ABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0277767.].
ABSTRACT
The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001-2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder.
Subject(s)
Fabry Disease , Male , Female , Humans , Middle Aged , Fabry Disease/diagnosis , Fabry Disease/epidemiology , Fabry Disease/genetics , alpha-Galactosidase/genetics , Genetic Testing , Genotype , Denmark/epidemiology , MutationABSTRACT
Bi-allelic pathogenic variants in MERTK cause retinitis pigmentosa (RP). Since deletions of more than one exon have been reported repeatedly for MERTK, CNV (copy number variation) analysis of next-generation sequencing (NGS) data has proven important in molecular genetic diagnostics of MERTK. CNV analysis was performed on NGS data of 677 individuals with inherited retinal diseases (IRD) and confirmed by quantitative RT-PCR analysis. Clinical evaluation was based on retrospective records. Clinical re-examination included visual field examination, dark adaption, scotopic and photopic full-field electroretinograms (ffERG), multifocal ERG (mfERG) and optic coherence tomography (OCT). Fourteen variants were detected in MERTK in six individuals, three of which were deletions of more than one exon. Clinical examinations of five out of six individuals revealed a severe phenotype with early-onset generalized retinal dystrophy with night blindness and progressive visual field loss; however, one individual had a milder phenotype. Three individuals had hearing impairments. We show that deletions represent a substantial part of the causative variants in MERTK and emphasize that CNV analysis should be included in the molecular genetic diagnostics of IRDs.
Subject(s)
Retinitis Pigmentosa/genetics , c-Mer Tyrosine Kinase/genetics , Adolescent , Adult , Age of Onset , Alleles , Causality , Child , DNA Copy Number Variations , Diagnostic Techniques, Ophthalmological , Disease Progression , Exons/genetics , Female , Gene Deletion , Hearing Loss/genetics , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Night Blindness/genetics , Pedigree , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/physiopathology , Visual Fields , c-Mer Tyrosine Kinase/deficiencyABSTRACT
PURPOSE: To describe clinical characteristics and response to verteporfin therapy (PDT) in eyes with retinal pigment epithelium detachment (PED) in the absence of primary disease other than characteristics compatible with central serous chorioretinopathy (CSC). METHODS: Retrospective review of 634 consecutive patients diagnosed with isolated PED or CSC in one or both eyes in the period from 2007 to 2014 at a single institution. RESULTS: Pigment epithelium detachment (PED) in the absence of primary pathology other than angiographic choroidal hyperpermeability in the incident or fellow eye or manifest CSC in the fellow eye was found in 22 eyes in 19 patients. Follow-up ranged from 4 to 61 months. Five of 19 patients (26%) had classic CSC in the fellow eye. Transition from isolated PED to manifest CSC in the eye with PED was observed in seven eyes (33%) over a median untreated period of observation of 11 months (range, 1-32 months). A single session of PDT followed up 1-6 months later showed full resolution of the PED in seven (78%) of nine eyes. Of the 13 untreated eyes, five eyes (38%) underwent spontaneous resolution of the PED. CONCLUSION: Fellow-eye findings, conversion to CSC, resolution of PED after PDT or, less commonly, spontaneously support that isolated PED is a manifestation of CSC that represents an intermediate stage between pachychoroid and classic CSC. The chance of experiencing resolution of the PED was roughly twice as high with PDT as with untreated observation.
