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1.
Pediatr Blood Cancer ; 67(4): e28061, 2020 04.
Article in English | MEDLINE | ID: mdl-31736229

ABSTRACT

BACKGROUND: The clinical course of neuroblastoma stage 4S or MS is characterized by a high rate of spontaneous tumor regression and favorable outcome. However, the clinical course and rate of the regression are poorly understood. METHODS: A retrospective cohort study was performed, including all patients with stage 4S neuroblastoma without MYCN amplification, from two Dutch centers between 1972 and 2012. We investigated the clinical characteristics, the biochemical activity reflected in urinary catecholamine excretion, and radiological imaging to describe the kinetics of tumor regression, therapy response and outcome. RESULTS: The cohort of 31 patients reached a 10-year overall survival of 84% ± 7% (median follow-up 16 years; range, 3.3-39). During the regressive phase, liver size normalized in 91% of the patients and catecholamine excretion in 83%, both after a median of two months (liver size: range, 0-131; catecholamines: range, 0-158). The primary tumors completely regressed in 69% after 13 months (range, 6-73), and the liver architecture normalized in 52% after 15 months (range, 5-131). Antitumor treatment was given in 52% of the patients. Interestingly, regression rates were similar for treated and untreated patients. Four of seven patients < 4 weeks old died of rapid liver expansion and organ compression. Three patients progressed to stage 4, 3 to 13 months after diagnosis; all had persistently elevated catecholamines. CONCLUSION: Patients < 4 weeks old with neuroblastoma stage 4S are at risk of fatal outcome caused by progression of liver metastases. In other patients, tumor regression is characterized by a rapid biochemical normalization that precedes radiological regression.


Subject(s)
Neoplasm Regression, Spontaneous/pathology , Neuroblastoma/pathology , Cohort Studies , Disease Progression , Female , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Risk Factors
2.
Eur J Cancer ; 72: 235-243, 2017 02.
Article in English | MEDLINE | ID: mdl-28061374

ABSTRACT

INTRODUCTION: Neuroblastoma (NBL) accounts for 10% of the paediatric malignancies and is responsible for 15% of the paediatric cancer-related deaths. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are most commonly analysed in urine of NBL patients. However, their diagnostic sensitivity is suboptimal (82%). Therefore, we performed in-depth analysis of the diagnostic sensitivity of a panel of urinary catecholamine metabolites. PATIENTS AND METHODS: Retrospective study of a panel of 8 urinary catecholamine metabolites (VMA, HVA, 3-methoxytyramine [3MT], dopamine, epinephrine, metanephrine, norepinephrine and normetanephrine [NMN]) from 301 NBL patients at diagnosis. Special attention was given to subgroups, metaiodobenzylguanidine (MIBG) non-avid tumours and VMA/HVA negative patients. RESULTS: Elevated catecholamine metabolites, especially 3MT, correlated with nine out of 12 NBL characteristics such as stage, age, MYCN amplification, loss of heterozygosity for 1p and bone-marrow invasion. The combination of the classical markers VMA and HVA had a diagnostic sensitivity of 84%. NMN was the most sensitive single diagnostic metabolite with overall sensitivity of 89%. When all 8 metabolites were combined, a diagnostic sensitivity of 95% was achieved. Among the VMA and HVA negative patients, were also 29% with stage 4 disease, which usually had elevation of other catecholamine metabolites (93%). Diagnostic sensitivity for patients with MIBG non-avid tumour was improved from 33% (VMA and/or HVA) to 89% by measuring the panel. CONCLUSIONS: Our study demonstrates that analysis of a urinary catecholamine metabolite panel, comprising 8 metabolites, ensures the highest sensitivity to diagnose NBL patients.


