Patterns of Penetrance and Expressivity of Long‐Term Outcomes in Classic Galactosemia

Long-term complications are common among patients with classic galactosemia (CG) and show both reduced penetrance and variable expressivity. Overall prevalence rates for complications in cognitive, motor, and speech/voice/language outcomes among US and European cohorts are known. However, age at presentation, whether these complications cluster, and what factors might associate with penetrance remain unknown. These gaps in knowledge limit prognostic accuracy for young patients and leave open the question of whether complications in different outcome domains may have shared modifiers. Here we addressed these questions using data from medical records and family survey responses from 164 patients and 77 controls. We found that for cases who experienced long-term complications, the median age at presentation of challenges in cognitive outcome was about 5 years, in motor outcome was about 3 years, and in speech/voice/language outcome was about 2 years. We also found highly significant clustering of complications in these three domains. Finally, we tested six factors for possible association with penetrance: history of severe neonatal symptoms, GALT genotype and predicted residual GALT activity, days of neonatal milk exposure, rigor of non-dairy galactose restriction in early childhood, peak red blood cell (RBC) galactose-1P level in infancy, and baseline RBC galactose-1P level in early childhood. Of these, only history of severe neonatal brain-related symptoms consistently associated with higher penetrance, and only detectable predicted residual GALT activity consistently associated with lower penetrance. Combined, these results substantially extend what is known about the natural history of long-term complications in CG.