Cerebral folate deficiency: a treatable cause of late deterioration in epilepsy with developmental delay.

A 25-year-old woman with childhood-onset refractory epilepsy and developmental delay experienced a gradually progressive marked deterioration in mobility and seizure control, with language regression. Investigation identified a homozygous deletion within the contactin-associated protein-like 2 gene (CNTNAP2), underlying her early presentation, but also cerebral folate deficiency that most likely contributed to her later deterioration. Following antiseizure medication adjustment and treatment with folinic acid, she stabilised with improved seizure control and limited improvement in language and motor function; she has remained neurologically stable for more than a decade. That the previously observed neurological decline was halted by folinic acid replacement supports this being due to cerebral folate deficiency. Metabolic conditions are less well recognised in adults and can be under-diagnosed. They are potentially treatable and should be considered even in the presence of another cause, particularly when the presentation is not fully compatible.

Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement.

Importance: Neural tube defects are among the most common congenital malformations in the US, with an estimated 3000 pregnancies affected each year. Many of these neural tube defects are caused by low folate levels in the body. Objective: The US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on the benefits and harms of folic acid supplementation. Population: Persons who are planning to or could become pregnant. Evidence Assessment: The USPSTF concludes that, for persons who are planning to or could become pregnant, there is high certainty that folic acid supplementation has a substantial net benefit to prevent neural tube defects in their offspring. Recommendation: The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. (A recommendation).

Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature.

BACKGROUND: Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature. RESULTS: Two siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465_466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements. CONCLUSION: We present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders.

The Utilization of Serum Folate and Homocysteine Tests and the Prevalence of Folate Deficiency in Reproductive-Age Korean Women during the COVID-19 Pandemic.

We investigated the prevalence of folate deficiency and associated factors in a large population of Korean women of reproductive age during the COVID-19 pandemic. We utilized different cut-offs and evaluated age, year of testing, geographical region, and the utilization of serum homocysteine levels. Out of the 27,758 women evaluated, the overall prevalence of folate deficiency was 12.5% (<4 ng/mL, metabolic indicator) and 5.4% (<3 ng/mL, hematologic indicator). Homocysteine testing was observed in 8.4% of women, with 2.7% having elevated homocysteine levels (>15.4 µmol/L). According to our multiple logistic regression analysis, younger women, particularly those aged 20 to 24 years, tested in 2020, and from Jeolla province, Gyeongsang province, and Jeju Island, were identified as being more prone to folate deficiency. Receiver operating characteristic curve analysis demonstrated that a cut-off of >8.4 µmol/L provided the most accurate definition of folate deficiency with serum folate levels <4 ng/mL, while a cut-off of >8.8 µmol/L best defined folate deficiency with serum folate levels <3 ng/mL, with both cut-offs being lower than 15.4 µmol/L. Our study emphasizes the prevalence of folate deficiency, associated factors, and the role of homocysteine in planning nutritional support programs in Korea.

Pseudo-thrombotic microangiopathy due to folate deficiency.

Classically, deficiencies of vitamin B12 and folate are associated with megaloblastic anaemia. Additionally, vitamin B12 is able to cause a haemolytic anaemia in the form of pseudo-thrombotic microangiopathy (pseudo-TMA). Here, we present a case of a middle-aged woman with a history of Roux-en-Y gastric bypass who presented with dyspnoea and fatigue and was found to have thrombocytopenia and a non-immune haemolytic anaemia. Work-up for haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, paroxysmal nocturnal haemoglobinuria, infection, malignancy and autoimmune conditions was unremarkable. Her haemolytic anaemia and thrombocytopenia resolved with folate replenishment. She was diagnosed as likely having pseudo-TMA secondary to folate deficiency.

Megaloblastic Anemia Masked by an Unrecognized Hemoglobinopathy.

