Abstract
Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.
Keywords:
5,10-methenyltetrahydrofolate synthetase; Folate; Folinic acid; Neurodegeneration; Neurometabolism.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Transport Systems, Acidic / cerebrospinal fluid
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Amino Acid Transport Systems, Acidic / deficiency*
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Amino Acid Transport Systems, Acidic / genetics
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Amino Acid Transport Systems, Acidic / metabolism
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Antiporters / cerebrospinal fluid
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Antiporters / deficiency*
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Antiporters / genetics
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Antiporters / metabolism
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Brain / metabolism
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Brain / pathology
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Carbon-Nitrogen Ligases / cerebrospinal fluid
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Carbon-Nitrogen Ligases / deficiency
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Carbon-Nitrogen Ligases / genetics*
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Carbon-Nitrogen Ligases / metabolism
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Epilepsy / cerebrospinal fluid
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Epilepsy / complications
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Epilepsy / genetics*
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Epilepsy / pathology
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Female
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Folate Receptor 1 / deficiency
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Hereditary Central Nervous System Demyelinating Diseases / cerebrospinal fluid
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Hereditary Central Nervous System Demyelinating Diseases / complications
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Hereditary Central Nervous System Demyelinating Diseases / genetics*
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Hereditary Central Nervous System Demyelinating Diseases / metabolism
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Humans
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Male
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Metabolic Diseases / cerebrospinal fluid
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Metabolic Diseases / complications
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Metabolic Diseases / genetics
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Metabolic Diseases / pathology
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Microcephaly / cerebrospinal fluid
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Microcephaly / complications
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Microcephaly / genetics*
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Microcephaly / pathology
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Mitochondrial Diseases / cerebrospinal fluid
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Mitochondrial Diseases / complications
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Mitochondrial Diseases / genetics*
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Mitochondrial Diseases / metabolism
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Nervous System Malformations / cerebrospinal fluid
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Nervous System Malformations / complications
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Nervous System Malformations / genetics
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Nervous System Malformations / metabolism
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Neuroaxonal Dystrophies
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Psychomotor Disorders / cerebrospinal fluid
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Psychomotor Disorders / complications
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Psychomotor Disorders / genetics*
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Psychomotor Disorders / metabolism
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Tetrahydrofolates / cerebrospinal fluid
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Tetrahydrofolates / metabolism
Substances
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Amino Acid Transport Systems, Acidic
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Antiporters
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Folate Receptor 1
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Tetrahydrofolates
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Carbon-Nitrogen Ligases
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5,10-methenyltetrahydrofolate synthetase
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5-methyltetrahydrofolate
Supplementary concepts
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Hypomyelination, Global Cerebral
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Neurodegeneration Due To Cerebral Folate Transport Deficiency