MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

• MeSH
• homocystein MeSH
• homocystinurie * diagnóza   farmakoterapie   MeSH
• kohortové studie MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   MeSH
• novorozenec MeSH
• psychotické poruchy MeSH
• retrospektivní studie MeSH
• svalová spasticita diagnóza   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

• MeSH
• betain škodlivé účinky   MeSH
• cystathionin-beta-synthasa MeSH
• homocystein MeSH
• homocystinurie * farmakoterapie   MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   MeSH
• psychotické poruchy * MeSH
• svalová spasticita MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

• MeSH
• dítě MeSH
• dospělí MeSH
• epilepsie diagnóza   patologie   MeSH
• homocystinurie diagnóza   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mentální retardace diagnóza   patologie   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• opožděná diagnóza MeSH
• psychotické poruchy diagnóza   patologie   MeSH
• retrospektivní studie MeSH
• svalová spasticita diagnóza   patologie   MeSH
• věk při počátku nemoci MeSH
• záchvaty diagnóza   patologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

• MeSH
• diploidie MeSH
• genotyp MeSH
• genová knihovna MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   fyziologie   MeSH
• missense mutace * MeSH
• mutační analýza DNA MeSH
• Saccharomyces cerevisiae genetika   MeSH
• substituce aminokyselin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

• MeSH
• acylkarnitin metabolismus   MeSH
• fenylalanin metabolismus   MeSH
• glycin-N-methyltransferasa nedostatek   metabolismus   MeSH
• homocystein metabolismus   MeSH
• homocystinurie diagnóza   metabolismus   MeSH
• karnitin analogy a deriváty   metabolismus   MeSH
• kyselina methylmalonová metabolismus   MeSH
• lidé MeSH
• methionin metabolismus   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   metabolismus   MeSH
• novorozenec MeSH
• novorozenecký screening metody   MeSH
• psychotické poruchy diagnóza   metabolismus   MeSH
• svalová spasticita diagnóza   metabolismus   MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• homocystinurie metabolismus   MeSH
• kojenec MeSH
• kyselina methylmalonová moč   MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   metabolismus   MeSH
• metylace MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• průřezové studie MeSH
• psychotické poruchy metabolismus   MeSH
• registrace MeSH
• retrospektivní studie MeSH
• svalová spasticita metabolismus   MeSH
• těhotenství MeSH
• věk při počátku nemoci MeSH
• vitamin B 12 metabolismus   MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   terapie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We 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.

• MeSH
• homocystein genetika   MeSH
• lidé MeSH
• methionin genetika   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   MeSH
• metylace účinky léků   MeSH
• protoonkogenní proteiny c-cbl nedostatek   MeSH
• vitamin B 12 farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cíl studie: určení výskytu a sledování mírné hyperhomocysteinémie (mHHC) u pacientů z metabolické ambulance s kardiovaskulární a perinatální zátěží. Typ studie: retrospektivní analýza dat z metabolické studie.Materiál a metody: 44 pacientů vybraných homo- a heterozygotů polymorfismu metylentetrahydrofolát reduktázy (MTHFR C677T a A1289C) s mHHC (>30 μmol/l) bylo vyšetřeno geneticky na určení homo- a heterozygotie MTHFR, a tito byli dále klinicko-biochemicky a metabolicky diferencováni a dokumentováni. Výsledky: autoři dokumentují a diskutují málo známou nosologickou jednotku mHHC ze snížené enzymatické aktivity MTHFR jako samostatné a relativně časté metabolické onemocnění. Následkem je nedostatek aktivního folátu pro enzymový systém remetylace, který toxický homocystein odstraňuje. Snížení enzymové aktivity MTHFR nastává u nositelů homozygotní TT až o 40 % . Prokázali jsme snížení plazmatického folátu, které negativně koreluje s jeho metabolickými důsledky - HHC (r = -0,853 u homozygotů; r = -0,635 u heterozygotů; u zdravých r = +0,259). Suplementace kyselinou listovou efektivně zvýšila plazmatický folát a snížila hladinu homocysteinu. Pozorování je doloženo kazuistikami typických pacientů, jejich rizikových rodokmenů a efektivity léčby. Závěr: mHHC z deficitu folátu následkem homozygozity nebo heterozygozity MTHFR je v naší populaci třetí nejčastější příčinou HHC hned po ledvinné insuficienci a po deficitu vitaminu B12 (holotranskobalaminu). Každá mHHC musí být diferencována, vysvětlena a odstraněna, aby se snížilo riziko možných vitaminových deficitů a vývoje nežádoucích vaskulárních či perinatálních komplikací. O preventivním účinku snížení homocysteinu na rozvoj kardiovaskulárních komplikací se pochybuje.

