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ABSTRACT: This article summarizes data and issues covered in the workshop on Glycine Encephalopathy using headings that cover important topics in our present knowledge of this disease.
Journal of Inherited Metabolic Disease 02/2004; 27(3):417-22. · 3.58 Impact Factor
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Human Genetics 11/2003; 113(5):465. · 5.07 Impact Factor
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ABSTRACT: We describe three novel deletions in the human AGT gene in three patients with primary hyperoxaluria type 1, an autosomal recessive disease resulting from a deficiency of the liver peroxisomal enzyme, alanine glyoxylate aminotransferase (AGT; EC 2.6.1.44). A deletion of 4 nucleotides in the exon 6/intron 6 splice junction (679-IVS6+2delAAgt) is expected to cause missplicing. It would also code for a K227E missense alteration in any mRNA successfully spliced. A 2-bp deletion in exon 11 (1125-1126del CG, cDNA) results in a frameshift. A deletion of at least 5-6 kb, EX1 EX5del, spanned exons 1-5 and contiguous upstream sequence. All three deletions are heterozygous with previously documented missense mutations; the intron 6 deletion with F152I, the exon 11 deletion with G82E, and EX1 EX5del with the common mistargeting mutation, G170R.
Molecular Genetics and Metabolism 12/2001; 74(3):314-21. · 3.19 Impact Factor
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ABSTRACT: Screening a DNA bank from 50 patients with enzymatic confirmation of their diagnosis of nonketotic hyperglycinemia gave allele frequencies of 5% for R515S of P-protein (glycine decarboxylase) and 7% for R320H of T-protein (aminomethyltransferase). In a previous report we found that 3% of the same patient alleles were positive for T-protein IVS7-1G>A. In total, testing for these three mutations identified 15% of alleles and positive results (one or two mutations) were found in 11 of the 50 patients. In addition, a novel point mutation in T-protein, N145I, was found in a single case and a PCR/restriction enzyme assay was developed for its detection.
Molecular Genetics and Metabolism 04/2001; 72(4):322-5. · 3.19 Impact Factor
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ABSTRACT: A novel splice site mutation (IVS7-1G-->A) in the T-protein gene (aminomethyltransferase, or AMT) of the glycine cleavage enzyme complex was found in a patient with nonketotic hyperglycinemia (NKH). A PCR/restriction enzyme method to detect this mutation was used to screen 100 NKH alleles and identified the mutation in three unrelated families.
Human Mutation 02/2001; 17(1):76. · 5.69 Impact Factor
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ABSTRACT: The investigation of 14 unrelated patients with nonketotic hyperglycinemia led to the identification of mutations in 4 cases. Patients were initially categorized into probable P- or T-protein defects of the glycine cleavage enzyme complex, by the use of the glycine exchange assay without supplemental H-protein, then screened for mutations in the P-protein and T-protein genes, respectively.
Molecular Genetics and Metabolism 07/2000; 70(2):116-21. · 3.19 Impact Factor
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ABSTRACT: We report three false negative prenatal diagnostic results, using direct measurement of glycine cleavage enzyme activity in uncultured chorionic villus tissue from 290 pregnancies at risk for non-ketotic hyperglycinaemia (NKH). Testing was done by two centres: Vancouver, Canada and Lyon, France. One false negative result had activity near the lower limit of the normal range but two samples gave completely normal results well within the control range. All three pregnancies continued and the three children were born affected with NKH. Because of the first result, we now counsel that there is a grey zone of uninterpretable activity where affected and normal enzyme values overlap. Because of the other two results we now counsel that there is an approximately 1% chance of a pregnancy with a normal CVS activity resulting in an affected child. The clinical and biochemical findings in the three families are discussed.
Prenatal Diagnosis 06/2000; 20(5):367-70. · 2.11 Impact Factor
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ABSTRACT: To determine how many children with specific types of inborn errors of metabolism are born each year in British Columbia, Canada. This population provides a relatively unique setting for collection of accurate and uniform incidence data because the diagnoses are all made through one laboratory in a population with universal access to government-funded medical care.
We used the records of the Biochemical Diseases Laboratory, Children's Hospital, Vancouver (the central referral point for all metabolic diagnoses in British Columbia) to identify all patients diagnosed with the metabolic diseases defined below. We obtained incidence figures by including only the children diagnosed with the diseases covered in this article who were confirmed as having been born within the province for the years 1969 to 1996. The diseases covered were diseases of amino acids, organic acids, the urea cycle, galactosemia, primary lactic acidoses, glycogen storage diseases, lysosomal storage diseases, and diseases involving specifically peroxisomal and mitochondrial respiratory chain dysfunction. Because the technology needed for diagnosis of specific disease groups was in place at different times our data for the different disease groups correspond to different time frames. We have also adjusted the time frames used to allow for the likelihood that some diseases may not come to medical attention for some time after birth. For instance the incidence of amino acid diseases was assessed throughout the whole of this time frame but the incidence of peroxisomal diseases was restricted to 1984 to 1996 because this was the time frame during which the technology needed for diagnosis was in place and reliable. Most disease group statistics included at least 400 000 births.
