X-linked paroxysmal dyskinesia and severe global retardation caused by defective thyroid hormone transporter MCT8

Background: Paroxysmal dyskinesias (PxD) are rare movement disorders that occur in brief episodes and may comprise any combination of dystonia, ballism, chorea, or athetosis. Few disease genes have been mapped by linkage analysis, but until recently, a definite gene causing the defect has not yet been demonstrated in any of the PxD subtypes.

Patient: Two unrelated patients, an 8-year-old German boy and a 3-year-old Canadian boy, showed severe motor and mental retardation and marked muscular hypotonia. In their second year of life they developed a peculiar movement disorder with paroxysms of dystonic version of the head and stretching of the left or right arm and leg provoked by certain manipulations, e.g. changing of the diapers or clothing.

Results: Thyroid hormone values showed an uncommon pattern (from 17 months onwards in patient 1, from neonatal age in patient 2) with low T4, elevated T3, low reverse T3 and elevated TSH. The similar though milder thyroid pattern was found in their mothers, who showed no neurological abnormalities. Recent characterization of the monocarboxylate transporter MCT8, encoded by XPCT on Xq13.2, as a specific thyroid hormone transporter prompted examination of this gene. A missense mutation Leu512Pro was detected in patient 1 and his mother, a single nucleotide deletion in exon 3 was found in patient 2 and his mother.

Conclusion: For the first time, a genetic defect causing PxD is identified. Characteristic clinical features and specific thyroid hormone pattern with elevated T3 will allow for identification of further patients with a deficiency of the thyroid hormone transporter MCT8.