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Annals of Indian Academy of Neurology
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Clinical, biochemical, radiological, and genetic profile of patients with homocysteine remethylation pathway defect and spastic paraplegia


1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
3 Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
4 Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Correspondence Address:
Atchayaram Nalini,
Professor of Neurology, Neuromuscular Specialist, Department of Neurology, Neuroscience Faculty Center, National Institute of Mental Health and Neurosciences, Bengaluru – 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_223_21

Objectives: The objective of this study is to describe the clinical, biochemical, radiological, and genetic profile of patients presenting with progressive spastic paraparesis due to homocysteine remethylation pathway defect. Methods: This was a retrospective study conducted by reviewing the medical records of patients with serum homocysteine levels >50 μmol/L between January 2015 and January 2019 at our hospital. We included patients presenting with progressive spastic paraparesis, having serum homocysteine >50 μmol/L with low or normal blood methionine suggesting disorders of homocysteine remethylation. Demographic details, clinical manifestations, biochemical abnormalities, neuroimaging findings, and genetic profile were analyzed. Results: A total of seven patients (M: F = 5:2) fulfilled the study eligibility criteria. The mean age at onset of the disease was 13.4 ± 2.4 years (range: 9–17 years). Spastic paraparesis was the presenting manifestation in 4/7 (57.1%) patients. Other manifestations included cognitive decline, poor scholastic performance, behavioral disturbances, seizures, and spastic bladder. Severe hyperhomocysteinemia (>100 μmol/L) was noted in 6/7 (85.7%) patients with median levels of serum homocysteine being 185.7 μmol/L (range: 85.78–338.5 μmol/L). Neuroimaging showed parieto-occipital predominant leukoencephalopathy in 5/7 (71.4%) and diffuse cerebral atrophy in 1/7 (14.2%). Genetic analysis in three patients revealed pathogenic missense variants c.459C >G (p.Ile153Met), c.973C >T (p.Arg325Cys), and c.1031G >T (p.Arg344Met) in MTHFR gene. All the patients received vitamin B12 (injection and oral), folic acid, and pyridoxine and two patients received betaine. At the last follow-up of a median duration of 12 months, there was a good clinical and biochemical response with reduction in the median value of serum homocysteine by 77.5 μmol/L. Conclusion: Evaluation of serum homocysteine and blood methionine in adolescents presenting with progressive spastic paraparesis gives clue to a treatable homocysteine remethylation disorders.


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