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Biomedical subjects

N Buist

Publications and source records attributed to N Buist.

11 recordsLinked to original sources
PubMed2001

Hepatic carnitine palmitoyl transferase 1 (CPT1 A) deficiency in North American Hutterites (Canadian and American): evidence for a founder effect and results of a pilot study on a DNA-based newborn screening program.

We describe six patients with hepatic carnitine palmitoyl transferase (CPT1 A) deficiency who are members of a large extended Hutterite kindred living in widely scattered communities in the United States and Canadian Prairies. Two patients have significant neurological impairment due to severe recurrent hypoglycemic crises. The remaining four patients with earlier detection and treatment have near normal outcomes. The Canadian and American Hutterite families share two common ancestors who married in 1812, about 60 years before the Hutterites arrived in North America and prior to their subdivision into the three groups (Schmiedeleut, Dariusleut, and the Lehrerleut). These patients share a common haplotype on chromosome 11q13 and are all homozygous for a common CPT1 A G710E mutation, suggesting a founder effect. The clustering of such a rare disorder of fatty acid oxidation prompted us to initiate a pilot DNA-based neonatal screening program to determine the carrier frequency of this mutation in Hutterite newborns with the participation and support of the community. To date our carrier frequency is 1/16, close to the predicted frequency based on diagnosed patients and number of births. We believe our newborn screening program for CPT1 A deficiency in the Hutterite community will serve as a prototype model for delivery of targeted genetic services to other similar unique genetic isolates.

Adolescent↗
PubMed2001

X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.

To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.

Amino Acid Sequence↗
PubMed2000

Novel mutations in 13 probands with galactokinase deficiency.

Galactokinase is an essential enzyme in the metabolism of galactose. Patients with deficiencies in galactokinase exhibit early-onset cataracts. We examined the sequence of the human galactokinase gene (GK1) from 13 patients exhibiting galactokinase deficiency and identified 12 novel mutations. One of the mutations occurred in six of the 13 probands examined, and the remaining 11 were unique mutations. Expression of each of the mutant GK1 genes in Xenopus oocytes resulted in very low galactokinase activity levels. These results provide important information regarding the types of GK1 mutations that occur in the human population.

Base Sequence↗
PubMed1999

Undiagnosed maternal phenylketonuria: the need for prenatal selective screening or case finding.

OBJECTIVES: The aims of this article are to report on a review of cases of maternal phenylketonuria in the International Maternal Phenylketonuria Collaborative Study that were initially diagnosed during or after a pregnancy, to alert health care practitioners to the possible existence of women with undiagnosed phenylketonuria whose fetuses are at risk, and to emphasize that not all adults with untreated phenylketonuria are mentally retarded. STUDY DESIGN: The study was conducted through retrospective database review. RESULTS: Of 414 women with live-born infants, 17 fulfilled our criteria. Six had phenylketonuria diagnosed after they had produced >/=1 affected offspring, 2 had phenylketonuria diagnosed as a result of transient postnatal hyperphenylalaninemia in an offspring, and 9 had phenylketonuria diagnosed by prenatal screening. Undiagnosed maternal phenylketonuria in North America and Europe is currently estimated at 1 case/100,000 births; this rate could be higher elsewhere. CONCLUSIONS: Physicians and midwives should consider a protocol of selective prenatal screening or case finding to detect undiagnosed phenylketonuria among their patients.

Adolescent↗
PubMed1997

Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping.

Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.

Alaska↗
PubMed1995

Isolated persistent hypermethioninemia.

New information has been obtained on 30 patients with isolated persistent hypermethioninemia, most of them previously unreported. Biopsies to confirm the presumptive diagnosis of partially deficient activity of ATP: L-methionine S-adenosyltransferase (MAT; E.C.2.5.1.6) in liver were not performed on most of these patients. However, none showed the clinical findings or the extreme elevations of serum folate previously described in other patients with isolated hypermethioninemia considered not to have hepatic MAT deficiency. Patients ascertained on biochemical grounds had no neurological abnormalities, and 27/30 had IQs or Bayley development-index scores within normal limits or were judged to have normal mental development. Methionine transamination metabolites accumulated abnormally only when plasma methionine concentrations exceeded 300-350 microM and did so more markedly after 0.9 years of age. Data were obtained on urinary organic acids as well as plasma creatinine concentrations. Patterns of inheritance of isolated hypermethioninemia were variable. Considerations as to the optimal management of this group of patients are discussed.

