Collapse, confusion, and clots: an acute presentation of late onset MTHFR deficiency, a treatable leukodystrophy

<h3></h3> A 29-year-old female of Pakistani-Indian origin presented with collapse and confusion on a background of 12 months of progressive leg weakness. Her medical history included significant psychiatric co-morbidity: initially bipolar affective disorder and depression, later revised to schizophrenia. On admission, she was encephalopathic with GCS 11(E3V3M5), and neurological examination revealed a moderate spastic paraparesis. CTPA demonstrated bilateral pulmonary emboli. Intracranial imaging showed extensive bilateral venous sinus thromboses with symmetrical parieto-occipital T2 hyperintensity suggestive of a leukodystrophy. Spinal imaging was normal. Metabolic testing revealed low- normal total B12 level 212ng/L(180-700ng/L), low folate 1.0ug/L(4.6-18.7ug/L), elevated homocysteine level 180umol/L(0-15umol/L), elevated MMA 340nmol/L(0-280nmol/L), and low methionine level 6umol/L on plasma amino acid profile- diagnostic of methylenetetrahydrofolate reductase (MTHFR) deficiency. Genetic testing confirmed likely pathogenic homozygous mutation, c.973C&gt;T; Arg325Cys, in MTHFR with 20% residual MTHFR activity, and homozygous common polymorphism, c.6777C&gt;T. Treatment included hydroxocobalamin, folinic acid, betaine and rivaroxaban alongside psychiatric management with no further deterioration in neurological deficit or further thromboses. Her siblings have been offered genetic testing. Homocysteine testing remains integral in young-onset stroke work-up. This case highlights the heterogenous adult presentation of treatable MTHFR deficiency. It is an important differential diagnosis in patients presenting with neuropsychiatric symptoms, spastic paraparesis, undifferentiated leukodystrophy, or thromboembolism.