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Juan M Pascual

Publications and source records attributed to Juan M Pascual.

13 recordsLinked to original sources
PubMed2006

[Glucose transport hereditary diseases].

Several heritable disorders of glucose transport across cellular membranes have been recently characterized both genetically and pathophysiologically. Diseases such as glucose-galactose malabsorption, Fanconi-Bickel syndrome and GLUT1 deficiency syndrome are caused by mutation of transporters located in bowel, liver and brain, respectively. For example, the glucose transporter type 1 deficiency syndrome, a prototypical neurometabolic disease, combines manifestations such as epilepsy and hypoglycorrhachia, and is caused by heritable mutation of the SLC2A1 gene. All known glucose transporter mutations induce loss of membrane function at important cellular interfaces, limiting glucose uptake by energy-consuming cells. The fundamental role served by glucose transport allows these pleomorphic conditions to cross the boundaries of traditional clinical disciplines.

Biological Transport↗
PubMed2006

A mouse model for Glut-1 haploinsufficiency.

Glut-1 deficiency syndrome (Glut-1 DS, OMIM #606777) is characterized by infantile seizures, developmental delay, acquired microcephaly and hypoglycorrhachia. It is caused by haploinsufficiency of the blood-brain barrier hexose carrier. Heterozygous mutations or hemizygosity of the GLUT-1 gene cause Glut-1 DS. We generated a heterozygous haploinsufficient mouse model by targeted disruption of the promoter and exon 1 regions of the mouse GLUT-1 gene. GLUT-1+/- mice have epileptiform discharges on electroencephalography (EEG), impaired motor activity, incoordination, hypoglycorrhachia, microencephaly, decreased brain glucose uptake as measured by positron emission tomography (PET) scan and decreased brain Glut-1 expression by western blot (66%). The GLUT-1+/- murine phenotype mimics the classical human presentation of Glut-1 DS. This GLUT-1+/- mouse model creates an opportunity to investigate Glut-1 function, to examine the pathophysiology of Glut-1 DS in vivo and to evaluate new treatment strategies.

Animals↗
PubMed2006

Nerve conduction abnormalities in patients with MELAS and the A3243G mutation.

BACKGROUND: Mitochondrial DNA point mutations are especially deleterious to tissues with high energy demand, including the peripheral nervous system. Neuropathy has been associated with several mitochondrial diseases, including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). OBJECTIVE: To evaluate nerve conduction in a genotypically and phenotypically homogeneous group of patients with MELAS and the A3243G mutation. DESIGN: We studied 30 patients with MELAS and the A3243G mutation using neurophysiological techniques, medical history questionnaires, laboratory tests, and a standardized neurological examination. RESULTS: Twenty-three subjects (77%) had abnormal nerve conduction measures. Symptoms suggestive of neuropathy were present in only half of the patients, but almost all had decreased reflexes or distal sensory findings on examination. Nerve conduction abnormalities were predominantly axonal and sensory and mainly present in the legs. Patients with nerve conduction abnormalities tended to be older and were more likely male. CONCLUSIONS: Peripheral nerve impairment is common in those with MELAS and the A3243G mutation, and may be subclinical. Male sex and older age may add to the genetic disposition to develop neuropathy.

Adult↗
PubMed2005

Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects.

Impaired glucose transport across the blood-brain barrier results in Glut-1 deficiency syndrome (Glut-1 DS, OMIM 606777), characterized by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and hypoglycorrhachia. We studied 16 new Glut-1 deficiency syndrome patients focusing on clinical and laboratory features, molecular genetics, genotype-phenotype correlation, and treatment. These patients were classified phenotypically into three groups. The mean cerebrospinal fluid glucose concentration was 33.1 +/- 4.9mg/dl equal to 37% of the simultaneous blood glucose concentration. The mean cerebrospinal fluid lactate concentration was 1.0 +/- 0.3mM, which was less than the normal mean value of 1.63mM. The mean V(max) for the 3-O-methyl-D-glucose uptake into erythrocytes was 996 fmol/10(6) red blood cells per second, significantly less (54 +/- 11%; t test, p < 0.05) than the mean control value of 1,847. The mean Km value for the patient group (1.4 +/- 0.5mM) was similar to the control group (1.7 +/- 0.5mM; t test, p > 0.05). We identified 16 rearrangements, including seven missense, one nonsense, one insertion, and seven deletion mutations. Fourteen were novel mutations. There were no obvious correlations between phenotype, genotype, or biochemical measures. The ketogenic diet produced good seizure control.

3-O-Methylglucose↗
PubMed2004

Rectal biopsy in the diagnosis of neuronal intranuclear hyaline inclusion disease.

Neuronal intranuclear hyaline inclusion disease is a neurodegenerative disorder of childhood characterized by eosinophilic intranuclear inclusions and neuronal loss throughout the nervous system. Although most cases have been diagnosed postmortem, rectal biopsy may be diagnostic during life. We identified two patients: an 11-year-old boy (P1) with new-onset bulbar weakness and parkinsonism and a 15-year-old boy (P2) with severe cognitive and motor deterioration of uncertain etiology who presented at 4 years of age with a gait disturbance and motor slowing. Both patients had a history of behavioral problems marked by frequent temper tantrums. Both had nondiagnostic magnetic resonance imaging of the head and metabolic work-ups. Rectal biopsy was diagnostic 1 year (P1) and 11 years (P2) after the initial evaluation. Rectal biopsies should be considered in children presenting with otherwise unexplained multisystem degeneration, particularly in the presence of both upper and lower motoneuron signs accompanied by behavioral problems.

