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C R Scriver

Publications and source records attributed to C R Scriver.

At least 73 records · Page 4Linked to original sources
PubMed1995

Response to treatment in hereditary metabolic disease: 1993 survey and 10-year comparison.

Knowledge about cause, pathogenesis, and manifestations of hereditary metabolic diseases puts them among the best known of all human diseases. On the other hand, outcomes of treatment are cause for uncertainty and concern. In 1985, Hayes et al. analyzed efficacy of treatment up to 1983 in 65 of these diseases selected randomly from the McKusick catalogs. Disease scores were calculated for seven parameters: longevity; reproductive capability; somatic and cognitive development; and handicaps affecting schooling, work, and cosmetic appearance. Scores of the untreated and treated phenotypes were then compared. We have now measured progress over the past decade by calculating scores on the same 65 diseases from data in several hundred new reports published since 1983. All seven parameters in the 1993 survey reflect improved efficacy of treatment in the 10-year interval. However, the percent of diseases for which all manifestations of the disease were removed by treatment has not changed (12% in 1983; 12% in 1993). The group in which manifestations were untouched by treatment has become smaller (48% in 1983; 31% in 1993), and the group partially ameliorated by treatment had increased reciprocally (40% in 1983; 57% in 1993). Progress in the treatment of hereditary metabolic disease is thus better than it was, but it is still only a partial success. The advances are attributable to greater success with organ and tissue transplantation, better pharmacotherapy, and better support systems. Restoration of normal homeostasis, the key to successful treatment, remains an elusive challenge and is a logical, major focus for research in human genetics.

Data Collection↗
PubMed1994

Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin.

Niemann-Pick type C is an autosomal-recessive, neurovisceral storage disorder that results from defective cholesterol esterification. Cholesterol-lowering agents have been demonstrated to decrease hepatic lipids in Niemann-Pick type C patients. The objective was to determine the effects of cholesterol-lowering agents on neurologic features and to develop a noninvasive method of monitoring clinical response. A 9-month-old boy with progressive hepatosplenomegaly and neurodevelopmental delay was studied. Water-suppressed proton magnetic resonance spectra from a supraventricular volume of central white and gray matter revealed an abnormal lipid signal. The patient was treated with cholesterol-lowering agents (i.e., cholestyramine, lovastatin). Repeat standardized neurodevelopmental assessments (Peabody and Griffith scales) at 13 and 19 months were normal and magnetic resonance spectra no longer detected the previously observed lipid resonance. Early treatment of Niemann-Pick type C patients with cholesterol-lowering agents appeared to have short-term beneficial effects. Magnetic resonance spectra provided a noninvasive means of monitoring CNS response.

Brain↗
PubMed1994

Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase complex (PDHC) is an intramitochondrial multienzyme complex essential for the aerobic oxidation of glucose. The majority of patients with PDHC deficiency have abnormalities in the major catalytic and regulatory subunit, E1 alpha, which is encoded on the X chromosome. The clinical spectrum of PDHC deficiency is heterogeneous, particularly in heterozygous females, and diagnosis may be difficult. Three affected infant girls with PDHC deficiency were investigated. All had dysmorphic features, microcephaly with profound global developmental delay, and hypotonia. Systemic acidosis was absent, although serum lactate and pyruvate were abnormally elevated. Magnetic resonance imaging revealed hypoplasia of the corpus callosum in all patients. Proton magnetic resonance spectroscopy of brain revealed large increases in relative signal intensities for lactic acid and decreases in the relative signal intensities of N-acetylaspartate, a marker of neuronal damage or less. Phosphorus MRS of muscle revealed abnormally low phosphorylation potentials for all these patients, although the degree of abnormality was variable and not directly correlated with the amount of brain lactate. It is proposed that cerebral dysgenesis and cerebral lactic acidemia as shown by magnetic resonance imaging and proton magnetic resonance spectroscopy are useful diagnostic clues to PDHC deficiency, particularly in females in whom variable patterns of X-inactivation reduce sensitivity of laboratory diagnosis based on the biochemical studies of peripheral tissues. In addition, muscle bioenergetic abnormalities in conjunction with CNS dysfunction may contribute to profound hypotonia in this disorder.

Acidosis, Lactic↗
PubMed1994

Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients.

Fibroblast cultures from five patients with early onset severe encephalopathy and lactic acidosis were studied for evidence of pyruvate dehydrogenase (PDH) deficiency. Three males had significantly reduced activity (0.29-0.45 nmol/mg protein/min versus normal controls 0.7-1.1 nmol/mg protein/min); two females had PDH activity within the normal range. However, as the majority of cases of PDH deficiency result from defects in the X-linked E1 alpha subunit and both females had biased patterns of X-inactivation (making it impossible to rule out the possibility that they were heterozygous for an E1 alpha gene defect) molecular genetic studies were performed. cDNA from the male patients was sequenced and mis-sense mutations found: Y243N (T-->A) in exon 7, D315A (G-->A) in exon 10 and R378H (G-->A) in exon 11. Single-strand conformation polymorphism analysis of amplified genomic DNA fragments and sequencing revealed a mis-sense mutation M282L (A-->C) in one female and a frameshift mutation caused by insertion of T (R288ins) in the other. Adding to recent descriptions of new mutations, this report emphasizes the allelic heterogeneity of the condition. The identification of mutations in females with a suggestive clinical phenotype, even when peripheral fibroblasts do not show deficient PDH activity, illustrates the importance of molecular analysis of this disease.

Base Sequence↗
PubMed1994

Evidence for origin, by recurrent mutation, of the phenylalanine hydroxylase R408W mutation on two haplotypes in European and Quebec populations.

The R408W mutation in the phenylalanine hydroxylase gene (PAH) of phenylketonuria patients occurs on haplotypes 2.3 and 1.8 in Europeans. The mutation involves a CpG dinucleotide; nonetheless, a single recombination event might also explain the two haplotype associations. By analysis of an STR in the PAH gene 5' to the 408 codon and of the VNTR system in the 3' UTR, we identified unique features of the haplotype 1.8 chromosome harbouring the R408W mutation which are not accounted for by recombination. We conclude that recurrent mutation is the origin of R408W on different PAH haplotypes in Europeans.

Alleles↗
PubMed1994

Science, medicine and phenylketonuria.

Science addresses ignorance; medicine uses facts. The scientific approach to phenylketonuria (PKU) led to the discovery of its causes, both ultimate (allelic heterogeneity at the PAH locus) and proximate (dietary phenylalanine), the proximal phenotype (phenylalanine hydroxylase deficiency), the associated metabolic phenotype and the major distal phenotype (impaired cognitive development and neuropsychological function) for which the pathogenesis is still being investigated. By applying knowledge through newborn screening, early diagnosis and treatment, the brain disease of PKU has been greatly ameliorated. The population approach, which converted incidence into cases, revealed genetic heterogeneity in hyperphenylalaninemia involving four other loci, controlling cofactor (BH4) synthesis and recycling, and non-random geographic distribution of mutant PAH alleles of which more than 170 were known in April 1994. Various mechanisms including founder effect, genetic drift, hypermutability and selection (perhaps) explain the polymorphic aggregate frequency (approximately 0.01) and spectrum of PKU mutations in human populations.

Alleles↗
PubMed1994

Mutation profiles of phenylketonuria in Quebec populations: evidence of stratification and novel mutations.

Independent phenylketonuria (PKU) chromosomes (n = 109) representing 80% of a proband cohort in Quebec province carry 18 different identified mutations in 20 different mutation/haplotype combinations. The study reported here, the third in a series on Quebec populations, was done in the Montreal region and predominantly on French Canadians. It has identified three novel mutations (A309D, D338Y, and 1054/1055delG[352fs]) and one unusual mutation/RFLP haplotype combination (E280K on Hp 2). The relative frequencies and distribution of PKU mutations were then compared in three regions and population subsets (eastern Quebec, French Canadian; western Quebec, French Canadian; and Montreal, non-French Canadian). The distributions of the prevalent and rare mutations are nonrandom and provide evidence for genetic stratification. The latter and the presence of eight unusual mutation/haplotype combinations in Quebec families with European ancestries (the aforementioned four and M1V, I65T, S349P, and R408W on Hp 1) corroborate demographic and anthropologic evidence, from elsewhere, for different origins of French Canadians in eastern and western Quebec.

