Biomedical subjects

J Campistol

Publications and source records attributed to J Campistol.

At least 19 recordsLinked to original sources

PubMed2003

Late-onset form of beta-electron transfer flavoprotein deficiency.

Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO). We report the clinical features and biochemical and molecular genetic analyses of a patient with a mild late-onset form of GAII due to beta-ETF deficiency. Biochemical data showed an abnormal urine organic acid profile, low levels of free carnitine, increased levels of C(10:1n-6), and C(14:1n-9) in plasma, and decreased oxidation of [9,10-3H]palmitate and [9,10-3H]myristate in fibroblasts, suggesting MAD deficiency. In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del). The present report delineates further the phenotype of mild beta-ETF deficiency and illustrates that the differential diagnosis of GAII is readily achieved by mutational analysis.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Plasma thiols and their determinants in phenylketonuria.

OBJECTIVE: Treatment of phenylketonuria (PKU) patients consists of a phenylalanine-restricted diet supplemented with a tyrosine-, vitamin- and oligoelement-enriched amino-acid mixture. Vitamins and oligoelements may be deficient when compliance with the supplemented special formula is poor. Plasma thiol concentrations (especially homocysteine) depend mainly on B-vitamin intake. Our aim was to evaluate the plasma thiol concentrations (homocysteine, cysteine and glutathione) and their determinants (methionine, cobalamin and folate) in PKU patients under dietary treatment compared with age-matched controls. DESIGN AND SETTING: Cross-sectional study performed in a tertiary care Hospital. SUBJECTS: PKU (42) patients under dietary treatment compared with 42 age-matched controls. INTERVENTIONS: Plasma total homocysteine, cysteine and glutathione were analyzed by HPLC with fluorescence detection. Plasma phenylalanine and methionine were analyzed by ion exchange chromatography. Serum folate and cobalamin were analyzed by radioimmunoassay procedures. RESULTS: Total homocysteine concentrations were significantly lower in the PKU patients compared with the control group (Students t-test; P<0.0001). Serum folate and cobalamin were significantly higher in the PKU group (t-Student; P<0.0001) compared with controls. A significantly negative correlation was observed between total homocysteine and folate (r=-0.378; P=0.016), and between cobalamin and phenylalanine concentrations (r=-0.367; P=0.022) in the PKU group. CONCLUSIONS: Plasma total homocysteine values are lower in the PKU group than in the controls, probably because of high folate values. High phenylalanine values, an indicator of poor dietary compliance, are negatively associated with cobalamin, which might be deficient in some cases.

Adolescent↗

PubMed2002

New approach to osteopenia in phenylketonuric patients.

AIM: To study bone mineralization in a group of phenylketonuric patients and to search for a possible relationship between bone mineral density, dietary control, serum minerals and nutrition intake. The response to treatment with low-dose 1.25-(OH)2 vitamin D in patients with osteopenia was evaluated. METHODS: Twenty-eight phenylketonuric patients (age range: 10-33 y) on dietary treatment were investigated. Bone density at the lumbar spine (Dual Energy X-ray Absorptiometry), bone formation markers (osteocalcin and bone alkaline phosphatase), serum minerals, index of dietary control and protein, vitamin D and mineral intakes were determined. RESULTS: Of the patients studied, 78.6% had good dietary compliance (462 +/- 89 micromol/L). Mean protein, vitamin D and mineral intakes met the recommended dietary allowances (RDAs). Nevertheless, 8 patients had calcium intakes lower than 1000 g/d, and a positive correlation between Z-score and calcium (r = 0.585; p = 0.002) or phosphorus intake (r = 0.546; p = 0.005) was observed. Osteopenia was detected in 14 patients (50%). Moreover, bone alkaline phosphatase in phenylketonuric patients older than 18 y of age was significantly lower than that in controls (p < 0.0001). No correlation was found between bone mineral density, age, serum minerals, bone formation markers or index of dietary control. Treatment with 0.25 microg/d calcitriol significantly increased bone density in 6 patients. CONCLUSION: A defect in bone mineralization was detected in 50% of patients in our series. The correct amount of formula intake seems to be necessary for bone mineralization in phenylketonuric patients. Calcitriol can be a useful treatment for these patients, although more studies are needed to confirm these results. Hypercalcaemia and hypercalciuria need to be carefully monitored.

Adolescent↗

PubMed2002

[Congenital errors of metabolism with epileptic seizures during the first years of life].

