Aminoacylase I deficiency: a novel inborn error of metabolism.

This is the first report of a patient with aminoacylase I deficiency. High amounts of N-acetylated amino acids were detected by gas chromatography-mass spectrometry in the urine, including the derivatives of serine, glutamic acid, alanine, methionine, glycine, and smaller amounts of threonine, leucine, valine, and isoleucine. NMR spectroscopy confirmed these findings and, in addition, showed the presence of N-acetylglutamine and N-acetylasparagine. In EBV transformed lymphoblasts, aminoacylase I activity was deficient. Loss of activity was due to decreased amounts of aminoacylase I protein. The amount of mRNA for the aminoacylase I was decreased. DNA sequencing of the encoding ACY1 gene showed a homozygous c.1057 C>T transition, predicting a p.Arg353Cys substitution. Both parents were heterozygous for the mutation. The mutation was also detected in 5/161 controls. To exclude the possibility of a genetic polymorphism, protein expression studies were performed showing that the mutant protein had lost catalytic activity.

Dancing eye syndrome and hyperphosphatasemia.

An 11-month-old boy with a relapsing dancing eye syndrome associated with elevation of serum alkaline phosphatase, lactate dehydrogenase, and aminotransferase activities is reported. During two clinical episodes the serum alkaline phosphatase activity increased up to four times the upper reference limit, remained elevated for a few weeks and normalized gradually in parallel with clinical improvement under steroid therapy. We found no evidence of liver or bone pathology nor of a neural crest tumor. The association between dancing eye syndrome and hyperphosphatasemia has not yet been described. The beneficial effect of the steroid therapy strengthens the hypothesis of an autoimmune origin.

Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy.

Evidence is emerging that primary systemic carnitine deficiency, a potentially lethal but eminently treatable inborn error of fatty acid oxidation, involves a cellular defect in the uptake of carnitine. We present four unrelated children with primary carnitine-responsive cardiomyopathy, weakness (with or without hypoketotic hypoglycemic encephalopathy), low serum and/or tissue carnitine concentrations, and severe renal carnitine leak. Dicarboxylic acids were absent in the urine of three children who were tested, and all four had a rapid and dramatic improvement in cardiac function, strength, and somatic growth after carnitine therapy. We studied carnitine uptake in cultured skin fibroblasts from all four children and seven of the eight healthy nonconsanguinous parents. [3H]L-carnitine uptake was evaluated in vitro under linear time kinetics. Substrate concentrations were varied from 0.1 to 1000 microM. Physiologic uptake was determined at carnitine concentrations between 0.1 and 50 microM. Nonspecific uptake was determined at a concentration of 10 mM. The four patients had negligible uptake throughout the physiologic range, implying a marked deficiency in the specific high-affinity, low-concentration, carrier-mediated uptake mechanism. At a concentration of 5 mumol/L, the mean velocity of uptake in the four patients was 2% of control values. Their parents showed intermediate maximal rates of carnitine uptake ranging from 13 to 44% of control Vmax values, but normal Km values, suggesting that the heterozygotes had a reduced number of normal functioning carnitine transporters. The observed reduction in Vmax values for the parents supports an autosomal recessive inheritance pattern and may be a more sensitive indicator of heterozygosity than serum carnitine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Multimodal evoked potential studies in leukodystrophies of children.

Evoked potentials were studied in 22 children with leukodystrophy [10 metachromatic leukodystrophy (MLD), 4 Pelizaeus-Merzbacher (PM), 3 Krabbes, 2 adrenoleukodystrophy (ALD), and one each of Alexander's, Canavan's and multiple sulphatase deficiency (MSD) diseases]. The ABRs were abnormal in all patients (except for the younger ALD), but varied with the type of leukodystrophy. The PM and Krabbes patients had abnormal ABRs with a loss of the rostral waves, accompanied in Krabbes with delayed I-III interpeak latencies; in MLD, ALD and MSD prolonged interpeak latencies were found. Three patients who had no clinical signs, but were positively diagnosed as MLD on the basis of absent arylsulphatase A, also had abnormal ABRs. The SEPs were abnormal in all patients. Cortical SEPs were absent in 16 and abnormal in 5 who were in the earlier stages of their disease. Cervical SEPs were within normal limits except for the Krabbes and MLD patients studied, who showed peripheral slowing. The VEPs were normal in only 6 and, unlike the ARBs and SEPs, did not seem to covary with clinical severity across the various leukodystrophies but did correlate with disease progression. Thus, multimodal EPs are useful in the diagnostic differentiation of the leukodystrophies.

Prognostic utility of SEPs in comatose children.

Somatosensory evoked potentials (SEPs) were recorded in 73 comatose children upon admission to the intensive care unit and were studied in respect to initial neurologic status and final outcome. SEP results were graded normal, increased interpeak latencies, and unilaterally or bilaterally absent cortical responses. Of the 50 patients with Glasgow Coma Scale scores less than 7 upon admission, only 3 had SEPs within the normal range, while 37 had unilaterally or bilaterally absent SEPs. None of the 27 who died had normal SEPs; 1 had increased interpeak latencies, 26 had more abnormal SEPs. The 14 with normal outcomes had normal (9 patients) or delayed (4 patients) SEPs; the latter group returned to normal within a few days. Repeat SEP studies were performed in 33 patients. SEPs were relatively stable during the intensive care observation, with the exception of 6 patients with Reye syndrome. Subsequent studies are recommended in all patients, but are essential in those with Reye syndrome in order to be useful prognostically. The utility of SEPs did not vary as a function of coma etiology. These data support the usefulness of SEPs in early prediction of neurologic outcome in comatose children.

Evoked potentials in comatose children: auditory brainstem responses.

Auditory brainstem responses (ABRs) were studied retrospectively in 80 children (ages 4 days to 19 years) with coma of various etiologies to determine their value as a predictor of outcome. The ABRs performed shortly after admission were analyzed with respect to initial neurologic status and final outcome. Of the 49 patients with initial Glasgow Coma Scale scores of less than 7, only 21 had severely abnormal ABRs. Eighteen had normal ABRs. Of these 18 patients, 10 died, and 8 were neurologically abnormal. Prolonged interpeak latencies were seen in 16 patients who experienced a range of clinical severity. Of the total of 17 children with absent ABRs or only the presence of waves I/III, three children survived, two with minimal neurologic abnormalities and one in a vegetative state. The efficacy of ABRs in comatose children as an early prognostic indicator was not confirmed by this study.