Occult macular dystrophy in an Italian family carrying a mutation in the RP1L1 gene.

Occult macular dystrophy (OMD) is an inherited macular disease characterized by progressive visual decline with the absence of visible retinal abnormalities. Typical alterations of the retinal structure are detectable by spectral domain optical coherence tomography (SD\u2011OCT). Mutations in the RP1L1 gene have been identified to be responsible for the disease in Asian subjects. The present study assessed the role of mutations in the RP1L1 gene in an Italian family with OMD. One patient with OMD and five related subjects (two male offspring affected by progressive visual decline and three asymptomatic siblings of the patient) were subjected to complete ophthalmological examination. SD\u2011OCT was also performed. All subjects were screened for OMD\u2011associated genetic mutations in the RP1L1 gene. The OMD patient and the two symptomatic offspring presented with a reduced best\u2011corrected visual acuity. Although no fundus abnormalities were observed, SD\u2011OCT examination showed that the external limiting membrane and the inner segment/outer segment band were not clearly identifiable and a focal disruption of the photoreceptor layer was present. The degree of photoreceptor alterations was correlated with the severity of visual impairment. Clinical and tomographic results in the three asymptomatic relatives were normal. A p.Arg45Trp mutation in the RP1L1 gene was identified in the OMD patient, in the two symptomatic offspring and also in two of the asymptomatic siblings of the patient. The identification of RP1L1 mutations in subjects with OMD may improve the accuracy of diagnosis of this rare condition and may aid in enhancing the efficacy of genetic counseling

Long-term rearrangement of retinal structures in a novel mutation of X-linked retinoschisis

The aim of the present study was to report a novel mutation in the retinoschisin 1 (RS1) gene in a Caucasian family affected by X-linked juvenile retinoschisis (XLRS) and to describe the long-term modification of retinal structure. Two brothers with an early onset maculopathy were diagnosed with XLRS. Fundus photography, fluorescein angiography, spectral domain optical coherence tomography and electroretinogram analyses were performed. Their sister was also examined. All subjects were screened for mutations in the RS1 gene. XLRS patients demonstrated a marked reduction of best-corrected visual acuity. SD-OCT scans reported a cystic degeneration primarily involving the inner nuclear layer, though some cysts were detected in the outer plexiform layer and in the ganglion cell layer. During the ten-year follow-up, a progressive retinal thickening and coalescence of the cysts was observed. Genetic testing revealed a novel mutation (p.Ile212Asn) in the RS1 gene in both XLRS patients, whereas their sister was not a genetic carrier. Several mutations of the RS1 gene were recognized to be responsible for XLRS. Although the correspondence between genotype and phenotype is still under debate, is reasonable that siblings affected by XLRS could share other genetic and/or epigenetic factors capable to influence clinical course of the disease

Non\u2011syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene

Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter- and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA

Expanding the spectrum of SPTLC1-related disorders beyond hereditary sensory and autonomic neuropathies: a novel case of the distinct "S331 syndrome"

Hereditary sensory and autonomic neuropathies (HSAN) encompass a group of peripheral nervous system disorders characterized by remarkable heterogeneity from a clinical and genetic point of view. Mutations in SPTLC1 gene are responsible for HSAN type IA, which usually starts from the second to fourth decade with axonal neuropathy, sensory loss, painless distal ulcerations and mild autonomic features, while motor involvement usually occur later as disease progresses

Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease

CARMIL2 is required for CD28-mediated co-stimulation of NF-kappa B signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD

Combined effects of genetic and non-genetic risk factors affect response to ranibizumab in exudative age-related macular degeneration

Purpose: To investigate whether genetic and non-genetic risk factors influence 12-month response to ranibizumab treatment for exudative age-related macular degeneration (AMD). Methods: A cohort of 94 Caucasian patients with unilateral exudative AMD received intravitreal ranibizumab. After a three-injection loading phase, a PRN regimen was followed. Patients were genotyped for three single-nucleotide polymorphisms: CFH rs1061170, ARMS2 rs10490924 and C3 rs2230199. Nongenetic risk factors [choroidal neovascularization (CNV) phenotype, smoking habit, hypertension and body mass index] were considered. The selected endpoint was the 12-month variation of number of ETDRS letters. Results: Complement factor H (CFH) risk alleles, smoking history and arterial hypertension each independently influenced treatment response, with worse 12- month BCVA outcomes (p = 0.036, 0.037, 0.043, respectively). A significant cumulative effect of these risk factors was also observed: patients homozygous for the CFH risk alleles and with a positive smoking history showed a mean loss of 8.0 ETDRS letters (p = 0.010). Patients with CFH risk alleles, smoking history and hypertension had a mean loss of 13.9 ETDRS letters (p = 0.013). CNV phenotypes did not influence visual outcomes, nor were they associated with other genetic/non-genetic risk factors. Conclusions: Complement factor H risk alleles, smoking history and hypertension affect the mid-term response to ranibizumab in exudative AMD

A Novel Missense Mutation in CAV3 Gene in an Italian Family With Persistent hyperCKemia, Myalgia and Hypercholesterolemia: Double-trouble

Caveolins are essential proteins in caveolae architecture, small plasma membrane invaginations that play a key role in a variety of cellular processes, including vesicular trafficking and signal transduction. Mutations in the gene encoding caveolin-3 (CAV3) cause a broad spectrum of clinical phenotypes, ranging from isolated hyperCKemia to most severe limb girdle muscular dystrophy and cardiomyopathy. We report a novel heterozygous p.Val44Met (c.130G > A) CAV3 mutation in two brothers presenting with persistent elevation of serum creatine kinase, myalgia and hypercholesterolemia. Immunofluorescence study with anticaveolin-3 antibodies on muscle biopsy of the proband confirmed a reduced immuno-reactivity of caveolin-3 on the sarcolemma. This findings support the pathogenic effect of this novel mutation and extend the genotypic and clinical spectrum of Caveolinopathies. Finally, we discuss the hypothesis that the association between CAV3 mutations and hypercholesterolemia may not be coincidental