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. 2014 Feb 14:9:24.
doi: 10.1186/1750-1172-9-24.

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

Matthis Synofzik  1 , Jennifer Müller vom Hagen, Tobias B Haack, Christian Wilhelm, Tobias Lindig, Stefanie Beck-Wödl, Sander B Nabuurs, André B P van Kuilenburg, Arjan P M de Brouwer, Ludger Schöls
Affiliations

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

Matthis Synofzik et al. Orphanet J Rare Dis. .

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.

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Figures

Figure 1
Figure 1
Pedigree, PRS enzymatic activity, conservation, and predicted protein structural effects of the novel Gln277Pro PRPS1 variant. (A) Pedigree of the family shows maternal inheritance of the PRPS1 mutation with variable phenotypic severity of disease, reaching from an unaffected state in the mother (I-1) to a mildly affected DFN2 phenotype in the sister of the index patient (II-1) to a severe Arts/CMTX5 overlap syndrome in the index patient (II-2). (B) The severity of the phenotype correlated with the PRS1 enzymatic activity in erythrocytes. (C) Protein alignment demonstrates high conservation for the mutated amino acid position 277 in the PRPS1 protein across mammals and non-mammals. (D) PRS1 catalyses the synthesis of phosphoribosylpyrophosphate (PRPP) from ribose 5-phosphate (R5P) and ATP, and is thought to be physiologically functional as a hexamer, consisting of three homodimers arranged in a propeller-like shape. In this hexamer, the N-terminal domains are located at the centre and the C-terminal domains at the outside. (E) Gln277 is predicted to interact with Gly251, which is close proximity to the R5P binding site The p.Gln277Pro change will result in a loss of this hydrogen bonding interaction potentially destabilizing the region surrounding the R5P binding site, thus affecting the PRPS1 catalytic active site.
Figure 2
Figure 2
Brain magnetic resonance imaging (MRI) of the two affected siblings. MRI shows diffuse parietal atrophy (arrows in A, C) and mild cerebellar atrophy (arrows in B, D) in the index patient II-2 at age 31 years (upper row) as well as in his sister II-1 at age 38 years (lower row) (A, C T1 axial; B, FLAIR coronar; D T2 axial).
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