An X-linked recessive disease with, in almost all patients, a fatal course in early childhood, occurring in a five-generation family is described. The 12 affected boys had early-onset floppiness, ataxia, liability to infections especially of the upper respiratory tract, deafness, and later, a flaccid tetraplegia and areflexia. Eleven boys died before the age of 5 years. One boy is still alive at the age of 12 years, but in addition to the above-mentioned signs, he must be ventilated at night and is nearly blind due to optic atrophy. In the only patient whose central nervous system could be examined at the time of autopsy, an almost complete absence of myelin in the posterior columns of the spinal cord was found. This may be the main pathological substrate for the neurological findings. No biochemical or immunological defects were detected. The family also counted 16 healthy male siblings and 13 definite of 28 possible female carriers. Some carriers developed a hearing impairment in early adulthood. As far as is known now, this disease has not been described before.
"Female carriers in families with Arts syndrome were known to sometimes exhibit some hearing impairment later in life (age >20 years) combined with ataxia and neuropathy [3,19]; yet prelingual hearing loss starting at birth - as observed in subject II-1 - has not yet been described in these families. Female carriers in families with CMTX5 are noted to be asymptomatic . "
[Show abstract][Hide abstract] ABSTRACT: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, and non-syndromic sensorineural deafness (DFN2) are allelic syndromes, caused by reduced activity of phosphoribosylpyrophosphate synthetase 1 (PRS-I) due to loss-of-function mutations in PRPS1. As only few families have been described, knowledge about the relation between these syndromes, the phenotypic spectrum in patients and female carriers, and the relation to underlying PRS-I activity is limited.
We investigated a family with a novel PRPS1 mutation (c.830A > C, p.Gln277Pro) by extensive phenotyping, MRI, and genetic and enzymatic tests.
The male index subject presented with an overlap of CMTX5 and Arts syndrome features, whereas his sister presented with prelingual DFN2. Both showed mild parietal and cerebellar atrophy on MRI. Enzymatically, PRS-I activity was undetectable in the index subject, reduced in his less affected sister, and normal in his unaffected mother.
Our findings demonstrate that CMTX5, Arts syndrome and DFN2 are phenotypic clusters on an intrafamilial continuum, including overlapping phenotypes even within individuals. The respective phenotypic presentation seems to be determined by the exact PRPS1 mutation and the residual enzyme activity, the latter being largely influenced by the degree of skewed X-inactivation. Finally, our findings show that brain atrophy might be more common in PRPS1-disorders than previously thought.
"Mutations in the gene encoding phosphoribosyl pyrophosphate synthetase (PRS)-I, PRPS1 (MIM 311850), have been reported in four syndromes: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5, or Rosenberg-Chutorian syndrome; MIM 311070),1,2 PRS-I superactivity (MIM 300661),3 Arts syndrome (MIM 301835),4,5 and nonsyndromic sensorineural deafness (DFN2; MIM 304500).6
PRPS1 belongs to a family that comprises three highly conserved genes: PRPS1, PRPS2 (MIM 311860), and PRPS1L1 (MIM 611566).7,8 "
[Show abstract][Hide abstract] ABSTRACT: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is caused by mutations in the gene encoding phosphoribosyl pyrophosphate synthetase I (PRPS1). There has been only one case report of CMTX5 patients. The aim of this study was to identify the causative gene in a family with CMTX with peripheral neuropathy and deafness.
A Korean family with X-linked recessive CMT was enrolled. The age at the onset of hearing loss of the male proband was 5 months, and that of steppage gait was 6 years; he underwent cochlear surgery at the age of 12 years. In contrast to what was reported for the first patients with CMTX5, this patient did not exhibit optic atrophy. Furthermore, there was no cognitive impairment, respiratory dysfunction, or visual disturbance. Assessment of his family history revealed two male relatives with very similar clinical manifestations. Electrophysiological evaluations disclosed sensorineural hearing loss and peripheral neuropathy. Whole-exome sequencing identified a novel p.Ala121Gly (c.362C>G) PRPS1 mutation as the underlying genetic cause of the clinical phenotype.
A novel mutation of PRPS1 was identified in a CMTX5 family in which the proband had a phenotype of peripheral neuropathy with early-onset hearing loss, but no optic atrophy. The findings of this study will expand the clinical spectrum of X-linked recessive CMT and will be useful for the molecular diagnosis of clinically heterogeneous peripheral neuropathies.
"Some patients also suffer from deafness and optic atrophy . Female carriers show only hearing loss (Arts et al., 1993). Although the function of Tendin in the central nervous system is not known, the disease symptoms fit well with the expression pattern of tendin and make it a candidate gene for Arts syndrome. "
[Show abstract][Hide abstract] ABSTRACT: Chondromodulin-I (CHM1) was identified recently as an angiogenesis inhibitor in cartilage. It is highly expressed in the avascular zones of cartilage but is absent in the late hypertrophic region, which is invaded by blood vessels during enchondral ossification. Blast searches with the C-terminal part of CHM1 in available databases led to the identification of human and mouse cDNAs encoding a new protein, Tendin, that shares high homology with CHM1. Based on computer predictions, Tendin is a type II transmembrane protein containing a putative proteinase cleavage and two glycosylation sites. Northern assays with mouse RNAs demonstrated strong expression of a 1.5-kb tendin transcript in the diaphragm, skeletal muscle, and the eye and low levels of expression in all other tissues investigated. In 17.5-day-old mouse embryos, in situ hybridization revealed high levels of tendin transcript in tendons and ligaments. Additional signals were detected in brain and spinal cord, liver, lung, bowels, thymus, and eye. Cartilage, where CHM1 is found, revealed low levels of tendin m-RNA. In adult mice, tendin is expressed in neurons of all brain regions and the spinal cord. The tendin gene is localized in the human Xq22 region, to which several human diseases have been mapped.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.