Subject(s)
Biomarkers, Tumor/urine , Catecholamines/urine , Neuroblastoma/urine , Adolescent , Catecholamines/metabolism , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Sensitivity and Specificity
3.
JIMD Rep ; 15: 39-45, 2015.
Article in English | MEDLINE | ID: mdl-24788355

ABSTRACT

Two sisters were diagnosed in their adulthood with aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM#608643). They experienced early myasthenia-like manifestations, myoclonic jerks, oculogyric crises, tremors, and developmental delay during childhood; clinical stabilization afterwards; and spontaneous improvement during adolescence and young adulthood. Two novel pathogenic mutations on DDC gene [p.Tyr37Thrfs*5 (c.105delC) and p.F237S (c.710 T>C)] were associated with undetectable enzyme activity in plasma and only a mild reduction of biogenic amines in cerebrospinal fluid (CSF). The increase of both 3-O-methyldopa and 5-hydroxytryptophan on CSF was the most relevant biochemical alteration denoting AADC defect in these subjects. Transdermal rotigotine remarkably improved their gross motor functions and the asthenic status they complained. The present cases broaden the phenotypic spectrum of AADC deficiency and suggest that (1) AADC defect is not a progressive neurological disease and behaves rather as a neurodevelopmental disorder that improves during the second decade of life; (2) treatment-naïve adults can still respond well to neurotransmitter therapy; and (3) the possibility of a mild presentation of AADC deficiency should be considered when examining young adults with asthenic and parkinsonian symptoms.

4.
J Inherit Metab Dis ; 37(5): 801-12, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24526388

ABSTRACT

ß-ureidopropionase (ßUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-ß-amino aciduria. To date, only 16 genetically confirmed patients with ßUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese ßUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant ßUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, ßUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human ßUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that ßUP deficiency is not as rare as generally considered and screening for ßUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.


Subject(s)
Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Amidohydrolases/deficiency , Brain Diseases/epidemiology , Brain Diseases/genetics , Movement Disorders/epidemiology , Movement Disorders/genetics , Mutation/genetics , Purine-Pyrimidine Metabolism, Inborn Errors/epidemiology , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Alleles , Amidohydrolases/chemistry , Amidohydrolases/genetics , Child , Child, Preschool , Female , Gene Frequency , HEK293 Cells , Humans , Infant , Infant, Newborn , Japan/epidemiology , Male , Models, Molecular , Mutation, Missense/genetics , Nervous System Diseases/etiology , Nervous System Diseases/genetics , Phenotype , Prevalence
5.
Mol Genet Metab ; 111(3): 404-407, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24100244

ABSTRACT

An infant carrying a heterozygous c.43_46delACTA and a heterozygous c.668 G>A mutation in the ALPL gene with hypophosphatasia in the absence of bone deformities presented with therapy-resistant seizures. Pyridoxal phosphate was extremely high in CSF and plasma. Pyridoxine treatment had only a transient effect and the severe encephalopathy was fatal. Repeated brain MRIs showed progressive cerebral damage. The precise metabolic cause of the seizures remains unknown and pyridoxine treatment apparently does not cure the epilepsy.


Subject(s)
Epilepsy/pathology , Hypophosphatasia/genetics , Hypophosphatasia/pathology , Pyridoxine/administration & dosage , Alkaline Phosphatase/genetics , Drug Resistance , Epilepsy/complications , Epilepsy/mortality , Humans , Hypophosphatasia/blood , Hypophosphatasia/cerebrospinal fluid , Hypophosphatasia/mortality , Infant , Male , Pyridoxal Phosphate/blood , Pyridoxal Phosphate/cerebrospinal fluid , Seizures/genetics , Seizures/pathology
6.
J Inherit Metab Dis ; 36(6): 967-72, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23392989

ABSTRACT

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.


Subject(s)
Folic Acid/therapeutic use , Rett Syndrome/drug therapy , S-Adenosylhomocysteine/blood , S-Adenosylhomocysteine/cerebrospinal fluid , S-Adenosylmethionine/blood , S-Adenosylmethionine/cerebrospinal fluid , Adolescent , Adult , Child , Child, Preschool , Dietary Supplements , Female , Folic Acid/analogs & derivatives , Folic Acid/cerebrospinal fluid , Folic Acid/pharmacology , Humans , Infant , Rett Syndrome/blood , Rett Syndrome/cerebrospinal fluid , Young Adult
7.
Biochim Biophys Acta ; 1822(7): 1096-108, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22525402

ABSTRACT

ß-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO(2). To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.


