Rett syndrome, classical and atypical: genealogical support for common origin.

AIMS OF THE STUDY By using genealogical methods in atypical females with Rett syndrome (RS) we looked for support for the assumption that atypical RS cases are true variants of classical RS. SUBJECTS We selected from the Swedish national RS series the "milder" RS cases, 10 years of age and older, fulfilling the criteria for the "forme fruste" (FF) type of RS. For 32 FF cases we were able to carry out complete genealogical analyses on 61 parental lines. The pedigrees contained details of about 3200 ancestors. COMMON GEOGRAPHICAL ORIGINS: Eleven (34%) of the FF females could be traced to a previously defined "Rett area" and no fewer than six females had their origin in the same homestead as another previously examined classical RS patient. ANCESTRY: In four pedigrees, two each contained one FF and two classical RS and two each contained one FF and one classical RS, all 10 being descendants of the same four couples who lived several generations ago. CONSANGUINITY: Consanguinity in four grandparents (6.6% (SD 3.2%)) is probably a higher frequency than in the average Swedish population and supported our findings from a series of classical RS. TRANSMISSION The data indicate that transmission starts with a premutation that over generations can result in a full mutation giving rise to RS. Both the X chromosomes and a pair of autosomes may be involved. CONCLUSION Many, or most, atypical FF cases are true variants of RS.