SYNGAP1 and Methylenetetrahydrofolate in Cerebrospinal Fluid: Cognitive Development after Oral Folate (5-Methyltetrahydrofolate) Supplementation in a 5-Year-Old Girl

Synaptic Ras GTPase-activating protein 1 (SYNGAP1), also called Ras-GAP 1 or RASA5, is a cerebral protein with a role in brain synaptic function. Its expression affects the development, structure, function, and plasticity of neurons. Mutations in the gene cause a neurodevelopment disorder termed mental retardation-type 5, also called SYNGAP1 syndrome. This syndrome can cause many neurological symptoms including pharmaco-resistant epilepsy, intellectual disability, language delay, and autism spectrum disorder. The syndrome naturally evolves as epileptic encephalopathy with handicap and low intellectual level. A treatment to control epilepsy, limit any decrease in social capacities, and improve intellectual development is really a challenging goal for these patients. The etiologic investigation performed in a 5-year-old girl with early epileptic absence seizures (onset at 6 months) and psychomotor delay (language) revealed a low methylenetetrahydrofolate level in cerebrospinal fluid in a lumbar puncture, confirmed by a second one (35 nmol/L and 50 nmol/L vs. 60–100 nmol/L normal), associated with normal blood and erythrocyte folate levels. Hyperhomocysteinemia, de vivo disease, and other metabolic syndromes were excluded by metabolic analysis. No genetic disorders (like methylenetetrahydrofolate reductase and methenyltetrahydrofolate synthetase) with folate metabolism were found. The physical examination showed only a minor kinetic ataxia. An oral folate (5-methyltetrahydrofolate) supplementation was started with oral vitamin therapy. The child showed good progress in language with this new treatment; epilepsy was well balanced with only one antiepileptic drug. The SYNGAP1 mutation was identified in this patient's genetic analysis. Since the start of folate supplementation/vitamin therapy, the patient's neurologic development has improved. To our knowledge, no association between these two pathologies has been linked and no patient with this SYNGAP1 mutation has ever showed much intellectual progress. Low cerebral methylenetetrahydrofolate levels could be associated with SYNGAP1 mutations. One of the hypotheses is the link of folate metabolism with epigenetic changes including methylation process. One inborn metabolic activity in folate metabolism may be associated with SYNGAP1 disease with epigenetic repercussions. Further studies should assess the link of SYNGAP1 and methyltetrahydrofolate and the evolution of SYNGAP1 patients with oral folate supplementation or vitamin therapy.

Assessment of Dietary Folate Intake and Pill Burden among Saudi Patients on Maintenance Hemodialysis

The aim of this study was to assess the adequacy of dietary folate intake and perceptions of pill burden among Saudi patients on maintenance hemodialysis (MHD). This was a cross-sectional study of adults (>18 years) on MHD (>3 months) attending the dialysis unit at King Saud University Medical City. Patient demographics, dietary folic acid intake, and perceptions of pill burden were collected. Fifty-four patients met the eligibility criteria, with a mean age of 57 ± 15.5 years. The majority were females (63%), and the most prevalent comorbidities were diabetes (43%) and hypertension (76%). The average number of medications/patients was 11 ± 2.9, and most patients were receiving folate supplementation (68.5%). The average dietary folate intake was 823 ± 530 mcg/day. Pill burden was bothersome, primarily due to taking too many medications (57%) while taking medications at the workplace was the least bothersome burden (17%). The reported high pill burden and adequate dietary folate intake by Saudi patients on MHD indicates that the omission of folate supplementation may be advantageous for this special population.

Folic acid and brain function in childhood

Folic acid supplementation does not only prevent neural tube defects in the foetus but is an essential ingredient in the growth and development of the cerebral cortex. This micronutrient promotes the thickness of the cerebral cortex; the extent of the thickness being directly proportional to the intelligent quotient, neurocognitive and psychological output of the child. Children with thin cortices are prone to poor cognitive performance, autism and psychiatric disorders such as depression. Folic acid supplementation in the first three months of pregnancy largely protects against neural tube defects; studies have shown that children whose mothers take folic acid supplement throughout pregnancy exhibit relatively higher levels of emotional intelligence. Nevertheless, in spite of long-standing recommendations that women of child-bearing age take folic acid to protect against neural impairment, a large proportion do not comply; less than half of the world’s population lives in countries that require folic acid fortification of grain products. A large portion of pregnant women in poor world countries do not attend antenatal care hence have no access to prescription of essential haematinic/folic acid. It is recommended that all women who are either planning or capable of pregnancy take a daily supplements containing 0.4 - 0.8 mg (400-800 μg) of folic acid. Fortified foods like some breads, juices, and cereals contain adequate folic acid; others are leafy green vegetables, like spinach, broccoli, and lettuce beans, peas, and lentils. Fruits like lemons, bananas, and melons are also rich sources of folate. There is need for more advocacy regarding antenatal care of pregnant mothers with emphasis on folate supplementation before and throughout pregnancy, to boost the intellectual and psychological capacity of children into adulthood.