Subject(s)
Amidohydrolases/deficiency , Amidohydrolases/genetics , Central Nervous System Diseases/genetics , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Pyrimidines/metabolism , Adult , Amino Acid Sequence , Amino Acid Substitution/physiology , Aminoisobutyric Acids/blood , Aminoisobutyric Acids/urine , Animals , Biocatalysis , Catalytic Domain/physiology , Central Nervous System Diseases/enzymology , Child , Child, Preschool , Drosophila melanogaster , Escherichia coli , Female , Genotype , Humans , Infant , Infant, Newborn , Male , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation, Missense , Point Mutation , Protein Conformation , Protein Interaction Domains and Motifs/physiology , Purine-Pyrimidine Metabolism, Inborn Errors/enzymology , Racial Groups/genetics , beta-Alanine/blood , beta-Alanine/urine
8.
JIMD Rep ; 4: 99-102, 2012.
Article in English | MEDLINE | ID: mdl-23430902

ABSTRACT

CASE: A 34-year-old woman was referred to our hospital with progressive movement disorders and neurodegeneration with brain iron accumulation and enlargement of the frontal diploe on the MRI. Metabolic testing revealed that she had α-mannosidosis (AMD), a lysosomal storage disorder. BACKGROUND: AMD is a rare genetic disorder that causes α-mannosidase deficiency resulting in lysosomal accumulation of undigested oligosaccharides. The symptoms of AMD consist of facial and skeletal deformities combined with progressive psychiatric and neurological complaints, especially ataxia and mental retardation. Bilateral patellar dislocation and hearing impairment are frequent. DISCUSSION: The movement disorders we found in our patient have not been reported previously, but they are likely late symptoms of this progressive disorder. The iron deposits in the basal ganglia have also not been reported in AMD and are yet of unknown significance. Lysosomal storage disorders, such as AMD, should be considered in patients with progressive neurologic conditions and neurodegeneration with brain iron accumulation on MRI.

9.
AIDS ; 25(17): 2149-55, 2011 Nov 13.
Article in English | MEDLINE | ID: mdl-21857491

ABSTRACT

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy and reduction in estimated glomerular filtration rate (eGFR), without accounting for the tubular secretion of creatinine. METHODS: A substudy was performed among 19 participants of a randomized 48-week trial, comparing continuing first-line zidovudine/lamivudine (ZDV/3TC) with switching to TDF/emtricitabine (FTC). GFR was measured with [(125)I]-iothalamate (mGFR) and effective renal plasma flow (ERPF) with [(131)I]-hippuran. eGFR and tubular effects were assessed using plasma and urine samples. RESULTS: Of the 19 patients, 18 were men, 15 whites, mean (SD) age 46.0 (8.9) years, plasma HIV-1 RNA less than 50 copies/ml in all. After 48 weeks, eGFR using Cockcroft-Gault equation and ERPF, but not mGFR, had significantly decreased, and urinary α1-microglobulin/creatinine and microalbumin/creatinine significantly increased in patients on TDF. Although phosphate metabolism on TDF was affected at week 4, differences between groups disappeared during follow-up. CONCLUSION: Replacing ZDV/3TC with TDF/FTC in this limited sample of virologically suppressed HIV-1-infected adults was associated with mild persistent tubular but not glomerular dysfunction over 48 weeks. The observed persistent decrease in Cockcroft-Gault-based eGFR, but not mGFR, rather than being indicative of glomerular dysfunction may be explained by TDF inhibiting tubular creatinine excretion.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/adverse effects , Glomerular Filtration Rate/drug effects , HIV Infections/drug therapy , HIV-1 , Kidney Tubules/drug effects , Organophosphonates/adverse effects , Adenine/adverse effects , Adult , Alpha-Globulins , Creatinine/metabolism , Female , Humans , Kidney Glomerulus/drug effects , Male , Middle Aged , Randomized Controlled Trials as Topic , Renal Plasma Flow, Effective/drug effects , Serum Albumin/metabolism , Tenofovir , Time Factors , Treatment Outcome
10.
J Inherit Metab Dis ; 34(1): 159-64, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21110228

ABSTRACT

We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and urine organic acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation defect (MADD, ethylmalonic/adipic acid syndrome). Subsequently, a profound flavin deficiency in spite of a normal dietary riboflavin intake was established in the plasma of all three children, suggesting a riboflavin transporter defect. Genetic analysis of these patients demonstrated mutations in the C20orf54 gene which encodes the human homolog of a rat riboflavin transporter. This gene was recently implicated in the Brown-Vialetto-Van Laere syndrome, a rare neurological disorder which may either present in infancy with neurological deterioration with hypotonia, respiratory insufficiency and early death, or later in life with deafness and progressive ponto-bulbar palsy. Supplementation of riboflavin rapidly improved the clinical symptoms as well as the biochemical abnormalities in our patients, demonstrating that high dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome as well as for the Fazio Londe syndrome which is considered to be the same disease entity without the deafness.


