Shi-Ping Chou

Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan.

Neonatal-type nonketotic hyperglycinemia treatment remains unsatisfactory, even if started early. A review of six patients who underwent treatment for neonatal-type nonketotic hyperglycinemia in our hospital is presented. All patients were treated with a standardized protocol. Medical histories were retrieved from case notes. All six patients had elevated cerebrospinal fluid plasma glycine levels initially. All but one had received sodium benzoate and dextromethorphan from 1 month of age. All suffered from intractable seizures and severe mental retardation, and only two patients remain alive. One patient died at 5 days of age. No resuscitation was attempted in accordance with the familys wish after genetic counseling. The prognosis of neonatal nonketotic hyperglycinemia remains poor with current treatment. Genetic counseling helps parents cope with this devastating genetic disease. (J Child Neurol 2004;19:39—42).

Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations

Ten cases of tetrahydrobiopterin (BH4) deficiency were identified in 1,337,490 newborns screened in a Chinese population in Taiwan. The high incidence of BH4 deficiency in the Taiwanese population may be explained by a founder effect, since all of the patients revealed 6-pyruvoyltetrahydropterin synthase gene mutations, and grouping N52S and P87S mutations together constituted 88.9% of the disease alleles. BH4 supplementation with restriction of high-protein foods gave control of plasma phenylalanine within normal range, and levadopa itself prevented seizure. However, the average intelligence quotient (IQ) score of these patients was only 76 ± 14 (56–98). Statistically, the age of starting medication, including 5-hydroxytrytophan (5-HTP), was inversely correlated to IQ scores of these patients. We suggest the combination of BH4, levodopa and 5-HTP as the standard protocol to commence the treatment of BH4 deficiency as early as possible, although prenatal brain damage could have existed.

A Chinese adult onset type II citrullinaemia patient with 851del4/1638ins23 mutations in the SLC25A13 gene.

Editor—Classical citrullinaemia (CTLN1) is a rare metabolic disease caused by the deficiency of argininosuccinate synthetase (ASS, E.C.6.3.4.5), which usually has its onset in neonates or young infants.1 These patients may present with acute onset of disturbance of consciousness and hyperammonaemia. ASS activity is very low in all tissues tested and over 30 mutations of the ASS gene have been identified in about 50 CTLN1 patients.2 However, in Japan, many cases with adult onset type II citrullinaemia (CTLN2) have been reported.3 A previous study in CTLN2 showed a specific deficiency of ASS protein in the liver, but no ASS gene mutation could be found.4 Recently, the gene responsible for CTLN2 was identified by homozygosity mapping.5 This gene, SLC25A13 , encodes a putative calcium dependent mitochondrial carrier protein (called citrin). A loss of organisation caused by the absence of functional citrin has been proposed to lead to the reduction of ASS protein in the liver. In this report, we present a Chinese patient with CTLN2. She was well until 40 years …

Metabolic function and liver histopathology in Reye-like illnesses

Forty children with Reye syndrome (RS) or Reye‐like illnesses were investigated to elucidate the underlying aetiologies. Extensive biochemical studies including patterns of organic acids and amino acids, liver histopathology, and, if available, a DNA approach were performed. In addition to classical RS (n= 10), the causes of Reye‐like conditions included hereditary organic acidaemias (n= 13), urea cycle defects (n= 4), mitochondrial disorders (n= 3), fulminant hepatitis (n= 2), tyrosinaemia (n= 1), valproate‐associated hepatotoxicity (n= 1), and other non‐specific generalized organic acid disorders (n= 6). It is important to collect specimens when encephalopathy with liver dysfunction of unknown causes is noted. When the underlying inherited metabolic disorders are confirmed, the prevention of the recurrence by adequate diet control and medications, and genetic counselling become possible.

Phenylalanine hydroxylase deficiency: intelligence of patients after early dietary treatment.

Neonatal screening for hyperphenylalaninemia (HPA) has been performed in Taiwan for more than 20 years. In this paper, we studied 21 cases of HPA caused by phenylalanine hydroxylase (PAH) deficiency. These patients were detected by a single newborn screening center over ten-years, and the incidence was one in 63,690. According to the initial plasma phenylalanine levels, four of the 21 patients belonged to classical phenylketonuria (PKU), seven were mild PKU, and ten were mild HPA. They commenced diet control at the age of 47 +/- 22 (17-106) days. Fourteen patients completed IQ tests, three of the 14 patients having classical PKU, five having mild PKU, and six having mild HPA. Their average IQ scores were within normal ranges (full-scale IQ 98 +/- 14, verbal IQ 92 +/- 8, and performance IQ 104 +/- 19), but patients with classical PKU tended to have lower IQ scores than other patients. Since classical PKU is rare in Taiwan, further studies including detailed neuropsychological tests will be required to evaluate the effect of treatment in this group of patients.

Phenotype and genotype analyses of ornithine transcarbamylase deficiency in Taiwanese

BACKGROUND AND PURPOSE Ornithine transcarbamylase (OTC) deficiency is the most common inherited urea cycle disorder. It is an X-linked semidominant disease with variable severity affecting both males and females. The characteristics and course have not been assessed in Taiwanese. This study analyzed the phenotype and genotype of OTC deficiency in Taiwanese. METHODS During the period from January 1993 to December 2001 inclusive, 8 patients had the diagnosis of OTC deficiency by the criteria of hyperammonemia, hypocitrullinemia, and orotic aciduria. All 10 exons of the OTC gene were analyzed for mutations. RESULTS Among the 8 cases, 3 belonged to the early-onset group (initial symptoms before or equal to age 28 days) and 5 belonged to the late-onset group (median onset age, 18 months; range, 8 months to 52 years). One case in the former group, and 4 cases in the latter group survived (mean survival, 8.2 years; range, 3 to 16 years). The average time between initial symptoms and diagnosis was 60 months in the late-onset group. Analysis of the OTC genes detected 5 different mutations in 5 patients, including 3 novel mutations: 42delT, 652G>A, and 791C>A. IQ tests, conducted in 3 patients, revealed low scores (mean, 53; range, 40 to 72). CONCLUSIONS Both early-onset and late-onset cases of OTC deficiency were identified in Taiwanese. The diagnosis was delayed in these patients, and their outcomes were poor. All mutations detected were different and most of them have not been reported in other populations, which may explain the variability of phenotypes in Taiwanese patients.