5-methyltetrahydrofolate and Intellectual-Disability

To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases.. We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data.. 69 patients had CFD (CSF 5MTHF level < 41 nmol/L), 25 of them had severe CFD (sCFD; ≤25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement.. CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.

Topics: Adolescent; Adult; Aged; Calcinosis; Cerebellar Diseases; Child; Child, Preschool; Female; Folic Acid; Folic Acid Deficiency; Follow-Up Studies; Humans; Infant; Infant, Newborn; Intellectual Disability; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondrial Diseases; Mutation; Proteins; Retrospective Studies; Tetrahydrofolates; White Matter; Young Adult

Cerebral folate deficiency (CFD) is increasingly recognized in various neurological conditions, raising the question of whether it might represent a clear-cut clinical syndrome.. Retrospective analysis of patients with low cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) values was performed.. 58 pediatric patients with low (-2nd to -3rd standard deviation) and 45 patients with very low 5MTHF values (<3rd standard deviation) were identified, including 22 patients with defined underlying neurological conditions. The leading symptoms were mental retardation (n=84), motor retardation (n=75), epilepsy (n=53), ataxia (n=44) and pyramidal tract signs (n=37). There was no relationship between 5MTHF levels and the severity of clinical disease, the duration of clinical disease, distinct neurological symptoms and antiepileptic drug treatment, respectively. Genetical analysis for mutations in the folate receptor 1 gene proved normal in all 16 children studied.. For the majority of patients CFD is not a clear-cut neurometabolic syndrome but the common result of different genetic, metabolic or unknown processes. Nevertheless, CFD may represent a treatable disease-modifying factor which should therefore be addressed in prospective studies.

Topics: Abnormalities, Multiple; Adolescent; Ataxia; Child; Child, Preschool; Epilepsy; Female; Folic Acid Deficiency; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Pyramidal Tracts; Retrospective Studies; Syndrome; Tetrahydrofolates; Young Adult

We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.

Topics: Adolescent; Autistic Disorder; Brain; Child; Child, Preschool; Developmental Disabilities; Dyskinesias; Epilepsy; Female; Folic Acid; Folic Acid Deficiency; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Pregnancy; Psychomotor Disorders; Reference Values; Regression, Psychology; Tetrahydrofolates

The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

Topics: Adaptation, Physiological; Autistic Disorder; Cerebral Cortex; Child; Developmental Disabilities; Disease Progression; Female; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intellectual Disability; Leucovorin; Mutation; Recovery of Function; Reduced Folate Carrier Protein; Seizures; Tetrahydrofolates; Transcription Factors; Treatment Outcome

Normal brain development and function depend on the active transport of folates across the blood-brain barrier. The folate receptor-1 (FR 1) protein is localized at the basolateral surface of the choroid plexus, which is characterized by a high binding affinity for circulating 5-methyltetrahydrofolate (5-MTHF).. We report on the clinical and metabolic findings among five children with normal neurodevelopmental progress during the first four to six months followed by the acquisition of a neurological condition which includes marked irritability, decelerating head growth, psychomotor retardation, cerebellar ataxia, dyskinesias (choreoathetosis, ballism), pyramidal signs in the lower limbs and occasional seizures. After the age of six years the two oldest patients also manifested a central visual disorder. Known disorders have been ruled out by extensive investigations. Cerebrospinal fluid (CSF) analysis included determination of biogenic monoamines, pterins and 5-MTHF.. Despite normal folate levels in serum and red blood cells with normal homocysteine, analysis of CSF revealed a decline towards very low values for 5-methyltetrahydrofolate (5-MTHF), which suggested disturbed transport of folates across the blood-brain barrier. Genetic analysis of the FR 1 gene revealed normal coding sequences. Oral treatment with doses of the stable compound folinic acid (0.5-1 mg/kg/day Leucovorin(R)) resulted in clinical amelioration and normalization of 5-MTHF values in CSF.. Our findings identified a new condition manifesting after the age of 6 months which was accompanied by low 5-MTHF in cerebrospinal fluid and responded to oral supplements with folinic acid. However, the cause of disturbed folate transfer across the blood-brain barrier remains unknown.

Topics: Blood-Brain Barrier; Brain Diseases, Metabolic, Inborn; Carrier Proteins; Child; Child, Preschool; DNA-Binding Proteins; Erythrocytes; Female; Folate Receptor 1; Folate Receptors, GPI-Anchored; Humans; Infant; Intellectual Disability; Leucovorin; Male; Membrane Proteins; Membrane Transport Proteins; Movement Disorders; Neurologic Examination; Paraplegia; Psychomotor Disorders; Receptors, Cell Surface; Replication Protein C; Spinocerebellar Degenerations; Tetrahydrofolates; Transcription Factors

3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is an inborn error of serine biosynthesis. Patients are affected with congenital microcephaly, psychomotor retardation, and intractable seizures. The effects of oral treatment with amino acids were investigated in 2 siblings. L-Serine up to 500 mg/kg/day was not sufficient for seizure control. Addition of glycine 200 mg/kg/day resulted in complete disappearance of seizures. Electroencephalographic abnormalities gradually resolved after 6 months. We conclude that 3-PGDH can be treated effectively by a combination of L-serine and glycine.

Topics: Carbohydrate Dehydrogenases; Child; Child, Preschool; Drug Therapy, Combination; Electroencephalography; Glycine; Humans; Infant, Newborn; Intellectual Disability; Male; Microcephaly; Phosphoglycerate Dehydrogenase; Seizures; Serine; Tetrahydrofolates