Arts Syndrome
Summary
Clinical characteristics.
Arts syndrome, which is part of the spectrum of PRPS1-related disorders, 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.
Diagnosis/testing.
The diagnosis of Arts syndrome can be established in a male proband with absent ribose-phosphate pyrophosphokinase 1 (PRS-I) enzyme activity in erythrocytes, or significantly lower PRS-1 enzyme activity in fibroblasts than in controls, or identification of a hemizygous pathogenic variant in PRPS1 by molecular genetic testing. The diagnosis of Arts syndrome can be established in a female proband with suggestive clinical features and identification of a heterozygous pathogenic variant in PRPS1 by molecular genetic testing.
Management.
Treatment of manifestations: Educational program tailored to individual needs. Sensorineural hearing loss has been treated with cochlear implantation with good results. Ataxia and visual impairment from optic atrophy are treated in a routine manner.
Prevention of secondary complications: Routine immunizations against common childhood infections and annual influenza immunization.
Surveillance: Regular neuropsychological, audiologic, and ophthalmologic examinations.
Genetic counseling.
Arts syndrome is inherited in an X-linked manner. If the mother is a carrier, the chance of transmitting the PRPS1 pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and may or may not be mildly affected. Males with Arts syndrome have not reproduced. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.
Diagnosis
Formal diagnostic criteria for Arts syndrome have not been established.
Suggestive Findings
Arts syndrome, part of the spectrum of PRPS1-related disorders, should be suspected in a male proband with the following clinical and laboratory features.
Clinical features
- Intellectual disability
- Profound congenital sensorineural hearing impairment
- Early-onset hypotonia
- Delayed motor development
- Ataxia
- Optic atrophy
- Liability to infections, especially of the upper respiratory tract
Laboratory features
- Serum uric acid concentration lower than average (0.13-0.16 mmol/L), although still within the normal range (i.e., 0.12-0.35 mmol/L) [de Brouwer et al 2007]Note: (1) Serum uric acid concentration is not zero because PRS-II, which has the same enzyme activity as PRS-I, is active in tissues such as liver, which consequently will result in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of PRS superactivity, in which serum uric acid concentration is usually high.
- Purine analysis in urine
- Absent/low hypoxanthine on analysis of purines in the urine
- When individuals with Arts syndrome are on a low-purine diet, the uric acid to creatinine ratio in urine may also tend to be at the lower end of normal, but not zero.
- Concentrations of other purines in urine within the normal range
Arts syndrome should be suspected in a female proband with late-onset (age >20 years) sensorineural hearing impairment.
Establishing the Diagnosis
Male proband. The diagnosis of Arts syndrome is established in a male proband with ANY of the following:
- Absent ribose-phosphate pyrophosphokinase 1 (PRS-I) enzyme activity in erythrocytes (because PRS-I is the only isoform present)
- Significantly lower ribose-phosphate pyrophosphokinase 1 (PRS-I) enzyme activity in fibroblasts than in controls [de Brouwer et al 2007]
- A hemizygous pathogenic variant in PRPS1 identified by molecular genetic testing (see Table 1)
Female proband. The diagnosis of Arts syndrome is usually established in a female proband with late-onset (age >20 years) sensorineural hearing impairment and identification of a heterozygous pathogenic variant in PRPS1 by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Arts syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Arts syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Arts syndrome molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of PRPS1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes PRPS1 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of Arts syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Arts Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PRPS1 | Sequence analysis 3, 4 | 4 families 5 |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
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.
- 4.
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 requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Four families reported to date [de Brouwer et al 2007, Synofzik et al 2014, Maruyama et al 2016]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
Arts syndrome is characterized by intellectual disability, early-onset hypotonia, ataxia, delayed motor development, profound congenital sensorineural hearing impairment, and progressive optic atrophy [Arts et al 1993, de Brouwer et al 2007].
At birth these symptoms can be present in various combinations. All symptoms except for the visual impairment become apparent in the first two years of life. Visual impairment usually becomes obvious after age two years.
Delayed motor nerve conduction velocities and an electromyography suggestive of denervation develop during early childhood and are consistent with clinical findings that suggest peripheral neuropathy.
