No abstract available.
Phenylketonurias*

No abstract available.
Phenylketonurias*

In this untreated classic phenylketonuria (PKU) case, mental retardation is severe; however, there have been individuals-like the mother of this case who have escaped mental retardation and all the other potential sequelae of phenylketonuria, despite having high blood phenylalanine levels, and very poor dietary control. It appears that they have nearly normal brain phenylalanine levels despite high blood phenylalanine (Phe) levels. A number of studies have now demonstrated considerable variability in blood vs. brain phenylalanine levels in phenylketonuria patients. Outcome of phenylketonuria appears to be related to brain phenylalanine levels. We report a case of "undiagnosed" maternal phenylketonuria syndrome. A female infant had low birth weight (2,400 g) with microcephaly. We examined her family and discovered that her mother was an undiagnosed phenylketonuria patient with a borderline intelligence quotient (IQ). The infant's sister, six years old, was diagnosed with phenylketonuria at the age of four years was mentally retarded and had received an operation for cleft lip and palate. the sister had also had a low birth weight (2,300 g). Her sister and mother were compound heterozygotes (mother: R243Q/Y325X; sister: Y325X/P407S). The infant and father were heterozygous carriers (baby: R243Q/-; father: P407S/-).
Brain ; Cleft Lip ; Fathers ; Female ; Heterozygote ; Humans ; Infant ; Infant, Low Birth Weight ; Infant, Newborn ; Intellectual Disability ; Intelligence ; Mentally Disabled Persons ; Microcephaly ; Mothers ; Palate ; Parturition ; Phenylalanine ; Phenylalanine Hydroxylase ; Phenylketonuria, Maternal ; Phenylketonurias ; Siblings ; United Nations

The Guthrie bacterial inhibition assay (BIA) tests for elevated phenylalanine (PHE) by measuring B. subtilis growth zone density in an agar medium. Dried blood spots with elevated PHE on initial BIA screening undergo repeat BIA testing and thin-layer chromatography (TLC). Specimens with elevated PHE by TLC or BIA on second-tier testing require recall. To streamline PKU screening and reduce the recall rate, we tested a modified BIA protocol incorporating autoclaving of dried blood spots. Autoclaving improves growth zone appearance and has been previously reported to reduce the number of specimen requiring repeat testing. From June to October 2006, dried blood spot samples with initially elevated PHE were autoclaved at 110°C for 5 min, then retested by BIA. Samples with still-elevated PHE were analyzed by TLC. 1078 of 37,268 samples (2.89%) had initially elevated PHE. After autoclaving, 1036 no longer exhibited elevated PHE decreasing to 42 (0.11%) the number requiring TLC. By comparison, the unmodified algorithm resulted in 3.14% of samples received from July - December 2006 requiring both repeat BIA and TLC testing. We have since modified our PKU screening algorithm to require repeat BIA testing from autoclaved samples prior to TLC analysis. This translates to a significant reduction in time and resources for second-tier testing and follow-up, and prevents stress for the parents of a newborn who would have been recalled unnecessarily.

OBJECTIVETo investigate the type and frequency of mutations in exon 7 of phenylalanine hydroxylase (PAH) gene among children with phenylketonuria (PKU) in Ningxia, China and to provide a basis for the genetic diagnosis and prenatal diagnosis of PKU in this region.

METHODSDirect sequencing of PCR product was performed to analyze the sequences of exon 7 and its flanking introns of 146 PAH alleles in 73 children with typical PKU (39 cases of Hui nationality and 34 cases of Han nationality) in Ningxia.

RESULTSSix mutations were detected, including R243Q (14.4%), R241C (6.8%), IVS7+2T→A (2.7%), L255S (0.7%), G247V (0.7%), and G247R (0.7%). The overall frequency of mutations (missense mutation and splice site mutation) in exon 7 was 26.0% (38/146). The detection rate of R241C mutation was significantly higher in children of Hui nationality than in children of Han nationality(10% vs 3%; P<0.05).

CONCLUSIONSIn Ningxia, R243Q mutation in exon 7 of PAH gene is most common in children with PKU, followed by R241C. The frequency of R241C mutation in exon 7 of PAH gene varies between children with PKU of Hui and Han nationality.

OBJECTIVETo establish a hyperphenylalaninemia related genes screening method using Ion Torrent Personal Genome Machine (PGM) for early detection and differential diagnosis of hyperphenylalaninemia (HPA).

METHODSThree children with known HPA mutations and a healthy control were used for setting up the method. Ten children with HPA with known mutations were recruited for validating the method. Ion Ampliseq PCR was used to amplify the 5' and 3' untranslated region, coding sequence, and flanking introns of PAH, GCH1, PTS, QDPR, and PCBD1 genes. After the enrichment with the Ion OneTouch system, the products were sequenced by PGM. Data from the PGM were processed with Torrent Suite v2.2 software package. All variations were confirmed by Sanger sequencing.

RESULTSFor the 4 samples, the PGM output was 94.22 Mb, with approximately 99.5% of reads mapping to the target regions. Among these samples, we detected 74 variations (28 positions) including 6 known mutations. Compared with database and results of Sanger sequencing, 55 (18 positions) polymorphisms and 13 (4 positions) false positive calls were confirmed. For the 10 samples, all the known mutations were successfully identified.

CONCLUSIONIon Torrent PGM sequencing is suitable for screening genetic mutation underlying HPA from the perspective of metabolic pathways, which can meet the clinical demand for individualized diagnosis and treatment.

