Clinical Diagnosis

X-linked Charcot-Marie-Tooth disease 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]. Such testing is available on a research basis only.

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].

Molecular Genetic Testing

Gene. PRPS1, encoding phosphoribosyl pyrophosphate synthetase I, is the only gene known to be associated with CMTX5.

Clinical testing

• Sequence analysis. Sequencing of the seven exons of the open reading frame (ORF) of PRPS1 detected a point mutation in both of the families known to have CMTX5 [Kim et al 2007].

Table 1. Summary of Molecular Genetic Testing Used in CMTX5

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PRPS1	Sequence analysis	Point mutations	100% 2	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Two families reported to date [Kim et al 2007]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a proband, identification of a disease-causing mutation in PRPS1 is necessary.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation 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 prior identification of the disease-causing mutation in an affected male relative.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The spectrum of PRPS1-related disorders includes three phenotypes, CMTX5, PRS superactivity, and Arts syndrome, previously thought to be distinct entities (see Table 2).

PRS superactivity phenotype can be divided into a severe and a mild phenotype.

The severe phenotype is characterized by infantile- or early-childhood-onset hyperuricemia and hyperuricosuria resulting in gouty arthritis that is usually accompanied by a variable combination of intellectual disability, sensorineural hearing loss, hypotonia, and ataxia [Nyhan et al 1969, Simmonds et al 1982, Becker et al 1988, Christen et al 1992]. Carrier females in families with the severe form of PRS superactivity can also show one or more of these features [Simmonds et al 1982, Christen et al 1992].

The milder phenotype is characterized by late-juvenile- or early-adult-onset hyperuricemia and hyperuricosuria. Obvious neurologic findings are not present [Sperling et al 1972, Becker et al 1973].

Arts syndrome is characterized by intellectual disability, early-onset hypotonia, ataxia, delayed motor development, profound congenital sensorineural hearing loss, and optic atrophy [Arts et al 1993, de Brouwer et al 2007]. Susceptibility to infections of especially the upper-respiratory tract often results in early death. Carrier females can show isolated and milder manifestations including hearing impairment, ataxia, hypotonia, and hyperreflexia.

Natural History

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

No correlation is known between specific PRPS1 point mutations and the three phenotypes in the PRPS1-related disorders.

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 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

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.

Surveillance

Regular neurologic and ophthalmologic evaluations to monitor disease progression are appropriate.

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications which are toxic or potentially toxic to persons with CMT comprise a range of risks including:

• Definite high risk. Vinca alkaloids (Vincristine)
  • This category should be avoided by all persons with CMT, including those who are asymptomatic
• Other potential risk levels. See Table 3. For more information, click here (pdf).

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 has been reported as benefiting 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 for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 gene mutation or may have inherited the disease-causing mutation 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 mutation.
• 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 disease-causing mutation in PRPS1, in which case his mother is not a carrier. The frequency of de novo mutations is not known.
  • His mother has a de novo disease-causing mutation in PRPS1, either (a) as a "germline mutation" (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 disease-causing mutation 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 disease-causing mutation, the chance of transmitting the PRPS1 mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and typically will not be affected.
  • If the disease-causing mutation 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 disease-causing mutation 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 disease-causing mutation, 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 mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified before prenatal testing can be performed. Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 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