| Two brothers are described who had juvenile-onset DHPR deficiency. Both were considered normal until six years of age when they developed a fluctuating and progressive encephalopathy combining mental retardation, epilepsy, pyramidal, cerebellar and extrapyramidal signs. ( info) |
2/203. Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis. The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient. This can be problematic when only part of the gene is examined or when relevant dna alterations are not recognized by standard methods. We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR. Diagnostic dna analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents. ( info) |
3/203. Progeny, pregnancy and phenylketonuria. Two sisters were diagnosed as having phenylketonuria at the age of 13 years and eight years and having Wechsler IQs of 48-58 and 71-81 respectively. Neither girl was treated with diet. At the age of 21 years the older girl became pregnant. Her blood phenylalanine level was 23mg/100 ml. A low phenylalanine diet, instituted from the 10th week of gestation, maintained her blood phenylalanine levels below 6mg/100ml for the rest of the pregnancy. A female baby, of birth weight 3216g and normal skull size, was delivered at term. The baby died at 14 days of congenital heart disease. pregnancy in a phenylketonuric woman carries high risks to the fetus. A generation of treated phenylketonuric girls is approaching reproductive life, and doctors and the girls themselves need to be alerted to these risks and the need for strict dietary control during pregnancy. There are probably unrecognised women in the community with phenylketonuria or with hyperphenylalaninaemia whose babies face similar risks. Identification of these women could be achieved by antenatal Guthrie testing. ( info) |
4/203. Late diagnosis of maternal PKU in a family segregating an arylsulfatase [corrected] E mutation causing symmetrical chondrodysplasia punctata. Mutations in the arylsulfatase E gene, located on the x chromosome, have been shown to cause chondrodysplasia punctata (CDP). A substitution of arginine with serine at amino acid 12 (R12S) was identified in a patient with typical features of mild symmetrical CDP including mild mental retardation. The proband was institutionalized and was found to have seven full and half siblings all of whom were microcephalic. Six siblings are alive and all are mentally retarded. The mother is borderline retarded. The mother and three daughters are carriers of the R12S change, but do not appear to have CDP. A son and three other daughters do not carry the R12S change. Further studies revealed that the mother had phenylketonuria (PKU) and the children maternal PKU. This suggests that the R12S change is not the primary cause of short stature, microcephaly, and mental retardation in this family. The relationship between CDP and PKU, both of which can cause short statue and mental retardation, is discussed. ( info) |
5/203. An investigation into diet treatment for adults with previously untreated phenylketonuria and severe intellectual disability. There is evidence in the literature which suggests that adults with previously untreated phenylketonuria (PKU) benefit from a low phenylalanine diet. A prospective study providing a phenylalanine-restricted diet to five subjects with severe intellectual disability arising from untreated PKU is reported. Physical, social and behavioural measures were used to monitor the effects of the diet Four out of the five subjects derived considerable benefit. It is concluded that the restricted diet is worth trying in most individuals with previously untreated PKU, and that possible benefits are in the areas of concentration, alertness, mood, irritability and adaptive behaviour. ( info) |
6/203. serum tryptophan to large neutral amino acid ratio and urinary tryptophan in three patients with phenylketonuria in a family. A clinical and biochemical study. In this work clinical and biochemical findings are presented in three untreated children with phenylketonuria in a family. Their clinical pictures were not typical for classical phenylketonuria. As a result, diagnosis was missed. It has been shown that patterns of large neutral amino acids in serum and urine were somewhat different. Significantly lower serum TRP/LNAA ratio was observed in all patients with phenylketonuria, compared to the control group. These findings suggest that there was subnormal tryptophan availability in the central nervous system leading to its decreased metabolism through the serotonin and kynurenine pathways. These results may explain decreased children's growth and their mental deficiency. ( info) |
