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(Continued) Linkage Mapping and Polymorphisms

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(Continued) Linkage Mapping and Polymorphisms Inborn Errors of Metabolism (continued) 965 966 Re-institution of dietary treatment in a PKU adult patient: cdinical and MRI Common point mutations in four patients with the late infantile form of improvement after one yer. (( E. Z h, A. Morronel, M.A DonatiI, E. galosialidosis. ((X.Y. Zhoul6, R. Willemsen2, N. Gillemans', A. Morroe3, Psquni', C Fonda2.)) 'Dept. of Pediatrica, University of Florence and 2Unit of P. Strisciuglo', G. Andria4, D.A. Applegarths and A. d'Azlzo.)) 'Dept. of Neuroradlology, Prato, Italy. Intro by: Luciano Felicetti Cell Biology and 2Clinical Genetics, Erasmus University, Rotterdam, The Retrospective and prospective studies Indicate deteroration of cognition and Netherlands; 3Dept. of Pediatrics, University of Florence, Italy; 'Dept. of neurpsyololcal performance in some PKU patients after treatment Pediatrics, University of Naples, Italy; and Dept. of Pediatrics, University of withdrawL. We report the results ofrestitution ofdiet low in pbenylalanine in Britiach Columbia, Vancouver, Canada. Intro. by E.F. Neufeld. a adult PKU patient with progreulve demyelinating clopathy. The dia of classical PKU was made at age of 4 years and d Uatment was Galactosialidosis is a lysosomal storage disorder caused by mutations in the sarted At 11 years the therapy was stopped: he was able to walk alone, to run, gene encoding the protective protein/cathepsin A. Patienta with the late to cycle, to climb stairs, to write. Since the age of 19 years be had seizures. At 21 infantile phenotype differ from early infantile or juvenile/adult types in that yeas he showed weakness, stiffness, dysarthria, difficulty in gait and swallowing. they have a better prognosis and no mental retration We have analyzed four Later ewas wheelchair-bound and his mother noted gradual deterioration in these his perforannce and behaviour. Al 30 years he came on our examination: he had of paties: one American, two Canadians and one Italian. em aery spastic eraple, ptural tremor of the head and bands, hyperrelexia with of their clinicl symptoms varies slightly, the American patient being the ks clonus CT and MRI of brain showed extensive demyelination of cerebral affected and the Italian the most. The paiens were found to be either homozy- henmspheres Serum p ylanine conentration was 1689 M. He was newly gous or compound eterozygous for two point mutons resulting in the ld on die low in phenylalanine (500 mg/die) One year lter he sbowed sbstitution of Phe42 to Val and of Tyrul to Am. TM American patient caris improvement or his performance and behaviour, decreased muscle tone, no the Auni amino acid change encoded by one allele and a single base deletion tremors; he was able to walk few metres, but spasticity was stifl apparent. MRI in the other, identfied as null allele by the absence of the c g showed a reduction of the extension and n in signal intensity of mRNA. Both Canadian piens have the A su o and one of them altered white matter are indicating partial re en The pomsibility of a pr ve demyelinig enbalopaty in adult PKU is a genetic compound for the two point mutations. The Val"2 amino acid patients without a trtd diet underlin the importance ofa lifelong dietary change is present in both alleles of the Italian patent. Analysis of the two treatment. Te re-institution of die therapy in adult PKU can avoid further mutant protective proteins in COS-1 cells de that the Asn mutati- brain damage or Improve, as our cme shows, reversible demyelination. Further on has a milder effect on the biochemical properties of the protin: the results studies on larger number of patients are needed to know if only certain patients might explain the clinical herety observed within this category of develope signcant abnormalities of cerebral white mater. An association galactosialidosis patients. between the genthype and the development of brain damage is probably 6 Address as from July 1, 1993: Dept. of Genetics, St. Jude Children's Re- search Hospital, Memphis, TN. Linkage Mapping and Polymorphisms 967 968 Mapping of a gene for rod monochromacy. ((K.L Anderson', R.A. Lewis', L Further evidence for a locus for familial juvenil nephronophthsis (NPHO Baird2, M.F. Leppert2, J.R. Lupskil)). 'Baylor College of Medicine, Houston, on chMosome 2p and evidence for genetic hetenIty. ((C Atignacl, M Texas, 2Unlversty of Utah Medical Center, Salt Lake City. Medhioubl, F. Benesayl, J. enn2, C Schroedr3, J. We 4, D. Cohen2, R. Habibl.)) IlqNISM U192, H6pltal Necker, Paris, 2CEPH, Paris, Rod monochromacy is Inherited as an autosomal recessive trait, 3Universty Hospital Ninegen, The Netherlands. }G;rthon, Evry, Prance. characterized by the total absence of color discrimination, photophobia, Intro. by: A. Munnich. nystagmus, and decreased visual acuity. The retinal cone photoreceptors do not develop or remain functionally defective and morphologically abnormal, NPH (or recessive medullary cystic kidney diseae) is an autosomal suggesting a developmental defect of the cone. This disorder has a recessive, chronic