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1.
Mol Genet Metab ; 125(1-2): 118-126, 2018 09.
Article in English | MEDLINE | ID: mdl-30031689

ABSTRACT

Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.


Subject(s)
Amino Acid Transport Systems, Acidic/deficiency , Antiporters/deficiency , Carbon-Nitrogen Ligases/genetics , Epilepsy/genetics , Hereditary Central Nervous System Demyelinating Diseases/genetics , Microcephaly/genetics , Mitochondrial Diseases/genetics , Psychomotor Disorders/genetics , Amino Acid Transport Systems, Acidic/cerebrospinal fluid , Amino Acid Transport Systems, Acidic/genetics , Amino Acid Transport Systems, Acidic/metabolism , Antiporters/cerebrospinal fluid , Antiporters/genetics , Antiporters/metabolism , Brain/metabolism , Brain/pathology , Carbon-Nitrogen Ligases/cerebrospinal fluid , Carbon-Nitrogen Ligases/deficiency , Carbon-Nitrogen Ligases/metabolism , Epilepsy/cerebrospinal fluid , Epilepsy/complications , Epilepsy/pathology , Female , Folate Receptor 1/deficiency , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/complications , Hereditary Central Nervous System Demyelinating Diseases/metabolism , Humans , Male , Metabolic Diseases/cerebrospinal fluid , Metabolic Diseases/complications , Metabolic Diseases/genetics , Metabolic Diseases/pathology , Microcephaly/cerebrospinal fluid , Microcephaly/complications , Microcephaly/pathology , Mitochondrial Diseases/cerebrospinal fluid , Mitochondrial Diseases/complications , Mitochondrial Diseases/metabolism , Nervous System Malformations/cerebrospinal fluid , Nervous System Malformations/complications , Nervous System Malformations/genetics , Nervous System Malformations/metabolism , Neuroaxonal Dystrophies , Psychomotor Disorders/cerebrospinal fluid , Psychomotor Disorders/complications , Psychomotor Disorders/metabolism , Tetrahydrofolates/cerebrospinal fluid , Tetrahydrofolates/metabolism
2.
PLoS One ; 7(8): e42688, 2012.
Article in English | MEDLINE | ID: mdl-22952606

ABSTRACT

BACKGROUND: Primary or secondary abnormalities of glycosylation have been reported in various brain diseases. Decreased asialotransferrin to sialotransferrin ratio in cerebrospinal fluid (CSF) is a diagnostic marker of leukodystrophies related to mutations of genes encoding translation initiation factor, EIF2B. We investigated the CSF glycome of eIF2B-mutated patients and age-matched normal individuals in order to further characterize the glycosylation defect for possible use as a biomarker. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a differential N-glycan analysis using MALDI-TOF/MS of permethylated N-glycans in CSF and plasma of controls and eIF2B-mutated patients. We found in control CSF that tri-antennary/bisecting and high mannose structures were highly represented in samples obtained between 1 to 5 years of age, whereas fucosylated, sialylated structures were predominant at later age. In CSF, but not in plasma, of eIF2B-mutated patient samples, we found increased relative intensity of bi-antennary structures and decreased tri-antennary/bisecting structures in N-glycan profiles. Four of these structures appeared to be biomarker candidates of glycomic profiles of eIF2B-related disorders. CONCLUSION: Our results suggest a dynamic development of normal CSF N-glycan profiles from high mannose type structures to complex sialylated structures that could be correlated with postnatal brain maturation. CSF N-glycome analysis shows relevant quantitative changes associated with eIF2B related disorders. This approach could be applied to other neurological disorders involving developmental gliogenesis/synaptogenesis abnormalities.


Subject(s)
Biomarkers/metabolism , Brain Diseases/cerebrospinal fluid , Brain Diseases/genetics , Cerebrospinal Fluid/metabolism , Developmental Disabilities/cerebrospinal fluid , Developmental Disabilities/genetics , Eukaryotic Initiation Factor-2B/genetics , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/genetics , Mutation , Polysaccharides/chemistry , Calibration , Child, Preschool , Female , Glycosylation , Humans , Infant , Male , Methylation , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
3.
Ann Neurol ; 65(6): 753-7, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19557856

ABSTRACT

We performed high-resolution in vitro proton nuclear magnetic resonance spectroscopy on cerebrospinal fluid and urine samples of 44 patients with leukodystrophies of unknown cause. Free sialic acid concentration was increased in cerebrospinal fluid of two siblings with mental retardation and mild hypomyelination. By contrast, urinary excretion of free sialic acid in urine was normal on repeated testing by two independent methods. Both patients were homozygous for the K136E mutation in SLC17A5, the gene responsible for the free sialic acid storage diseases. Our findings demonstrate that mutations in the SLC17A5 gene have to be considered in patients with hypomyelination, even in the absence of sialuria.


