Charcot-Marie-Tooth Neuropathy X Type 5
Summary
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 pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.
Diagnosis
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].
Molecular Genetic Testing
Gene. PRPS1, encoding phosphoribosyl pyrophosphate synthetase I, is the only gene in which pathogenic variants are known to cause CMTX5.
Table 1.
Molecular Genetic Testing Used in CMTX5
| Gene 1 | Method | Variants Detected 2 | Variant Detection Frequency by Method 3 |
|---|---|---|---|
| PRPS1 | Sequence analysis 4 | Sequence variants | 100% 5, 6, 7 |
| Deletion/duplication analysis 8 | Exon/whole-gene deletions or duplications | Unknown 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants.
- 3.
The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Two families reported to date [Kim et al 2007]
- 6.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.
- 7.
Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.
- 8.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
- 9.
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 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 Characteristics
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.
Differential Diagnosis
Peripheral 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):
- CMTX type 1 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.
Management
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.
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