tubulo-interatitial disod, with the formation of cysts at prevalence rate of approximately 1 per 300,000 and is typically observed in the cortico-medullary Junction. NPH leads to end-stage renal filhre (13SRP) isolated sibships or In the offspring of consanguineous parentage. In this in adolence and counts for 15% of EMKIn children. NPH is associated study, 10 U.S. families were evaluated and DNA was obtained from 65 with Leber amaurodsi (termed Senior-bk.. SYd ) or with later onset Individuals (23 of these were affected and the rest were unaffected family retinitis pigmentosa In about 16% of cases. Using microsatellite marker members). Previously, we reported that a rod monochromacy patient with a AFMmze3 at the D2S160 locus which gave a lbd score of 4.77 atS - 0.05 In 18 14;14 Robertsonien translocation had maternal isodisomy for all portions of multilex NPH families, we hew recently mapped a gene for the purely renal chromosome 14 tested, suggesting that a genetic location for this disorder form of NPH to chromosone 2p (C Antignac et al., Nature Genet 1993). We maps to chromosome 14. A series of dinucleotide repeat polymorphisms have extended this study to four additional families with isolated NPH and have been characterized for chromosome 14 spanning the region from peforme linkage analysis with 6 polymorphic microsatelite markers closely 14q1 1.2 to 14q32.33. Flanking primers for 13 of these dinucleotide repeat linked to the NPH gene. Based on haplotype analyses and specific polymorphisms were obtained and conditions were established to develop a multiple recombination events, the following order of the lod was d : 2el - repeat-based PCR assay with a multiplex strategy to analyze the AFMI72xc3 - AFM262xbS - NPH/AFM220ze3.- AFMO87xa1 - AFM234te1 - genotypes for all these individuals for each of the 13 polymorphisms AFMO16yc5. This allow us to localize the NPH gene between AFM262xb5 and examined. These data were used for linkage analysis to localize this disorder AFM087xal, and therefore to narrow the NPH region to about 7cM. to a specific region of chromosome 14. Heterozygosity values for these Furthermore, the haplotype analyses show unequivocally that four families dinucleotide repeat polymorphisms range from 0.51 to 0.83, so that family are not linked to h om 2, although there is no clinical or patho Il members are fully informative for many of the polymorphisms examined. feature present in these families that could separate them from the families Results from the linkage analysis suggested evidence against linkage for linked to markers of the NPH region. This reveals significance evidence for each of the 13 loci examined to date, excluding approximately 50% of the genetic In the rnal form of NPH. chromosome 14 genetic map. hetogeneity purey 969 970 Angiotensinogen acandidate gene in d in pr-eclampsia? ((R. Arngrlmssont.4, J.J. Usher syndrome type I in the French Acedian population: fine mappiLg Walker2, F. Soubir3, R.T. ei 4, Y.U. K evtsev3, S. Purandarel, & Brnsson2, and haplotype analysis.((R. Ayyagari. R.J.H. Smith, E.C. Lee, V.J. H. BjWmsson5, J.M. Connor1.)) IDuncan Guthrie nte of Medical Genefics, Yortill, Kimberling, S.P. Daiger, IZ. Pelias, B.J.B. Keats, M. Jay, A. Glasgow G3 8SJ, Scoband, 2Glasgow Royal Maternity Hospital, Scotland, 31nserm U36, Bird, W. Reardon, M. Guest, and J.F. HejtmanciLk.)) National Eye Paris France, 4Dept. Obstetrics and Gynecology, National University Hospital, Institute, National Institutes of Health, Bethesda, MD 20892. Reykjavik, Ieland and 5 9ttistical Division, Agriculture Research Institute, Rekavik, Usher syndromes are a group of autosomal recessive disorders Iceland. characterized by congenital sensorineural hearing loss, progressive visual impairment secondary to progressive pigmentary retLnopathy There is strong evidence to suggest a genetic influence on the d of and sometimes vestibular involvement. Based on clinical symptoms three types of Usher syndromes have been described. Usher syndrome preclampsia (PE), but the mechanism of inheritanc has ben controvesial. We have type I has been mapped to three different locl: (1) Chromosome 14q thus studied 17 families where the proband had proteinuric PE and bive families with in a group of French families, (2) Chromosome llq in a group of eclampsia (E) from Icd and Scotland using affected sib pairs and the affected families from Scandinavian, Irish, SwedLsh, South African, American pedigree member method (APM). The affected relative were scored I.R.S and weighting and Brltish population and (3) Chromosome llp in familles of French factors for allle frequencies (1/sqrt(p)) and family size were used. Simulation studies for AcMdian origin. Fine mapping of the Usher syndrome type I locus on the datasets were caried outto estimate epirical p-values. the chromosome llp wys carried out with 16 mLcrosatellite markers. Positive lod scores were obtalned with markers D11S569(t.-1.79), Using angiotensinogen (C-An) microsatellites as genoty , the affcted sib pairs DllS419(Z-4.20), D118902(-6.44), DllS926(Z-1.45), D118921(Z-3.31), in PE and Efamilies shoed significant increase in albeh sharing (T1.28; p.0.02).
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