Goal: incidence and monitoring of mild hypeorhomocysteinemias in patients with cardiovascular risk attending the meta - bolic unit. Type of Study: retrospective analysis of a metabolic study. Patients and Methods: 44 patients – from metabolic unit- selected homozygotes or heterozygotes confirmed by molecu - lar-genetics methods for polymorphism of methylenetetrahydrofolate reductases (MTHFR C677T and A1298C) and ac - companied with mild hyperhomocysteinemia (> 30 μmol/l of homocysteine in blood) were further metabolically analyzed and documented. Results: authors discuss and postulate till now not described form of mild hyperhomocysteinemia caused only by de - creased enzymatic activity of MTHFR as a relatively often metabolic disturbance of folate metabolism. Due to defficient enzyme aktivity of MTHFR C677T in TT homozygotes (< 40%) the levels of plasmatic folates are decreased and the remeth - ylation of homocysteine in the methionine cyclus is diminished.The negative correlation of lowered plasmatic folate with hyperhomocysteinemia in TT homozygotes (r= -0.853) and in CT heterozygotes (r = -0.635) was proved. In healthy control (r = +0.259). Supplementation of these patients with folic acid effectively increased folate plasmatic levels and decreased homocysteine levels. Typical clinical cases are documented with metabolic schemes or pedigrees. The therapeutical effect of homocysteine decrease on prognosis of cardiovascular risk has not been till now observed. Conclusion: mild hyperhomocysteinemias from folate defficiency due to homozygozity or heterozygozity of MTHFR in the Czech population represent the 3 rd most cause of hyperhomocysteinemias: 1 st kidney diseases, 2 nd deficiency of holo- transcobalamin. All mild hyperhomocysteinemias detected within routine laboratory practice must be differenciated and with adequate therapeutical effort established. Otherwise the routine estimation of homocysteine could be missused only for economical purposes.

• MeSH
• dospělí MeSH
• genotyp MeSH
• homocystein MeSH
• hyperhomocysteinemie * diagnóza   etiologie   klasifikace   MeSH
• kardiovaskulární nemoci etiologie   prevence a kontrola   MeSH
• kyselina listová terapeutické užití   MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) genetika   nedostatek   MeSH
• mladiství MeSH
• polymorfismus genetický MeSH
• retrospektivní studie MeSH
• spina bifida prevence a kontrola   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH

BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

• MeSH
• ataxie genetika   MeSH
• betain terapeutické užití   MeSH
• dítě MeSH
• fenotyp MeSH
• genetické asociační studie metody   MeSH
• homocystinurie farmakoterapie   enzymologie   genetika   MeSH
• kyselina listová terapeutické užití   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• methionin terapeutické užití   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   genetika   MeSH
• mutace genetika   MeSH
• nemoci míchy genetika   MeSH
• psychotické poruchy farmakoterapie   enzymologie   genetika   MeSH
• retrospektivní studie MeSH
• svalová spasticita farmakoterapie   enzymologie   genetika   MeSH
• vitamin B 12 terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.

• MeSH
• databáze genetické MeSH
• homocystinurie genetika   MeSH
• katalytická doména MeSH
• lidé MeSH
• methylentetrahydrofolátreduktasa (NADPH2) chemie   nedostatek   genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mutace * MeSH
• novorozenec MeSH
• novorozenecký screening MeSH
• psychotické poruchy genetika   MeSH
• svalová spasticita genetika   MeSH
• věk při počátku nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH