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  • 1
    Abstract: X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk alpha subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.
    Type of Publication: Journal article published
    PubMed ID: 9600238
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  • 2
    ISSN: 1432-1076
    Keywords: Vitamin B12 unresponsive methylmalonic acidemia ; Protein intolerance ; Dietary therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The biochemical and therapeutic responses to dietary therapy were studied in a 25-month-old girl and a 1-month-old girl with methylmalonic acidemia (MMA-emia), which was unresponsive to vitamin B12. The minimum daily intake of protein which patients could tolerate and display a good development was between 1.0 and 1.2 g per kg body weight. Supplementation with amino acid mixture devoid of toxic amino acids was required to prevent protein malnutrition when daily protein intake was restricted to 0.6 g per kg body weight. Caloric intake should be sufficient, not only to promote growth but also to prevent a rise in MMA level, especially when a patient has ketoacidosis. It was found that MMA excretion per mg creatinine in random urine specimens correlated significantly with serum MMA and twenty four-hour output of MMA per kg body weight. Therefore measurement of MMA in a single urine specimen is useful for evaluating the in vivo accumulation of MMA.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1076
    Keywords: d-lactic acidosis ; Short bowel syndrome ; Lactobacillus ; Kanamycin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two cases of d-lactic acidosis associated with short bowel syndrome are described. The administration of kanamycin to the patients showed a decrease in d-lactate in blood and urine in parallel with disappearance of metabolic acidosis. Bacteriological analyses of the fecal flora showed an increase in Lactobacillus buchneri in the first patient and Lactobacillus fermenti IVa in the second; both bacteria were sensitive to kanamycin. Quantification of in vitro production of d-lactate by each species of bacteria isolated from the feces revealed that Lactobacillus produced more d-lactate than other species of bacteria. These observations indicate that Lactobacillus may play an important role in the induction of d-lactic acidosis in patients with short bowel syndrome.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1076
    Keywords: Mitochondrial myopathic symdrome ; Lactic acidosis ; Endothelium ; Ultrastructural study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The quadriceps femoris muscle and the muscularis mucosae of the rectum from two children with mitochondrial myopathic syndrome associated with lactic acidosis were studied by electron microscopy. Striking morphological abnormalities of mitochondria were noted not only in the skeletal but also in the smooth muscle cells. Endothelial cells of blood capillaries distributed in these affected muscles were so greatly swollen that the capillary lumen was almost occluded. In contrast, surface epithelial and glandular epithelial cells of the rectum contained normal mitochondria, and fenestrated capillaries in the propria mucosae remained intact. Long-term ischemia resulting from occlusive changes of the capillary wall may be responsible for the mitochondrial alterations of muscle cells.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1076
    Keywords: Ornithine transcarbamylase deficiency ; Heterozygote ; Immunohistochemical analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Females heterozygous for the X-linked urea cycle disorder, ornithine transcarbamylase (OTC) deficiency have a significant risk of developing hyperammonaemia. Diagnosis of this genetic defect in a proband is the essential starting point for family studies. By an immunohistochemical analysis of the liver specimens fixed in 10% formalin, we confirmed heterozygous status for OTC deficiency in two female patients, a 15-year-old girl and a 2-year-old girl, who died of hyperammonaemia. Since most affected males lack cross reactive materials (CRM), an immunochemical analysis should be useful for the diagnosis of most heterozygous females.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1076
    Keywords: Atypical PKU ; Deficiency of dihydrobiopterin ; Neurotransmitter treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A fourteen month-old boy with atypical phenylketonuria was treated with 5-hydroxytryptophan, L-dopa and peripheral aromatic amino acid decarboxylase inhibitor (Ro 4-4602:benserazide). Despite the good control of plasma phenylalanine on a low phenylalanine diet, he had shown no improvement in his development but progressive neurological symptoms, such asiirritability, convulsions and decrease voluntary movement. After beginning neurotransmitter therapy, his irritability disappeared promptly and the other symptoms diminished. He gradually reached his developmental milestones. At two and a half years of age, he had recovered sufficiently to be able to walk freely on treatment with 13 mg/kg/day of 5-hydroxytryptophan, 11 mg/kg/day of L-dopa and 2.7 mg/kg/day of benserazide in combination with slight restriction of phenylalanine intake (100 mg/kg/day). Levels of serotonin and 5-hydroxyindoleacetic acid were low in the patient's CSF. His urinary biopterin (Crithidia factor) excretion was low. An increase in serum biopterin following L-phenylalanine loading was not found. Dihydropteridine reductase activity in his skin fibroblasts was normal. He excreated large amounts of erythro- and threo-neopterins (but only a trace of biopterin) in his urine. After loading with phenylalanine the urinary excretion of neopterins was even more enhanced, but biopterin remained at low levels. These findings indicated that the patient has a dihydrobiopterin synthetase deficiency.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1076
