title: X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation.
abstract: 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.
authors: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.
authors: Matthis
authors: M
authors: Synofzik
authors: Jennifer
authors: J
authors: Müller vom Hagen
authors: Tobias B
authors: TB
authors: Haack
authors: Christian
authors: C
authors: Wilhelm
authors: Tobias
authors: T
authors: Lindig
authors: Stefanie
authors: S
authors: Beck-Wödl
authors: Sander B
authors: SB
authors: Nabuurs
authors: André B P
authors: AB
authors: van Kuilenburg
authors: Arjan P M
authors: AP
authors: de Brouwer
authors: Ludger
authors: L
authors: Schöls
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D054062:Deaf-Blind Disorders / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012268:Ribose-Phosphate Pyrophosphokinase / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase