods exacerbates the severity of the disease and produces the acute episodes observed. The isovaleric acid is believed to be oxidized by an a>-l oxidation process (Tanaka et al, 1968), which occurs simultaneously with co-oxidation of fatty acids in liver (Den, 1965). This is supported to some extent by the finding of low concentrations of methylsuccinic acid in urine, which had been stored for several years, from a patient with isovaleric acidaemia (Baerlocher etal, 1973). 

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