Subject(s)
Bulbar Palsy, Progressive/genetics , Membrane Transport Proteins/genetics , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapy , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/diagnosis , Riboflavin/metabolism , Bulbar Palsy, Progressive/complications , Bulbar Palsy, Progressive/diagnosis , Bulbar Palsy, Progressive/therapy , Child , Diagnosis, Differential , Female , Hearing Loss, Sensorineural/complications , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/therapy , Humans , Infant , Male , Metabolism, Inborn Errors/genetics , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/genetics , Siblings
11.
PLoS One ; 5(5): e10635, 2010 May 14.
Article in English | MEDLINE | ID: mdl-20498721

ABSTRACT

BACKGROUND: The polyunsaturated fatty acid (PUFA) composition of (nerve) cell membranes may be involved in the pathophysiology of depression. Studies so far, focussed mainly on omega-3 and omega-6 PUFAs. In the present study, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and PUFAs of the omega-3, -6 and -9 series in plasma and erythrocytes of patients with recurrent major depressive disorder (MDD-R) were compared with controls. METHODOLOGY AND PRINCIPAL FINDINGS: We carried out a case-control study. The sample consisted of 137 patients with MDD-R and 65 matched non-depressed controls. In plasma and erythrocytes of patients with MDD-R the concentrations of most of the SFAs and MUFAs, and additionally erythrocyte PUFAs, all with a chain length > 20 carbon (C) atoms, were significantly lower than in the controls. In contrast, the concentrations of most of the shorter chain members (< or = 18C) of the SFAs and MUFAs were significantly higher in the patients. Estimated activities of several elongases in plasma of patients were significantly altered, whereas delta-9 desaturase activity for C14:0 and C18:0 was significantly higher. CONCLUSIONS/SIGNIFICANCE: The fatty acid status of patients with MDD-R not only differs with regard to omega-3 and omega-6 PUFAs, but also concerns other fatty acids. These alterations may be due to: differences in diet, changes in synthesizing enzyme activities, higher levels of chronic (oxidative) stress but may also result from adaptive strategies by providing protection against enhanced oxidative stress and production of free radicals.


Subject(s)
Depression/blood , Erythrocytes/metabolism , Fatty Acids/blood , Acetyltransferases/blood , Adult , Antidepressive Agents/therapeutic use , Case-Control Studies , Depression/drug therapy , Education , Erythrocytes/enzymology , Fatty Acid Desaturases/blood , Fatty Acid Elongases , Fatty Acids/metabolism , Female , Humans , Male , Metabolic Networks and Pathways , Recurrence , Waist Circumference/physiology
12.
Mol Genet Metab ; 94(4): 403-409, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18502672

ABSTRACT

BACKGROUND: Sepiapterin reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far. METHODS: We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis. RESULTS: Both patients suffered from a progressive and complex L-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X). CONCLUSIONS: Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with L-dopa, is illustrated again in our cases.


Subject(s)
Alcohol Oxidoreductases/genetics , Metabolism, Inborn Errors/enzymology , Alcohol Oxidoreductases/cerebrospinal fluid , Alcohol Oxidoreductases/metabolism , Alcohol Oxidoreductases/urine , Biosynthetic Pathways , Child , Female , Fibroblasts/enzymology , Greece , Homovanillic Acid/cerebrospinal fluid , Homovanillic Acid/urine , Humans , Hydroxyindoleacetic Acid/cerebrospinal fluid , Hydroxyindoleacetic Acid/urine , Metabolism, Inborn Errors/cerebrospinal fluid , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/urine , Mutation , Neurotransmitter Agents/cerebrospinal fluid , Neurotransmitter Agents/urine , Pterins/cerebrospinal fluid , Pterins/urine , Siblings
13.
Mol Genet Metab ; 91(2): 157-64, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17383919

