Severe Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: A Case Report of Nonclassical Homocystinuria

Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Journal of child neurology (Impact Factor: 1.72). 07/2008; 23(7):823-8. DOI: 10.1177/0883073808315410
Source: PubMed


Severe methylenetetrahydrofolate reductase deficiency is an autosomal recessive metabolic disorder of folate metabolism causing elevated plasma homocysteine levels and homocystinuria (MIM 236250). A developmentally delayed 10-year-old girl presented with symptoms of progressive ataxia, dysarthria, tremor, mental status changes, and white-matter changes on magnetic resonance imaging. These changes occurred during a 3- to 4-month time period, with an acceleration of symptoms during 2 to 3 weeks. The patient was found to have extremely high serum homocysteine and low-normal serum methionine. She received treatment with vitamin B12, folate, betaine, multivitamins, and aspirin, with subsequent improvement of her symptoms and reduction in her serum homocysteine level. This case emphasizes the need to include homocystinuria in the differential diagnosis of children with acute/subacute neurological changes, particularly in the context of developmental delay.

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    • "Another condition involved in MTHFR deficiency is an inborn error of metabolism, which results in a severe deficiency in the enzyme and leads to homocystinuria. Patients with a severe MTHFR deficiency have significantly elevated levels of homocysteine and reduced levels of methionine and present with neurological and vascular complications [11] [12] [13]. "
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM). In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT), which is involved in neuro-transmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and γ-aminobutyric acid in within the cerebellum and hippocampus. Mthfr −/− mice had reduced levels of glutamate in the amygdala and γ-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-D-aspartate receptor in brain tissue might alter levels of glutamate and γ-aminobutyric acid.
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    • "The mechanism through with MTHFR may influence white matter integrity in schizophrenia remains uncertain; however, the lack of an interactive effect of MTHFR genotype and FA on error-related dACC activation suggests that the two deficits may be relatively independent sequelae of having the T allele. Interestingly, MTHFR deficiency has been associated with leukoencephalopathy (Bishop et al. 2008; Tallur et al. 2005; Walk et al. 1994), and the 677T allele has been linked to white matter lesions in large cohorts of elderly subjects (Hong et al. 2009; Kohara et al. 2003). These reports speculate that the observed white matter changes are due to homocysteine elevations, a direct metabolic consequence of low MTHFR activity. "
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    ABSTRACT: Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C>T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity.
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    ABSTRACT: Tremor in childhood is not commonly described in the literature; but it is also likely underappreciated. The etiology of childhood tremor encompasses a wide variety of pathologic processes. Tremor may occur in isolation, or in association with other neurologic findings or systemic disorders. This article aims to provide an overview of tremorogenic mechanisms with respect to neuroanatomy and neurophysiology, particularly as they relate to children. Classification of tremors, diagnostic entities in childhood, and treatment will also be discussed. With improved recognition and characterization of childhood tremors, we may gain a better understanding of the pathophysiology of the disease and determine more age-appropriate treatment strategies.
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