Adolescent↗
PubMed2004

GLUT1 deficiency and other glucose transporter diseases.

We review the three genetically determined disorders of glucose transport across cell membranes. Diseases such as glucose-galactose malabsorption, Fanconi-Bickel syndrome and De Vivo disease (GLUT1 deficiency syndrome (GLUT1DS)) arise from heritable mutations in transporter-encoding genes that impair monosaccharide uptake, which becomes rate-limiting in tissues where the transporters serve as the main glucose carrier systems. We focus in greater detail on De Vivo disease as a prototype of a brain energy failure syndrome, for which the greatest pathophysiological detail is known, but which presents the most therapeutic challenges. The study of these diseases illustrates fundamental aspects of energetic metabolism, while providing the basis for their diagnosis by simple metabolic screening and for their treatment by dietary modification.

Animals↗
PubMed2003

Functional studies of threonine 310 mutations in Glut1: T310I is pathogenic, causing Glut1 deficiency.

We have previously reported on a patient with the Glut1 deficiency syndrome (Online Mendelian Inheritance in Man number 606777) carrying a heterozygous T310I missense mutation in the GLUT1 gene (Klepper, J., Wang, D., Fischbarg, J., Vera, J. C., Jarjour, I. T., O'Driscoll, K. R., and De Vivo, D. C. (1999) Neurochem. Res. 24, 587-594). To investigate the molecular basis for the associated functional deficit, we constructed T310A, T310S, and T310I human GLUT1 mutants for expression in Xenopus laevis oocytes via cRNA injection. For all mutants, glucose transport was decreased, and osmotic water permeability (Pf) was increased. Km values for 3-O-methylglucose (3-OMG) uptake under zero-trans influx and equilibrium exchange influx conditions were, respectively, 13 +/- 1 and 68 +/- 5 mm for wild-type Glut1, 5 +/- 1 and 25 +/- 6 mm for T310A, 6 +/- 3 and 30 +/- 6 mm for T310I, and 5 +/- 1 and 48 +/- 5 mm for T310S. Compared with wild-type Glut1, we determined the following. (a). Zero-trans and equilibrium exchange influx values of 3-OMG were significantly decreased, respectively, 15 and 5% in T310A, 8 and 3% in T310I, and 40 and 34% in T310S mutants. (b). Zero-trans efflux of 3-OMG and dehydroascorbic acid uptake were significantly decreased in mutants. (c). The relative Pf values for T310A, T310I, and T310S were increased 3-, 4.8-, and 3.5-fold compared with wild-type values. We found a very high negative correlation between the rate of glucose uptake and Pf (-0.93), and between hydropathy and uptake (-0.92), a moderate correlation between hydropathy and Pf (0.73), and a minimal correlation between uptake, Pf, and molecular weight. These findings are consistent with a central role for hydropathy rather than size at position 310 of this mutation.

Animals↗
PubMed2002

Changes in glucose transport and water permeability resulting from the T310I pathogenic mutation in Glut1 are consistent with two transport channels per monomer.

We studied glucose and water passage across wild type (WT) glucose transporter Glut1 and its T310I pathogenic mutant, expressing them in Xenopus laevis oocytes. We found that the T310I mutation produced a 8-fold decrease in glucose transport (zero-trans influx, 13 +/- 2% compared with WT), accompanied by a 2.8-fold increase in the osmotic water permeability (P(f) 280 +/- 40% compared with WT), and no change in the diffusional water permeability (P(d)). The dependence of glucose and water transports on the amounts of mutant cRNA injected was identical exponential buildups (k = 19.7 ng), suggesting that they depend similarly on the quaternary structure. The E(a) values for P(f) were 16 +/- 0.4 (WT) and 11 +/- 1 kcal mol(-1) (T310I). We report for the first time that 10 mm d-glucose and l-glucose inhibit P(f) by approximately 45% in the WT but not in the T310I mutant. In addition, 10 mm maltose reduces P(f) (15-20%) in both cases. However, 5 mm l-glucose increased the P(f) of T310I, consistent with a cooperative effect. These experimental observations and an analysis of our three-dimensional model strongly suggest the presence of two channels per Glut1 monomer, one of which can be blocked by the mutation T310I.

Animals↗
PubMed2002

Imaging the metabolic footprint of Glut1 deficiency on the brain.

Cerebral 18F-fluorodeoxyglucose positron emission tomography in 14 patients with microcephaly, developmental delay, seizures, and mutations of the glucose transporter Glut1 (Glut1 deficiency syndrome) showed distinct abnormalities. Within a global context of diminished cortical uptake, more severe hypometabolism was found in the mesial temporal regions and thalami, accentuating a relative signal increase in the basal ganglia. In contrast, the structure of the brain appeared preserved in patients additionally investigated by magnetic resonance imaging. This metabolic footprint was relatively constant in all patients regardless of age, seizure history, or therapies and therefore constitutes a radiological signature of the disease. The full expression of the signature in the youngest patient (aged 19 months) indicates that the state of haploinsufficiency caused by Glut1 mutation leaves a permanent footprint on the nervous system from its earlier postnatal stages of development. The potential benefit of prompt diagnosis, aided by 18F-fluorodeoxyglucose positron emission tomography, and early initiation of available therapies is underscored by our results.

Adolescent↗