The Benefits of Early versus Late Therapeutic Intervention in Fabry Disease.

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants of the GLA gene. Heterozygous female patients may show much more variability in clinical manifestations, ranging from asymptomatic to full-blown disease. Because of this heterogeneous clinical picture in women, the diagnosis of FD has typically been delayed for more than a decade, and the optimal time to initiate treatment remains controversial. Case Presentation. Here, we present two unrelated female patients diagnosed with FD harbouring the same pathogenic GLA variant. We discuss the implications of initiating specific therapy at different stages of the disease, with and without organ involvement (early versus late therapeutic intervention). Conclusions: These clinical cases suggest that initiating specific treatment at an earlier age in women with FD may prevent organ involvement and associated clinical events.

Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study.

RATIONALE & OBJECTIVE: Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. OBSERVATIONS: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2). LIMITATIONS: The relatively small size of this series from a single country, potentially limiting generalizability. CONCLUSIONS: Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

Acute Effects of a Brief Physical Exercise Intervention on Somatosensory Perception, Lumbar Strength, and Flexibility in Patients with Nonspecific Chronic Low-Back Pain.

BACKGROUND: Evidence-based clinical guidelines consider physical exercise one of the best nonpharmacological interventions for low-back pain (LBP), but it is necessary to clarify the exercise-induced hypoalgesia effect of different modalities of exercise in chronic pain populations. PURPOSE: This study focused on exploring acute changes in tactile and pressure-pain perception and lumbar strength and flexibility in patients with nonspecific chronic LBP (NSCLBP) after performing one of three 20-minute physical exercise modalities. METHODS: A total of 81 patients with NSCLBP were pseudorandomly distributed into three groups of 20-minute physical exercise - 1) aerobic (n=21, mean age 42±9.72 years, nine men), 2) stretching (n=21, mean age 40±11.37 years, ten men), and 3) strengthening (n=20, mean age 35.80±11.56 years, ten men) - and 4) a control group (n=19, mean age 38.64±10.24 years, eight men), and completed self-reported questionnaires during the same period. Tactile and pressure-pain thresholds and isometric lumbar muscle endurance and flexibility were assessed before and after this brief exercise-based intervention. RESULTS: All groups were comparable in terms of sociodemographic and clinical data, cardiovascular capacity, and self-reported data onphysical disability, mood, motivation, psychological response to stimulus properties of physical exercise, and physical activity enjoyment. Our analyses revealed higher tactile sensitivity (p<0.001) and pressure-pain thresholds (p<0.001) at the forefinger than other body locations. We also found lower pain sensitivity (p=0.010) and pressure pain-intensity ratings (p=0.001) and higher lumbar flexibility (p<0.001) after intervention. After calculation of absolute pre-post differences, higher tactile sensitivity was observed at the gluteus medius muscle than the erector spinal muscle only after aerobic intervention (p=0.046). CONCLUSION: These results add some evidence about different modalities of exercise-induced hypoalgesia in NSCLBP. However, the fact that we also found improvements in the control group limits our conclusions.

Nefropatía asociada a mutación del gen MYH9 / MYH9 Associated nephropathy

Las enfermedades relacionadas con mutaciones del gen MYH9 son un grupo de patologías genéticas raras. Su herencia sigue un patrón autosómico dominante en donde el gen MYH9, codifica la cadena pesada de la miosina IIA no muscular que se expresa en diferentes tejidos pero especialmente en los podocitos y en las células mesangiales. Este trastorno se caracteriza por la presencia de macrotrombocitopenia, inclusiones leucocitarias y un riesgo variable de desarrollar insuficiencia renal, hipoacusia y cataratas en edad juvenil o adulta. Describimos el caso de una mujer de 27 años, de raza caucásica, diagnosticada inicialmente de púrpura trombocitopénica idiopática. Tras una detallada historia familiar y el desarrollo de síntomas clínicos posteriores con afectación renal e hipoacusia, se le realizó un estudio genético que nos permitió el diagnóstico de nefropatía asociada a la mutación en el gen MYH9. Este caso destaca el retraso del diagnóstico y la utilidad del estudio genético en pacientes con enfermedades muy poco frecuentes. Se procede a la revisión de la enfermedad en este artículo

MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided

MYH9 Associated nephropathy. / Nefropatía asociada a mutación del gen MYH9.

MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided.