The overall minimum incidence of the metabolic diseases surveyed in children born in British Columbia is approximately 40 cases per 100 000 live births. This includes phenylketonuria (PKU) and galactosemia which are detected by a newborn screening program. Metabolic diseases, which were not screened for at birth, ie, those with PKU and galactosemia subtracted from the total, have a minimal incidence of approximately 30 cases per 100 000 live births. This diagnostic dilemma group would present to pediatricians for diagnosis. Not all metabolic diseases have been surveyed and our data are restricted to the following metabolic disease groups. Approximately 24 children per 100 000 births (approximately 60% of the total disease groups surveyed) have a disease involving amino acids (including PKU), organic acids, primary lactic acidosis, galactosemia, or a urea cycle disease. These children all have metabolic diseases involving small molecules. Approximately 2.3 children per 100 000 births ( approximately 5%) have some form of glycogen storage disease. Approximately 8 per 100 000 births (20%) have a lysosomal storage disease; approximately 3 per 100 000 births (7%-8%) have a respiratory chain-based, mitochondrial disease and approximately 3 to 4 per 100 000 (7%-8%) of births have a peroxisomal disease. The diseases involving subcellular organelles represent approximately half of the diagnostic dilemma group. The incidence of each of the specific diseases diagnosed, including apparently rare diseases such as nonketotic hyperglycinemia, is to be found in the text. The metabolic diseases reported in this survey represent over 10% of the total number of single gene disorders in our population.
Our data provide a good estimate of metabolic disease incidence, for the disease groups surveyed, in a predominantly Caucasian population. Incidence data for metabolic diseases are hard to collect because in very few centers are diagnoses centralized for a population with uniform access to modern health care and this has been the case for our population during the course of the study. (ABSTRACT TRUNCATED)
PEDIATRICS 01/2000; 105(1):e10. · 4.47 Impact Factor
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ABSTRACT: The diagnosis of nonketotic hyperglycinemia is considered to depend upon the presence of increased cerebrospinal fluid glycine and an increased cerebrospinal fluid to plasma glycine ratio. We studied two siblings who have the neurologic and peripheral biochemical features of the atypical variant of nonketotic hyperglycinemia but have normal cerebrospinal fluid glycine and cerebrospinal fluid to plasma glycine ratios. The proband had reduced liver glycine cleavage system activity of 17% and 21% of mean normal values, confirmed in two independent laboratories. Her lymphoblast glycine cleavage system activity was normal. Nonketotic hyperglycinemia can be present in the absence of increased cerebrospinal fluid glycine. Measurement of liver glycine cleavage system activity is indicated when nonketotic hyperglycinemia is suggested by clinical features and peripheral glycine levels but cerebrospinal fluid glycine is normal.
Journal of Child Neurology 08/1999; 14(7):464-7. · 1.75 Impact Factor
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ABSTRACT: Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme iduronate-2-sulfatase. We sequenced genomic DNA and RT-PCR products in the iduronate sulfatase (IDS) gene in 6 unrelated patients with Hunter syndrome to assess genotype/phenotype relationships and offer carrier testing where required. Six novel mutations were identified: four missense mutations, one four-base pair deletion (596-599delAACA) and a cryptic splice site mutation. Three of the missense mutations were significant amino acid substitutions (S143F, S491F, E341K) of which the latter two involve amino acids conserved amongst sulfatase enzymes. The patients identified with these mutations all had a severe clinical phenotype. One missense mutation with a minimal amino acid substitution (H342Y), in a non-conserved region of the gene, was associated with a mild clinical phenotype. We identified a novel cryptic splice site (IVS5+934G>A) with some normal (wild type) mRNA processing. We predict that the normal mRNA product confered some residual functional enzyme, resulting in a mild phenotype associated with the absence of overt central nervous system disease.
Human Mutation 02/1999; 13(4):338. · 5.69 Impact Factor
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ABSTRACT: To develop a protocol capable of identifying deletions in mitochondrial DNA and use it to identify the breakpoints of a mtDNA deletion in a patient with chronic progressive external ophthalmoplegia (CPEO).
Deletions in mtDNA were identified by a combination of long range PCR and Southern blotting. The precise breakpoints were determined by automated DNA sequencing.
A series of DNA samples from patients with suspected mitochondrial disease was subjected to a protocol, which combines long range PCR and Southern blotting. We found a unique deletion in a patient with CPEO and we identified the precise location of this deletion through DNA sequencing.