OBJECTIVE: In this paper we review the main aetiologies of metabolic origin which cause epilepsy in children aged between 1 and 10 years. DEVELOPMENT: There are many aetiological causes of convulsive seizures. Seizures and epilepsies due to congenital errors of metabolism are a minority but should be known. Their identification is not easy although at present there is a wide range of diagnostic methods to confirm the diagnosis when this is suspected. In this review we have only considered the congenital errors of metabolism which start between the ages of 12 months and 10 years, with convulsive seizures. We have divided the conditions into two subgroups depending on whether epilepsy was one of the main symptoms or only part of a set of neurological symptoms and signs. Finally we establish the possible diagnoses of congenital errors of metabolism with seizures occurring in this age group. CONCLUSIONS: In neuropaediatrics the paediatrician and epileptolgist must be aware of congenital errors of metabolism as being responsible for epilepsy, especially in cases of drug resistant epilepsy or when accompanied by other systemic features, neurological deterioration or unexplained biochemical alterations.

Amino Acids↗

PubMed2002

[Teratogenic effects of epilepsy and anti epileptic drugs].

OBJECTIVE: In this paper we review the main studies on teratogenicity related to epilepsy and especially use of anti epileptic drugs (AED), with special emphasis on recently acquired knowledge regarding the new AED. DEVELOPMENT: When considering the teratogenic effects of epilepsy and the anti epileptic drugs it should be remembered that there are a series of premises and considerations which undoubtedly play an important part in causing possible damage to the foetus. These factors include changes caused during pregnancy, the passage of drugs across the placenta barrier , malformations occurring in the children and relations of women with epilepsy and finally the effect of seizures on the foetus. We then review the mechanisms of the teratogenicity of the classical AED and the new AED. Little is known about the adverse effects of the new AED, and many are used together as polytherapy. Multicenter studies involving large numbers of participants are therefore necessary to obtain results which can be extrapolated to the whole population. Unfortunately, at present, this is not yet so and there are no clear recommendations for their use during pregnancy. The EURAP was designed for this reason. It is one of the multicenter studies being carried out in Europe at present with many Spanish specialists participating. CONCLUSIONS: Multicenter studies with many participants are necessary to obtain reliable data on the teratogenicity of the various AED, used as monotherapy and bitherapy, particularly regarding the new AED. We conclude by considering measures to try to reduce, as far as possible, the teratogenic effects in pregnant women.

Abnormalities, Drug-Induced↗

PubMed2002

[Visuo-constructive disorders in periventricular leukomalacia].

INTRODUCTION: Cerebral palsy involves not only motor impairment but also the impairment of cognitive functions. Visuo spatial impairment has often been reported in preterm children with spastic diplegia due to periventricular leukomalacia. PATIENTS AND METHODS: Eight children with periventricular leukomalacia diagnosis. When examined their ages were between 3 and 13 years. RESULTS: We found visuo spatial anomalies in all subjects. These anomalies don't result in reading and writing learning difficulties. CONCLUSION: Constructional dyspraxia is frequently found in children with periventricular leukomalacia and correlates with reduction of peritrigonal white matter in parietal lobe.

Adolescent↗

PubMed2001

Phenotype and genotype heterogeneity in Mediterranean citrullinemia.

We summarize the diagnosis, outcome, and molecular studies of five Mediterranean patients with citrullinemia: four neonatal classical forms and one subacute form, who also suffers from Down syndrome and presented with severe hepatic encephalopathy at age 7. Mutational analysis revealed three alleles with a common mutation and five new mutations: two Moroccan siblings are homozygous for G390R, the subacute form is compound heterozygous for G390R/G117D (new mutation), and the two other neonatal forms are compound heterozygous for four new mutations: V69A/E270Q and T119I(R108L)/?.

Argininosuccinate Synthase↗

PubMed2001

Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes.

Phenylketonuria is one of the most common genetic diseases in humans, affecting 1 in 10,000 whites. Deletions are generally uncommon in genes in which no long highly homologous segments are present, and in phenylalanine hydroxylase (PAH) deficiency they represent only 5% of cases. We present the case of a girl affected by classical phenylketonuria who has been screened for mutations in the PAH gene. During the molecular study a large de novo deletion has detected in 12qter, including PAH, and the genes for insulin-like growth factor 1 (IGF1), human achaete-scute homolog 1 (ASCL1), and tumor rejection antigen (TRA1). The patient showed phenylketonuria, short stature, and pathological electro-oculography results in both eyes, with high affectation of the relative electrogenesis of the photoreceptor-pigment epithelium complex. She had previously been misdiagnosed as homozygous for the IVS8nt-7A-G mutation, instead of heterozygous for a mutation and a de novo deletion. As a result incorrect genetic counseling had been given. The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome. We stress the relevance of polymorphic marker haplotype analysis and the importance of family study in genetic recessive diseases, such as phenylketonuria, to avoid incorrect diagnosis and genetic counseling.