Subject(s)
N-Acetylneuraminic Acid/cerebrospinal fluid , Organic Anion Transporters/genetics , Sialic Acid Storage Disease/genetics , Symporters/genetics , Adolescent , Child , Diagnosis, Differential , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Hereditary Central Nervous System Demyelinating Diseases/genetics , Hereditary Central Nervous System Demyelinating Diseases/urine , Humans , N-Acetylneuraminic Acid/genetics , N-Acetylneuraminic Acid/urine , Nuclear Magnetic Resonance, Biomolecular/methods , Sialic Acid Storage Disease/cerebrospinal fluid , Sialic Acid Storage Disease/diagnosis , Sialic Acid Storage Disease/urine , Young Adult
4.
Eur J Paediatr Neurol ; 12(4): 348-50, 2008 Jul.
Article in English | MEDLINE | ID: mdl-17881259

ABSTRACT

Autosomal recessive Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a hypomyelinating disorder of the central nervous system (CNS) with virtually identical phenotype to Pelizaeus-Merzbacher disease (PMD). PMLD1 is caused by mutations in GJA12 gene, PMD is due to mutations in PLP1 gene. Elevated levels of N-acetylaspartylglutamate (NAAG), the most abundant peptide neuromodulator in the human brain, have been recently reported in cerebral spinal fluid (CSF) of patients with PMD. Using capillary electrophoresis, we analyzed for the first time, the CSF from a girl with PMLD1 and detected high concentrations of NAAG. This finding confirms the hypothesis that NAAG may be involved in myelination-related processes and can be considered as a useful diagnostic marker not only for patients with the PLP1 related disorder, but also in those with Pelizaeus-Merzbacher like hypomyelinating disease due to other defined genetic causes, such as PMLD1.


Subject(s)
Connexins/genetics , Dipeptides/cerebrospinal fluid , Mutation , Pelizaeus-Merzbacher Disease/diagnosis , Child, Preschool , Electrophoresis/methods , Female , Genes, Recessive , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Hereditary Central Nervous System Demyelinating Diseases/genetics , Humans , Pelizaeus-Merzbacher Disease/cerebrospinal fluid , Pelizaeus-Merzbacher Disease/genetics
5.
Clin Chem ; 51(11): 2031-42, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16155092

ABSTRACT

BACKGROUND: A biomarker for the diagnosis of childhood-onset ataxia and central nervous system hypomyelination (CACH)/vanishing white matter disease (VWM) would have clinical utility and pathophysiologic significance. METHODS: We used 2-dimensional gel electrophoresis/mass spectrometry to compare the cerebrospinal fluid proteome of patients with mutation-confirmed CACH/VWM with that of unaffected controls. We characterized selected spots by in-gel digestion, matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry, and nanospray Fourier transform mass spectrometry. RESULTS: A specific transferrin spot pattern was detected in the CSF samples of the CACH/VWM group (n = 7), distinguishing them from the control group (n = 23) and revealing that patients with CACH/VWM have a deficiency of the asialo form of transferrin usually present in healthy cerebrospinal fluid. The glycopeptide structure, determined from isolated transferrin spots by use of in-gel digestion and extraction, was found to be consistent with earlier reports. CONCLUSIONS: The transferrin isoform abnormality in the cerebrospinal fluid of patients with CACH/VWM appears unique and is a potential clinical diagnostic biomarker. The rapid, efficient diagnosis of this disorder would have a significant impact on clinical studies exploring new strategies for the management and treatment of this disease.


