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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Disorders related to deficiency of methylenetetrahydrofolate reductase (MTHFR) need to be distinguished from polymorphisms incidentally found on genetic testing. MTHFR deficiency is an autosomal recessive disorder due to pathogenic variants in the MTHFR gene that severely reduce the enzyme activity. Patients with MTHFR deficiency have symptoms of both high homocysteine and deficiency of methyl donors, typically with childhood onset of significant intellectual disability, epilepsy, and other features of homocystinuria. Rare late-onset cases of MTHFR deficiency present with a demyelinating leukoencephalopathy characterized by spastic paraparesis, recurrent or subacute encephalopathy, psychosis, or epilepsy.
Hyperhomocysteinemia: a trigger for complement-mediated TMA?
Published in Acta Clinica Belgica, 2021
J Bernards, P Doubel, G Meeus, E Lerut, A Corveleyn, L P Van Den Heuvel, W Meersseman, D K Kuypers, KJ Claes
To our knowledge, this is the first report of a patient with isolated hyperhomocysteinemia due to documented MTHFR deficiency and biopsy-proven TMA. The potential contribution of the isolated elevation in homocysteine on the one hand and the possibly pathogenic mutations in the genes encoding CFH and CFB on the other hand remains elusive. We hypothesize that the marked elevation in homocysteine might have led to endothelial dysfunction triggering the uncontrolled activation of a defective alternative complement pathway. However, the differential diagnosis with malignant hypertension remains, despite the absence of hypertension in the history of this patient. Circumstantial evidence does give some indication of the possible vasculopathic influence of the MTHFR polymorphism. Hyperhomocysteinemia caused by the MTHFR polymorphism has been linked to hypertension induced by vasoconstriction, renal dysfunction and sodium reabsorption [12–14]. MTHFR deficiency as a cause of hypertension has been studied in different populations with conflicting results [15–17]. In patients with idiopathic vascular lesions on kidney biopsy, prothrombotic mutations such as the MTHFR polymorphism showed to be more prevalent than in a control population [18]. Besides vascular edema and presence of thrombi intima fibrosis was found in the kidney biopsy of our patient .
Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice
Published in Nutritional Neuroscience, 2022
Jamie E. Abato, Mahira Moftah, Greg O. Cron, Patrice D. Smith, Nafisa M. Jadavji
The Mthfr+/- mouse models traits of the human polymorphism, including reduced levels of enzyme activity and elevated levels of homocysteine [16, 17]. Using the MTHFR-deficient mice and the photothrombosis induced ischemic damage, our previous research has demonstrated that aged Mthfr+/- mice are more vulnerable to damage after ischemic stroke through reduced neuronal and astrocyte viability [18–20]. The mechanisms through which the Mthfr+/- mice are more impaired after ischemic damage requires more investigation. The aim of this study was to investigate the cellular response through which MTHFR deficiency regulates the brain’s vulnerability to ischemic stroke.
Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population
Published in International Journal of Neuroscience, 2023
Dilsad Turkdogan, Ayberk Turkyilmaz, Gunes Sager, Gulten Ozturk, Olcay Unver, Merve Say
WES study diagnosed methylene tetrahydrofolate reductase (MTHFR) deficiency in patient #31 whose early metabolic work-up showed hyperhomocysteinemia and severe vitamin B12 deficiency, even in the mother. Specific metabolic treatment of MTHFR deficiency impressively improved seizure control and social development. The patient also had one VUS and one pathogenic variant of RPGRIP1L linked to Joubert syndrome 7 (OMIM: #611560) (Table 2). Lack of specific clinical and neuroradiological findings excludes the causality between those variants and the present phenotype.