7/203. guanosine triphosphate cyclohydrolase I deficiency: a rare cause of hyperphenylalaninemia. Tetrahydrobiopterin (BH4) deficiencies are a heterogeneous group of disorders caused by a defect in two of the three enzymes involved in its biosynthesis or in the two recycling enzymes. Except for the deficiency of dehydratase, an enzyme catalyzing a reaction in the recycling pathway, all other variants of BH4 deficiency are characterized by developmental delay, progressive neurological deterioration, hypokinesis, drooling, swallowing difficulty, truncal hypotonia, increased limb tone, myoclonus and brisk deep tendon reflexes. A deficiency of guanosine triphosphate cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway of BH4, is described in a 14-month-old male infant with hyperphenylalaninemia, developmental delay, hypertonia of the extremities, seizures, feeding difficulties, and vomiting. Urinary pteridine screening revealed very low levels of neopterin and biopterin which was highly suggestive of GTPCH deficiency. Low cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid concentrations, together with no detectable neopterin and decreased concentrations of biopterin and folate, agreed with the diagnosis of GTPCH deficiency. Subsequently measured neopterin and biopterin synthesis in cytokine-stimulated skin fibroblasts confirmed GTPCH deficiency, albeit indirectly. The patient showed marked improvement on a low-protein low-phenylalanine diet with neurotransmitter precursor administration. The favorable outcome in this patient clearly shows that not only newborns with elevated phenylalanine levels but also older children with neurological signs and symptoms should be screened for a BH4 deficiency in order to have maximum benefit of the treatment. ( info) |
8/203. Isolated central form of tetrahydrobiopterin deficiency associated with hemizygosity on chromosome 11q and a mutant allele of PTPS. 6-Pyruvoyl-tetrahydropterin synthase (PTS or PTPS) is involved in tetrahydrobiopterin (BH(4)) biosynthesis, the cofactor for various enzymes including the aromatic amino acid hydroxylases. Inherited PTPS deficiency is a heterogeneous disease with different phenotypes leading to BH(4) depletion. The severe form of PTPS deficiency causes hyperphenylalaninemia and monoamine neurotransmitter deficiency, whereas the mild form gives rise to hyperphenylalaninemia only. From 228 patients with PTPS deficiency at least 32 different mutant alleles have been identified on its corresponding gene, located on chromosome 11q22.3-q23.3. Here we describe a new allele from a child with PTPS deficiency who exhibited a mild but transient form of hyperphenylalaninemia, yet was deficient in CSF monoamines. The patient was found to carry, on her genomic dna and cDNA, a homozygous A>G transition, leading to PTPS codon alteration Tyr99 to Cys (Y99C). The mother and several members of the maternal family were carriers of the Y99C allele, also verified by the reduced PTPS enzyme activity in erythrocytes. By cytogenetic, molecular, and FISH analyses, a de novo deletion spanning from 11q14 to 11q23.3 on the patient's paternal chromosome was mapped, establishing hemizygosity of the Y99C allele. The PTPS mutation observed in this patient generates a novel phenotype with an apparently isolated central form of BH(4) deficiency. ( info) |
9/203. diagnosis and treatment of 6-pyruvoyl-tetrahydropterin synthase deficiency. We detected a case of 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency during a neonatal mass screening and considered the differentiation and treatment of the peripheral form of PTPS deficiency. Although single treatment of BH4 had been started, because of the lowered biopterin (B) value, elevated neopterin (N) value, and N/B ratio in the cerebrospinal fluid (CSF), the peripheral form was judged negative and combined treatment with L-dopa and 5-hydroxy tryptophan (5-HTP) was started. Follow-up study will be necessary to confirm the diagnosis of PTPS deficiency. ( info) |
| Phenylketonuria (PKU), an autosomal recessive disorder caused be a deficiency of hepatic phenylalanine hydroxylase (PAH), is clinically very heterogeneous. At the molecular level, more than 400 mutations in the PAH gene are known to date, which in different genotype combinations could account for biochemical and clinical variability of symptoms. in vitro expression studies on R68G and R68S mutations causing mild phenylketonuria are presented. ( info) |