Genotypic and phenotypic correlations of biotinidase deficiency in the Chinese population.

Biotinidase deficiency is an autosomal recessive disorder that affects the endogenous recycling and release of biotin from dietary protein. This disease was thought to be rare in East Asia. In this report, we delineate the phenotype of biotinidase deficiency in our cohort. The genotypes and phenotypes of patients diagnosed with biotinidase deficiency from a medical center were reviewed. The clinical manifestations, laboratory findings, and molecular test results were retrospectively analyzed. A total of 6 patients were evaluated. Three patients (50%) were diagnosed because of a clinical illness, and the other three (50%) were identified by newborn screening. In all patients, the molecular results confirmed the BTD mutation. The three patients with clinical manifestations had an onset of seizure at the age of 2 to 3 months. Two patients had respiratory problems (one with apnea under bilevel positive airway pressure (BiPAP) therapy at night, and the other with laryngomalacia). Hearing loss and eye problems were found in one patient. Interestingly, cutaneous manifestations including skin eczema, alopecia, and recurrent fungal infection were less commonly seen compared to cases in the literature. None of the patients identified by the newborn screening program developed symptoms. Our findings highlight differences in the genotype and phenotype compared with those in Western countries. Patients with biotinidase deficiency benefit from newborn screening programs for early detection and management.

Hepatocyte transplantation in bile salt export pump-deficient mice: selective growth advantage of donor hepatocytes under bile acid stress.

The bile salt export pump (Bsep) mediates the hepatic excretion of bile acids, and its deficiency causes progressive familial intrahepatic cholestasis. The current study aimed to induce bile acid stress in Bsep(-/-) mice and to test the efficacy of hepatocyte transplantation in this disease model. We fed Bsep(-/-) and wild-type mice cholic acid (CA) or ursodeoxycholic acid (UDCA). Both CA and UDCA caused cholestasis and apoptosis in the Bsep(-/-) mouse liver. Wild-type mice had minimal liver injury and apoptosis when fed CA or UDCA, yet had increased proliferative activity. On the basis of the differential cytotoxicity of bile acids on the livers of wild-type and Bsep(-/-) mice, we transplanted wild-type hepatocytes into the liver of Bsep(-/-) mice fed CA or CA + UDCA. After 1-6 weeks, the donor cell repopulation and canalicular Bsep distribution were documented. An improved repopulation efficiency in the CA + UDCA-supplemented group was found at 2 weeks (4.76 ± 5.93% vs. 1.32 ± 1.48%, P = 0.0026) and at 4-6 weeks (12.09 ± 14.67% vs. 1.55 ± 1.28%, P < 0.001) compared with the CA-supplemented group. Normal-appearing hepatocytes with prominent nuclear staining for FXR were noted in the repopulated donor nodules. After hepatocyte transplantation, biliary total bile acids increased from 24% to 82% of the wild-type levels, among which trihydroxylated bile acids increased from 41% to 79% in the Bsep(-/-) mice. We conclude that bile acid stress triggers differential injury responses in the Bsep(-/-) and wild-type hepatocytes. This strategy changed the balance of the donor-recipient growth capacities and was critical for successful donor repopulation.

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 family's 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.

Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation.

The spectrum of phenylalanine hydroxylase (PAH) gene mutations was determined in 25 families of hyperphenylalaninemia identified by a neonatal screening program in Taiwan. The coding sequence and exon-flanking intron sequences of PAH gene were amplified and sequenced. Mutations were identified in forty-five of the 50 chromosomes. R241C was the most common mutation (36% of the chromosomes), followed by R408Q (14% of the chromosomes). The remaining mutations were rare and seven mutations have not been reported before: p.F233L (c.697T>C), p.R252Q (c.756G>A), p.E286K (c.856G>A), p.G312V (c.935G>T), p.P314T (c.940C>A), p.I95del (c.284_286delTCA), and p.T81fsX6 (c.241_256del). Both p.R241C and p.R408Q are classified as mild phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) mutation, which may explain the fact that classical PKU is very rare in Taiwan (n=4, or one in 413,035). This strong founder effect for the p.R241C mutation has been described neither in the Caucasian populations, nor in other reports from Chinese. Since most of the populations in Taiwan are derived from Southeastern China, the spectrum of PAH gene mutations in Southeastern China should be different from other Chinese populations. This report not only disclose a specific spectrum of PAH gene mutation in Taiwan, but may also give clues to the movement of populations in Mainland China.

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.