BACKGROUND: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, 
and non-syndromic sensorineural deafness (DFN2) are allelic syndromes, caused by 
reduced activity of phosphoribosylpyrophosphate synthetase 1 (PRS-I) due to 
loss-of-function mutations in PRPS1. As only few families have been described, 
knowledge about the relation between these syndromes, the phenotypic spectrum in 
patients and female carriers, and the relation to underlying PRS-I activity is 
limited.
METHODS: We investigated a family with a novel PRPS1 mutation (c.830A > C, 
p.Gln277Pro) by extensive phenotyping, MRI, and genetic and enzymatic tests.
RESULTS: The male index subject presented with an overlap of CMTX5 and Arts 
syndrome features, whereas his sister presented with prelingual DFN2. Both 
showed mild parietal and cerebellar atrophy on MRI. Enzymatically, PRS-I 
activity was undetectable in the index subject, reduced in his less affected 
sister, and normal in his unaffected mother.
CONCLUSIONS: Our findings demonstrate that CMTX5, Arts syndrome and DFN2 are 
phenotypic clusters on an intrafamilial continuum, including overlapping 
phenotypes even within individuals. The respective phenotypic presentation seems 
to be determined by the exact PRPS1 mutation and the residual enzyme activity, 
the latter being largely influenced by the degree of skewed X-inactivation. 
Finally, our findings show that brain atrophy might be more common in 
PRPS1-disorders than previously thought.