Antigens, Neoplasm↗

PubMed2001

Is there a relationship between plasma phenylalanine and cholesterol in phenylketonuric patients under dietary treatment?

OBJECTIVES: To study the lipid profile in a group of treated phenylketonuric patients (PKU; n = 61) compared with a group of inborn error of intermediary metabolism patients (IEM; n = 22), a group of hyperphenylalaninemic children (HPA; n = 37), and a control group without dietary restriction (n = 41). DESIGN AND METHODS: Phenylalanine was analyzed by ion exchange chromatography and triglycerides, cholesterol and HDL were determined by standard procedures with the Cobas Integra analyzer. RESULTS: Serum total cholesterol concentrations were significantly lower in PKU patients compared with IEM patients (whose cholesterol daily intake was similar to those of PKU patients), HPA children and the control group. A negative correlation was observed between cholesterol and phenylalanine concentrations in the PKU patients. CONCLUSIONS: Our findings support the hypothesis of a relationship between high plasma phenylalanine levels and an inhibition of cholesterogenesis, although the low cholesterol intake of the special diets may also decrease serum cholesterol values.

Adolescent↗

PubMed2001

Plasma phenylalanine is associated with decreased serum ubiquinone-10 concentrations in phenylketonuria.

Decreased serum ubiquinone-10 concentrations is a common condition in patients with phenylketonuria (PKU) under dietary treatment. Our aim was to investigate the implication of the metabolic abnormalities of PKU (low concentrations of tyrosine and high concentrations of phenylalanine) and the effect of treatment with phenylalanine-restricted diets in decreased ubiquinone-10 concentrations in PKU patients. We studied 30 PKU patients (age range 5 months to 35 years; median age 7 years) under dietary treatment. Correlation between plasma tyrosine or phenylalanine and serum ubiquinone-10 concentrations was investigated. Daily cholesterol intake was calculated from the data obtained through a dietary questionnaire. The index of dietary control (IDC) was calculated as the average of the medians of plasma phenylalanine concentrations obtained every 6 months in the metabolic control of patients. Negative correlations were observed between serum ubiquinone and the IDC (r=-0.46; p<0.01) in PKU patients. No correlation was observed between tyrosine or daily cholesterol intake and serum ubiquinone concentrations. After adjustment for daily cholesterol intake by multiple linear regression analysis, for each 113 units of increase in IDC values serum ubiquinone decreased 0.1 micromol/L. According to our results, the main factor associated with the decreased serum ubiquinone concentrations was high plasma phenylalanine values. Although daily cholesterol intake seems to be associated with ubiquinone concentrations, it may not be relevant if we take into account the low intake of cholesterol in treated PKU patients.

Adolescent↗

PubMed2000

Potential relationship between genotype and clinical outcome in propionic acidaemia patients.

Propionic acidaemia (PA) is an autosomal recessive disorder caused by mutations in either of the PCCA or PCCB genes which encode the alpha and beta subunits, respectively, of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). In this work we have examined the biochemical findings and clinical outcome of 37 Spanish PA patients in relation to the mutations found in both PCCA and PCCB genes. We have detected 27 early-onset and 101 late-onset cases, showing remarkably similar biochemical features without relation to either the age of onset of the disease or the defective gene they have. Twenty-one of the patients have so far survived and three of them, now adolescents, present normal development. Different biochemical procedures allowed us to identify the defective gene in 9 PCCA deficient and 28 PCCB deficient patients. Nine putative disease-causing mutations accounting for 77.7% of mutant alleles were identified among PCCA deficient patients, each one carrying a unique genotypic combination. Of PCCB mutant alleles 98% were characterised. Four common mutations (ins/del, E168K, 1170insT and A497V) were found in 38/52 mutant chromosomes investigated, whereas the remainder of the alleles harbour 12 other different mutations. By examining the mutations identified both in PCCA and PCCB genes and the clinical evolution of patients, we have found a good correlation between certain mutations which can be considered as null with a severe phenotype, while certain missense mutations tend to be related to the late and mild forms of the disease. Expression studies, particularly of the missense mutations identified are necessary but other genetic and environmental factors probably contribute to the phenotypic variability observed in PA.