PURPOSE: Phenylketonuria(PKU) is an inborn error of metabolism and a genetic disorder resulting from a deficiency of phenylalanine hydroxylase(PAH) and decreased activity of tetrahydrobiopterin(BH4).In this study the correlation between the DNA mutation and clinical manifestations was investigated and PAH DNA mutations were compared bewteen Asian and Caucasian populations. METHODS: DNA was isolated from peripheral leukocytes. The PAH gene was amplified by Polymerase Chain Reaction(PCR) and the sequence was analyzed with Multiplex Ligation-dependent Probe Amplification(MLPA). RESULTS: We characterized the PAH gene of 102 independent Korean patients with PKU. PAH nucleotide sequence analysis revealed 44 different mutations, including 10 novel mutations comprising 9 missense mutations(N207D, K95del, A447P, G344D, P69S, S391I, A202T, G103S, and I306L) and 1 novel splice-site variant mutation(IVS10-3C>G). R243Q was the most prevalent mutation in this study. A259T has not previously been reported in Asian populations, but we found that this mutation had a frequency of 10.1% in our study. Furthermore, the genotypes of BH4 responsive patients were analyzed and were divided into two groups: BH4 medication-only group and BH4 medication with diet therapy group. In the BH4 medication-only group and BH4 medication with diet therapy group, R241C was the most common mutation. CONCLUSION: Novel mutations in the PAH gene of PKU patients are still being discovered. Additional information as to the frequency of mutations in the tetrahydrobiopterine responsive gene is also accumulating. We anticipate that knowledge of these PKU gene mutations will assist the diagnosis, genetic counseling, and therapeutic treatment of PKU patients in future.
Asian Continental Ancestry Group ; Base Sequence ; DNA ; Genetic Counseling ; Genotype ; Humans ; Leukocytes ; Phenylalanine ; Phenylalanine Hydroxylase ; Phenylketonurias

Tetrahydrobiopterin(BH4) deficiency is a rare type of hyperphenylalaninemia and usually leads to a progressive neurologic deterioration despite early dietary control of blood phenylalanine concentration. We experienced two cases of BH4 deficiency in brother and sister, confirmed by biochemical study of blood and urine. They had suffered from a progressive neurologic illness such as mental retardation, severe hypotonia, seizure, and athetotic movements started at 3 months of their age. Blood amino-acid analysis showed mild hyperphenylalaninemia with elevated urinary neopterin, and reduced urinary biopterin. Their neurologic deteriorations were dramatically improved after replacement of BH4 and dopamine agonist.
Biopterin ; Dopamine Agonists ; Humans ; Intellectual Disability ; Muscle Hypotonia ; Neopterin ; Phenylalanine ; Phenylketonurias* ; Seizures ; Siblings

PURPOSE: While treating 14 phenylketonuria(PKU) patients, we evaluated bone density, changes in bone age, andbony changes such as spiculation or metaphyseal widening. MATERIALS AND METHODS: A total of 14 PKU patients agedbetween 1 month and 14 years(mean, 6.4 years) were under dietary treatment. Eight and eleven patients underwentradiography of the left hand and wrist and bone densitometry(BMD) of the lumbar spine, respectively. The resultswere reviewed with regard to abnormal bony changes, delayed bone age, and osteopenia. Patients were assigned toeither the early or late treatment group, depending on whether or not dietary therapy was started before 3 monthsof age. Those in whom a blood phenylalanine level of under 10 mg/dl was maintained were assigned to the 'goodcontrol' group; others were classified as 'variable control'. The findings of radiographs of the left hand andlumbar BMD were evaluated in relation to the time of dietary therapy, and adequacy of treatment. RESULTS: Onlumbar BMD, four of 11 patients (36%) showed reduced bone density of more than 1 S.D. None of the 11 who underwentradiography of the left hand showed bony abnormalities such as spiculation or metaphyseal widening. In four of the11, bone age was less than chronological age by at least one year. According to Fisher's exact test there was norelation between delayed bone age , osteoporosis and the time and adequacy of dietary therapy (p >0.05). CONCLUSION: None of the 14 PKU patients who underwent dietary therapy had bony abnormalities such as spiculationor metaphyseal widening. In four of the 11, bone age was at least one year less than chronological age, and onlumbar BMD, osteoporosis was seen. For the evaluation of bone change in PKU patients, plain radiography and BMDare thus complementary.
Bone Density ; Bone Diseases, Metabolic ; Hand ; Humans ; Metabolism ; Osteoporosis ; Phenylalanine ; Phenylketonurias* ; Radiography ; Spine ; Wrist

PURPOSE: The purpose of this study was to evaluate MR findings among patients with phenylketonuria (PKU). MATERIALS AND METHODS: Eleven patients with biochemically documented PKU underwent MR imaging ; In nine, the typical classic form was seen, and two were atypical. We evaluated signal intensity, the distribution of abnormal signal intensity, the extent of brain atrophy, and possible clinical correlation between IQ scores of the patients and abnormal signal intensity. RESULTS: Varying degrees of symmetrical high signal intensity were noted on T2-weighted sequences in the parietal white matter of six patients ; the periventricular deep white matter was most seriously affected, but there was no evidence of brain atrophy. In one advanced case, high signal intensity of both the parietal and frontal lobes was seen on T2-weighted images, and brain atrophy and gyriform enhancementon contrast enhanced T1-weighted images. In five patients, findings were normal. no abnormality was found in the basal ganglia, brain stem or cerebellum. There was no correlation between IQ level and severity of high signal intensity. CONCLUSION: Although MR findings were nonspecific, PKU patients showed symmetrical high signal intensity, predominantly in the peritrigonal region. In the advanced case, the lesion, as seen on T2-weighted images, extended to the periventricular and subcortical white matter.
Atrophy ; Basal Ganglia ; Brain ; Brain Stem ; Cerebellum ; Frontal Lobe ; Humans ; Magnetic Resonance Imaging* ; Phenylketonurias* ; Rabeprazole