Elevated total plasma homocysteine (hyperhomocysteinemia) is a marker of cardiovascular, thrombotic, and neuropsychological disease. It has multiple causes, including the common nutritional vitamin B12 or folate deficiency. However, some rare but treatable, inborn errors of metabolism (IEM) characterized by hyperhomocysteinemia can be missed due to variable presentations and the lack of awareness. The aim of this study is to identify undiagnosed IEM in adults with significantly elevated homocysteine using key existing clinical data points, then IEM specific treatment can be offered to improve outcome. We conducted a retrospective study with data mining and chart review of patients with plasma total homocysteine >30 μmol/L over a two-year period. We offer biochemical and genetic testing to patients with significant hyperhomocysteinemia without a clear explanation to diagnose IEM. We identified 22 subjects with significant hyperhomocysteinemia but no clear explanation. Subsequently, we offered genetic testing to seven patients and diagnosed one patient with classic homocystinuria due to cystathionine beta-synthase deficiency. With treatment, she lowered her plasma homocysteine and improved her health. This study stresses the importance of a thorough investigation of hyperhomocysteinemia in adults to identify rare but treatable IEM. We propose a metabolic evaluation algorithm for elevated homocysteine levels.

• MeSH
• dospělí MeSH
• homocystein MeSH
• homocystinurie * diagnóza   genetika   MeSH
• hyperhomocysteinemie * diagnóza   genetika   MeSH
• kyselina listová MeSH
• lidé MeSH
• retrospektivní studie MeSH
• vitamin B 12 terapeutické užití   MeSH
• vrozené poruchy metabolismu * diagnóza   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

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

Úvod: Dědičně podmíněné poruchy metabolismu (DPM) aminokyselin (AMK), organických kyselin (OA) a cyklu močoviny (UCD) představují heterogenní skupinu 135 různých onemocnění způsobených porušenou syntézou, transportem či odbouráváním AMK, OA a amoniaku. Jednotlivá onemocnění jsou vzácná, ale celkový výskyt v populaci je 1 : 3000–4000. Metodika: Práce shrnuje klinické, diagnostické a terapeutické aspekty nejčastějších DPM-AMK, OA a UCD. Osm nemocí je součástí laboratorního novorozeneckého screeningu, diagnostika ostatních DPM závisí na klinickém podezření, stanovení amoniaku v krvi a rychlé indikaci selektivního metabolického screeningu. Výsledky: DPM-AMK, OA a UCD se klinicky projevují akutním nebo subakutním rozvratem metabolismu s metabolickou alkalózou nebo acidózou a následným postižením funkcí jater, ledvin a/nebo mozku nebo pomalu progredujícím postižením CNS se zpomalením vývoje a poruchou kognitivních funkcí. Do první skupiny patří OA, tyrosinemie typu 1, leucinóza a UCD, které se projevují hromaděním toxických metabolitů vznikajících při degradaci aminokyselin. Do druhé skupiny patří fenylketonurie a homocystinurie, u které se přidružuje i postižení očí, kostí a/nebo tromboembolické příhody. Závěr: Adekvátní terapie závisí na včasné diagnostice. U pacientů s akutním postižením mozku, například při těžké hyperamonemii, se používají eliminační metody. U pacientů s pomaleji progredujícím onemocněním se uplatňuje celoživotní nízkobílkovinná dieta suplementovaná potravinami pro zvláštní lékařské účely, vitaminoterapie a chaperonová terapie podporující aktivity postižených enzymů a snaha blokovat či aktivovat alternativní metabolické dráhy. Zvyšuje se počet onemocnění, u kterých se používá enzymová substituční terapie či transplantace jater nebo ledvin. Nově probíhají trialy s genovou terapií.

Introduction: Inborn errors of amino acid (AA), organic acid (OA) metabolism and disorders of the urea cycle (UCD) represent a heterogeneous group of 135 different diseases caused by impaired synthesis, transport or degradation of AA, OA and ammonia. Individual diseases are rare, but the overall incidence in the population is 1:3000–4000. Methodology: The work summarizes the clinical, diagnostic and therapeutic aspects of the most common inborn errors of AA, OA metabolism and UCD. Eight diseases are part of laboratory neonatal screening, diagnosis of other IEMs depends on clinical suspicion, determination of ammonia in the blood and rapid indication of selective metabolic screening. Results: Inborn errors of AA, OA metabolism and UCD are clinically manifested by acute or subacute metabolic disruption with metabolic alkalosis or acidosis and subsequent hepatic, renal and / or cerebral impairment or slowly progressive brain impairment with developmental delay and cognitive decline. The first group includes OA, tyrosinemia type 1, leucinosis and UCD, which are manifested by the accumulation of toxic metabolites arising from amino acid degradation. The second group includes phenylketonuria and homocystinuria, which are associated with eye, bone and / or thromboembolic events. Conclusion: Adequate therapy depends on early diagnosis. Elimination methods are used in patients with acute brain involvement, such as severe hyperammonaemia. In patients with chronic disease, a lifelong low-protein diet supplemented with foods for special medical purposes, vitamin therapy and chaperone therapy supporting the activities of affected enzymes and efforts to block or activate alternative metabolic pathways are used. The number of diseases in which enzyme replacement therapy or liver or kidney transplantation is used is increasing. Trials with gene therapy are underway.