Adolescent↗
PubMed1994

Carbohydrate-deficient glycoprotein syndrome: not an N-linked oligosaccharide processing defect, but an abnormality in lipid-linked oligosaccharide biosynthesis?

The carbohydrate-deficient glycoprotein syndrome (CDGS) is a developmental disease associated with an abnormally high isoelectric point of serum transferrin. Carbohydrate analyses of this glycoprotein initially suggested a defect in N-linked oligosaccharide processing, although more recent studies indicate a defect in the attachment of these sugar chains to the protein. We studied both serum glycoproteins and fibroblast-derived [2-3H]mannose-labeled oligosaccharides from CDGS patients and normal controls. While there was a decrease in the glycosylation of serum glycoproteins of affected individuals, differences were not seen in either monosaccharide composition or oligosaccharide structures. The lectin-binding profiles of glycopeptides from [2-3H]-mannose-labeled fibroblasts were likewise indistinguishable. However, the incorporation of [2-3H]mannose into both glycoproteins and the dolichol-linked oligosaccharide precursor was significantly reduced. Thus, at least in some patients, CDGS is not due to a defect in processing of N-linked oligosaccharides, but rather to defective synthesis and transfer of nascent dolichol-linked oligosaccharide precursors. This abnormality could result in both a failure to glycosylate some sites on some proteins, as well as secondary abnormalities in overall glycoprotein processing and/or function.

Blood Proteins↗
PubMed1991

Identification of a splice-site mutation in the aldolase B gene from an individual with hereditary fructose intolerance.

Hereditary fructose intolerance (HFI) is a potentially fatal autosomal recessive disease of carbohydrate metabolism. HFI patients exhibit a deficiency of fructose 1-phosphate aldolase (aldolase B), the isozyme expressed in tissues that metabolize fructose. The eight protein-coding exons, including splicing signals, of the aldolase B gene from one HFI patient were amplified by PCR. Dot-blot hybridization of the amplified DNA with allele-specific oligonucleotide (ASO) probes revealed a previously described A149P mutation in one allele from the proband. The mutation in the other allele was identified by direct sequencing of the double-stranded PCR-amplified material from the proband. The nucleotide sequence of exon 9 revealed a 7-base deletion/1-base insertion (delta 7 + 1) at the 3' splice site of intron 8 in one allele. This mutation was confirmed by cloning PCR-amplified exon 9 of the proband and determining the sequence of each allele separately. ASO analysis of 18 family members confirmed the Mendelian inheritance of both mutant alleles. The implications of this unique splice-site mutation in HFI are discussed.

Adolescent↗
PubMed1990

Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency.

We assessed lung function, liver function, and smoking attitudes and behavior in 22 adolescents with homozygous alpha 1-antitrypsin deficiency whose condition had been detected through neonatal screening in the early 1970s. All subjects had normal lung volumes, expiratory flow rates, and diffusing capacity except for two siblings with mild asthma whose values reverted to the normal range after administration of an inhaled bronchodilator. Liver function was normal in all subjects with the exception of one boy who had an isolated elevation of alkaline phosphatase activity. Smoking attitudes, as determined by questionnaire, did not differ from those of 130 control subjects, but smoking initiation rates were significantly lower (p = 0.02). We believe that the issue of neonatal screening for alpha 1-antitrypsin deficiency should be reexamined because augmentation therapy for adults with emphysema is now available, and screening followed by family-based smoking intervention may lead to a nonsmoking life-style. The latter is especially important because the current weight of epidemiologic evidence strongly suggests that in nonsmokers with this condition, severe emphysema may never develop or, if it does, it will do so at a much later age than in smokers.

Adolescent↗