Alternative titles; symbols
SNOMEDCT: 763460007; ORPHA: 99014; DO: 0110210;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.3 | Charcot-Marie-Tooth disease, X-linked recessive, 5 | 311070 | X-linked recessive | 3 | PRPS1 | 311850 |
A number sign (#) is used with this entry because X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5) is caused by loss-of-function mutation in the PRPS1 gene (311850) on chromosome Xq22.
Loss-of-function PRPS1 mutations, resulting in decreased enzyme activity, can also cause Arts syndrome (ARTS; 301835) and X-linked deafness-1 (DFNX1; 304500). There is considerable phenotypic overlap between CMTX5, Arts syndrome, and DFNX1, as well as intrafamilial variability depending on gender, X-inactivation ratio, residual enzyme activity, and additional factors. Males tend to be more severely affected than females in all 3 disorders, although some females can show severe features. These disorders are best considered as representing a phenotypic spectrum (summary by Almoguera et al., 2014; Synofzik et al., 2014).
Another allelic disorder, PRPS-related gout (300661), results from increased PRPS1 enzyme activity. Some affected patients also have neurologic symptoms, including sensorineural deafness.
The phenotype of X-linked Charcot-Marie-Tooth disease-5 typically comprises the triad of optic atrophy, deafness, and polyneuropathy. However, patients without optic atrophy have been reported (summary by Park et al., 2013).
For a discussion of genetic heterogeneity of X-linked Charcot-Marie-Tooth disease, see CMTX1 (302800).
See 165199 and 258650 for possible autosomal dominant and autosomal recessive forms of the disorder.
Rosenberg and Chutorian (1967) reported 2 brothers with early-onset hearing loss, lower leg weakness and atrophy beginning in childhood, and progressive loss of vision beginning with optic atrophy at about age 20 years. The older brother had pes cavus, and both brothers required a cane for walking by age 15 years. As adults, both had severe distal weakness and atrophy in all extremities, with broad-based gait and atrophy of the intrinsic hand muscles. Deep tendon reflexes were absent in the legs, there was marked reduction of all sensory modalities below the elbows and knees. Nerve conduction was moderately reduced. Intellect was not affected. A 3.5-year-old nephew showed the same triad of features. Later evidence suggested that the mother, grandmother, and great-grandmother of the affected nephew may also have had slowly progressive hearing loss, suggesting X-linked semidominant inheritance (Pauli, 1984).
Pauli (1984) reported a family (family 'A') in which 3 males had infantile or congenital onset of bilateral sensorineural hearing loss and childhood-onset of peripheral neuropathy. There was slow progression, but the 2 older patients developed severe motor disability by ages 27 and 35 years. Two also had visual loss, 1 with optic atrophy. Five female family members had hearing loss.
Kim et al. (2005) reported a Korean family in which 6 males were affected with early-onset hearing loss, decreased visual acuity, and motor impairment in an X-linked recessive pattern of inheritance. Bilateral profound sensorineural hearing loss was present at an early age. The patients had onset of progressive weakness of the lower extremities and gait disturbances from ages 10 to 12 years. All developed bilateral progressive visual failure starting at 8 to 13 years. The proband had bilateral optic disc pallor and decreased visual evoked potentials, indicating optic nerve dysfunction. Obligate female carriers were unaffected. Kim et al. (2005) noted that the phenotype resembled that reported by Rosenberg and Chutorian (1967).
Clinical Variability
Park et al. (2013) reported a 17-year-old Korean boy with hearing loss since infancy and gait abnormalities with frequent falls since age 6 years. Neurologic examination showed distal muscle weakness and atrophy, which was more prominent in the lower limbs, and distal sensory impairment. Deep tendon reflexes were absent in all extremities. Electrophysiologic studies showed a sensorimotor peripheral neuropathy, and EMG suggested a neurogenic process. Laboratory studies showed mildly increased serum creatine kinase, but normal uric acid. The patient had cochlear surgery and began using a hearing aid. He had no visual abnormalities. Family history revealed 2 maternally related male relatives with a similar disorder beginning in childhood; 1 became wheelchair-bound at age 40. Both also had hearing loss but normal vision. The findings in this family expanded the phenotypic spectrum of CMTX5.
