vitamin-b-12 and Muscle-Spasticity

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.

Topics: Folic Acid; Folic Acid Deficiency; Homocystinuria; Humans; Infant, Newborn; Metabolic Networks and Pathways; Methylenetetrahydrofolate Dehydrogenase (NADP); Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders; Vitamin B 12; Vitamin B 12 Deficiency

Severe hyperhomocysteinemia (>100 µmol/L) is often associated with inborn errors of homocysteine metabolism. It manifests typically in neonatal period with developmental delay, hypotonia, feeding problems or failure to thrive. Adult-onset forms are rare and include less severe manifestations. Early diagnosis is crucial because effective treatment is available. A 23-year-old man presented with a 3-week history of speech and gait impairment, and numbness in lower limbs. Neurological examination revealed dysarthria, decreased vibratory sensation in both legs and appendicular and gait ataxia. Brain MRI revealed T2-hyperintense symmetric white matter lesions and cortical atrophy. He had folate and vitamin B

Topics: Age of Onset; Betaine; Dysarthria; Folic Acid; Gait Ataxia; Homocystinuria; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders; Tremor; Vitamin B 12; Young Adult

Topics: Aged; Betaine; Female; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

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.

Topics: Alcoholism; Amino Acid Metabolism, Inborn Errors; Diagnosis, Differential; Female; Folic Acid; Folic Acid Deficiency; Homocysteine; Homocystinuria; Humans; Infant, Newborn; Metabolic Networks and Pathways; Methionine; Methylation; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Muscle Spasticity; Psychotic Disorders; Vitamin B 12

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.. 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.. 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.

Topics: Adolescent; Adult; Age of Onset; Amino Acid Metabolism, Inborn Errors; Child; Child, Preschool; Cross-Sectional Studies; Disease Progression; Europe; Female; Homocystinuria; Humans; Infant; Infant, Newborn; Male; Methylation; Methylenetetrahydrofolate Reductase (NADPH2); Methylmalonic Acid; Muscle Spasticity; Phenotype; Pregnancy; Psychotic Disorders; Registries; Retrospective Studies; Vitamin B 12; Young Adult

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.. 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.. 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.. 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.

Topics: Ataxia; Betaine; Child; Female; Folic Acid; Genetic Association Studies; Homocystinuria; Humans; Intellectual Disability; Male; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Mutation; Phenotype; Psychotic Disorders; Retrospective Studies; Spinal Cord Diseases; Vitamin B 12

A 35-year-old woman was admitted with subacute intellectual deterioration. Laboratory studies showed elevated total homocysteine and decreased folic acid. MRI revealed leukoencephalopathy with a posterior predominance, and hyperintensity in the pyramidal tracts on T2-weighted and FLAIR images. The enzyme assay showed a deficiency of methylenetetrahydrofolate reductase (MTHFR) activity with low residual activity of 4.2% of the mean control value in cultured fibroblasts. Sequence analysis of the MTHFR gene demonstrated two homozygous missense mutations, c.677C>T (p.Ala222Val) and c.685A>C (p.Ile225Leu). c.677C>T (p.Ala222Val) is known as a common polymorphism and c.685A>C (p.Ile225Leu) is considered to be a novel polymorphism. A diagnosis of MTHFR deficiency was made. Treatment with folic acid, vitamin B12 and B6 made significant improvement of intellectual deterioration and reduction in the total homocysteine level. They also made marked resolution of leukoencephalopathy. Posterior-predominant leukoencephalopathy was found to be an excellent marker of MTHFR deficiency, and may help to establish the diagnosis.

Topics: Adult; Biomarkers; Female; Folic Acid; Homocysteine; Homocystinuria; Humans; Leukoencephalopathies; Magnetic Resonance Imaging; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Mutation, Missense; Polymorphism, Single Nucleotide; Psychotic Disorders; Treatment Outcome; Vitamin B 12; Vitamin B 6

There is considerable evidence that elevated plasma homocysteine levels are associated with a prothrombotic milieu, whereas activation of the coagulation cascade is an important component of the pathogenesis of sepsis. The protein C pathway has been reported to play a central role both in the propagation of sepsis and a hyperhomocysteinemia-induced hypercoagulable state. Our primary aim was to measure plasma homocysteine levels in mechanically ventilated patients with severe sepsis/septic shock and to assess the association of these levels with relevant clinical outcomes.. The study cohort included 102 mechanically ventilated patients with severe sepsis or septic shock. Demographics, comorbidities, clinical data and severity scores were recorded. Plasma homocysteine, vitamin B12, folate, creatinine, and protein C levels were measured in all study subjects upon enrollment, and genotyping for the C677T and A1298C polymorphisisms of the methylenetetrahydrofolate reductase (MTHFR) gene and for factor V Leiden (FVL) mutations was performed as well. The primary outcomes were mortality at 28 and 90 days; secondary outcomes included the number of days without renal or cardiovascular failure and the ventilator-free days during the study period.. Homocysteine levels were not significantly associated with any primary or secondary outcomes in the multivariable analysis. In addition, a synergistic effect of homocysteine with protein C levels was not detected.. Our data suggest that plasma homocysteine levels may not inform the prognosis of mechanically ventilated patients with severe sepsis/septic shock.

Topics: Activated Protein C Resistance; Aged; Blood Coagulation Tests; Cohort Studies; Comorbidity; Factor V; Female; Folic Acid; Homocysteine; Homocystinuria; Hospital Mortality; Humans; Hyperhomocysteinemia; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Muscle Spasticity; Point Mutation; Protein C; Psychotic Disorders; Respiration, Artificial; Sepsis; Shock, Septic; Thrombophilia; Vitamin B 12

Phenylketonuria (PKU) is a disorder characterized by several biochemical mechanisms which may impair the brain functions in PKU, leading to neurological problems. Our case report concerns a 19 year-old man with phenylketonuria who was evaluated with the onset of stiffness following the abandonment of the phenylalanine-restricted diet. He was assessed with grade-4 spasticity according to Modified Aschworth scale. The deep tendon reflexes had increased and the plantar reflexes were positive. Knee extensions were limited due to the shortening of the hamstring muscles. Serum phenylalanine concentration was elevated and plasma vitamin B12 level was low. Cranial magnetic resonance imaging scan revealed demyelinization area in periventricular deep white matter. We administered a phenylalanine-restricted diet and a rehabilitation program. Following the treatment, spasticity was reduced to grade-1 and patient could walk without aid. This case shows that, the combination of diet, medication and a rehabilitation program is an effective treatment model on adult PKU with upper motor neuron involvement.

Topics: Botulinum Toxins, Type A; Combined Modality Therapy; Cryotherapy; Humans; Male; Motor Neuron Disease; Muscle Spasticity; Phenylalanine; Phenylketonurias; Vitamin B 12; Young Adult

Topics: Anemia, Pernicious; Central Nervous System Diseases; Diagnosis; Humans; Intrinsic Factor; Muscle Spasticity; Paralysis; Spinal Cord; Spinal Diseases; Vitamin B 12