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1.
J Inherit Metab Dis ; 31(3): 395-8, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18392751

ABSTRACT

The characteristic elevation of plasma glycine concentrations observed in propionic acidaemia (PA) and other 'ketotic hyperglycinaemias' has been attributed to secondary inhibition of the hepatic glycine cleavage system (GCS) by accumulating CoA derivatives of branched-chain amino acid metabolites. In nonketotic hyperglycinaemia (NKH), cerebrospinal fluid (CSF) and plasma glycine levels and their ratio are increased due to primary deficiency of central nervous system (CNS) as well as hepatic GCS. Whether the GCS in the CNS is also inhibited in PA is unclear, as there are scant data available on CSF glycine levels in this disorder. We studied the relation of CSF and plasma glycine levels in 6 paired samples from 4 PA patients, including one PA patient with bacterial meningitis who underwent ventriculoperitoneal shunting and multiple CSF analyses (n = 26). In contrast to the CSF glycine levels which were generally elevated in all four PA patients, the CSF/plasma glycine concentration ratios in paired samples were normal (0.016-0.029), with the exception of a single sample (0.132) with extremely high CSF protein concentration (2010 mg/L) during the course of meningitis indicating a disturbed blood-brain barrier. This finding of normal CSF/plasma glycine ratio in PA suggests that the observed elevations of CSF glycine levels are a reflection of the concurrent hyperglycinaemia resulting from secondary inhibition of hepatic GCS, but that brain GCS is not affected, in contrast to the situation in NKH. The neurological sequelae in PA are therefore unlikely to be related to disturbed glycine metabolism.


Subject(s)
Amino Acid Metabolism, Inborn Errors/metabolism , Glycine/blood , Glycine/cerebrospinal fluid , Propionates/blood , Brain/metabolism , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male
2.
J Inherit Metab Dis ; 27(3): 417-22, 2004.
Article in English | MEDLINE | ID: mdl-15272469

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.


Subject(s)
Hyperglycemic Hyperosmolar Nonketotic Coma , Animals , Disease Models, Animal , Humans , Hyperglycemic Hyperosmolar Nonketotic Coma/diagnosis , Hyperglycemic Hyperosmolar Nonketotic Coma/genetics , Hyperglycemic Hyperosmolar Nonketotic Coma/physiopathology , Mice
4.
Mol Genet Metab ; 74(3): 314-21, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11708860

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.


Subject(s)
Hyperoxaluria, Primary/genetics , Transaminases/genetics , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , DNA Mutational Analysis , Family Health , Female , Humans , Hyperoxaluria, Primary/enzymology , Infant , Male , Molecular Sequence Data , Mutation , Polymorphism, Genetic , Sequence Deletion , Transaminases/drug effects , Transaminases/metabolism
5.
Mol Genet Metab ; 74(1-2): 139-46, 2001.
Article in English | MEDLINE | ID: mdl-11592811

ABSTRACT

Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage enzyme complex (GCS). GCS is a complex of four proteins encoded on four different chromosomes. In classical neonatal NKH, levels of cerebrospinal fluid (CSF) glycine and CSF/plasma glycine ratio are very high but the CSF results, in particular, may be more difficult to interpret in later-onset, milder, or otherwise atypical NKH. Enzymatic confirmation of NKH requires a liver sample. Delineation of which protein of the complex is defective is necessary to screen for mutations in the appropriate gene. Except for Finnish NKH patients, few recurrent mutations have yet been found, although analysis of the P-protein gene (the site of the defect in the majority of patients) is at an early stage. Prenatal diagnosis by GCS assay in chorionic villus biopsies is not completely reliable and will be replaced by molecular analysis in families where the mutations are known.


Subject(s)
Glycine/blood , Hyperglycinemia, Nonketotic/diagnosis , Molecular Diagnostic Techniques/methods , Animals , Female , Fetal Diseases/blood , Fetal Diseases/diagnosis , Fetal Diseases/enzymology , Fetal Diseases/genetics , Genetic Carrier Screening , Glycine/metabolism , Humans , Hyperglycinemia, Nonketotic/blood , Hyperglycinemia, Nonketotic/enzymology , Hyperglycinemia, Nonketotic/genetics , Liver/enzymology , Metabolism, Inborn Errors/blood , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/enzymology , Metabolism, Inborn Errors/genetics , Pregnancy , Prenatal Diagnosis/methods
6.
Mol Genet Metab ; 72(4): 322-5, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11286506

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.