BACKGROUND: Deficiency of vitamin B(12) or folate causes megaloblastic anemia (MA). The disease presents with pancytopenia due to the excessive cellular apoptosis of hematopoietic progenitor. MA is characterized by the presence of high mean corpuscular volume in the blood routine test and hyperlobulation nuclei of the granulocytes in the peripheral blood smears, and megaloblasts in the bone marrow. METHODS: We report a rare case, in which megaloblastic anemia was masked by an unrecognized hemoglobinopathy and presented with normocytic anemia and atypical morphological features of bone marrow. RESULTS: The patient was finally diagnosed with coexistence of MA and a-thalassemia minor due to determination of folate deficiency and genetic mutation for a-thalassemia. CONCLUSIONS: The case focuses on the contribution of the peripheral circulating blood smear examination in the diagnosis of anemia.

[Metabolic disorders in hereditary optic neuropathies]. / Metabolicheskie narusheniya pri nasledstvennykh opticheskikh neiropatiyakh.

Folate metabolism disorders are known to have a potential involvement in the pathophysiology of mitochondrial diseases. Many researchers suggest that profound systemic folate deficiency may contribute to mitochondrial folate deficiency. Folic acid metabolism is closely related to vitamin B12 and homocysteine. Considering that hereditary optic neuropathies (HON) are mitochondrial diseases, it is important to study the folate status, the content of vitamin B12 and homocysteine in patients with this pathology. OBJECTIVE: To compare the content of folic acid, vitamin B12 and homocysteine in the blood serum of patients with Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON), optic neuropathy of other genesis, and the comparison group. MATERIAL AND METHODS: The study involved 58 patients with LHON and ARON, the control group of 49 patients with ischemic, inflammatory, traumatic and compressive optic neuropathies, and the comparison group of 20 healthy volunteers. RESULTS: A decrease in blood folic acid levels was revealed (4.0±1.6 ng/mL) in patients with HON compared to the control group (p=1.3·10-8) and the comparison group (p=1·10-17). The content of vitamin B12 in patients with HON was 380.8±168.1 pg/mL, which was significantly lower than in the comparison group (p=0.0001). The homocysteine content was 14.1±5.6 µmol/L in patients with HON, which was significantly higher than in the control group (p=0.0007) and the comparison group (p=0.000003). At the same time, an increase in homocysteine level of more than 10 µmol/L was revealed in 75% of patients with HON. Similar metabolic disorders were found in groups with various mutations in mitochondrial and nuclear DNA. CONCLUSION: Patients with HON showed marked decrease in the levels of folic acid and vitamin B12, as well as hyperhomocysteinemia. It is very important to identify the causes of metabolic disorders in order to determine the role of folate deficiency in the development of HON, as well as the possibility of its pharmacological treatment.

[Anaemia, thrombocytopenia and folic acid deficiency interpreted as HELLP syndrome in pregnant woman].

This is a case report of a 24-year-old woman at pregnancy week 30, who presented with abdominal pain, nausea, dizziness, fatigue, intermittent headaches, and hyperreflexia. Haemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome was suspected due to blood tests showing low haemoglobin- and thrombocyte levels, and elevated lactate dehydrogenase level. The baby was delivered by acute caesarean section shortly after hospitalization. After delivery, the patient's condition did not improve. Additional testing showed folic acid deficiency, probably contributing to the anaemia. Further anamnesis showed, that the patient had untreated coeliac disease, contributing to folic acid deficiency.

Cobalamin and folic acid deficiencies presenting with features of a thrombotic microangiopathy: a case series.

Case presentation We report three cases of vitamin B12 and/or folic acid deficiencies presenting with non-immune hemolytic anemia and thrombocytopenia. This presentation, with features of a thrombotic microangiopathy (TMA), has earlier been described as 'pseudo-TMA'.

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 haemoglobin 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.

Folate Deficiency in an Urban Safety Net Population.