Almoguera et al. (2014) reported 4 females from a 3-generation Spanish family with variable manifestations of a complex neurologic disorder resulting from PRPS1 deficiency. The proband, who was the most severely affected, had progressive visual loss due to optic atrophy, retinitis pigmentosa, macular atrophy beginning at age 4 years, congenital nystagmus, mild developmental delay, and hypotonia. She developed hearing impairment at age 21 years, and peripheral neuropathy as a young adult. Other features included cataracts, pes cavus, ataxia, and cerebellar atrophy. Some of these features were reminiscent of Arts syndrome. The patient's sister and mother had similar but less severe features with later onset. The sister developed optic atrophy at age 16 and retinitis pigmentosa at age 23; the mother developed both at age 47. The sister did not have hearing impairment or peripheral neuropathy, but the mother developed hearing loss at age 50 and peripheral neuropathy and ataxia at age 55. All 3 patients had essential tremor. Erythrocyte PRPS1 activity was severely decreased in the proband, moderately decreased in the sister, and mildly decreased in the mother. A deceased female relative also had retinitis pigmentosa and ataxia, but additional clinical details were unavailable. The findings indicated that females can show severe or intermediate manifestations of PRPS1 deficiency, even early in life, and that there is intrafamilial variability.
Robusto et al. (2015) reported 2 unrelated families with a mild form of CMTX5. Both families were ascertained from a teenaged male proband with sensorineural hearing loss. Subsequent neurologic evaluation of mutation-carrying family members showed signs of a subclinical peripheral neuropathy that differed between males and females. Female mutation carriers showed subclinical signs, such as pes cavus, reduced or absent deep tendon reflexes, and chronic denervation in distal muscles of lower limbs. Male mutation carriers showed more evident findings of neuropathy, although these features were mainly sensory, such as absent deep tendon reflexes, paresthesias, and cramps. EMG showed chronic denervation in most male and female patients, whereas only males showed mild/moderate axonal neuropathy. The neurologic phenotype in 1 family was consistent with an axonal sensorimotor neuropathy, whereas that in the other family was predominantly a motor neuropathy. All patients, both male and female, also had hearing loss, except for 1 female who had only peripheral neuropathy. The findings expanded the phenotype associated with PRPS1 loss-of-function mutations, which can result in a continuous spectrum of clinical feature that vary even within a family.
By X-chromosome-wide linkage analysis of a Korean family, Kim et al. (2005) identified a 15.2-cM candidate disease locus, termed CMTX5, on chromosome Xq21.32-q24 between markers DXS990 and DXS8067 (maximum lod score of 3.62 at DXS8077). The locus did not overlap with CMTX1, CMTX2 (302801), CMTX3 (302802), or Cowchock syndrome (CMTX4; 310490).
In affected members of the families reported by Rosenberg and Chutorian (1967) and Kim et al. (2005), Kim et al. (2007) identified 2 different mutations in the PRPS1 gene (311850.0009 and 311850.0010, respectively). The mutations were shown to result in decreased enzyme activity; none of the affected individuals had increased uric acid or gout. Kim et al. (2007) noted that both PRPS1 superactivity and CMTX5 phenotypes share neurologic features.
In a young Korean man with CMTX5 with early-onset sensorineural deafness but without optic atrophy, Park et al. (2013) identified a hemizygous missense mutation in the PRPS1 gene (A121G; 311850.0018) inherited from his unaffected mother. The mutation was found by whole-exome sequencing.
In 4 females from a 3-generation Spanish family with variable manifestations of CMTX5, Almoguera et al. (2014) identified a heterozygous missense mutation in the PRPS1 gene (S16P; 311850.0020). Erythrocyte PRPS1 activity from 3 affected females showed variably decreased levels, which correlated with the age at onset. The proband (IV-3), who was the most severely affected, had significantly skewed X inactivation (82%) of the paternal allele and showed lack of expression of the wildtype allele in lymphocyte mRNA. The proband's sister and mother, who carried the mutation but were less severely affected clinically, did not show significantly skewed X-inactivation.
