Discinesia paroxística cinesigénica familiar: descripción de una familia / Familial paroxysmal kinesigenic dyskinesia. A case description

Las discinesias paroxísticas son trastornos del movimiento caracterizadas por episodios repentinos de movimientos involuntarios. Se dividen en cinesigénicas, no cinesigénicas e inducidas por el ejercicio. Los autores enfatizan la importancia de la historia clínica y de la descripción de los episodios en el diagnóstico diferencial. Adolescente de 12 años con episodios de torsión de la lengua y posturas distónicas de las extremidades superiores desencadenados por movimientos súbitos como empezar a correr o bajar escaleras y al comienzo del ejercicio, cesando espontáneamente segundos después. Algunos episodios eran desencadenados por el estrés. En la historia familiar, el padre, tío paterno y hermana también presentaban episodios paroxísticos. El examen neurológico intercrítico fue normal. Se identificó una mutación en el gen PRRT2 asociado con trastornos neurológicos como discinesia paroxística cinesigénica, convulsiones infantiles con coreoatetosis, migraña, ataxia episódica, tortícolis paroxística y retraso cognitivo. El tratamiento con carbamacepina fue eficaz

Paroxysmal dyskinesias are movement disorders characterized by sudden episodes of involuntary movements. They are divided into kinesigenic, non-kinesigenic, and exerciseinduced dyskinesias. Emphasis is made on the importance of the clinical history and fully describing the episodes in the differential diagnosis. The case is presented of a twelve year-old female with paroxysmal episodes of tongue torsion and dystonic postures of the upper limbs when start running or descending stairs and in the beginning of physical exercise, which ceased spontaneously seconds later. Some episodes were triggered by stress. In family history her father, paternal uncle, and sister also had paroxysmal movements. Interictal neurological examination was normal. Laboratory tests revealed a mutation in PRRT2 gene, which is related to neurological disorders such as paroxysmal kinesigenic dyskinesia, infantile convulsions and choreoathetosis migraine, episodic ataxia, paroxysmal torticollis, and intellectual disability. Treatment with carbamazepine was effective

Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress.

CONTEXT: We studied two sisters with congenital hypothyroidism and choreoathetosis but not respiratory distress. OBJECTIVE: The aim of this study was to establish the genetic defect that causes this phenotype and study the molecular mechanisms of the pathology by means of functional analysis. DESIGN: Sequencing of DNA, expression vectors generation, EMSAs, transfections experiments as well as bioinformatics analysis were performed. RESULTS: We found a new single deletion (825delC) in one allele of the TITF1/NKX2.1 gene. The mutation located in the C-terminal domain generates a nonsense thyroid transcription factor 1 (TTF1) protein, with 22 amino less and rich in positive charges. This protein shows diminished binding to DNA, does not interfere with wild-type (wt) TTF1 binding, and fails to activate reporter genes harboring the thyroglobulin (Tg), thyroperoxidase (TPO), or surfactant protein B (SP-B) promoters. In addition, the mutant (mut) protein has a dominant-negative effect on the transcriptional activity of wt TTF1 in a promoter-specific manner, inhibiting the transcription of Tg and TPO but not of SP-B. Using a Gal4 reporter system, we demonstrate that the mut protein is not transcriptionally active and does not likely compete with the wild type for coactivators. Interestingly, the mut protein impairs the wt capacity to synergize with paired box 8 (PAX8). This cooperation is necessary for Tg and TPO transcription but dispensable for SP-B expression. CONCLUSION: These results are concordant with the phenotype of the two sisters studied and demonstrate a differential role for TTF1 in the different tissues in which it is expressed.