Arts Syndrome

A number sign (#) is used with this entry because of evidence that Arts syndrome (ARTS) is caused by loss-of-function mutation in the PRPS1 gene (311850) on chromosome Xq22.

Loss-of-function PRPS1 mutations, resulting in decreased enzyme activity, can also cause X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) and X-linked deafness-1 (DFNX1; 304500). There is considerable phenotypic overlap between Arts syndrome, CMTX5, and DFNX1, as well as intrafamilial variability depending on gender, X-inactivation ratio, residual enzyme activity, and additional factors. Males tend to be more severely affected than females in all 3 disorders, although some females can show severe features. These disorders are best considered as representing a phenotypic spectrum (summary by Almoguera et al., 2014; Synofzik et al., 2014).

Another allelic disorder, PRPS-related gout (300661), results from increased PRPS1 enzyme activity. Some affected patients also have neurologic symptoms, including sensorineural deafness.

Description

Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy (de Brouwer et al., 2007). Susceptibility to infections, especially of the upper respiratory tract, can result in early death.

Clinical Features

In 12 boys in 3 generations of a kindred in an X-linked recessive pattern of inheritance, Arts et al. (1993) described a disorder leading to death in early childhood. The manifestations were early-onset floppiness, ataxia, liability to infections, especially of the upper respiratory tract, deafness, and later, a flaccid tetraplegia and areflexia. Although 1 boy was still alive at the age of 12 years, 11 had died before the age of 5 years. The surviving boy required ventilation at night and was nearly blind due to optic atrophy. In the only patient in whom the central nervous system (CNS) could be examined at autopsy, almost complete absence of myelin in the posterior columns of the spinal cord was found. Among the female carriers, hearing impairment in early adulthood appeared to be a feature.

Kremer et al. (1996) noted that infections were the cause of death before the age of 6 years in 11 of the 12 boys reported by Arts et al. (1993). The oldest patient, then 16 years of age, had become nearly blind owing to optic atrophy and lived in an institution for the visually and mentally handicapped. Clinical signs indicated impairment of the posterior columns, peripheral motor and sensory neurons, and the second and eighth cranial nerves and/or nuclei. In addition to perceptive hearing loss, ataxic diplegia, extensor plantar reflexes, hypotonia, and hyper- or hyporeflexia were thought to be features of the heterozygous state. Kremer et al. (1996) noted the phenotypic similarities to the family reported by Schmidley et al. (1987) (301790).

Moran et al. (2012) reported a young boy with a complex phenotype comprising Arts syndrome and PRPS1 superactivity. He had developmental delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing loss, and a Chiari I malformation. Laboratory studies showed increased serum uric acid and increased urinary hypoxanthine consistent with PRPS1 superactivity, but he did not have gout. In addition, he had recurrent infections and early death at age 27 months from infection, consistent with Arts syndrome. A maternal uncle with similar symptoms had died of pneumonia at age 2.

Clinical Variability

Synofzik et al. (2014) reported a German family with variable manifestations of PRPS1 deficiency, illustrating that the disorder can present as a continuous spectrum of clinical features, even within the same family. The proband was a 36-year-old man with a protracted form of Arts syndrome, including prelingual hearing loss since birth, progressive visual loss due to optic atrophy, recurrent infections in childhood, and late-onset ataxia. He developed mild mental retardation, cognitive impairment, and behavioral abnormalities at age 16 and was able to finish school, but he later showed cognitive abilities below the stage of an adolescent. He had aggressive behavior with low frustration tolerance and episodes of infantile-regressive behavior, necessitating institutionalization as an adult. Brain imaging showed mild cerebellar and parietal cortical atrophy. Nerve conduction studies showed a florid predominant axonal sensorimotor neuropathy associated with increased serum creatine kinase, consistent with CMTX5. The proband's 42-year-old sister had only prelingual hearing loss without symptoms of neurologic dysfunction, consistent with DFNX1; however, her brain MRI also showed cerebellar and parietal atrophy. The mother of these sibs had no hearing deficit or neurologic dysfunction at age 66. Serum uric acid was normal in all 3 individuals. Genetic analysis identified a missense mutation in the PRPS1 gene (Q277P; 311850.0019) that was heterozygous in the females and hemizygous in the male proband. Erythrocyte PRPS1 activity was not detectable in the proband, was decreased in the sister, and was normal in the mother. X-chromosome inactivation was extremely skewed in the sister (94%; 6%), but only moderately skewed in the mother (80%; 20%).

Mapping

Using linkage analysis, Kremer et al. (1996) localized the gene (or genes) responsible for the Arts syndrome phenotype to Xq21.33-q24 between DXS1231 and DXS1001 with a maximum lod score of 6.97. They noted that the gene encoding proteolipid protein (300401), which codes for 2 myelin proteins of the central nervous system, is located in this region and should be considered as a candidate gene for the disorder. However, no mutations were found in the protein-coding part of the gene.

By linkage analysis in a Dutch family and an Australian family, de Brouwer et al. (2007) mapped the candidate gene to Xq22.1-q24.

Molecular Genetics

Using oligonucleotide microarray expression profiling in fibroblasts from 2 probands of a Dutch family with Arts syndrome, de Brouwer et al. (2007) found reduced expression levels of the PRPS1 gene (311850). Sequencing of PRPS1 led to the identification of 2 different missense mutations, L152P (311850.0011) in the Dutch family and Q133P (311850.0012) in the Australian family. Both mutations resulted in a loss of PRPS1 activity, as was shown in silico by molecular modeling and in vitro by enzyme assays in erythrocytes and fibroblasts from patients. Gain-of-function mutations in PRPS1 result in PRPS-related gout (see 300661). The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which was supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. De Brouwer et al. (2007) suggested that treatment with S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy to replenish low levels of purines. A clinical trial involving the 2 affected Australian brothers was underway. De Brouwer et al. (2010) reported preliminary results of the 2 Australian brothers with Arts syndrome, which revealed some improvement of their condition.

In a patient with a complex phenotype comprising Arts syndrome and PRPS1 superactivity, Moran et al. (2012) detected a missense mutation in the transversion in exon 4 of the PRPS1 gene (V142L; 311850.0017). Both the mother and grandmother were heterozygous for the mutation. Molecular modeling predicted that the substitution would disrupt allosteric sites involved in inhibition of PRPS1, resulting in a gain of enzyme function, and the ATP-binding site, resulting in a loss of enzyme function. Patient fibroblasts showed normal PRPP synthetase activity, whereas erythrocytes showed a loss of enzyme activity, suggesting that the effect of the V142L mutation on protein activity depends on cell type. Moran et al. (2012) postulated a gain-of-function effect in proliferating cells and a loss-of-function effect in postmitotic cells. The report indicated that PRPS1 missense mutations can cause a continuous spectrum of features ranging from progressive nonsyndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites affected.