Adult↗

PubMed2000

Children with stroke: polymorphism of the MTHFR gene, mild hyperhomocysteinemia, and vitamin status.

The aim of this study was to investigate a possible association among the thermolabile polymorphism, nucleotide 677 cytosine to thymidine point mutation (677 C-->T) of the methylenetetrahydrofolate reductase (MTHFR) gene, hyperhomocysteinemia, serum folate, vitamins B12 and B6, and stroke in children. Allele and genotype frequencies for the 677 C-->T polymorphism in 21 children with stroke and 28 healthy children of the same age were studied. No differences in allelic frequency were detected between the two populations. However, the prevalence of homozygous 677 C-->T was doubled in the stroke population (28.6%) compared to the healthy group (14.3%). Total plasma homocysteine (tHcy) levels were significantly increased in children aged 2 months to 15 years with stroke compared to reference values. No association was observed between the homozygous genotype (T/T) and hyperhomocysteinemia, nor between the T/T genotype and low folate levels (below the 95th percentile) in this group of patients. Vitamin concentrations in patients were not significantly different from reference values. Significant negative correlations were found between tHcy and folate and between tHcy and cobalamin, but not between tHcy and B6 concentrations. In summary, a higher prevalence of hyperhomocysteinemia and the 677 C-->T polymorphism were observed in children with stroke, but were not always associated. The systematic study of both abnormalities in children with stroke is recommended, so that hyperhomocysteinemia of any genetic origin can be corrected with vitamin supplementation. Moreover, the 677 C-->T genotype is a strong factor for predisposition to hyperhomocysteinemia and recurrent risk of stroke that might also be prevented with folate supplementation.

Adolescent↗

PubMed2000

Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct.

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia and pathologically by neural degeneration of the caudate and putamen. Studies of metabolite excretion allowed us to categorize 43 GA I Spanish patients into two groups: group 1 (26 patients), those presenting with high excretion of both glutarate and 3-hydroxyglutarate, and group 2 (17 patients), those who might not be detected by routine urine organic acid analysis because glutarate might be normal and 3-hydroxyglutarate only slightly higher than controls. Single-strand conformation polymorphism (SSCP) screening and sequence analysis of the 11 exons and the corresponding intron boundaries of the GCDH gene allowed us to identify 13 novel and 10 previously described mutations. The most frequent mutations in group 1 were A293T and R402W with an allele frequency of 30% and 28%, respectively. These two mutations were also found in group 2, but always in heterozygosity, in particular in combination with mutations V400M or R227P. Interestingly, mutations V400M and R227P were only found in group 2, and at least one of these mutations was found in 11 of 15 unrelated alleles, accounting together for 53% of the mutant alleles in group 2. Therefore, it seems clear that two genetically and biochemically distinct groups of patients exist. The severity of the clinical phenotype seems to be closely linked to the development of encephalopathic crises rather than to residual enzyme activity or genotype. Comparison of GCDH protein with other acyl-CoA dehydrogenases (whose x-ray crystal structure has been determined) reveals that most of the mutations identified in GCDH protein seem to affect folding and tetramerization, as has been described for a number of mutations affecting mitochondrial beta-oxidation acyl-CoA dehydrogenases.

Alleles↗

PubMed2000

[Epileptic syndromes in the first year of life and congenital errors of metabolism].

INTRODUCTION: Early infantile epileptic encephalopathy includes two epileptic syndromes of the neonatal period: the Ohtahara syndrome and early myoclonic epilepsy of Aicardi. Both conditions are severe forms of neonatal epilepsy with bad prognosis (both neurological and vital). Some cases are due to metabolic defects or cortical dysplasia-type cerebral malformations. DEVELOPMENT: We propose to establish two major syndrome groups according to aetiology: cryptogenic and secondary (as determined in West's syndrome). West's syndrome has many aetiologies, including congenital errors of metabolism. The incidence of cases due to phenylketonuria or hypoglycemia is falling. However, new metabolic diseases, such as the syndromes of glycoproteins deficient in carbohydrates, biotinidase deficit or glucose protein transporter, appear to be responsible for clinical pictures of West's syndrome. In all these cases, and especially the idiopathic ones, it is useful to do extensive metabolic investigations since sometimes metabolic diseases give rise to these syndromes, so the prognosis, treatment and genetic counselling may be modified. CONCLUSION: In the text we review the congenital errors of metabolism involved in the aetiology of the epileptic syndromes seen in the first year of life.

Brain↗

PubMed2000

[Antiepileptic drugs and carnitine].