PURPOSE: Since mandatory fortification of grain products with folic acid in the United States in 1998, folate deficiency has become rare. Some have suggested that serum folate levels should be tested rarely in countries with mandatory folic acid fortification, given low rates of deficiency, high cost per deficiency diagnosis, and low rates of supplementation for those diagnosed as deficient. Given persistent racial, ethnic, and socioeconomic disparities in folate deficiency, these suggestions may not apply to all populations. We examine the rate at which serum testing detected folate deficiency in an urban safety net hospital and the characteristics of folate-deficient patients. METHODS: We reviewed the charts of all inpatients and emergency department patients with low serum folate results at a safety net hospital in Boston in 2018. We collected data concerning demographics, social determinants of health, clinical factors, and whether folate supplementation was prescribed. Finally, we performed a cost analysis. RESULTS: Of 1368 patients tested, 76 (5.5%) met criteria for folate deficiency. Overall, 86.8% of these patients were anemic, and 17.1% had macrocytic anemia; 42% were diagnosed with malnutrition. Common social determinants in folate-deficient patients included birth outside of the United States, homelessness, and alcohol use disorder. Of folate-deficient patients, 88% were newly prescribed folic acid supplementation at discharge. The estimated charge per deficient test was $1278. CONCLUSION: Compared with a nearby institution, serum folate testing at our safety net hospital detected deficiency at a higher rate, incurred a lower charge per deficient test, and was more likely to impact management.

Reference Interval for Korean Serum Folate Assay Traceable to the WHO International Standard.

BACKGROUND: Little is known about the reference interval of serum folate concentration if using recently re-standardized assays traceable to the World Health Organization (WHO) international standard reference 03/178 in a Korean population. This study aimed to investigate serum folate levels in Korean subjects without macrocytic anemia or increased homocysteine, for the assessment of folate deficiency. METHODS: We retrospectively reviewed data from Korean adults whose hemoglobin, mean corpuscular volume, and serum total homocysteine values were within reference limits. RESULTS: The median (interquartile range) serum folate level was 7.8 (5.4 - 12.6) ng/mL in men and 10.2 (6.9 - 15.6) ng/mL in women. The reference interval for serum folate (2.5th and 97.5th percentiles) ranged from 2.9 to 38.0 ng/ mL. From among 723 Korean adults, the lower limit of reference intervals of serum folate for folate deficiency, defined as the 2.5th percentile, was 2.9 ng/mL. The prevalence of folate deficiency was higher in men (6.5%) than in women (1.2%, p < 0.05) when a cutoff value of 3.0 ng/mL was applied. Using the cutoff value of 4 ng/mL for folate deficiency, which is in accordance with the instructions from the manufacturer of the new assay and the WHO 2012 guideline for homocysteine as a metabolic indicator before assay standardization, about 5% of subjects were reclassified as folate deficient. CONCLUSIONS: Our study suggests that any change of reference limits using a re-standardized assay needs to be verified in clinical laboratories.

Red blood cell folate and severe abdominal aortic calcification: Results from the NHANES 2013-2014.

BACKGROUND AND AIMS: Abdominal aortic calcification (AAC) has been introduced as a good predictor of cardiovascular disease (CVD) events, but no previous study has investigated the relationship between folate levels and AAC. The present study aims to explore the relationship between red blood cell (RBC) folate, a better indicator reflecting long-term folate intake, and severe AAC in the United States (US) middle-aged and elderly population. METHODS AND RESULTS: Cross-sectional data were derived from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 of 2818 men and women aged 40 years or older. Multivariable logistic regression models were used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for severe AAC of each RBC folate quintile category. The restricted cubic spline model was used for the dose-response analysis. A U-shaped dose-response relation between RBC folate and the odds of severe AAC was found after adjustment for multiple potential confounding factors, p for nonlinear = 0.0032. With the third quintile category of RBC folate as the reference, multivariable-adjusted ORs and 95% CIs of the lowest, second, fourth, and the highest quintile categories were 2.34 (1.37-4.00), 1.24 (0.70-2.19), 1.58 (0.92-2.70), and 2.26 (1.35-3.76), respectively. CONCLUSIONS: Individuals with either low or high levels of RBC folate were at increased risks of severe AAC in a representative sample of US adults. While folate deficiency is widely recognized as harmful, these results highlight the need to investigate the potential adverse health outcomes of high folate level.

[Chorioretinal atrophy in pediatric cerebral folate deficiency-a preventable disease?] / Chorioretinale Atrophie bei kindlichem zerebralem Folatmangel ­ eine vermeidbare Erkrankung?