Efficacy and Safety of an Aflibercept Treat-and-Extend Regimen in Treatment-Naïve Patients with Macular Oedema Secondary to Central Retinal Vein Occlusion (CRVO): A Prospective 12-Month, Single-Arm, Multicentre Trial.

OBJECTIVES: To evaluate efficacy and safety of an aflibercept treat-and-extend (TAE) regimen in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO). DESIGN SETTING AND PATIENTS: Phase IV, prospective, open-label, single-arm trial in 11 Spanish hospitals. Treatment-naïve patients with <6 month diagnosis of MO secondary to CRVO and best-corrected visual acuity (BCVA) of 73-24 ETDRS letters were included between 23 January 2015 and 17 March 2016. INTERVENTION: Intravitreal aflibercept 2 mg monthly (3 months) followed by proactive individualized dosing. MAIN OUTCOMES: Mean change in BCVA after 12 months. RESULTS: 24 eyes (24 patients) were included; mean (SD) age: 62.8 (15.0) years; 54.2% male; median (IQR) time since diagnosis: 7.6 (3.0, 15.2) days. Mean BCVA scores significantly improved between baseline (56.0 (16.5)) and Month 12 (74.1 (17.6)); mean (95% CI) change: 14.8 (8.2, 21.4); P=0.0001. Twelve (50.0%) patients gained ≥15 ETDRS letters. Foveal thickness improved between baseline (mean: 569.4 (216.8) µm) and Month 12 (mean 257.4 (48.4) µm); P < 0.0001. At Month 12, 8.3% patients had MO. The mean (SD) number of injections: 8.3 (3.0). No treatment-related AEs were reported. Five (20.8%) patients experienced ocular AEs. Two nonocular serious AEs were reported. CONCLUSIONS: An aflibercept TAE regimen improves visual acuity in patients with MO secondary to CRVO over 12 months with good tolerability.

Progression of retinal pigmentation mimicking unilateral retinitis pigmentosa after bilateral pars planitis: a case report.

BACKGROUND: To report our findings in a young patient with unilateral retinitis pigmentosa (RP)-like appearance who developed pigmentary changes in his left retina after an episode of bilateral pars planitis. CASE PRESENTATION: A 17-year-old man presented with 6 months of blurry vision in both eyes. He was diagnosed with bilateral pars planitis. Progressive, intraretinal bone crepuscule pigmentation developed in his left retina during the following three months. An electroretinogram showed subnormal response only in the left eye, suggesting the diagnosis of unilateral pseudoRP. CONCLUSION: An inflammatory disease like pars planitis can accelerate the pigmentation of the retina and mimic a RP in young patients. Causes of pseudoRP may be considered, especially in those rare cases with unilateral affection.

Next-generation sequencing reveals a new mutation in the LTBP2 gene associated with microspherophakia in a Spanish family.

BACKGROUND: Microspherophakia is a rare autosomal recessive eye disorder characterized by small spherical lens. It may present as an isolated finding or in association with other ocular and/or systemic disorders. This clinical and genetic heterogeneity requires the study of large genes (ADAMTSL4, FBN1, LTBP2, ADAMTSL-10 and ADAMTSL17). The purpose of the present study is to identify the genetic cause of this pathology in a consanguineous Spanish family. METHODS: A clinical exome sequencing experiment was executed by the TruSight One® Sequencing Panel (TSO) from Illumina©. Sanger sequencing was used to validate the NGS results. RESULTS: Only the insertion of an adenine in exon 36 of the LTBP2 gene (c.5439_5440insA) was associated with pathogenicity. This new mutation was validated by Sanger sequencing and segregation analysis was also performed. Haplotype analyses using the polymorphic markers D14S1025, D14S43 and D14S999 close to the LTBP2 gene indicated identity by descent in this family. CONCLUSION: We describe the first case of a microspherophakia phenotype associated with a novel homozygous mutation in the LTBP2 gene in a consanguineous Caucasian family by means of NGS technology.

Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.

