Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment

This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl‐dependent remethylation. Acquired and inborn Cbl‐related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl‐dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net‐effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.

Section: Mthfd1 Deficiencymentioning

confidence: 92%

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Huemer

Baumgartner

2019

“…All 14 patients presented with moderately increased MMA and five of these patients had hyperhomocysteinaemia (Yu et al 2013). In two of the five published patients with methylenetetrahydrofolate dehydrogenase 1 deficiency, tHcy concentrations were moderately elevated (Burda et al 2015) (Table 4). …”

Section: Which Parameters Allow Valid and Timely Laboratory Diagnosis?mentioning

confidence: 97%

“…The recently discovered MTHFD1 deficiency (Watkins and Rosenblatt 2012) affects folate metabolism and can cause mild hyperhomocysteinaemia. The five patients described so far displayed severe megaloblastic anaemia and pancytopenia, immunological problems and renal microangiopathy (Burda et al 2015). …”

Section: Which Clinical Signs Are Characteristic For Remethylation Dementioning

confidence: 99%

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Huemer

Diodato

Schwahn

et al. 2016

230

368

BackgroundRemethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.ObjectiveTo summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.Data sourcesReview, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.Key recommendationsWe strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9991-4) contains supplementary material, which is available to authorised users.

“…All affected patients had biallelic mutations in MTHFD1 encoding a trifunctional protein involved in cellular folate metabolism. The three reactions catalyzed by the MTHFD1 trifunctional protein are 5,10‐methylenetetrahydrofolate dehydrogenase, 5,10‐methenyltetrahydrofolate cyclohydrolase and 10‐formyltetrahydrofolate synthetase, which condense formate with tetrahydrofolate to provide the primary entry point of single carbons into folate‐dependent one‐carbon metabolism in the cytosol . In MTHFD1 deficiency, impaired nuclear de novo dTMP biosynthesis is thought to underlie both the megaloblastic anaemia and the SCID .…”

Section: Inborn Errors Of Folate Transport and Metabolismmentioning

confidence: 99%

Cerebral folate deficiency: Analytical tests and differential diagnosis

Pope

Artuch

Heales

et al. 2019

Cerebral folate deficiency is typically defined as a deficiency of the major folate species 5‐methyltetrahydrofolate in the cerebrospinal fluid (CSF) in the presence of normal peripheral total folate levels. However, it should be noted that cerebral folate deficiency is also often used to describe conditions where CSF 5‐MTHF is low, in the presence of low or undefined peripheral folate levels. Known defects of folate transport are deficiency of the proton coupled folate transporter, associated with systemic as well as cerebral folate deficiency, and deficiency of the folate receptor alpha, leading to an isolated cerebral folate deficiency associated with intractable seizures, developmental delay and/or regression, progressive ataxia and choreoathetoid movement disorders. Inborn errors of folate metabolism include deficiencies of the enzymes methylenetetrahydrofolate reductase, dihydrofolate reductase and 5,10‐methenyltetrahydrofolate synthetase. Cerebral folate deficiency is potentially a treatable condition and so prompt recognition of these inborn errors and initiation of appropriate therapy is of paramount importance. Secondary cerebral folate deficiency may be observed in other inherited metabolic diseases, including disorders of the mitochondrial oxidative phosphorylation system, serine deficiency, and pyridoxine dependent epilepsy. Other secondary causes of cerebral folate deficiency include the effects of drugs, immune response activation, toxic insults and oxidative stress. This review describes the absorption, transport and metabolism of folate within the body; analytical methods to measure folate species in blood, plasma and CSF; inherited and acquired causes of cerebral folate deficiency; and possible treatment options in those patients found to have cerebral folate deficiency.