Cerebral folate deficiency (CFD) results in neurological alterations and a massive degeneration of the choroid/retina if left untreated, which limit the visual field and visual acuity. This article reports the case of a female patient with CFD, who developed autistic personal characteristics prior to reaching school age and first started to speak at the age of 3 years. At the age of 6 years she was presented because of unclear reduced visual acuity in the right eye. At that time mild bilateral peripheral chorioretinal atrophy was present, which subsequently became more pronounced. Additionally, a centrally emphasized chorioretinal atrophy further developed. Visual acuity of both eyes progressively deteriorated until stagnating at 0.1 at the age of 14 years. The causal assignment of the findings of the patient was not possible for many years. Choroideremia was excluded by molecular genetic testing (CHM gene with no mutations) and gyrate atrophy was ruled out by a normal ornithine level. The existence of a mitochondrial disease was almost completely excluded by exome sequencing. After the onset of further nonocular symptoms, e.g. neuromuscular disorders, electroencephalograph (EEG) alterations and autistic disorder, intensified laboratory diagnostics were performed in the treating pediatric hospital. Finally, an extremely low level of the folic acid metabolite 5­methyltetrahydrofolate was detected in the cerebrospinal fluid (CSF) leading to the diagnosis of CFD. High-dose substitution treatment with folic acid was subsequently initiated. After excluding the presence of a pathogenic mutation of the FOLR1 gene for the cerebral folate receptor 1, a high titer blocking autoantibody against cerebral folate receptor 1 was detected as the cause.

Treatable Cause of Pancytopenia, Recurrent Infections and Refractory Epilepsy: Secondary to Hereditary Folate Malabsorption (HFM) Due to Novel Pathogenic Variant.

Hereditary folate malabsorption (HFM) is a rare disorder of proton-coupled folate transporter deficiency. It is characterized by macrocytic anemia, recurrent infections, and epilepsy. A five-year-old girl presented with recurrent pneumonia, diarrhea, and mouth ulcers. On examination, pallor, microcephaly with spastic quadriparesis was noted. On investigations, leukopenia and thrombocytopenia with megaloblastic bone marrow picture and low folate levels was found. HFM was diagnosed at two years of age and the child was treated with folinic acid. Her diagnosis was confirmed by whole-exome sequencing which revealed a novel pathogenic homozygous frameshift insertion variation (c.620dupG) in the exon 2 of the SLC46A1 gene which was further confirmed by Sanger sequencing. The child improved significantly except for a partial improvement in neurological symptoms.

[Remethylation disorders: about two cases]. / Troubles de la reméthylation : à propos de deux cas.

In order to propose a course of action to be taken in the face of any hyperhomocysteinemia, we have reported for the first time in a French journal the recommendations made within the framework of the European E-HOD project for the diagnosis and treatment of remethylation disorders. The remethylation route ensures homocysteine-methionine conversion. It is linked to the folate cycle and the intracellular metabolism of cobalamins. Remethylation disorders can be classified into three groups: 1) isolated disorders (cblD-HC, cblE, cblG) corresponding to an isolated deficit in the production of methylcobalamin, cofactor of methionine synthase; 2) combined disorders (cblC, cblD-MMA/HC, cblF, cblJ) corresponding to an alteration of the transport and intracellular metabolism of cobalamins, which causes a defect in the synthesis of the two functional forms of cobalamin: methylcobalamin and adenosylcobalamin, a cofactor for methyl malonylCoA mutase; 3) MTHFR deficit, an abnormality of the folate cycle. The biological anomalies observed are hyperhomocysteinemia and hypomethioninaemia associated in the case of disorders combined with increased urinary excretion of methylmalonic acid. The clinical presentation is however heterogeneous according to the remethylation disorder but also for the same pathology according to the age. Given the large number of pathologies grouped together in remethylation disorders, this point is illustrated by only two clinical cases concerning the same deficit (deficit in MTHFR) but with different discovery circumstances: a neonatal form and a late form.