To highlight the clinical spectra in three cases of reversible paraparesis caused by gene defects resulting in Biotidinase and Methylenetetrahydrofolate deficiency.

Case 1: A 20-year-old female presented with progressive stiffening of both lower limbs with a history of frequent falls, a phase of transient cognitive decline and seizure episodes. Examination revealed weakness of all 4 limbs, exaggerated deep tendon reflexes, ataxic gait and impaired bilateral finger-nose test. Serial neuroimaging and autoimmune panels were unrevealing. Genetic testing revealed MTHFR and BTD gene defects. Treatment with oral biotin, folinic acid and betaine supplementation showed significantly improved symptoms.

Case 2: A 20-year-old female presented with progressive weakness of all 4 limbs, unsteady gait with impaired hearing and vision. Examination revealed facial myokymia, horizontal gaze restriction with slow saccades (Round-The-House sign+), quadriparesis, mute deep tendon reflexes, spasticity in both lower limbs, hypotonic upper limbs and cerebellar dysfunction. Neuroimaging showed spinal and cerebellar atrophy. Genetic testing revealed BTD and KIF5A gene defects, indicating biotidinase deficiency complicated by spastic paraplegia 10. The patient is being treated with oral biotin and folinic acid.

Case 3: A 23-year-old male presented with gradually progressive spastic paraparesis with seizures and poor scholastic performance. Examination revealed hypertonia of both lower limbs, brisk reflexes, bilateral extensor plantar response and spastic gait. Elevated serum homocysteine, white matter hyperintensities involving the frontal and occipital lobes on neuroimaging and MTHFR gene defect were discovered. Symptomatic improvement was seen on treatment with B12, Folic Acid and Pyridoxine.

MTHFR and Biotidinase deficiencies are rare but treatable causes of spastic quadriparesis, which can closely mimic HSP and other autoimmune aetiologies. Genetic testing and early metabolic screening and diagnosis is crucial as timely treatment with supplementation can halt or even regress the progression of disease.