Methylmalonic acidemias

Tiglylglycine C5 l ILE Propionic acidemia Methylmalonic acidemias Ketothiolase deficiency... 

Fig. 3.1.6 GC-MS TIC organic acid profile of a patient with methylmalonic acidemia, a sample volume corresponding to 0.25 mg creatinine (standard procedure), b 10 x dilution (0.025 mg creatinine). Peak legend 1 methylmalonic acid (note the characteristic broad shape and spike, 2 urea, 3 citric acid, 4 2-methylcitric acid (two peaks). There was a fourfold difference in the measurement of methylmalonic acid excretion between the two analyses, with a substantial underestimation in the undiluted specimen...

Fig. 3.2.5 Profiles of acylcarnitines as their butyl esters in plasma (precursor of m/z 85 scan) of a normal control (a) and patients with various organic acidemias. Propionylcarnitine (C> m/z 274 peak 3) is the primary marker for both propionic acidemia (b) and methylmalonic acidemias (c). Note that an elevation of methylmalonylcarnitine (C4-UC m/z 374) is not typically found in patients with methylmalonic acidemias. In the three cases of ethylmalonic encephalopathy (d) analyzed in our laboratory, elevations of ,- (m/z 288 peak 4) and C5-acylcarnitine (m/z 302 peak 5) species were noted. Isolated C5-acylcarnitine elevations are encountered in patients with isovaleric acidemia (e), where it represents isovalerylcarnitine. Cs-Acylcarnitine is also elevated in patients with short/branched chain acyl-CoA dehydrogenase deficiency, where it represents 2-methylbutyrylcarnitine (see Fig. 3.2.4), and in patients treated with antibiotics that contain pivalic acid, where it represents pivaloylcarnitine [20, 59, 60]. Patients with /3-ketothio-lase deficiency (f) present with elevations of tiglylcarnitine (C5 i m/z 300 peak 6) and C5-OH acylcarnitine (m/z 318 peak 7). In most cases of 3-methylcrotonyl-CoA carboxylase deficiency (g) Cs-OH acylcarnitine is the only abnormal acylcarnitine species present. The differential diagnosis of C5-OH acylcarnitine elevations includes eight different conditions (Table 3.2.1). Also note that C5-OH acylcarnitine represents 3-hydroxy isovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency (g), and 2-methyl 3-hydroxy butyrylcarnitine in / -ketothiolase deficiency...

Morel CF, Watkins D, Scott P, Rinaldo P, Rosenblatt DS (2005) Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport. Mol Genet Metab 86 160-171... 

Methylmalonic acidemia <0.5 Conversion of propionyl-CoA to succinyl-CoA Methylmalonyl-CoA mutase Vomiting convulsions mental retardation early death... 

The propionyl-CoA derived from these three amino acids is converted to succinyl-CoA by a pathway described in Chapter 17 carboxylation to methylmalonyl-CoA, epimerization of the methylmalonyl-CoA, and conversion to succinyl-CoA by the coenzyme B independent methylmalonyl-CoA mutase (see Fig. 17-11). In the rare genetic disease known as methylmalonic acidemia, methylmalonyl-CoA mutase is lacking—with serious metabolic consequences (Table 18-2 Box 18-2). 

Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (pro ducing acetyl CoA) until the last three carbons (propionyl CoA). This compound is con verted to methylmalonyl CoA (a reaction requiring biotin), which is then converted to succinyl CoA by methylmalonyl CoA mutase (requiring vitamin B )- A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. 

Patients with propionic or methylmalonic acidemia also secrete 2,3-butanediols (d-,l- or meso) and usually also 1,2-propandiol in their urine. Secretion of 1,2-propanediol is also observed during... 

Propionic acidemia Methylmalonic acidemia Intrinsic factor... 