Subject(s)
Amino Acid Oxidoreductases/genetics , Glycine/blood , Hydroxymethyl and Formyl Transferases/deficiency , Hydroxymethyl and Formyl Transferases/genetics , Hyperglycinemia, Nonketotic/genetics , Mutation , Aminomethyltransferase , DNA Primers/chemistry , Exons , Gene Frequency , Glycine/metabolism , Glycine Dehydrogenase (Decarboxylating) , Heterozygote , Humans , Hyperglycinemia, Nonketotic/enzymology , Imines , Infant, Newborn , Ketosis , Liver/enzymology , Polymerase Chain Reaction , Prenatal Diagnosis
7.
Hum Mutat ; 17(1): 76, 2001.
Article in English | MEDLINE | ID: mdl-11139253

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.


Subject(s)
Amino Acid Oxidoreductases/genetics , Carrier Proteins/genetics , Hydroxymethyl and Formyl Transferases/genetics , Hyperglycinemia, Nonketotic/genetics , Multienzyme Complexes/genetics , Mutation/genetics , RNA Splice Sites/genetics , Transferases/genetics , Aminomethyltransferase , Genetic Carrier Screening , Humans , Hyperglycinemia, Nonketotic/enzymology , Introns/genetics , Polymerase Chain Reaction
8.
Brain ; 124(Pt 1): 209-18, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11133798

ABSTRACT

Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease. The majority of LHON patients harbour one of three point mutations of the mitochondrial DNA (mtDNA) complex I, or NADH:ubiquinone oxidoreductase (ND) genes (G11778A in ND4, G3460A in ND1, T14484C in ND6). As a consequence, screening for these mutations has become part of the routine clinical investigation of young adults who present with bilateral optic neuropathy, and the absence of these mutations is interpreted as indicating there is a low likelihood that an optic neuropathy is LHON. However, there are many individuals who develop the clinical features of LHON but who do not harbour one of these primary LHON mutations. We describe two LHON pedigrees that harbour the same novel point mutation within the mtDNA ND6 gene (A14495G). This mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on two independent occasions. This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutations. Protein modelling studies indicate that all of these pathogenic mutations lie within close proximity to one another in a hydrophobic cleft or pocket. This is the first evidence for a relationship between a specific disease phenotype and a specific structural domain within a mitochondrial respiratory chain subunit. These findings suggest that the mtDNA ND6 gene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mutations.


Subject(s)
DNA, Mitochondrial/genetics , Mutation/genetics , NADH, NADPH Oxidoreductases/genetics , Optic Atrophies, Hereditary/diagnosis , Optic Atrophies, Hereditary/genetics , Adolescent , Adult , Amino Acid Substitution , Conserved Sequence , DNA Mutational Analysis , Electron Transport Complex I , Female , Humans , Male , Middle Aged , Mitochondria/enzymology , Mitochondria/genetics , Pedigree , Polymorphism, Genetic , Protein Structure, Secondary/genetics , Protein Structure, Tertiary/genetics
10.
Mol Genet Metab ; 70(2): 116-21, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10873393

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.


Subject(s)
DNA Mutational Analysis , Hyperglycinemia, Nonketotic/genetics , Methyltransferases/genetics , Amino Acid Sequence , DNA Primers/chemistry , Exons , Female , Glycine/metabolism , Homocysteine S-Methyltransferase , Humans , Hyperglycinemia, Nonketotic/enzymology , Infant, Newborn , Introns , Liver/enzymology , Male , Methyltransferases/metabolism , Molecular Sequence Data , Pedigree
11.
Prenat Diagn ; 20(5): 367-70, 2000 May.
Article in English | MEDLINE | ID: mdl-10820402

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.


Subject(s)
Amino Acid Oxidoreductases/analysis , Amino Acid Oxidoreductases/deficiency , Amino Acid Oxidoreductases/metabolism , Carrier Proteins/analysis , Carrier Proteins/metabolism , Chorionic Villi Sampling , Hyperglycinemia, Nonketotic/diagnosis , Hyperglycinemia, Nonketotic/enzymology , Liver/enzymology , Multienzyme Complexes/analysis , Multienzyme Complexes/deficiency , Multienzyme Complexes/metabolism , Transferases/analysis , Transferases/deficiency , Transferases/metabolism , Consanguinity , False Negative Reactions , Fatal Outcome , Female , Humans , Hyperglycinemia, Nonketotic/genetics , Infant, Newborn , Male , Pregnancy
12.
Pediatrics ; 105(1): e10, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10617747

ABSTRACT

OBJECTIVE: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSIONS: 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)


Subject(s)
Metabolism, Inborn Errors/epidemiology , British Columbia/epidemiology , Health Surveys , Humans , Incidence , Infant, Newborn
13.
Biochem Cell Biol ; 78(6): 725-30, 2000.
Article in English | MEDLINE | ID: mdl-11206584

