The diagnostic utility of folate receptor autoantibodies in blood
; RAMAEKERS, Vincent ;
in Clinical Chemistry & Laboratory Medicine (2012)Detailed reference viewed: 4 (1 ULg)
Clinical recognition and aspects of the cerebral folate deficiency syndromes
RAMAEKERS, Vincent ; ;
in Clinical Chemistry & Laboratory Medicine (2012)Detailed reference viewed: 6 (0 ULg)
Clinical utility gene card for: Biotinidase deficiency
; RAMAEKERS, Vincent ; et al
in European Journal of Human Genetics (2012), 20(5), 592Detailed reference viewed: 7 (0 ULg)
Role of folate receptor autoantibodies in infantile autism
RAMAEKERS, Vincent ; ;
in Molecular Psychiatry (2012)Detailed reference viewed: 9 (0 ULg)
Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants.
; ; et al
in Molecular Genetics & Metabolism (2011), 102(3), 368-73
The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid-compulsive behavior ... [more ▼]
The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid-compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4(1/2)years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells. [less ▲]Detailed reference viewed: 13 (2 ULg)
Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport.
; ; RAMAEKERS, Vincent
in Molecular Genetics & Metabolism (2010), 101(1), 48-54
Metabolic breakdown of valproate (VPA), carbamazepine (CBZ) and phenytoin (PHT) by the cytochrome P450 pathway generates toxic drug intermediates and reactive oxygen species (ROS). This mechanism has been ... [more ▼]
Metabolic breakdown of valproate (VPA), carbamazepine (CBZ) and phenytoin (PHT) by the cytochrome P450 pathway generates toxic drug intermediates and reactive oxygen species (ROS). This mechanism has been suspected to play a role in the pathogenesis of secondary cerebral folate deficiency (CFD). Using KB-cell cultures, highly expressing the folate receptor 1 (FOLR1), the effect of antiepileptic drugs (AEDs) and reactive oxygen species (ROS) on the FOLR1 dependent 5-methyltetrahydrofolate (MTHF) uptake was studied. MTHF uptake is time and concentration dependent and shows saturation kinetics. At physiological MTHF concentrations the high-affinity FOLR1 represents the predominant mechanism for cellular incorporation, while at high MTHF concentrations other transport mechanisms participate in folate uptake. Exposure to PHT for more than 8h led to a higher MTHF uptake and decreased cell count, whereas MTHF uptake remained unaltered by VPA and CBZ. However, exposure to superoxide and hydrogen peroxide radicals significantly decreased cellular MTHF uptake. By specific elimination and downregulation of FOLR1 using phosphatidyl-inositol-specific phospholipase C (PIPLC) and siRNA silencing, it was shown that ROS not only inhibited FOLR1 mediated MTHF uptake but also affected all other mechanisms of membrane-mediated MTHF uptake. Generation of ROS with the use of AED might therefore provide an additional explanation for the disturbed folate transfer across the blood-CSF barrier in patients with CFD. [less ▲]Detailed reference viewed: 4 (0 ULg)
Cerebral folate deficiency and CNS inflammatory markers in Alpers disease.
; ; RAMAEKERS, Vincent et al
in Molecular Genetics & Metabolism (2010), 99(1), 58-61
We describe a 3.5-year-old female with Alpers disease with a POLG genotype of p.A467T/p.G848S and with a lethal outcome. Laboratory investigation revealed elevated CSF neopterin, IL-6, IL-8, IFN-gamma ... [more ▼]
We describe a 3.5-year-old female with Alpers disease with a POLG genotype of p.A467T/p.G848S and with a lethal outcome. Laboratory investigation revealed elevated CSF neopterin, IL-6, IL-8, IFN-gamma, reduced CSF 5-methyltetrahydrofolate (5MTHF), and increased serum as well as CSF folate receptor blocking autoantibodies. Treatment with oral Leucovorine (5-formyl-tetrahydrofolate) was initiated at 0.25mg/kg bid, and later increased to 4mg/kg bid. Under treatment CSF levels of 5MTHF, seizure frequency and communicative abilities improved. Over a time span of 17months, CSF levels of IL-6 and IFN-gamma decreased, levels of folate receptor blocking autoantibodies continued to raise, whereas CSF IL-8 remained elevated 1500-fold above normal. The child died without apparent stress at the age of 5.5years. Alpers disease, a neurodegenerative disease usually presents in the first years of life as a progressive encephalopathy with multifocal myoclonic seizures, developmental regression, cortical blindness and early death. The underlying genetic defect has been attributed to mutations of the catalytic subunit of the mitochondrial DNA polymerase-gamma leading to an organ-specific mitochondrial DNA depletion syndrome with reduced activity of respiratory chain enzyme complexes in the brain and the liver. A curative therapy is not available. This case report of Alpers disease provides new insights into the pathophysiology of Alpers disease, where mitochondrial dysfunction in conjunction with inflammatory cytokines and blocking folate receptor autoantibodies may lead to a secondary cerebral folate deficiency syndrome. The treatment of the latter provides relief to the patient without stopping the underlying disease. [less ▲]Detailed reference viewed: 2 (0 ULg)
Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.
; ; et al
in Proceedings of the National Academy of Sciences of the United States of America (2009), 106(14), 5842-7
We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic ... [more ▼]
We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.2-23.3. Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects. These mutations alter highly conserved amino acids and are absent among control chromosomes. Many of these mutations have been shown to cause loss of function in related K(+) channels. These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME. KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization, in cochlea, where it is involved in the generation of endolymph, and on the basolateral membrane in the distal nephron. We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects. Mice deficient for KCNJ10 show a related phenotype with seizures, ataxia, and hearing loss, further supporting KCNJ10's role in this syndrome. These findings define a unique human syndrome, and establish the essential role of basolateral K(+) channels in renal electrolyte homeostasis. [less ▲]Detailed reference viewed: 3 (0 ULg)
Progressive encephalopathy in a child with cerebral folate deficiency syndrome.
; RAMAEKERS, Vincent ; et al
in Journal of Child Neurology (2008), 23(12), 1460-3
Cerebral folate deficiency syndrome, a recently recognized cause of developmental delay, regression, and seizures, is associated with autoantibodies against folate receptors. A female child with ... [more ▼]
Cerebral folate deficiency syndrome, a recently recognized cause of developmental delay, regression, and seizures, is associated with autoantibodies against folate receptors. A female child with developmental delay and a history of seizures who presented with seizures and unexplained coma is reported. Extensive testing to evaluate the patient's coma and subsequent developmental regression were unrevealing until the results of her cerebrospinal fluid neurotransmitter analysis returned. These showed low levels of methyltetrahydrofolate, the active metabolite of folate in the cerebrospinal fluid; subsequently, elevated titers of autoantibodies against folate receptors were found. Despite treatment with folinic acid, she developed intractable epilepsy and severe developmental delay. [less ▲]Detailed reference viewed: 5 (0 ULg)