The phenotype of X-linked Charcot-Marie-Tooth disease-5 comprises the triad of optic atrophy, deafness, and polyneuropathy. See 165199 and 258650 for possible autosomal dominant and autosomal recessive forms of the disorder.
For a discussion of genetic heterogeneity of ...The phenotype of X-linked Charcot-Marie-Tooth disease-5 comprises the triad of optic atrophy, deafness, and polyneuropathy. See 165199 and 258650 for possible autosomal dominant and autosomal recessive forms of the disorder. For a discussion of genetic heterogeneity of X-linked Charcot-Marie-Tooth disease, see CMTX1 (302800)
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, ...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)
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 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 CMT5X phenotypes share neurologic features
X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by the following:...
DiagnosisClinical DiagnosisX-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by the following:Peripheral neuropathyMotor 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 lossPure 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 neuropathyFundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy.Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100.Electroretinogram is normal.TestingPhosphoribosylpyrophosphate 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].Molecular Genetic TestingGene. PRPS1, encoding phosphoribosyl pyrophosphate synthetase I, is the only gene in which mutations are known to cause CMTX5.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in CMTX5View in own windowGene 1Test MethodMutations DetectedMutation Detection Frequency by Test Method 2Test AvailabilityPRPS1Sequence analysisSequence variants 3100% 4,5,6ClinicalDeletion/duplication analysis 7Exonic/whole-gene deletions or duplicationsUnknown 81. See Table A. Genes and Databases for chromosome locus and protein name.2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. Two families reported to date [Kim et al 2007]5. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.8. No deletions or duplications of PRPS1 have been reported to cause Charcot-Marie-Tooth neuropathy X type 5.Testing Strategy To confirm/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 either (a) prior identification of the disease-causing mutation 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 mutation is identified, by deletion/duplication analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersThe spectrum of PRPS1-related disorders includes four phenotypes, CMTX5, PRS superactivity, Arts syndrome, and DFNX1 (DFN2) nonsyndromic hearing loss and deafness (see Table 2).Table 2. Major Clinical Findings in PRPS1-Related Disorders by PhenotypeView in own windowPhenotypeGouty Arthritis 1Peripheral NeuropathyIntellectual DisabilitySNHLOtherPRS superactivityInfantile onset+-+/-+/-Hypotonia; ataxiaLate-juvenile/ early-adult onset+----CMTX5-+-Early onsetOptic atrophyArts syndrome--+Profound congenitalHypotonia; ataxia; optic atrophy; ↑ risk infectionDFNX1 (DFN2) nonsyndromic hearing loss and deafness ---Postlingual progressive, severe to profound / congenital-SNHL = sensorineural hearing loss+/- = variably present1. Associated with hyperuricemia, hyperuricosuriaPhosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by hyperuricemia and hyperuricosuria and is divided into a severe phenotype with infantile or early-childhood onset and a milder phenotype with late-juvenile or early-adult onset. Variable combinations of sensorineural hearing loss, hypotonia, and ataxia observed in the severe type are not usually present in the mild type. In the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled. Arts syndrome is characterized by profound congenital sensorineural hearing impairment, early-onset hypotonia, delayed motor development, mild to moderate intellectual disability, ataxia, and increased risk of infection, all of which (with the exception of optic atrophy) present before age two years. Signs of peripheral neuropathy develop during early childhood. Twelve of 15 boys from the two Dutch families reported with Arts syndrome died before age six years of complications of infection. Carrier females can show late-onset (age >20 years) hearing impairment and other findings. DFNX1 (DFN2) nonsyndromic hearing loss and deafness. Individuals with DFNX1 nonsyndromic hearing loss and deafness (DFN2) have postlingual progressive nonsyndromic hearing loss, although in one family congenital profound nonsyndromic hearing loss was reported [Liu et al 2010]. Affected individuals have normal intellect.
The symptom triad of CMTX5 is peripheral neuropathy, sensorineural hearing loss, and optic neuropathy....
Natural HistoryThe 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].
Across the four disease phenotypes included as PRPS1-related disorders, only missense mutations have been reported to date. No correlation is known between specific PRPS1 missense mutations and the phenotypes....
Genotype-Phenotype CorrelationsAcross the four disease phenotypes included as PRPS1-related disorders, only missense mutations have been reported to date. No correlation is known between specific PRPS1 missense mutations and the phenotypes.
Peripheral neuropathy. See Charcot-Marie-Tooth Hereditary Neuropathy Overview....