• MeSH
• dítě MeSH
• fenylketonurie diagnóza   terapie   MeSH
• homocystinurie diagnóza   terapie   MeSH
• lidé MeSH
• neketotická hyperglycinemie diagnóza   terapie   MeSH
• nemoc s močí javorového sirupu diagnóza   terapie   MeSH
• tyrosinemie diagnóza   terapie   MeSH
• vrozené poruchy metabolismu aminokyselin * diagnóza   terapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.

• MeSH
• cystathionin-beta-synthasa nedostatek   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• homocystinurie diagnóza   farmakoterapie   enzymologie   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• methionin krev   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• opožděná diagnóza MeSH
• předškolní dítě MeSH
• pyridoxin terapeutické užití   MeSH
• registrace MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa 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

BACKGROUND: The main genetic causes of homocystinuria are cystathionine beta-synthase (CBS) deficiency and the remethylation defects. Many patients present in childhood but milder forms may present later in life. Some countries have newborn screening programs for the homocystinurias but these do not detect all patients. RESULTS: HCU Network Australia is one of the very few support groups for patients with homocystinurias. Here we report the results of its survey of 143 patients and caregivers from 22 countries, evaluating current diagnostic pathways and management for the homocystinurias. Most (110) of the responses related to patients with CBS deficiency. The diagnosis was made by newborn screening in 20% of patients and in 50% of the others within 1 year of the initial symptom but in 12.5% it took over 15 years. The delay was attributed mainly to ignorance of the disease. Physicians need to learn to measure homocysteine concentrations in children with neurodevelopmental problems, and in patients with heterogeneous symptoms such as thromboembolism, dislocation of the optic lens, haemolytic uraemic syndrome, and psychiatric disease. Even when the diagnosis is made, the way it is communicated is sometimes poor. Early-onset CBS deficiency usually requires a low-protein diet with amino acid supplements. More than a third of the participants reported problems with the availability or cost of treatment. Only half of the patients always took their amino acid mixture. In contrast, good adherence to the protein restriction was reported in 98% but 80% said it was hard, time-consuming and caused unhappiness. CONCLUSIONS: There is often a long delay in diagnosing the homocystinurias unless this is achieved by newborn screening; this survey also highlights problems with the availability and cost of treatment and the palatability of protein substitutes.

• MeSH
• cystathionin-beta-synthasa MeSH
• dítě MeSH
• homocystinurie * diagnóza   MeSH
• lidé MeSH
• novorozenec MeSH
• osoby pečující o pacienty MeSH
• spokojenost pacientů MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Austrálie 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

• MeSH
• alkaptonurie diagnóza   terapie   MeSH
• fenylketonurie diagnóza   etiologie   terapie   MeSH
• Hartnupova nemoc diagnóza   terapie   MeSH
• homocystinurie diagnóza   terapie   MeSH
• kožní manifestace MeSH
• lidé MeSH
• tyrosinemie diagnóza   terapie   MeSH
• vrozené poruchy metabolismu aminokyselin * patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Classical homocystinuria (HCU) is the most common inherited disorder of sulfur amino acid metabolism caused by deficiency in cystathionine beta-synthase (CBS) activity and characterized by severe elevation of homocysteine in blood and tissues. Treatment with dietary methionine restriction is not optimal, and poor compliance leads to serious complications. We developed an enzyme replacement therapy (ERT) and studied its efficacy in a severe form of HCU in mouse (the I278T model). Treatment was initiated before or after the onset of clinical symptoms in an effort to prevent or reverse the phenotype. ERT substantially reduced and sustained plasma homocysteine concentration at around 100 μM and normalized plasma cysteine for up to 9 months of treatment. Biochemical balance was also restored in the liver, kidney, and brain. Furthermore, ERT corrected liver glucose and lipid metabolism. The treatment prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass. In addition, structurally defective ciliary zonules in the eyes of I278T mice contained low density and/or broken fibers, while administration of ERT from birth partially rescued the ocular phenotype. In conclusion, ERT maintained an improved metabolic pattern and ameliorated many of the clinical complications in the I278T mouse model of HCU.

• MeSH
• aminokyseliny sírové krev   metabolismus   MeSH
• cystathionin-beta-synthasa aplikace a dávkování   chemie   MeSH
• enzymová substituční terapie * MeSH
• fenotyp * MeSH
• glukosa metabolismus   MeSH
• homocystinurie diagnóza   metabolismus   terapie   MeSH
• játra účinky léků   metabolismus   MeSH
• metabolismus lipidů MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• oxidační stres MeSH
• polyethylenglykoly chemie   MeSH
• preklinické hodnocení léčiv MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• Klíčová slova
• hyperfenylalaninémie,
• MeSH
• alkaptonurie diagnóza   etiologie   farmakoterapie   patofyziologie   MeSH
• fenylalanin metabolismus   MeSH
• fenylketonurie diagnóza   dietoterapie   etiologie   patofyziologie   MeSH
• Hartnupova nemoc diagnóza   etiologie   patofyziologie   terapie   MeSH
• homocystinurie diagnóza   etiologie   patofyziologie   terapie   MeSH
• kožní nemoci * diagnóza   etiologie   patofyziologie   terapie   MeSH
• lidé MeSH
• tyrosinemie diagnóza   dietoterapie   etiologie   patofyziologie   MeSH
• vrozené poruchy metabolismu aminokyselin * dietoterapie   etiologie   farmakoterapie   patofyziologie   MeSH
• Check Tag
• lidé MeSH