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

Written informed consent was obtained from the patients for the publication of this report and any accompanying images.

A 36 year-old male patient from non-consanguineous German parents (subject II-2; for pedigree, see Figure 1A; for clinical details see Table 1) presented with prelingual hearing loss since birth, recurrent severe infections from age 6 to 8 years with subsequent partially remitting bulbar paresis and flaccid tetraparesis which never fully resolved, and progressive visual loss due to optic atrophy since age 12 years (current vision at age 36 years: 0.1 right eye, 0.3 left eye). Gait and trunk ataxia started at age 30, leading to a dependency on a walking-frame at age 34 years. Disease severity on the Scale for the Assessment and Rating of Ataxia (SARA) yielded 14 out of 40 points [14]. Behavioural and mental disturbances started at age 16 years, yet the patient was still able to finish secondary school. Already at this time, the patient showed a severely reduced attention span, mental rigidity, low frustration tolerance and aggression to persons including family members. He was unable to perceive and describe his own physical problems during medical visits, rejected social contacts, and neglected the need for medical and rehabilitative treatment. In the following years, he developed attacks of verbal and physical aggression, e.g. repeatedly pulling his mother down to the floor by her hairs at age 35 years. Cycles of aggressive and impulsive behaviour alternated rapidly with cycles of infantile-regressive behaviour, e.g. shouting and crying at age 35 years when confronted with the need for a medical blood sampling. The lack of compliance and cooperative behaviour led to the cessation of examinations required for pre-surgery evaluation for cochlea implants. His cognitive capacities and insight at age 36 years seemed to be below the stage of an adolescent, but no formal neuropsychological testing was possible given his severe hearing and visual impairments and lack of cooperative behaviour. The combined load of physical, mental and behavioural disturbances required an institutionalization in long-term care since age 35 years. Cerebral MRI demonstrated mild cerebellar and parietal cortical atrophy (Figure 2A,B). Nerve conduction studies showed florid predominant axonal sensorimotor neuropathy (Table 1) with positive sharp waves on EMG of the tibial anterior muscle. Repeated lab testing revealed markedly increased serum creatinkinase (>1000 U/l, ref < 190 U/l), probably caused by progressive muscle cell turnover due to florid peripheral neuropathy. In addition, liver transaminases were constantly mildly elevated (AST 60 U/l; ref <50 U/l; ALT 90 U/l; ref < 50 U/l), with abdominal sonography showing no structural liver abnormalities.

His sister (subject II-1; Figure 1A) had developed prelingual sensorineural hearing loss in the first years of life, without any further signs of neurological dysfunction at current age of 42 years. This phenotype is fully compatible with the diagnosis of X-linked non-syndromic sensorineural hearing loss (DFN2) [5]. Her MRI showed discrete parietal and cerebellar atrophy as well (Figure 2C,D). The mother of the two subjects (subject I-1) did not show any hearing deficit or neurological dysfunction at the current age of 66 years. Uric acid in serum was normal in all three subjects (for an overview of all clinical and lab details, see Table 1).

Based on the initial clinical assumption of an autosomal-recessive ataxia, the index patient was assessed by extensive serum testing for biomarkers indicative of recessive ataxias (alpha-feto protein, lactate, vitamin E, very long chain fatty acids, phytanic acid, coeruloplasmin, cholesteanol, lysosomal enzymes, carbohydrate-deficient transferrin, quantitative assessment of amino acids) [15], and genetic testing of FRDA, POLG, PEO1/Twinkle, WFS1, and ABHD12. All results were normal. Sequencing of PRPS1 revealed a novel hemizygous c.830A > C, p.Gln277Pro variant changing a highly conserved amino acid residue (PhyloP score 4.6; Figure 1C), predicted to be damaging by all in silico predictions (PolyPhen-2 score: 0.991; SIFT score: 0.01; MutationTaster: disease causing), and not found in 4,200 ethnically-matched control X-chromosomes or in the 6,500 exomes (= 10,562 alleles) of the NHLBI Exome Variant Server (EVS). The same variant was identified in the sister (II-1) and the mother (I-1) of the index patient in a heterozygous state (for electropherograms, see Additional file 3).

Gln277 is located in the C-terminal domain of PRPS1 and is close to the catalytic active site, which consists of an ATP binding site and a ribose-5-P binding site (Figure 1D). The p.Gln277Pro change results in two sequential prolines, which very likely disrupts the alpha-helical structure of this short helical segment and destabilizes the C-terminal PRPS1 domain. In addition, Gln277 interacts with Gly251, which is close proximity to the R5P binding site (Figure 1E). The p.Gln277Pro change will result in a loss of this hydrogen bonding interaction potentially destabilizing the region surrounding the ribose-5-P binding site, thus affecting the PRPS1 catalytic active site. When comparing the protein structural effects of all known PRPS1 mutations and their relations to PRPS1-phenotypic clusters, the p.Gln277Pro (Q277P) mutation falls in between CMTX5 and Arts syndrome PRPS1 mutations. Like other Arts syndrome mutations (and in contrast to CMTX5 PRPS1 mutations), it is predicted to disrupt the local PRS-I structure. However, unlike the other Arts syndrome mutations and in line with the CMTX PRPS1 mutations, it is not predicted to disturb the allosteric site II or to affect the dimer interface (Table 2).

PRS-I activity was not detectable in erythrocytes the index patient II-2 (<0.005 nmol/[min.mg protein]; reference value: 0.41-1.46 nmol/[min.mg protein]), reduced to 0.10 nmol/[min.mg protein] in his sister (II-1), and normal in their mother (I-1; 1.04 nmol/[min.mg protein]) (Figure 1B).

XCI was extremely skewed (defined as ratio > 90%:10% [16]) in II-1 (94%:6%), but only moderately skewed in I-1 (80%:20%).