DNA Mutational Analysis↗
PubMed1993

Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families.

We describe mutations identified in stored skin fibroblast cell lines from two original probands (JB and JM), first reported with 2-methylacetoacetic aciduria, and shown later to have a deficiency of the K(+)-activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a 4-base insertion (GCAG) which is derived mutation. The primary mutation is an AG/gt to AG/gc transition at the 5'-splice-junction site in intron 11. An alternative splice site 4 bp downstream (Ggcag/gt) is used which causes a frame shift and replaces 39 C-terminal residues by 70 nonfunctional residues. JM is homozygous for a mutation in the translation-initiation codon (ATG to AAG). By expression analyses the JB mutation (IVS11nt2) causes an unstable T2 polypeptide and the JM mutation (M1K) severely impairs T2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).

Acetyl-CoA C-Acetyltransferase↗
PubMed1993

Methylmalonic acidemia with a severe chemical but benign clinical phenotype.

A 5-year-old boy of West African origin had methylmalonic acidemia with a mut- enzyme phenotype, no clinical response to hydroxycobalamin, and metabolite measurements indicative of the severe form of mutase deficiency. His development, both mental and physical, was satisfactory and he had no episodes of metabolic decompensation. The explanation for the neurotoxic effects and metabolic decompensation in typical methylmalonic acidemia and the (allelic) genotype that explains this patient's phenotype are uncertain.

Amino Acid Metabolism, Inborn Errors↗
PubMed1993

Parental origin of mutant allele does not explain absence of gene dose in X-linked Hyp mice.

The expectation for a gene dose effect in an X-linked phenotype is that the corresponding metrical trait in heterozygous females will lie between values for affected hemizygous males and unaffected males and females. We made sequential measurements (at 30, 60, 90, 120 and 150 days) of serum phosphate concentration and tail length in mice with X-linked hypophosphatemia (genotypes: Hyp/Y, Hyp/+ and Hyp/Hyp) and in their normal litter-mates (genotypes: +/Y, +/+). We also measured renal mitochondrial 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase) activity in 5 to 7-month-old mice fed control and low phosphate diets and representing all five genotypes. The animals were obtained by controlled breeding under uniform environmental conditions. The mutant animals all had uniformly and significantly lower serum phosphate levels, shorter tail length and higher 24-hydroxylase activity relative to unaffected litter-mates. There was no evidence of a gene dose effect because values were not significantly different among the three mutant genotypes. We also studied the influence of gamete of origin on serum phosphate, tail length and renal mitochondrial 24-hydroxylase activity in the Hyp/+ offspring of affected males (Hyp/Y) or affected females (Hyp/+ or Hyp/Hyp). We found no effect on the distribution of trait values. We conclude that parental origin of mutant allele does not explain the absence of a gene dose effect in Hyp mice.

Alleles↗
PubMed1993

Familial cold urticaria.

Familial cold urticaria (FCU) is a rare autosomal dominant condition, first described in 1940. The onset is in early life in all reported cases. Symptoms are triggered by generalized exposure to cold air, particularly in damp and windy weather. The cutaneous lesions consist of erythematous macules or plaques, urticarial lesions and sometimes petechiae. Associated fever, chills, joint pains, nausea, stiffness and swelling of the hands and feet frequently occur. The symptoms are variable, ranging from mild to incapacitating. The pathogenesis of FCU remains unknown. To our knowledge only 10 pedigrees have been published, seven from the USA and one each from Holland, France and South Africa. We wish to report another extensive pedigree after having had the opportunity to investigate one member of the family in detail. A short form of this pedigree has been published elsewhere.