    Keywords: Valproic acid ; Hyperammonaemia ; Aminoacidaemia ; Mitochondrial dysfunction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Serum amino acid pattern, blood ammonia, and serum valproic acid (VPA) levels were estimated in 75 epileptic children with and without VPA therapy. The incidence of patients with hyperammonaemia (〉60 μmol/l) in patients treated with only VPA or with a combination of VPA and other antiepileptic drugs was 19% and 20% respectively. Hyperammonaemia was not observed in patients receiving other drugs. Elevated levels of serum glycine, alanine and serine were more common in epileptic patients treated with VPA alone and with VPA in combination with other drugs than in patients receiving other drugs. A significant positive correlation was found between the serum levels of glycine and alanine, of glycine and serine, and of serine and alanine. These findings may indicate a mitochondrial dysfunction caused by VPA.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1076
    Keywords: Methylmalonic acidaemia ; Type 4 renal tubular acidosis ; Chronic renal disease ; Tubulo-interstitial nephritis ; Hyporeninaemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A 10-month-old male infant with vitamin B12 non-responsive methylmalonic acidaemia is reported. Laboratory results revealed hyperkalaemic, hyperchloraemic, metabolic acidosis with slight azotaemia. The urinary pH decreased (below 5.5) to compensate for acidaemia. Levels of plasma renin activity and plasma aldosterone concentration were low. The renal biopsy showed tubulo-interstitial nephritis. We suggested the diagnosis of type 4 renal tubular acidosis, subtype 2, i.e. hyporeninaemic hypoaldosteronism. We suggest that chronic renal disease may be a common complication of methylmalonic acidaemia.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Mutations in the glycine decarboxylase gene (GLDC) cause nonketotic hyperglycinemia (NKH), an inborn error of metabolism characterized by severe neurological disturbance. We have determined the structure of GLDC and of its pseudogene (ψ GLDC) and studied their expression for a molecular analysis of NKH. The GLDC gene spans at least 135 kb and consists of 25 exons. All donor and acceptor sites adhere to the canonical GT-AG rule, except for the donor site of intron 21, where a variant form GC is used instead of GT. The transcription initiation site has been assigned to a residue 163 bp upstream from the translation initiation triplet by primer extension analysis. The ψ GLDC gene has no intron and shares 97.5% homology with the coding region of functional GLDC, suggesting that ψ GLDC is a processed pseudogene that arose from the GLDC transcript about 4–8 million years ago. RNA blotting analysis has revealed that GLDC is expressed in human liver, kidney, brain, and placenta. We have also examined a patient with NKH with no detectable GLDC mRNA in his lymphoblasts. Exons 1–3 of the functional GLDC gene from this patient are not amplified by polymerase chain reaction (PCR), whereas those from control subjects are. These results suggest a large homozygous deletion (at least 30 kb) in the patient. Furthermore, we have devised a semi-quantitative PCR to estimate the number of GLDC alleles by using ψ GLDC as an internal control and have confirmed the homozygosity and heterozygosity of the deletion in the patient and his parents, respectively. Structural information of GLDC and ψ GLDC should facilitate the molecular analysis of NKH.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1076
    Keywords: Key words Biotin ; Holocarboxylase synthetase ; Multiple carboxylase deficiency ; Splice error
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Holocarboxylase synthetase (HCS) deficiency is a disorder of biotin metabolism characterised by metabolic ketoacidosis and skin lesions due to reduced activities of multiple biotin-dependent carboxylases. The onset of this disease is usually between the neonatal and infantile period. Here we report the molecular analysis of an atypical case of HCS deficiency, where the patient developed his first episode of acidosis at age 8 years and had an exceptionally slow response to biotin therapy. A homozygous mutation was identified at the +5 position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g → a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the amount of normal HCS mRNA may account for the atypical, late-onset phenotype of this patient. Conclusion Molecular analysis is a useful tool for understanding the phenotypic variations in holocarboxylase synthetase deficiency.
    Type of Medium: Electronic Resource
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