Isolated (biotin‐resistant) 3‐methylcrotonyl‐CoA carboxylase deficiency: four sibs devoid of pathology

Abstract

Isolated deficiency of 3-methylcrotonyl-CoA carboxylase (MCC; McKusick 210200) is a rare disorder of the catabolic pathway for leucine. Only a few subjects from a few families with this enzyme defect have been described (Sweetman and Williams 1995), having a wide range of clinical presentation or being totally asymptomatic. In most patients, after apparently normal health and development during the first or even second year, metabolic stress such as intercurrent infection has precipitated metabolic and neurological decompensation (Reye-like syndrome) and caused complications. Owing to the enzyme block, 3-methylcrotonyl-CoA accumulates within the mitochondria, and, by alternative mechanisms, 3-methyl-crotonylglycine and 3-hydroxyisovaleryl-CoA are formed. Whereas 3-methylcrotonyl-glycine can directly cross mitochondrial membranes, 3-hydroxyisovaleryl-CoA can do this only after deacylation or conjugation with carnitine. After reaching the cytosol, all the compounds are readily excreted in the urine, leading to secondary carnitine deficiency.A 1-year-old boy with mild developmental delay was screened for metabolic disorders and showed in urine the metabolic pattern of isolated 3-methylcrotonyl-CoA carboxylase deficiency. He is the third of four children of healthy unrelated parents. He was born after a 38-week pregnancy with oligohydramnion. Birth weight was 2450 g. The first year of life was uneventful. On clinical investigation he was, except for mild developmental delay, without any neurological symptoms. MRI scan of the brain was normal.Laboratory investigations by gas chromatography-mass spectrometry revealed markedly elevated urinary excretion of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid. On quantitative determination of these metabolites by ~H NMR spectroscopy, the following concentrations were found: 3-methylcrotonylglycine in urine 1.25 mmol/mol creatinine, in plasma and CSF not detectable; 3-hydroxyisovaleric acid in urine 6.3mmol/mol creatinine, in plasma and CSF 600 and 540/~mol/L, respectively. Amino acids in serum were normal while L-carnitine was decreased (free 4/~mol/L, normal >20; total 10/zmol/L, normal >25). Diagnosis of MCC deficiency was established in cultured fibroblasts. Incorporation of [l-laC]isovalerate into trichloroacetic acid precipitable material of the patient's intact fibroblasts was only 3% of controls and was not increased by addition of biotin to the culture medium. In direct measurements, MCC activity was undetectable, while the activities of other carboxylases, propionyl-CoA carboxylase and pyruvate carboxylase, were within the normal range. Culturing the cells in biotin-enriched 643

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment

“…The disorder may include a large share of milder phenotypes of as yet unknown clinical significance. In Germany, expanded NBS et al [1982]; Kobori et al [1989]; Tsai et al [1989]; Jurecki and Packman [1992]; Mourmans et al [1995]; Pearson et al [1995]; Ihara et al [1997] Bartlett et al [1984]; Gitzelmann et al [1987]; Kobori et al [1989]; Layward et al [1989]; Tsai et al [1989]; Steen et al [1999]; Baykal et al [2005] Mild imbalance of blood gas analysis 5 13.5 Beemer et al [1982]; Bartlett et al [1984]; Gitzelmann et al [1987]; Kobori et al [1989]; Layward et al [1989] Bannwart et al [1992]; Lehnert et al [1996]; Murayama et al [1997]; Steen et al [1999]; Baumgartner et al [2004] Other neurological symptoms 18 48. 6 Beemer et al [1982]; Bartlett et al [1984]; Gitzelmann et al [1987]; Kobori et al [1989]; Rolland et al [1991]; Bannwart et al [1992]; Tuchman et al [1993]; Pearson et al [1995]; Lehnert et al [1996]; Murayama et al [1997]; Wiesmann et al [1998]; Steen et al [1999] pilot programs have been established since 1999 having voluntary participation and parental consent as prerequisite for participation.…”

“…The death of one individual at the age of 6.5 months appears not directly related to MCCD (cardiac arrest after accidental obstruction of the endotracheal tube) [Wiesmann et al, 1998]. Nine children [Beemer et al, 1982;Kobori et al, 1989;Tsai et al, 1989;Jurecki and Packman, 1992;Mourmans et al, 1995;Pearson et al, 1995;Ihara et al, 1997] and one adult [Visser et al, 2000] did not show any clinical signs (27%), while a large subgroup developed mild, mostly neurological, symptoms. The time points when first clinical symptoms arise are spread between the first day of life [Bannwart et al, 1992;Murayama et al, 1997;Wiesmann et al, 1998] and 4.7 years of age [Beemer et al, 1982].…”

“…1). The clinical course has been shown to vary considerably, ranging from entirely asymptomatic to death in infancy [Bannwart et al, 1992;Mourmans et al, 1995]. Severe and mild phenotypes are not clearly defined.…”

The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

“…Clinical and biochemical data of ten patients have been reported in the literature: 001 (3), 002 (2), 003 (19), 004 (20), 006 (21), 007 (22), 010 (23), 011 (24), 012 (25), and 016 (4). Fibroblasts or DNA of the remaining patients were referred by B.T.…”

3-Methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father

“…Asymptomatic relatives, such as her father, or mildly aected relatives in MCC de®ciency, as her brother, have been documented before [5,6,12]. Severe carnitine de®ciency was reported in seven of them, of whom four showed no symptoms [6,12], while three had muscular hypotonia [5]. This emphasises the importance of investigating all members of families with MCC de®ciency since aected individuals might bene®t from carnitine therapy.…”