Adequate intake and supplementation of B vitamins, in particular folic acid, can play a protective role in bone health

: In vitro and animal model studies have shown that B vitamins (VB) deficiency have negative consequences on bone, as a result of direct or mediated activity of hyperhomocysteinemia. However, there are still no precise indications regarding a possible VB role in order to maintain bone health. So, the aim of this narrative review was to consider the state of the art on correlation between VB dietary intake, blood levels and supplementation and bone health (bone mineral density (BMD), bone turnover markers and fractures risk) in humans. This review included 29 eligible studies. Considering VB blood levels, the 14 studies considered have shown that low serum folate can be a factor risk for reduced BMD and fractures in elderly, particularly women; no independent association was found for other VB. Studies that evaluate relationship between VB dietary intake and BMD are only 2; one, conducted on 1869 women, demonstrated a positive effect of folate intake on BMD, another demonstrated a dose-dependent inverse relationship between vitamin B6 dietary intake and risk of hip fracture, but only for 35298 female participants. Regarding the relationship between BV supplementation and bone health (9 studies with only VB and 4 with other nutrients), all studies that considered patients with hyperhomocysteinemia or with low folate blood levels, are in agreement in demonstrating that folate supplementation (500mcg-5mg) is useful in improving BMD. In conclusion, a request for folate and homocysteine blood levels in elderly patients with osteopenia/osteoporosis is mandatory. For patients with hyperhomocysteinemia or with low folate blood levels, folate supplementation (500mcg-5mg) is crucial.

Implication of folate deficiency in CYP2U1 loss of function

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

Extensive Cerebral Venous Thrombosis Secondary to Recreational Nitrous Oxide Abuse

Nitrous oxide, colloquially known as “whippets,” is a commonly abused inhalant by adolescents and young adults. There are limited data describing the adverse effects of this abuse. We present a 16-year-old girl with no medical history who presented to the emergency department for confusion, hallucinations, weakness, and headaches. Imaging revealed extensive cerebral thrombosis. She had no prior history of venous or arterial thrombosis. Hypercoagulability workup demonstrated an elevated homocysteine level. She was treated with effective anticoagulation and vitamin B12 folate supplementation. To our knowledge, there are a very few cases in the medical literature of cerebral venous thrombosis following the use of nitrous oxide. The pathophysiology of the disorder appears to be linked to the metabolism of vitamin B12 inducing hyperhomocysteinemia and a procoagulant state.

Prevention and Treatment of Methotrexate-induced Hepatotoxicity: Potential of Natural Phytobioactive Compounds

Methotrexate (MTX) is a potent drug for the treatment of various diseases globally amidst being a chemotherapeutic and immunosuppressant agent. However, hepatotoxicity induced by MTX could be life-threatening if left untreated. Folate supplementation is concurrently applied to reduce the adverse effects of MTX, albeit efficacy compromise. Therefore, there is the need to understand the process for the prevention and treatment strategies for MTX induced hepatotoxicity (MIH). In recent times, preliminary preclinical and clinical findings indicate the potential of natural phytobioactive compounds for MIH prevention and treatment. This mini review therefore summarizes proposed mechanisms of MIH and recent advances in the prevention and treatment prospects of natural phytobioactive compounds on MIH.

Relationship between disease severity and folate status of children with sickle cell anaemia in Enugu, South East Nigeria

Background: Repeated crises in children with sickle cell anaemia (SCA), which is a manifestation of disease severity, results in depletion of their minimal tissue folate stores, with higher likelihood of folate deficiency. The study aimed to determine the relationship between disease severity and the folate status of children with SCA attending University of Nigeria Teaching Hospital (UNTH), Enugu. Methods: This was a hospital based, cross-sectional study conducted between September 2018 and March 2019. One hundred participants were recruited, consisting of 50 children having sickle cell crisis and 50 age and gender matched hae- moglobin AA genotype controls. Relevant information was documented using a pretested questionnaire. Sickle cell severity score was determined using frequency of crisis, admissions and transfusions in the preceding one year, degree of liver and splenic enlargement, life-time cummulative frequency of specific complications of SCA, leucocyte count and haematocrit. Results: Folate deficiency was observed in eight percent of the subjects and none of the controls. The difference was not significant (Fisher’s exact = 4.167, p=0.117). The odds of being folate deficient was 8.5 times more likely during anaemic crisis than in vaso-occlusive crisis, though not significant (95% C.I 0.05 – 89.750, p = 0.075). The mean SCA severity score was 8.06 ± 3.64, signifying a moderate SCA severity in the study population. There was a no relationship between folate status and severity of SCA (Fisher’s exact = 0.054, p = 0.949) Conclusion: Folate status in children with SCA is not affected by their disease severity. Therefore, there may be no need for additional folate supplementation with increasing severity of sickle cell anaemia. Keywords: Sickle cell anaemia; disease severity; folate status; children; Enugu.