Cold Temperature↗
PubMed1993

What young people think and do when the option for cystic fibrosis carrier testing is available.

We report findings in phase II of a pilot study of cystic fibrosis (CF) carrier screening/testing by mutation analysis. Phase I has been reported elsewhere. Eligible participants in phase II (n = 815) were students (15 to 17 years of age) in public high schools. An educational component (exchange of information and discussion about common genetic disorders including CF) preceded, by one week or more, voluntary participation in the screening component which required a blood sample. The uptake rate for screening was 42%. Nine carriers (2pq = 0.0260) were identified, all with the delta F508 mutation; students were also tested for G551D, G542X, W1282X, and -549-mutations, but no carriers of these alleles were found. Carriers had positive views of the education and testing experiences. Persons identified as 'non-carriers' were also surveyed (n = 135, response rate 41%). As in phase I, the majority (83%) again understood that a negative DNA test had not excluded them from possible carrier status. Students who participated in the informational component but were not screened served here as controls in the follow up survey (n = 208, response rate 53%). Their views were similar to those of the screened non-carriers, and similar also to those held by students, adults, pregnant women, couples, and CF relatives in other communities.

Adolescent↗
PubMed1993

'Celtic' phenylketonuria chromosomes found? Evidence in two regions of Quebec Province.

We analyzed mutations, RFLP haplotypes (H), and a VNTR polymorphism at the phenylalanine hydroxylase locus (PAH) in 12 French-Canadian patients with phenylketonuria (PKU) from the eastern region of Quebec province and 13 non-French-Canadian PKU patients from the Montreal region. There were 10 different mutation/H/VNTR haplotype combinations on the 50 PKU chromosomes: one set of 5 and another of 8 accounted for 88 and 77% of these chromosomes in the French-Canadian and non-French-Canadian patients, respectively. The differences in PKU haplotypes between the two groups of probands reflect the different histories of the two populations. Three PKU haplotype combinations were shared by the two groups: IVS12nt1:H-3:VNTR-8, I65T:H-9:VNTR-8, and R408W:H-1:VNTR-8. The IVS12nt1 mutation (18% of the total sample) is prevalent in northern Europeans. The I65T-H-9 and R408W:H-1 haplotypes have seldom been reported in Europeans but when encountered tend to be found in northwestern regions. The R408W mutation is usually on H-2 in Europeans. In Quebec the R408W:H-1 and I65T:H-9 haplotypes accounted for 20% of PKU chromosomes, clustered in two geographic regions, and in every family where they occurred an Irish or Scottish ('Celtic') ancestor could be inferred. We propose that I65T:H-9:VNTR-8 and R408W:H-1:VNTR-8 chromosomes are markers for a diaspora of 'Celtic' descendants. Our findings predict the distributions of these unusual PKU haplotypes in contemporary Europeans.

Chromosomes, Human, Pair 12↗
PubMed1993

A Pst+ polymorphism in the HEXA gene with an unusual geographic distribution.

A polymorphic variant in the human HEXA gene is described. This gene encodes the alpha-subunit of hexosaminidase A, the enzyme which is deficient in Tay-Sachs disease (TSD). In individuals carrying the polymorphism there is a T-->C transition at position -6 in intron 13. The substitution creates a site for the restriction endonuclease Pst1. This variant has an unusual ethnogeographic distribution. It occurs on 1.4% of non-TSD carrier chromosomes in Ashkenazi Jews. All individuals ascertained carrying the Pst+ allele have ancestry in Lithuania, Belarus and Ukraine. By contrast, no individuals carrying the Pst+ allele have been detected among non-Jewish Lithuanians, Jews of Sephardic origin or in several other ethnic groups. Two unrelated non-Jewish families have been identified in which the Pst+ variant occurs. In both cases the variant occurs on a chromosome carrying a novel TSD mutation (G772C) association with the B1 phenotype. The Pst+ G772C chromosomes are of Scots-Irish descent.

Alleles↗