INTRODUCTION: Carnitine is an nonproteic nitrogenated compound acid present in all mammalian tissue and its principal activity is the long-chain fatty acid transport across the mitochondrial membrane for beta-oxidation. DEVELOPMENT: Carnitine levels are maintained by absorption from dietary, endogenous synthesis in the liver and renal reabsorption. An alteration in concentration could be due to an abnormality in some of mentioned mechanism or to inherited errors in metabolism. A reduction in serum carnitine levels have been reported in patients with antiepileptic drugs (AED) use. While valproic acid as monotheraphy or in combination with other AED have been associated principally, some contradictory studies demonstrated that other AED specifically carbamazepine, phenytoin and phenobarbital, also cause carnitine deficiency in about 21% of the patients whom they are administered. CONCLUSION: This study was designed to investigated the relationship between the carnitine levels and the presence of symptoms in patients with seizures whom are treated with a AED alone or in combination.

Adolescent↗

PubMed1999

Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency.

A deletion of at least 11.5 cM in the paternal X chromosome mapping between microsatellites DXS989 and DXS1003 and encompassing the genes for ornithine transcarbamylase (OTC), retinitis pigmentosa GTPase regulator (RPGR) and dystrophin, was associated with the loss of band Xp21 in a female patient with OTC deficiency. Another four female patients were heterozygous for point mutations in the OTC gene: the nonsense mutation Q69X or the missense mutations I172F, G188V and G197R. In the OTC amino acid sequence, I172 and G197 are proximate to residues involved in catalysis, and G188 is within a loop joining helix 5 and strand 6 in the core of the ornithine-bindingdomain. Therefore, the mutations of these residues may cause structural changes affecting catalysis and/or the architecture of the ornithine domain. The mutation appeared "de novo" in the patients or, in one case, in the mother of the patient, in agreement with the predominance of "de novo" mutations in female patients of OTC deficiency. There was full agreement between the results of mutational analysis and of allopurinol testing in the patients and their female relatives, supporting the value of the allopurinol test in the detection of carriers of OTC deficiency. This deficiency is a genetically heterogeneous X-linked condition.

Allopurinol↗

PubMed1999

Biochemical phenotype and its relationship with genotype in hyperphenylalaninemia heterozygotes.

The molecular detection of heterozygotes for hyperphenylalaninemia is difficult due to the large number of mutations in the PAH gene. For this reason, various indexes that measure plasma concentrations of phenylalanine (Phe) and tyrosine (Tyr), as an expression of Phe metabolizing capacity, have been used for the detection of carriers for mutations in the PAH gene. In this study, we contrast the biochemical and the molecular data in order to know if this is an accurate method. Familial genetic analysis of the PAH gene in 93 parents of hyperphenylalaninemia patients allows the study of the biochemical expression of the different mutant alleles. Molecular study was performed by SSCP and DGGE analyses of PAH genes, and plasma amino acid analysis by ion-exchange chromatography. Then the biochemical and molecular data were compared by the Student t test. The results found show a relationship between the severity of PKU/HPA mutations in the PAH gene and their biochemical phenotype (Phe/Tyr, Phe2/Tyr) as an expression of the residual enzymatic activity. The study adds further information about the prevalent Mediterranean allele mutations.

Female↗

PubMed1999

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation.

Hyperphenylalaninemia (HPA) is a group of diseases characterized by the persistent elevation of phenylalanine levels in tissues and biological fluids. It is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian populations and about 1 in 6,600 in Catalonia. We report the mutational spectrum of phenylalanine hydroxylase deficiency in the population living in Catalonia and the genotype-phenotype correlation. The molecular study was performed in 383 samples corresponding to 115 patients from 99 unrelated families and 268 relatives. We have characterized 90% of the mutant alleles; there were 57 different mutations, 49 of which have previously been described, 8 being novel mutations and two being large deletions. The 57 mutations detected corresponded to: five nonsense, seven frameshift, and eight splice defects, the remainder being missense mutations. These mutations cause 72 different genotypes in the 83 families characterized, confirming the mutational heterogeneity of phenylketonuria (PKU) in the Mediterranean population. According to our biochemical classification, our HPA population is composed of 40 PKU (35%), 36 variant PKU (31%), and 39 non-PKU HPA (34%). Mutations such as IVS 10, A403 V, and E390G correlated as expected with the phenotype and the predicted residual activity in vitro. However, in four cases (165 T, V388 M, R261Q, and Y414 C), the observed metabolic phenotype was not consistent with the predicted genotypic effect. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counselling for the patient's relatives.

Alleles↗