The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy

Robusto, Michela; Fang, Mingyan; Asselta, Rosanna; Castorina, Pierangela; Previtali, Stefano C.; Caccia, Sonia; Benzoni, Elena; Cristofaro, Raimondo De; Cong, Yu Sheng; Cesarani, Antonio; Liu, Xuanzhu; Li, Wangsheng; Primignani, Paola; Ambrosetti, Umberto; Xu, Xun; Duga, Stefano; Soldà, Giulia

doi:10.1038/ejhg.2014.168

Cited by 23 publications

(35 citation statements)

References 23 publications

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“…Sensory motor neuropathy was a second symptom in the present patient and was usually associated with deafness, like other reported male patients and symptomatic female carriers . The main symptoms indicated progressive length‐dependent neuropathy, with weakness, wasting and sensory loss, starting from legs to arms.…”

Section: Discussionsupporting

confidence: 76%

“…Except for the visual acuity loss, the main symptoms, as well as genetic and enzymatical findings in the present patient, were consistent with the features of CMTX5. The initial symptom was congenital sensorineural deafness, which was described in reported Korean patients . Deafness was the most common symptom in reported patients with or without other symptoms .…”

Section: Discussionmentioning

confidence: 97%

“…Mild PRPS1 deficiency with PRPS1 mutation results in X‐linked non‐syndromic sensorineural hearing deafness (DFNX‐2), moderate PRPS1 deficiency causes X‐linked CMT disease‐5 (CMTX5) with peripheral neuropathy, optic neuropathy and prelingual progressive sensorineural hearing loss, while severe PRPS1 deficiency results in Arts syndrome, characterized by profound bilateral sensorineural hearing loss, hypotonia, delayed motor development, intellectual disability, ataxia, and increased risk of infection (in the upper respiratory tract). In addition, some patients showed macular coloboma‐like lesions with retinal dystrophy, severe short stature and diabetes insipidus . Here, we identified the first Chinese patient with CMTX5 caused by a novel PRPS1 mutation.…”

Section: Introductionmentioning

confidence: 92%

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A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

Meng

Wang

et al. 2019

Neuropathology

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X‐linked Charcot‐Marie‐Tooth disease‐5 (CMTX5) is a rare hereditary disorder caused by mutations in the gene for phosphoribosyl pyrophosphate synthetase‐1 (PRPS1). We investigated a boy with a novel PRPS1 mutation (c.334G>C, p.V112L) via genetic, neuropathological and enzymatic tests. The proband was a 13‐year‐old boy with congenital non‐syndromic sensorineural deafness. At 3 year old, he developed progressive distal weakness of all limbs with muscle atrophy of both hands and shanks. Nerve conduction study revealed the loss of sensory nerve action potentials, and slowing down of motor nerve conduction velocities with a decrease of amplitudes of compound motor action potentials. Visual evoked potentials and brainstem auditory evoked potentials were not bilaterally evocable. Sural biopsy proved the loss of myelinated nerve fibers, with axonal degeneration, regenerating clusters and onion bulbs. Enzymatically, PRPS1 activity was close to zero in the proband and mildly reduced in his mother, compared with controls. To our knowledge, this is the first report of CMTX5 in a Chinese population. The genetic finding has expanded the genotypic spectrum of PRPS1 mutations.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 92%

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A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

Meng

Wang

et al. 2019

Neuropathology

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“…Because there are only anecdotal reports on PRS1 activities of DFNX1 cases, the degree of deficiency of PRS1 activity leading to SNHL has not been documented to date. Previously, significant differences in PRS1 activities between syndromic patients and nonsymptomatic carriers were reported . However, the enzyme activity from nonsyndromic SNHL, which is obligatorily related to a lower degree of PRS1 deficiency, would provide a better indication of the minimal therapeutic level of PRS1.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, significant differences in PRS1 activities between syndromic patients and nonsymptomatic carriers were reported. 32,33 However, the enzyme activity from nonsyndromic SNHL, which is obligatorily related to a lower degree of PRS1 deficiency, would provide a better indication of the minimal therapeutic level of PRS1. Indeed, in the present study, there was a much smaller difference of PRS1 activities between the affected nonsyndromic SNHL subjects and nonsymptomatic PRPS1 carriers and the experimental value of PRS1 activity (0.11) was at or above the normal level in which hearing is maintained.…”

Section: It Wasmentioning

confidence: 99%

Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention

Kim

et al. 2016

J Gene Med

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Background The symptoms of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency diseases have been reported to be alleviated by medication. Herein, we report biochemical data to favor PRPS1 deficiency-related hearing loss as a potential target for pharmaceutical treatment. Methods We recruited 42 probands from subjects under the age of 15 years with a moderate degree of nonsyndromic autosomal-recessive or sporadic sensorineural hearing loss (SNHL) in at least one side. Molecular genetic testing, including targeted exome sequencing (TES) of 129 deafness genes, and in silico prediction were performed. Results A strong candidate variant—p.A82P—of PRPS1 is co-segregated with SNHL in X-linked recessive inheritance from one Korean multiplex SNHL family. Subsequent measurement of in vitro enzymatic activities of PRPS1 from erythrocytes of affected and unaffected family members as well as unrelated normal controls has confirmed a pathogenic role of this variant. In detail, compared with normal hearing controls (0.23 – 0.26 nmol/ml/h), the proband, affected sibling, and their normal hearing mother demonstrated a significantly decreased PRPS1 enzymatic activity (0.07, 0.03, and 0.11 nmol/ml/h, respectively). This novel loss-of-function mutation of PRPS1—p.A82P—is the 9th and 6th most reported mutation in the world and in Asia, respectively. Conclusions DFNX1 turned out to account for about 2.4% (1/42) of moderate SNHL in a Korean pediatric population. Confirmation of PRPS1 activity deficiency and an audiologic phenotype that initially begins in a milder form of SNHL, as in our family, should indicate the necessity for rigorous genetic screening as early as possible.

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Novel PRPS1 gain‐of‐function mutation in a patient with congenital hyperuricemia and facial anomalies

Porrmann

Betcheva-Krajcir

Donato

et al. 2017

American J of Med Genetics Pt A

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Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.

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The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy

Cited by 23 publications

References 23 publications

A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention

Novel PRPS1 gain‐of‐function mutation in a patient with congenital hyperuricemia and facial anomalies

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