ABSTRACT

The H-protein is one of the four essential components (H-, L-, P-, and T-proteins) of the mammalian glycine cleavage enzyme complex, the major degradative pathway of glycine. We have isolated the full-length cDNA of the H-protein gene from the rabbit (Oryctolagus caniculus) by reverse transcription of liver poly-A mRNA and determined its nucleotide sequence (GenBank Acc. No. BankIt 31828


Subject(s)
Amino Acid Oxidoreductases , Carrier Proteins/chemistry , Carrier Proteins/genetics , Amino Acid Sequence , Amino Acid Substitution , Animals , Base Sequence , Cattle , Chickens , Cloning, Molecular , Codon , Conserved Sequence , DNA, Complementary , Glycine Decarboxylase Complex H-Protein , Glycine Dehydrogenase (Decarboxylating) , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Rabbits , Sequence Alignment , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid , Species Specificity
14.
J Child Neurol ; 14(7): 464-7, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10573469

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.


Subject(s)
Epilepsy, Complex Partial/etiology , Epilepsy, Complex Partial/metabolism , Glycine/metabolism , Hyperglycinemia, Nonketotic/diagnosis , Hyperglycinemia, Nonketotic/metabolism , Adolescent , Child , Female , Glycine/blood , Glycine/cerebrospinal fluid , Glycine/urine , Humans , Hyperglycinemia, Nonketotic/complications , Male
15.
J Paediatr Child Health ; 35(4): 399-400, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10457302

ABSTRACT

We report a case of galactose-1-phosphate uridyl transferase (GALT) deficiency in a full-term Chinese neonate, who presented with atypical biochemical features of hyperammonaemia in addition to the classical presenting features of jaundice and lethargy after feeding. Red cell GALT activity was virtually absent in the patient while 50% of normal activity was found in parents and a sibling. Mutation screening excluded both Q188R and N314D as the causative mutation in GALT gene, which suggested a possible genetic segregation among ethnic groups. Data from a Taiwan screening program suggested that the incidence of the disease was approximately 1 in 400 000 in the Chinese population which was a sixth of that in Caucasian populations.


Subject(s)
Asian People , Galactosemias/ethnology , Ammonia/blood , China/epidemiology , Female , Galactosemias/diagnosis , Galactosemias/prevention & control , Humans , Incidence , Infant, Newborn , Japan/epidemiology , Male , Neonatal Screening , Taiwan/epidemiology , UTP-Hexose-1-Phosphate Uridylyltransferase/deficiency
16.
Hum Mutat ; 13(4): 338, 1999.
Article in English | MEDLINE | ID: mdl-10220152

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.


Subject(s)
Iduronate Sulfatase/genetics , Gene Deletion , Genotype , Humans , Mucopolysaccharidosis II/genetics , Mutation, Missense , Phenotype , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA
17.
J Paediatr Child Health ; 35(4): 399-400, 1999 Aug.
Article in English | MEDLINE | ID: mdl-28871650

ABSTRACT

We report a case of galactose-1-phosphate uridyl transferase (GALT) deficiency in a full-term Chinese neonate, who presented with atypical biochemical features of hyperammonaemia in addition to the classical presenting features of jaundice and lethargy after feeding. Red cell GALT activity was virtually absent in the patient while 50% of normal activity was found in parents and a sibling. Mutation screening excluded both Q188R and N314D as the causative mutation in GALT gene, which suggested a possible genetic segregation among ethnic groups. Data from a Taiwan screening program suggested that the incidence of the disease was approximately 1 in 400 000 in the Chinese population which was a sixth of that in Caucasian populations.

19.
Clin Biochem ; 31(8): 627-32, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9876894

ABSTRACT

OBJECTIVES: 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). DESIGN AND METHODS: Deletions in mtDNA were identified by a combination of long range PCR and Southern blotting. The precise breakpoints were determined by automated DNA sequencing. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Blotting, Southern/methods , DNA, Mitochondrial/analysis , Ophthalmoplegia/genetics , Polymerase Chain Reaction/methods , Sequence Deletion , Adolescent , Blepharoptosis/genetics , Humans , Kearns-Sayre Syndrome/genetics , Male , Mitochondrial Encephalomyopathies/genetics , Ophthalmoplegia, Chronic Progressive External/genetics , Sensitivity and Specificity
20.
J Med Genet ; 34(6): 493-8, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9192271

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.


Subject(s)
Cerebroside-Sulfatase/genetics , Leukodystrophy, Metachromatic/enzymology , Leukodystrophy, Metachromatic/genetics , Mutation , Adult , Age of Onset , Alleles , Animals , Base Sequence , COS Cells , Cerebroside-Sulfatase/deficiency , Child , Child, Preschool , DNA Primers/genetics , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Mutagenesis, Site-Directed , Nova Scotia , Pedigree , Phenotype , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational
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