ABSTRACT
One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6-pyruvoyltetrahydropterin synthase (PTS) gene-disrupted (Pts(-/-)) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts(-/-) mice by transgenic introduction of human PTS cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency. The DPS-rescued (Pts(-/-), DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency. Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.
Subject(s)
Biopterins/analogs & derivatives , Dopamine/metabolism , Norepinephrine/metabolism , Phenylketonurias/physiopathology , Phosphorus-Oxygen Lyases/genetics , Adrenal Glands/physiology , Animals , Biopterins/deficiency , Biopterins/metabolism , Dopamine beta-Hydroxylase/genetics , Gene Expression Regulation, Enzymologic , Genes, Reporter , Growth Disorders/genetics , Growth Disorders/mortality , Growth Disorders/physiopathology , Humans , Mesencephalon/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neostriatum/physiology , Nucleus Accumbens/physiology , Olfactory Bulb/physiology , Phenylketonurias/genetics , Phenylketonurias/mortality , Phosphorus-Oxygen Lyases/metabolism , Promoter Regions, Genetic , Tyrosine 3-Monooxygenase/metabolism , WeaningABSTRACT
The records of 17 people with intellectual disability and untreated phenylketonuria (12 females and five males), who were resident in the Stoke Park Group of Hospitals, Bristol, England, 25 years ago, were re-examined for life expectancy. Six subjects had died (five females and one male). The oldest deceased female was 69 years of age. The average age at death was 55.8 years. Eleven subjects were still alive (seven females and four males). The oldest living male was 79 years of age. The average age of the survivors was 55.7 years.
Subject(s)
Life Expectancy , Phenylketonurias/mortality , Adult , Aged , England/epidemiology , Female , Humans , Institutionalization/statistics & numerical data , Intellectual Disability/mortality , Male , Middle AgedSubject(s)
Phenylketonurias/mortality , Adolescent , Adult , Aged , Child , Female , Hospitalization , Humans , Intellectual Disability , Male , Middle AgedABSTRACT
By January 1973, a total of 146 homozygotes (born between 1875 and 1972) for phenylketonuria (PKU) had been identified in Norway. This is an incomplete total, particularly in respect of PKU cases born before 1950, because of the PKU mortality rate. Between 1951 and 1972, the observed incidence of PKU was unchanged at 0.07 plus and minus 0.01 per 1000 live births. Haematological screening of about one-third of all births in Norway between 1966 and 1972 indicated an incidence of 0.07 plus and minus 0.02 per 1000 liveborn screened. As expected, this was well below the observed incidence of 0.11 plus and minus 0.01 per 1000 from screening data from Denmark, and considerably higher than the observed value of 0.03 plus and minus 0.01 per 1000 screened in Sweden. In comparison, indirect estimates, using the inbreeding coefficent of parents of PKUs and that of the general population in Norway in the corresponding years (1874-1972), suggested a fall in incidence of PKU in Norway from 0.14 plus and minus 0.15 per 1000 live births in 1918, to 0.08 plus and minus 0.08 per 1000 in 1941, and to 0.06 plus and minus 0.06 per 1000 live births in 1972. The present level of inbreeding in Norway (obtained from the Medical Registration of Bith) is discussed and compared with information in the 1891 census, with the parish registers between 1889and 1902, and with the parochial lists for the years 1903-1941.