In affected members of 2 unrelated families with variable manifestations of CMTX5, Robusto et al. (2015) identified different missense mutations in the PRPS1 gene (M115V, 311850.0022 and V309F, 311850.0023). The 2 probands were ascertained from a cohort of 16 unrelated male probands with X-linked familial hearing loss who underwent sequencing of the PRPS1 gene. The mutations resulted in a greater than 60% reduction in PRPS1 activity compared to controls, with greater reductions in male compared to female carriers.
Almoguera, B., He, S., Corton, M., Fernandez-San Jose, P., Blanco-Kelly, F., Lopez-Molina, M. I., Garcia-Sandoval, B., del Val, J., Guo, Y., Tian, L., Liu, X., Guan, L., Torres, R. J., Puig, J. G., Hakonarson, H., Xu, X., Keating, B., Ayuso, C. Expanding the phenotype of PRPS1 syndromes in females: neuropathy, hearing loss and retinopathy. Orphanet J. Rare Dis. 9: 190, 2014. Note: Electronic Article. [PubMed: 25491489] [Full Text: https://doi.org/10.1186/s13023-014-0190-9]
Kim, H.-J., Hong, S. H., Ki, C.-S., Kim, B.-J., Shim, J.-S., Cho, S.-H., Park, J.-H., Kim, J.-W. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology 64: 1964-1967, 2005. [PubMed: 15955956] [Full Text: https://doi.org/10.1212/01.WNL.0000163768.58168.3A]
Kim, H.-J., Sohn, K.-M., Shy, M. E., Krajewski, K. M., Hwang, M., Park, J.-H., Jang, S.-Y., Won, H.-H., Choi, B.-O., Hong, S. H., Kim, B.-J., Suh, Y.-L., Ki, C.-S., Lee, S.-Y., Kim, S.-H., Kim, J.-W. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (CMT5X). Am. J. Hum. Genet. 81: 552-558, 2007. [PubMed: 17701900] [Full Text: https://doi.org/10.1086/519529]
Park, J., Hyun, Y. S., Kim, Y. J., Nam, S. H., Kim, S., Hong, Y. B., Park, J.-M., Chung, K. W., Choi, B.-O. Exome sequencing reveals a novel PRPS1 mutation in a family with CMTX5 without optic atrophy. J. Clin. Neurol. 9: 283-288, 2013. [PubMed: 24285972] [Full Text: https://doi.org/10.3988/jcn.2013.9.4.283]
Pauli, R. M. Sensorineural deafness and peripheral neuropathy. (Letter) Clin. Genet. 26: 383-384, 1984. [PubMed: 6094052] [Full Text: https://doi.org/10.1111/j.1399-0004.1984.tb01076.x]
Robusto, M., Fang, M., Asselta, R., Castorina, P., Previtali, S. C., Caccia, S., Benzoni, E., De Cristofaro, R., Yu, C., Cesarani, A., Liu, X., Li, W., Primignani, P., Ambrosetti, U., Xu, X., Duga, S., Solda, G. The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy. Europ. J. Hum. Genet. 23: 766-773, 2015. [PubMed: 25182139] [Full Text: https://doi.org/10.1038/ejhg.2014.168]
Rosenberg, R. N., Chutorian, A. Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology 17: 827-832, 1967. [PubMed: 6069085] [Full Text: https://doi.org/10.1212/wnl.17.9.827]
Synofzik, M., Muller vom Hagen, J., Haack, T. B., Wilhelm, C., Lindig, T., Beck-Wodl, S., Nabuurs, S. B., van Kuilenburg, A. B. P., de Brouwer, A. P. M., Schols, L. 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. Orphanet J. Rare Dis. 9: 24, 2014. Note: Electronic Article. [PubMed: 24528855] [Full Text: https://doi.org/10.1186/1750-1172-9-24]