Subject(s)
Asialoglycoproteins/cerebrospinal fluid , Ataxia/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Transferrin/analogs & derivatives , Asialoglycoproteins/chemistry , Ataxia/complications , Child , Electrophoresis, Gel, Two-Dimensional , Glycopeptides/chemistry , Hereditary Central Nervous System Demyelinating Diseases/complications , Humans , Mass Spectrometry , Protein Isoforms/cerebrospinal fluid , Transferrin/cerebrospinal fluid , Transferrin/chemistry
6.
J Child Neurol ; 20(3): 181-4, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15832605

ABSTRACT

Insulin-like growth factor 1 increases both the number of oligodendrocytes and the amount of axonal myelin produced. The aim of this study was to see whether insulin-like growth factor 1 played a role in white-matter diseases of children. We studied insulin-like growth factor 1 in the cerebrospinal fluid of children with various white-matter diseases: (1) children with acute demyelinating events: acute disseminated encephalomyelitis (n = 5), acute transverse myelitis in multiple sclerosis (n = 1), and infarct of the medial cerebral artery causing secondary white-matter changes (n = 1), and (2) children with chronic diseases: delayed myelination (n = 3) and progressive leukodystrophies (n = 4). Insulin-like growth factor 1 was determined by radioimmunoassay with commercially available kits (Mediagnost, Tubingen, Germany). We found markedly lower concentrations of cerebrospinal fluid insulin-like growth factor 1 in the patients than in the 28 age-matched control children (P < .0005). Low cerebrospinal fluid insulin-like growth factor 1 can play a role in the pathology of both acute and chronic white-matter diseases of children.


Subject(s)
Brain Diseases/cerebrospinal fluid , Encephalomyelitis, Acute Disseminated/cerebrospinal fluid , Hemiplegia/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Insulin-Like Growth Factor I/cerebrospinal fluid , Myelitis, Transverse/cerebrospinal fluid , Acute Disease , Adolescent , Case-Control Studies , Child , Child, Preschool , Chronic Disease , Female , Humans , Male
7.
Neurology ; 61(5): 648-54, 2003 Sep 09.
Article in English | MEDLINE | ID: mdl-12963756

ABSTRACT

BACKGROUND: Childhood ataxia with CNS hypomyelination (CACH) is a leukodystrophy with extreme rarefaction of white matter caused by mutations in one of the five subunits of the translation initiation factor 2B (eIF2B). METHODS: Seven children with this disease and nine age-matched control subjects were studied with proton-decoupled phosphorus magnetic resonance (MR) spectroscopy. RESULTS: In patients with CACH, cerebral concentrations of high-energy phosphate metabolites were abnormal. Of the metabolites involved in biosynthesis and catabolism of membrane phospholipids, glycerophosphorylethanolamine was reduced (0.24 +/- 0.18 mmol/kg brain vs 0.44 +/- 0.14; p < 0.02), and phosphorylethanolamine was increased (2.32 +/- 0.53 vs 1.53 +/- 0.22; p < 0.01), whereas the choline-containing phosphorylated metabolites were unchanged. Nucleoside triphosphate (NTP) was reduced (2.44 +/- 0.34 mmol/kg brain tissue vs 3.09 +/- 0.58; p < 0.01), phosphocreatine was elevated (4.11 +/- 0.63 vs 3.27 +/- 0.33; p < 0.01), and inorganic phosphate was reduced (0.77 +/- 0.32 vs 1.06 +/- 0.26; p < 0.05). Intracellular pH was elevated in patients (7.03 +/- 0.04 vs 6.99 +/- 0.02; p < 0.02). CONCLUSIONS: The authors found an altered energy state of the residual cell population investigated. Together with previously identified replacement of white matter by CSF, the present findings raise the possibility that the genetic defect in eIF2B may result in impairment of myelin membrane synthesis or myelin membrane transport in the in vivo CACH brain. Ethanolamine metabolites constitute the plasmalogens, and the present findings may include a defect in plasmalogen metabolism.


Subject(s)
Ataxia/metabolism , Hereditary Central Nervous System Demyelinating Diseases/metabolism , Phospholipids/metabolism , Adolescent , Body Water , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Child , Child, Preschool , Energy Metabolism , Female , Hereditary Central Nervous System Demyelinating Diseases/cerebrospinal fluid , Hereditary Central Nervous System Demyelinating Diseases/pathology , Humans , Hydrogen-Ion Concentration , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Phosphates/metabolism , Phosphorylation
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