Clinical characteristics.

X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by peripheral neuropathy, early-onset (prelingual) bilateral profound sensorineural hearing loss, and optic neuropathy. The onset of peripheral neuropathy is between ages five and 12 years. The lower extremities are affected earlier and more severely than upper extremities. Initial manifestations often include foot drop or gait disturbance. Onset of visual impairment is between ages seven and 20 years. Intellect and life span are normal. Carrier females do not have findings of CMTX5.

Diagnosis/testing.

Diagnosis is based on clinical findings, family history consistent with X-linked inheritance, and identification of a pathogenic variant in PRPS1, the only gene in which pathogenic variants are known to cause CMTX5.

Management.

Treatment of manifestations: Peripheral neuropathy, hearing loss, and visual impairment are managed in a routine manner.

Surveillance: Regular neurologic and ophthalmologic evaluations to monitor symptom development and disease progression.

Agents/circumstances to avoid: Medications known to cause acquired peripheral neuropathy.

Evaluation of relatives at risk: It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss.

Genetic counseling.

CMTX5 is inherited in an X-linked manner. Carrier women have a 50% chance of transmitting the PRPS1 pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and typically will not be affected. Males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variant has been identified in the family.

Clinical Diagnosis

X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by the following:

Peripheral neuropathy

• Motor nerve conduction velocities (NCVs) of affected males reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy.
• Compound motor/sensory action potentials are not induced.
• Needle electromyography (EMG) reveals polyphasic potentials with a prolonged duration and reduced recruitment pattern.

Early-onset sensorineural hearing loss

• Pure tone audiograms demonstrate bilateral profound sensorineural hearing loss.
• Auditory brain stem response waveforms may not be obtained.
• Temporal bone computed tomography reveals no abnormal findings.

Optic neuropathy

• Fundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy.
• Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100.
• Electroretinogram is normal.

Testing

Phosphoribosylpyrophosphate synthetase (PRS) enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [Torres et al 1996].

PRS enzyme activity in three individuals with CMTX5 was decreased compared to controls [Kim et al 2007].

Note: Because it is difficult to assay PRS1 enzyme activity separately from that of the other two isoforms (PRS2 and PRS3), decrease in PRS enzyme activity is assumed to reflect decreased activity of PRS1, not PRS2 or PRS3.

Serum uric acid concentrations measured in three individuals with CMTX5 of Korean descent and two of European descent (originally reported as having Rosenberg-Chutorian syndrome) were within the normal range [Kim et al 2007].

Testing Strategy

To confirm/establish the diagnosis in a proband, identification of a pathogenic variant in PRPS1 is necessary.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and are not known to be at risk of developing clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the pathogenic variant in an affected male relative or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis and then, if no pathogenic variant is identified, by deletion/duplication analysis.

Prenatal diagnosis and preimplantation genetic testing for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Description

The symptom triad of CMTX5 is peripheral neuropathy, sensorineural hearing loss, and optic neuropathy.

The age at onset of symptoms of peripheral neuropathy ranges from five to 12 years. The initial manifestation is often foot drop or gait disturbance. Deep tendon reflexes are usually absent. Motor signs predominate, but impairment of sensory function may accompany motor dysfunction or develop during disease progression. Lower extremities are affected earlier and more severely than upper extremities.

Typically, boys with CMTX5 have early-onset (prelingual) sensorineural hearing loss.

The age at onset of visual impairment ranged from seven to 20 years.

Affected individuals have normal intellect.

Both peripheral neuropathy and optic neuropathy progress with time. With advancing disease, affected individuals may become dependent on crutches or a wheelchair. There is no evidence that life span is shortened in individuals with CMTX5 [Rosenberg & Chutorian 1967, Kim et al 2007].

Carrier females do not have findings of CMTX5.

Sural nerve biopsy demonstrates demyelination and axonal loss. Electron microscopic examination reveals onion bulb formation [Kim et al 2007].

Genotype-Phenotype Correlations

Across the four disease phenotypes included as PRPS1-related disorders, only pathogenic missense variants have been reported to date. No correlation between specific PRPS1 pathogenic missense variants and phenotype is known.

Penetrance

Penetrance is complete for CMTX5.

Prevalence

Prevalence has not been estimated. Two families with CMTX5 have been identified worldwide [Rosenberg & Chutorian 1967, Kim et al 2007].

CMTX5 appears to be very rare; however, it may be underdiagnosed as a result of under-recognition by physicians.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CMTX5, the following evaluations are recommended:

• Neurologic examination
• Pure tone audiograms, auditory brain stem response test
• Evaluation of visual acuity, fundoscopic examination
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Peripheral neuropathy. See Charcot-Marie-Tooth Hereditary Neuropathy Overview, Management.

Sensorineural hearing loss. See Deafness and Hereditary Hearing Loss Overview, Management.

Optic atrophy. Use of routine low-vision aids as needed is appropriate.

Prevention of Secondary Complications

Daily heel cord stretching exercises are desirable to prevent Achilles’ tendon shortening from peripheral neuropathy, which can occur in individuals with CMTX5.

Surveillance

Individuals should be evaluated regularly by a team comprising otologists, ophthalmologists, neurologists, physiatrists, and physical and occupational therapists to determine neurologic status and functional disability. While profound hearing loss begins during infancy, optic neuropathy and peripheral neuropathy in CMTX5 vary in age of onset of manifestations and progression. Thus, regular ophthalmologic and neurologic exams are warranted to monitor symptom development and progression.