Long range PCR has the advantages of speed, minimal samples requirements, and sensitivity. Southern blotting is better able to evaluate heteroplasmy and detect duplications. We suggest a protocol that enables us to identify precisely the breakpoints in a unique mutation of mtDNA in a patient with CPEO.
Clinical Biochemistry 12/1998; 31(8):627-32. · 2.08 Impact Factor
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The Lancet 05/1998; 351(9110):1207-8. · 38.28 Impact Factor
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ABSTRACT: Metachromatic leucodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulphatase A. We have identified a child with infantile onset MLD who is homozygous for an A212V mutation, a mutation previously reported but not further characterised. We have introduced this mutation into an arylsulphatase A expression vector by site directed mutagenesis. Transient expression of this mutant plasmid in COS cells yields very low levels of arylsulphatase A activity consistent with the patient's phenotype. The arylsulphatase A pseudodeficiency also segregates in this family causing difficulty in interpreting enzyme levels in the absence of DNA data. Two other patients from the same province, also carrying the A212V allele, have juvenile and adult onset MLD and are heterozygous for P426L ("A" allele) and I179S alleles respectively, known late onset alleles.
Journal of Medical Genetics 07/1997; 34(6):493-8. · 6.36 Impact Factor
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ABSTRACT: A 16-year-old boy had intermittent chorea, delirium, and vertical gaze palsy precipitated by febrile illness. Nonketotic hyperglycinemia was confirmed by measurement of liver and lymphoblast glycine cleavage enzyme activity. Deficient but residual enzyme activity was demonstrated in both tissues, possibly accounting for the mild phenotype. Confirmation of an atypical variant of nonketotic hyperglycinemia with residual glycine cleavage enzyme activity has important implications for diagnosis and treatment.
Journal of Pediatrics 03/1996; 128(2):243-6. · 4.11 Impact Factor
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ABSTRACT: As an initial step toward the generation of a murine model for mucopolysaccharidosis type I, we have identified and characterized a full-length murine alpha-L-iduronidase cDNA. Expression of the murine cDNA in COS-1 cells results in the production of alpha-L-iduronidase enzyme activity at a level 20-fold higher than that of the endogenous gene. The murine cDNA shows strong homology with the coding region of both the human and the canine homologs with 78 and 75% nucleotide sequence identity, respectively. In contrast to the coding region, significant diversity of sequence exists for the 5' and 3' untranslated regions between the murine and both the human and the canine sequence. The 3' UTR of the murine transcript is 1193 bp in length, as compared to the human (100 bp) and canine (139 bp), and contains a CA dinucleotide repeat not seen in either the human or the canine genes. A portion of the murine iduronidase coding sequence overlaps with sequence reported for the 3' UTR of the murine SAT-1 cDNA. The sequence overlap involves the proposed exon II of murine iduronidase and covers 141 bp of sequence with the transcripts generated in opposite orientation. We report here the characterization of murine alpha-L-iduronidase cDNA and its relationship to SAT-1.
Genomics 12/1994; 24(2):311-6. · 3.02 Impact Factor
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Human Molecular Genetics 06/1994; 3(5):821-3. · 7.64 Impact Factor
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ABSTRACT: Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the glucocerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genomic DNA nucleotide position 6683) from a Gaucher disease patient of Jewish-Polish-Russian descent with type 1 Gaucher disease. It is a G-->A transition in exon 11 that results in 496Arg-->496His of glucocerebrosidase. This missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A-->G transition at cDNA nucleotide position 1226 which creates an XhoI cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease.(ABSTRACT TRUNCATED AT 250 WORDS)
American Journal of Medical Genetics 06/1994; 51(2):156-60.
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Journal of Inherited Metabolic Disease 02/1994; 17(3):330-2. · 3.58 Impact Factor
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Journal of Inherited Metabolic Disease 02/1994; 17(5):627-8. · 3.58 Impact Factor
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ABSTRACT: Clinical differentiation between forms of progressive dementia can prove difficult, particularly when relatively rare forms of dementia are involved. Factors such as family history of dementia, age at onset, presenting features such as personality change, cognitive deficits, psychiatric symptoms, and clinical course (progressive deterioration; retention of skills over time) may prove useful for directing investigations to identify underlying pathology and genetic implications. This is illustrated by two patient reports. Each patient had the onset of memory/behavioral problems at approximately age 40 years, was initially given a psychiatric, non-dementing diagnosis, and had a positive family history for early onset behavioral and memory problems. After longitudinal assessment, the diagnosis of Alzheimer disease was confirmed at autopsy in one patient and a diagnosis of familial, adult-onset metachromatic leukodystrophy in the other.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 12/1993; 20(4):312-8. · 0.97 Impact Factor
