TY  - JOUR
A1  - Burlina, Alessandro P.
A1  - Sims, Katherine B.
A1  - Politei, Juan M.
A1  - Bennett, Gary J.
A1  - Baron, Ralf
A1  - Sommer, Claudia
A1  - Moller, Anette Torvin
A1  - Hilz, Max J.
T1  - Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel
JF  - BMC Neurology
N2  - Background: 

Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. 

Methods: 

An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. 

Results: 

We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. 

Conclusions: 

Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.
KW  - Enzyme replacement therapy
KW  - Quality of life
KW  - Small-fiber neuropathy
KW  - Rochester diabetic neuropathy
KW  - Randomized controlled trial
KW  - Agalsidase beta therapy
KW  - Outcome survey
KW  - Pharmacological management
KW  - Clinical manifestations
KW  - Alpha galactosidase
KW  - Diagnosis
KW  - Fabry
KW  - Disease
KW  - Neuropathy
KW  - Pain
KW  - Treatment
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135309
VL  - 11
IS  - 61
ER  - 
TY  - JOUR
A1  - Yin, Jun
A1  - Brocher, Jan
A1  - Fischer, Utz
A1  - Winkler, Christoph
T1  - Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa
JF  - Molecular neurodegeneration
N2  - Background: 
Retinitis pigmentosa (RP) is an inherited eye disease characterized by the progressive degeneration of rod photoreceptor cells. Mutations in pre-mRNA splicing factors including PRPF31 have been identified as cause for RP, raising the question how mutations in general factors lead to tissue specific defects. 

Results: 
We have recently shown that the zebrafish serves as an excellent model allowing the recapitulation of key events of RP. Here we use this model to investigate two pathogenic mutations in PRPF31, SP117 and AD5, causing the autosomal dominant form of RP. We show that SP117 leads to an unstable protein that is mislocalized to the rod cytoplasm. Importantly, its overexpression does not result in photoreceptor degeneration suggesting haploinsufficiency as the underlying cause in human RP patients carrying SP117. In contrast, overexpression of AD5 results in embryonic lethality, which can be rescued by wild-type Prpf31. Transgenic retina-specific expression of AD5 reveals that stable AD5 protein is initially localized in the nucleus but later found in the cytoplasm concurrent with progressing rod outer segment degeneration and apoptosis. Importantly, we show for the first time in vivo that retinal transcripts are wrongly spliced in adult transgenic retinas expressing AD5 and exhibiting increased apoptosis in rod photoreceptors.

Conclusion: 
Our data suggest that distinct mutations in Prpf31 can lead to photoreceptor degeneration through different mechanisms, by haploinsufficiency or dominant-negative effects. Analyzing the AD5 effects in our animal model in vivo, our data imply that aberrant splicing of distinct retinal transcripts contributes to the observed retina defects.
KW  - Factor gene PRPF31
KW  - TRI-SNRNP
KW  - Transgenic zebrafish
KW  - Homebox gene
KW  - Chinese family
KW  - Mutations
KW  - RP11
KW  - Expression
KW  - Disease
KW  - Protein
KW  - Retinitis pigmentosa (RP)
KW  - PRPF31
KW  - AD5 mutation
KW  - SP117 mutation
KW  - haploinsufficiency
KW  - dominant-negative
KW  - rod degeneration
KW  - apoptosis
KW  - splicing defect
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141090
VL  - 6
IS  - 56
ER  -