Differential DiagnosisPeripheral neuropathy. See Charcot-Marie-Tooth Hereditary Neuropathy Overview.X-linked Charcot-Marie-Tooth disease (CMTX). CMTX5 is clearly distinguishable from the five other forms of X-linked Charcot-Marie-Tooth disease [Kim et al 2005] (see Charcot-Marie-Tooth Neuropathy X Type 1):CMTX1 is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families. The gene in which mutation is causative is GJB1 (Cx32).CMTX2 with intellectual disability maps to Xp22.2 [Ionasescu et al 1991, Ionasescu et al 1992].CMTX3 with spasticity and pyramidal tract signs maps to Xq26 [Ionasescu et al 1991, Ionasescu et al 1992, Huttner et al 2006].CMTX4 (Cowchock syndrome) with deafness and intellectual disability resulting from mutation in AIFM1 [Cowchock et al 1985, Priest et al 1995, Rinaldi et al 2012].CMTX6, resulting from mutation in PDK3. Males have childhood onset of a slowly progressive motor and sensory neuropathy that is largely axonal (variable mild conduction slowing) with steppage gait and absent tendon reflexes. Carrier females may have a mild sensory motor axonal neuropathy [Kennerson et al 2013].Sensorineural hearing loss. It is important to suspect CMTX5 when boys with early-onset sensorineural hearing loss develop gait disturbance and visual disturbance.See Deafness and Hereditary Hearing Loss Overview.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with CMTX5, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with CMTX5, the following evaluations are recommended:Neurologic examinationPure tone audiograms, auditory brain stem response testEvaluation of visual acuity, fundoscopic examinationMedical genetics consultationTreatment of ManifestationsPeripheral 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 ComplicationsDaily heel cord stretching exercises are desirable to prevent Achilles’ tendon shortening from peripheral neuropathy, which can occur in individuals with CMTX5. SurveillanceIndividuals 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 AvoidObesity 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 asymptomaticOther potential risk levels. See Table 3. For more information, click here (pdf).Table 3. Medications Potentially Toxic to Persons with CMTView in own windowModerate to Significant Risk 1- Amiodarone (Cordarone) - Bortezomib (Velcade) - Cisplatin & Oxaliplatin - Colchicine (extended use) - Dapsone - Didanosine (ddI, Videx) - Dichloroacetate - Disulfiram (Antabuse) - Gold salts - Leflunomide (Arava) - Metronidazole/Misonidazole (extended use) - Nitrofurantoin (Macrodantin, Furadantin, Macrobid) - Nitrous oxide (inhalation abuse or vitamin B12 deficiency) - Perhexiline (not used in the US) - Pyridoxine (mega dose of vitamin B6) - Stavudine (d4T, Zerit) - Suramin - Taxols (paclitaxel, docetaxel) - Thalidomide - Zalcitabine (ddC, Hivid)Click here (pdf) for additional medications in lesser-risk categories.The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996], Nishikawa et al [2008], and Porter et al [2009].Evaluation of Relatives at RiskIt 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 InvestigationDietary 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 for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Charcot-Marie-Tooth Neuropathy X Type 5: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCMTX5PRPS1Xq22.3Ribose-phosphate pyrophosphokinase 1IPN Mutations, PRPS1 PRPS1 @ LOVD PRPS1 homepage - Leiden Muscular Dystrophy pagesPRPS1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Charcot-Marie-Tooth Neuropathy X Type 5 (View All in OMIM) View in own window 311070CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 5; CMTX5 311850PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1Normal allelic variants. PRPS1 is located on the chromosome band Xq21.32-q24 and spans 23 kb with seven exons. Two other PRPS genes have been identified: PRPS2 (OMIM 311860) maps to chromosome Xp22 and PRPS3 (or PRPS1L1; OMIM 611566) maps to chromosome 7 and appears to be transcribed only in testis [Becker 2001].Kim et al [2007] described their observation of a synonymous variant, c.447G>A, with an allele frequency of 1.1%, while resequencing PRPS1 in control chromosomes of Korean descent. See Table 4.Pathologic allelic variants. Two missense mutations of PRPS1 have been reported in individuals with CMTX5. The p.Glu43Asp mutation was reported in a Korean family with CMTX5 [Kim et al 2007]. The p.Met115Thr mutation was detected in an affected family of European descent, originally reported as having Rosenberg-Chutorian syndrome [Rosenberg & Chutorian 1967, Kim et al 2007]. See Table 4.Table 4. PRPS1 Allelic Variants Discussed in This GeneReviewView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference SequencesNormalc.447G>A 2(Pro149Pro)NM_002764.3 NP_002755.1Pathologicc.129A>Cp.Glu43Aspc.344T>Cp.Met115ThrSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Observed with an allele frequency of 1.1% (2/185) in control chromosomes of Korean descent [Kim et al 2007]Normal gene product. PRPS1 encodes a 318-amino acid protein, the PRPS1 (phosphoribosyl pyrophosphate synthetase 1) enzyme. The enzyme catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis.Abnormal gene product. Four loss-of-function missense mutations have been reported in PRPS1: two in CMTX5 (Table 4), and two in Arts syndrome. The PRS enzyme activity was shown to be decreased in cells of affected males [de Brouwer et al 2007, Kim et al 2007].