Agents/Circumstances to Avoid

Obesity makes walking more difficult.

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list.

Evaluation of Relatives at Risk

It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Dietary S-adenosylmethionine (SAM) supplementation could theoretically alleviate some of the symptoms of Arts syndrome by providing an oral source of purine nucleotide precursor that is not PRPP dependent. Furthermore, SAM is known to cross the blood-brain barrier. An adult with HPRT deficiency is reported to have benefitted neurologically from SAM administration without untoward side effects [Glick 2006].

An open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome is continuing [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia]. Oral SAM supplementation is presently set at 30 mg/kg/day. The boys appear to have had significant benefit from this therapy based on decreased number of hospitalizations and stabilization of nocturnal BIPAP requirements; however, slight deterioration in their vision has been noted.

Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Whether treatment with SAM supplementation would benefit individuals with allelic disorders (PRS superactivity, Charcot-Marie-Tooth neuropathy X type 5) remains to be investigated.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

CMTX5 is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier:
  • A mother who is a carrier may have a de novo pathogenic variant or may have inherited the pathogenic variant from either her mother or her father.
  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo pathogenic variant in PRPS1, in which case his mother is not a carrier. The frequency of de novo pathogenic variants is not known.
  • His mother has a de novo pathogenic variant in PRPS1, either (a) as a "germline variant" (i.e., present at the time of her conception and therefore in every cell of her body) or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
  • His mother has a pathogenic variant that she inherited from a maternal female ancestor.

Sibs of the proband

• The risk to the sibs of a proband depends on the genetic status of the parents:
  • If the mother has a pathogenic variant, the chance of transmitting the PRPS1 pathogenic variant in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and typically will not be affected.
  • If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• No instances of germline mosaicism have been reported, but it remains a possibility.

Offspring of a male proband. Males pass the pathogenic variant to all of their daughters and none of their sons.

Other family members of the proband. If the mother of a proband also has a pathogenic variant, her female family members may be at risk of being carriers and her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Carrier Detection

Carrier testing is possible if the pathogenic variant has been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Revision History

• 8 June 2023 (ma) Chapter retired: covered in Phosphoribosylpyrophosphate Synthetase Deficiency
• 6 June 2013 (me) Comprehensive update posted live
• 18 January 2011 (cd) Revision: additions to therapies under investigation
• 23 September 2010 (cd) Revision: prenatal testing available clinically
• 10 June 2010 (cd) Revision: edits to agents and circumstances to avoid
• 26 August 2008 (cg) Review posted live
• 3 June 2008 (jwk) Original submission

Literature Cited

• Becker MA. Phosphoribosylpyrophosphate synthetase and the regulation of phosphoribosylpyrophosphate production in human cells. Prog Nucleic Acid Res Mol Biol. 2001;69:115–48. [PubMed: 11550793]
• Cowchock FS, Duckett SW, Streletz LJ, Graziani LJ, Jackson LG. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet. 1985;20:307–15. [PubMed: 3856385]
• de Brouwer AP, Williams KL, Duley JA, van Kuilenburg AB, Nabuurs SB, Egmont-Petersen M, Lugtenberg D, Zoetekouw L, Banning MJ, Roeffen M, Hamel BC, Weaving L, Ouvrier RA, Donald JA, Wevers RA, Christodoulou J, van Bokhoven H. Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet. 2007;81:507–18. [PMC free article: PMC1950830] [PubMed: 17701896]
• Glick N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis. 2006;29:687. [PubMed: 16906475]
• Huttner IG, Kennerson ML, Reddel SW, Radovanovic D, Nicholson GA. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology. 2006;67:2016–21. [PubMed: 17159110]
• Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C. Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet. 1991;48:1075–83. [PMC free article: PMC1683112] [PubMed: 1674639]
• Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve. 1992;15:368–73. [PubMed: 1557086]
• Kennerson ML, Yiu EM, Chuang DT, Kidambi A, Tso SC, Ly C, Chaudhry R, Drew AP, Rance G, Delatycki MB, Züchner S, Ryan MM, Nicholson GA. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet. 2013;22:1404–16. [PMC free article: PMC3596851] [PubMed: 23297365]
• Kim HJ, Hong SH, Ki CS, Kim BJ, Shim JS, Cho SH, Park JH, Kim JW. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology. 2005;64:1964–7. [PubMed: 15955956]
• Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY, Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim JW. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). Am J Hum Genet. 2007;81:552–8. [PMC free article: PMC1950833] [PubMed: 17701900]
• Liu X, Han D, Li J, Han B, Ouyang X, Cheng J, Li X, Jin Z, Wang Y, Bitner-Glindzicz M, Kong X, Xu H, Kantardzhieva A, Eavey RD, Seidman CE, Seidman JG, Du LL, Chen ZY, Dai P, Teng M, Yan D, Yuan H. Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2. Am J Hum Genet. 2010;86:65–71. [PMC free article: PMC2801751] [PubMed: 20021999]
• Priest JM, Fischbeck KH, Nouri N, Keats BJ. A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26. Genomics. 1995;29:409–12. [PubMed: 8666389]
• Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2012;91:1095–102. [PMC free article: PMC3516602] [PubMed: 23217327]
• Rosenberg RN, Chutorian A. Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology. 1967;17:827–32. [PubMed: 6069085]
• Torres RJ, Mateos FA, Puig JG, Becker MA. Determination of phosphoribosylpyrophosphate synthetase activity in human cells by a non-isotopic, one step method. Clin Chim Acta. 1996;245:105–12. [PubMed: 8646809]