Affected males usually have mild to moderate intellectual disability; however, cognitive abilities can be difficult to assess in the presence of combined visual and hearing impairment.
Liability to infections, especially upper-respiratory tract infections, resulted in death before age six years in 12 of 15 boys from the two Dutch families reported with Arts syndrome. During infection, the slowly progressive muscle weakness is punctuated by acute deterioration in muscle strength, which may result in respiratory failure requiring mechanical ventilation.
Heterozygous females can show isolated and/or milder manifestations, most notably late-onset (age >20 years) hearing impairment. Ataxia (in 2 females), hypotonia (1 female), and hyperreflexia (1 female) have been reported as well [Arts et al 1993].
MRI shows no recognizable abnormalities (e.g., reduction of white matter in the brain, which would indicate demyelination) [de Brouwer et al 2007].
Sural nerve biopsy in a boy age five years with Arts syndrome from the original Dutch family showed a loss of myelinated fibers, but no signs of demyelination or axonal degeneration [Arts et al 1993]. Sural nerve biopsy of a boy age two years from the Australian family, who had absent lower-limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy, showed mild paranodal demyelination indicative of peripheral neuropathy [de Brouwer et al 2007].
Autopsy of one individual who died at age five and a half years revealed complete absence of myelinated axons in the posterior columns of the spinal cord, although their number and appearance were normal in the other tracts [Arts et al 1993]. A number of dorsal root nerves showed the same abnormalities as posterior columns. No abnormalities were seen in the brain stem or in the gray and white matter of the cerebral and cerebellar hemispheres.
Genotype-Phenotype Correlations
Computer-assisted molecular modeling showed that pathogenic variants causing Arts syndrome and CMTX5 disturb the ATP binding site of PRS-I.
Pathogenic variants that result in PRS superactivity disturb either one or both allosteric sites that are involved in the inhibition of PRS-I enzyme activity.
Pathogenic variants that lead to DFNX1 nonsyndromic hearing loss and deafness (DFN2) either disturb local stability of PRS-I or moderately affect interactions in the trimer interface.
Penetrance
Penetrance in males is complete.
Prevalence
Four kindreds with Arts syndrome have been identified worldwide [de Brouwer et al 2007, Synofzik et al 2014, Maruyama et al 2016].
Differential Diagnosis
See Genetically Related Disorders.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Arts syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Neurologic evaluation for manifestations of hypotonia, ataxia, presence/absence of tendon reflexes
- Audiometry for evidence of hearing loss
- Eye examination for evidence of optic atrophy
- Assessment of intellectual abilities
- Analysis of the family pedigree for other possible affected individuals and carrier females
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Intellectual disability. An individualized educational support program tailored to the individual’s needs and based on assessment of cognitive abilities should be provided.
Ataxia. See Hereditary Ataxias, Management.
Sensorineural hearing loss. See Hereditary Hearing Loss and Deafness Overview, Management. Cochlear implantation in the two affected Australian males was associated with improved communication skills.
Optic atrophy. No treatment is available.
Prevention of Secondary Complications
Because of immune system compromise in males with Arts syndrome, the following are recommended:
- An annual influenza immunization
- Routine immunizations against other common childhood infections (e.g., measles, mumps)
Surveillance
Cognitive impairment appears to be non-progressive, but repeat neuropsychologic assessments are recommended to help guide educational support programs.
Although the sensorineural deafness appears to be static (albeit very severe), regular audiologic assessment is recommended so that educational support can be optimized.
Visual impairment appears to be progressive; thus, regular evaluation by an ophthalmologist is recommended.
Evaluation of Relatives at Risk
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 phosphoribosyl pyrophosphate dependent. Furthermore, SAM is known to cross the blood-brain barrier. An adult with HPRT deficiency has been reported to benefit neurologically from SAM administration without untoward side effects [Glick 2006].
In an open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia], oral SAM supplementation was set at 30 mg/kg/day. The brothers 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 was noted. Eventually, they died at ages 19 and 18 years of respiratory failure associated with a severe lower respiratory tract infection.
Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested.
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