ABSTRACT

Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and it catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine to N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, respectively. To date, only nine individuals have been reported suffering from a complete DHP deficiency. We report two siblings presenting with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. One of the siblings had a severe delay in speech development and white matter abnormalities, whereas the other one was free of symptoms. Analysis of the DHP gene (DPYS) showed that both patients were compound heterozygous for the missense mutation 1078T>C (W360R) in exon 6 and a novel missense mutation 1235G>T (R412M) in exon 7. Heterologous expression of the mutant enzymes in Escherichia coli showed that both missense mutations resulted in a mutant DHP enzyme without residual activity. Analysis of the crystal structure of eukaryotic DHP from the yeast Saccharomyces kluyveri and the slime mold Dictyostelium discoideum suggests that the W360R and R412M mutations lead to structural instability of the enzyme which could potentially impair the assembly of the tetramer.


Subject(s)
Amidohydrolases/deficiency , Amidohydrolases/biosynthesis , Amidohydrolases/chemistry , Amidohydrolases/genetics , Amino Acid Sequence , Animals , Brain/abnormalities , Child, Preschool , Crystallography, X-Ray , Dictyostelium/enzymology , Enzyme Stability , Escherichia coli/enzymology , Humans , Language Development Disorders/physiopathology , Magnetic Resonance Imaging , Male , Models, Molecular , Molecular Sequence Data , Mutation, Missense , Protein Conformation , Saccharomyces/enzymology , Siblings , Thymine/analogs & derivatives , Thymine/blood , Thymine/cerebrospinal fluid , Thymine/urine , Uracil/analogs & derivatives , Uracil/blood , Uracil/cerebrospinal fluid , Uracil/urine
14.
Epilepsia ; 47(1): 215-7, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16417553

ABSTRACT

UNLABELLED: Beta-ureidopropionase is the third enzyme in the catabolic pathway of uracil and thymine. To date, only three other patients are reported with this inborn error of metabolism. We report the clinical presentation of a male patient who presented at the age of 4 months after an ALTE-like event (ALTE = acute life-threatening event) with febrile status epilepticus. Such a clinical presentation has not been reported before in this condition. Diagnosis was based on biochemical, enzymatic and molecular studies. MRI (magnetic resonance imaging) at the age of 11 months demonstrated large subdural hematomata and global supratentorial atrophy. At that time the patient showed severe psychomotor retardation with muscular hypotonia, extremely limited visual contact and poorly controlled epilepsy. CONCLUSIONS: Pyrimidine degradation defects should be included in the differential diagnosis of convulsions, (febrile) status epilepticus, psychomotor retardation and possibly also ALTE-like events.


Subject(s)
Amidohydrolases/deficiency , Fever/diagnosis , Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis , Status Epilepticus/diagnosis , Thymine/metabolism , Uracil/metabolism , Amidohydrolases/genetics , Atrophy , Central Nervous System Diseases/enzymology , Central Nervous System Diseases/etiology , Central Nervous System Diseases/pathology , Diagnosis, Differential , Fever/metabolism , Hematoma, Subdural/diagnosis , Hematoma, Subdural/pathology , Humans , Infant , Magnetic Resonance Imaging , Male , Mutation , Psychomotor Disorders/diagnosis , Purine-Pyrimidine Metabolism, Inborn Errors/metabolism , Seizures, Febrile/diagnosis , Status Epilepticus/metabolism
15.
Hum Mol Genet ; 13(22): 2793-801, 2004 Nov 15.
Article in English | MEDLINE | ID: mdl-15385443

ABSTRACT

beta-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No beta-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the beta-ureidopropionase protein. Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E). Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-beta-amino aciduria in these patients is due to a deficiency of beta-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency. An analysis of the presence of the two splice site mutations and the missense mutation in 95 controls identified one individual who proved to be heterozygous for the IVS8-1G>A mutation. Thus, a beta-ureidopropionase deficiency might not be as rare as is generally considered.


