Adolescent/adult-onset homocysteine remethylation disorders characterized by gait disturbance with/without psychiatric symptoms and cognitive decline: a series of seven cases

Homocysteine remethylation disorders are rare inherited disorders caused by a deficient activity of the enzymes involved in the remethylation of homocysteine to methionine. The adolescent/adult-onset remethylation disorders are rarely reported. We analyzed the clinical and genetic characteristics of seven cases with adolescent/adult remethylation disorders, including 5 cases of the cobalamin C disease (cblC) and 2 cases of the methylenetetrahydrofolate reductase deficiency. The average onset age was 21.1 (range 14 to 40) years. All patients complained of gait disturbances. Other common symptoms included psychiatric symptoms (5/7) and cognitive decline (4/7). Acute encephalopathy, dysarthria, anorexia, vomiting, ketoacidosis, anemia, cataract, and hand tremor were also observed. The mean total homocysteine in serum when the patients were diagnosed was 94.6 (range 53.1–154.5) mol/L. Electrophysiological studies revealed neuropathy in the lower limbs (6/7). The brain MRI showed reversible altered signal from the dorsal portions of the cerebellar hemispheres (1/7), periventricular hyperintensity (2/7), and delayed/impaired myelination (2/7). The sural nerve biopsy performed in one case showed a modest loss of myelinated fibers. Five patients showed heterozygous mutations of the MMACHC gene, including c.482G>A (5/5), c.609G>A (2/5), and c.658-660delAAG (3/5). Two patients showed heterozygous mutations of the MTHFR gene, including c.698C>A (2/2), c.698C>G (1/2), and c.236+1G>A (1/2). The patients responded well to the treatments with significant improvements. Adolescent/adult-onset remethylation disorders are easily misdiagnosed. We recommend testing the serum homocysteine concentrations in young/adult patients with unexplained neuro-psychotic symptoms. Furthermore, individuals with significantly elevated serum homocysteine concentrations should be further tested by organic acid screening and genetic analysis.