Answer The catabolism of the carbon skeletons of valine, isoleucine, and methionine is impaired because of the absence of a functional methylmalonyl-CoA mutase. This enzyme requires coenzyme B12 as a cofactor, and a deficiency of this vitamin leads to elevated methylmalonic acid levels (methylmalonic acidemia). The symptoms and effects of this deficiency are severe (see Table 18-2 and Box 18-2). 

As discussed in Section 10.8.2, moderate vitamin B12 deficiency results in increased accumulation of methylmalonyl CoA, and methylmalonic aciduria and methylmalonic acidemia. This can be exploited as both a means of detecting subclinical deficiency and monitoring vitamin B12 status in patients with pernicious anemia who have been treated with parenteral vitamin. As they become depleted, the excretion of methylmalonic acid, especially after a loading dose of valine, will provide a sensitive index of depletion of vitamin Bi2 reserves. 

Ampola, M. G., Mahoney, M. J., Nakamura, E., and Tanaka, K. (1975). Prenatal therapy of a patient with vitamin Bi2-responsive methylmalonic acidemia. N. Engl.. Med. 293, 313-317. 

A large number of disorders are associated with cobalamin deficiency in infancy or childhood. Of these, the most commonly encountered is the Imerslund-Graesbeck syndrome, a condition that is characterized by inability to absorb vitamin B,2, with or without IF, and proteinuria. It appears to be due to an inability of intestinal mucosa to absorb the vitamin B,2 IF complex. The second most common of these is congenital deficiency of gastric secretion of IF. Very rarely, congenital deficiency of vitamin B12 in a breast-fed infant is due to deficiency of vitamin B12 in maternal breast milk as a result of unrecognized pernicious anemia in the mother. This is rare because most women with undiagnosed and untreated pernicious anemia are infertile. Additionally, there are some rare methylmalonic acidemias (acidurias) caused by inborn errors in homocysteine and methionine metabolism that are responsible for disorders in vitamin B status. ... 

Figure 55-2 Multi-analyte approach to the prenatal diagnosis of methylmalonic acidemia (cb/C complementation group) by metabolite analysis in ceil-free supernatant of amniotic fluid collected at 16 weeks of gestational age. The symbol marks internal standards. A, Determination of total homocysteine by LC-MS/MS (selected reaction monitoring, SRM, transition m/z 136 to m/z 90 and m/z 140 to m/z 94 for the d -labeled internal standard). The concentration of total homocysteine was l5.7pmol/L (0.7 to 2.0pmol/L). B, Determination of methylmalonic acid by LC-MS/MS (SRM, transition m/z 231 to m/z 119 and m/z 234 to m/z 122 for the d3-labeled internal standard). The concentration of methylmalonic acid was 8.7pmol/L, the reference interval for 16 to 19 weeks of gestational age is 0.2 to 0.7)j,mol/L. C, Determination of propionylcarnitine by LC-MS/MS (parent of m/z 85 scan, the [M+H] ion of C3 is m/z 274, m/z 277 for the interna standard). The concentration was 5.6pmol/L (i.5 to l.8pmoi/L),the C3/C4 ratio was 6.9 (0.9 to 2.6).

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are panethnic disorders, but their combined incidence varies considerably, with estimates ranging from 1 2000 to 1 5000 (Saudi Arabia) to 20 times lower. However, there is a general consensus that many patients with this disorder die undiagnosed, being masked by a variety of catastrophic processes (sepsis and intraventricular hemorrhage). In the United States, screening for these disorders by means of MS/MS detection of propionylcarnitine is not offered in 31 states, corresponding to 69% of all babies born... 

Duran M> Ketting D, Wadman SK, Trijbels JM, Bakkeren JA, Waelkens JJ. Propionic acid, an artefact which can leave methylmalonic acidemia undiscovered. Clin Chim Acta 1973 49 177-9. 

Nyhan WL, Ozand PT. Propionic acidemia and methylmalonic acidemia. In Nyhan WL, Ozand PT, eds. Atlas of metabolic diseases. London Chapman 8t Had Medical, 1998 4-23. 

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