Subject(s)
Amidohydrolases/deficiency , Central Nervous System Diseases/genetics , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Pyrimidines/metabolism , Amidohydrolases/genetics , Aminoisobutyric Acids/blood , Aminoisobutyric Acids/cerebrospinal fluid , Aminoisobutyric Acids/urine , Central Nervous System Diseases/enzymology , Central Nervous System Diseases/etiology , Female , Humans , Infant , Liver/enzymology , Male , Mutation , Oxidative Stress , Purine-Pyrimidine Metabolism, Inborn Errors/complications , Purine-Pyrimidine Metabolism, Inborn Errors/enzymology , beta-Alanine/blood , beta-Alanine/cerebrospinal fluid , beta-Alanine/urine
16.
Biochem J ; 379(Pt 1): 119-24, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-14705962

ABSTRACT

DPD (dihydropyrimidine dehydrogenase) constitutes the first step of the pyrimidine degradation pathway, in which the pyrimidine bases uracil and thymine are catabolized to beta-alanine and the R-enantiomer of beta-AIB (beta-aminoisobutyric acid) respectively. The S-enantiomer of beta-AIB is predominantly derived from the catabolism of valine. It has been suggested that an altered homoeostasis of beta-alanine underlies some of the clinical abnormalities encountered in patients with a DPD deficiency. In the present study, we demonstrated that only a slightly decreased concentration of beta-alanine was present in the urine and plasma, whereas normal levels of beta-alanine were present in the cerebrospinal fluid of patients with a DPD deficiency. Therefore the metabolism of beta-alanine-containing peptides, such as carnosine, may be an important factor involved in the homoeostasis of beta-alanine in patients with DPD deficiency. The mean concentration of beta-AIB was approx. 2-3-fold lower in cerebrospinal fluid and urine of patients with a DPD deficiency, when compared with controls. In contrast, strongly decreased levels (10-fold) of beta-AIB were present in the plasma of DPD patients. Our results demonstrate that, under pathological conditions, the catabolism of valine can result in the production of significant amounts of beta-AIB. Furthermore, the observation that the R-enantiomer of beta-AIB is abundantly present in the urine of DPD patients suggests that significant cross-over exists between the thymine and valine catabolic pathways.


Subject(s)
Aminoisobutyric Acids/metabolism , Dihydropyrimidine Dehydrogenase Deficiency , Purine-Pyrimidine Metabolism, Inborn Errors/metabolism , Thymine/metabolism , Valine/metabolism , beta-Alanine/metabolism , Aminoisobutyric Acids/blood , Aminoisobutyric Acids/cerebrospinal fluid , Aminoisobutyric Acids/chemistry , Aminoisobutyric Acids/urine , Brain Diseases, Metabolic, Inborn/enzymology , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/metabolism , Dihydrouracil Dehydrogenase (NADP)/genetics , Fluorouracil/pharmacokinetics , Homeostasis , Humans , Inactivation, Metabolic/genetics , Neurotransmitter Agents/metabolism , Purine-Pyrimidine Metabolism, Inborn Errors/enzymology , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Stereoisomerism , Uracil/metabolism , beta-Alanine/blood , beta-Alanine/cerebrospinal fluid , beta-Alanine/urine
17.
Turk J Pediatr ; 44(1): 49-53, 2002.
Article in English | MEDLINE | ID: mdl-11859869

ABSTRACT

Hyperphenylalaninemia result from a block in the conversion of phenylalanine into tyrosine due to a defect in either the enzyme phenylalanine hydroxylase (98% of subjects) or in the metabolism of the cofactor tetrahydrobiopterin. Phenylalanine hydroxylase deficiency is the most common form of inherited hyperphenylalaninemia disorders, with a prevalence between 1/4,000-1/40,000. Glycogen storage disease (GSD) type III is caused by debranching enzyme deficiency of glycogen degradation. The clinical features vary in relation to the localization of the enzyme defect. Two clinical entities exist: a combined hepatic myogenic form (GSD IIIa) and a purely hepatic form (GSD IIIb). The inheritance is autosomal recessive. We describe a Turkish family in which two girls were found to have phenylketonuria, while in two other sisters glycogen storage disease type III was diagnosed. The parents of these children are cousins and they have had 12 children.


Subject(s)
Glycogen Storage Disease/genetics , Phenylketonurias/genetics , Child , Consanguinity , Female , Glycogen Debranching Enzyme System/blood , Glycogen Storage Disease/complications , Glycogen Storage Disease/metabolism , Humans , Phenylketonurias/complications , Phenylketonurias/metabolism , Pterins/urine
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