OBJECTIVES: Our aim was to determine the molecular cause of autosomal dominant familial retinal arteriolar tortuosity (FRAT) in a family with three affected subjects. MATERIAL AND METHODS: Ophthalmologic evaluation included determination of best-corrected visual acuity (BCVA), slit-lamp and dilated fundus inspection, applanation tonometry, fundus photography, and fluorescein retinal angiography (FA). Molecular methods included whole exome sequencing analysis and Sanger sequencing validation of putative causal mutation in DNA from affected individuals. RESULTS: Typical signs of familial retinal arteriolar tortuosity were observed in all three patients. Exome sequencing identified a heterozygous c.1528G > A (p. Gly510Arg) mutation in COL4A1. Sanger sequencing confirmed that all three patients harbored the same pathogenetic mutation in COL4A1. The p. Gly510Arg variant in COL4A1 was absent in DNA from an available unaffected daughter, from a set of control alleles, and from publicly available databases. CONCLUSIONS: The molecular basis of familial retinal arteriolar tortuosity was identified for the first time, thus expanding the human phenotypes linked to COL4A1 mutations. Interestingly, the COL4A1 p.Gly510Arg mutation has been previously identified in a family with HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps), a multisystemic disease featuring retinal arteriolar tortuosity. No cerebral, neurologic, renal, cardiac or vascular anomalies were recognized in the pedigree described here. These data indicate that identical mutations in COL4A1 can originate both eye-restricted and systemic phenotypes.

Repositioning of dexamethasone intravitreal implant (Ozurdex) migrated into the anterior chamber.

Ozurdex (Allergan Inc., Irvine, CA, USA) is a biodegradable implant of dexamethasone (0.7 mg) injected into the vitreous cavity to treat macular oedema. We report a case of migration of Ozurdex into the anterior chamber in a patient who had a previous iris-claw lens implantation. Surgical removal of the implant was avoided due to the absence of anterior complications and the loss of effectiveness of the drug delivery system. Repositioning of the implant to the posterior segment is described. This case illustrates the efficacy of this technique in cases of migration into the anterior chamber in eyes without corneal decompensation.

Combined retinal detachment and candida chorioretinitis.

To report a case of slowly progressive traction and rhegmatogenous retinal detachment after successfully managed candida chorioretinitis. A 44-year-old immunocompromised woman was treated with voriconazole for fungal chorioretinitis. Six months after onset she developed a combined retinal detachment. Slow progression of retinal detachment was observed and vitrectomy was performed. The macular area remained attached and visual acuity was maintained. Ophthalmologists should be aware of this unusual complication after the resolution of active candida chorioretinitis.

Pupillary block glaucoma in phakic eyes using 5000 centistoke silicone oil.

PURPOSE: To describe pupillary block glaucoma in phakic patients undergoing vitrectomy and 5000 centistoke silicone oil injection. DESIGN: Observational case reports. METHODS: Vitrectomy and higher-viscosity silicone oil injection was performed in two phakic patients with proliferative diabetic retinopathy. RESULTS: Both patients developed a pupillary block in the early postoperative period (1 week and 1 month after surgery). Unnoticed zonulysis during surgery, thought to be the main contributory cause, allowed access of the silicone oil between the iris and the lens. Although higher-viscosity silicone oil was used in both cases, an acute glaucoma developed. An inferior iridotomy was performed, resulting in a temporary resolution of the pupillary block. CONCLUSION: Vitreoretinal surgeons should be aware of silicone-induced pupillary block glaucoma in phakic eyes, even when higher-viscosity silicone oils are used.

A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen.

PURPOSE: To describe the clinical and genetic characteristics of the second family with a recently described recessive syndrome characterized by posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disk drusen. DESIGN: Observational case report. METHODS: Three affected subjects and one healthy sibling from a consanguineous marriage from Spain were studied. Complete ophthalmologic examinations including A- and B-mode ultrasonography (US), electroretinography (ERG), fluorescein retinal angiography (FA), and optical coherence tomography (OCT) were performed in each individual. Genetic analysis included polymerase chain reaction amplification and direct nucleotide sequencing of the complete MFRP gene. RESULTS: All three affected siblings had bilateral shortening of the posterior ocular segment associated with high hyperopia and normal anterior segment dimensions. Best-corrected visual acuity ranged from 20/200 to 20/60. Funduscopy, ERG, and FA were compatible with retinitis pigmentosa, and B-mode ultrasound showed optic disk drusen. OCT analysis revealed outer retinal layer schisis with absence of foveal pit. Inheritance of this syndrome followed an autosomal recessive pattern. Molecular analysis revealed a novel homozygous 1-bp deletion (c.498delC) in exon 5 of MFRP, predicting a prematurely truncated protein (P166fsX190). A healthy sister demonstrated to be a carrier of the mutation. CONCLUSIONS: We confirmed that the syndrome of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disk drusen constitutes a distinct autosomal recessive entity. The novel frameshift mutation identified in the family described here validates MFRP as the gene responsible for this particular disease, which characteristically involves structures located at the posterior segment of the eye.