Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

Mutations in SAMD7 cause autosomal-recessive macular dystrophy with or without cone dysfunction.

Sterile alpha motif domain containing 7 (SAMD7) is a component of the Polycomb repressive complex 1, which inhibits transcription of many genes, including those activated by the transcription factor Cone-Rod Homeobox (CRX). Here we report bi-allelic mutations in SAMD7 as a cause of autosomal-recessive macular dystrophy with or without cone dysfunction. Four of these mutations affect splicing, while another mutation is a missense variant that alters the repressive effect of SAMD7 on CRX-dependent promoter activity, as shown by in vitro assays. Immunostaining of human retinal sections revealed that SAMD7 is localized in the nuclei of both rods and cones, as well as in those of cells belonging to the inner nuclear layer. These results place SAMD7 as a gene crucial for human retinal function and demonstrate a significant difference in the role of SAMD7 between the human and the mouse retina.

Natural history of Usher type 2 with the c.2299delG mutation of USH2A in a large cohort.

BACKGROUND: The c.2299delG mutation is prevalent and accounts for 24.5% USH2A pathogenic variants, with promising prospects for customized gene therapy. MATERIALS AND METHODS: We compared the ocular and auditory phenotypes in a retrospective cohort of 169 Usher type 2 patients, with and without the c.2299delG allele, including visual acuity, slit-lamp examination, optical coherence tomography, kinetic perimetry, and audiometric assessment to define the hearing disability. Statistical methods used were covariate balancing propensity score and adjusted survival curves log-rank test for the analysis of visual acuity. RESULTS: We compare 54 Usher patients (31%) carrying at least one c.2299delG allele to 109 patients without this variant. The mean ages at onset of night blindness (14 years) and onset of peripheral vision deficiency (24 years) were similar in both groups, as was the severity of hearing loss (p = 0.731), even in homozygotes (p = 0.136). Based on the covariate balancing propensity score, the c.2299delG carrier patients developed cataract and reached a BCVA of 20/63 earlier than patients without this mutation (mean age 36 versus 42 y.o.; and 52.2 versus 55.1 y.o., respectively). Using adjusted survival curves and a log-rank test based on inverse probability weighting, patients with the c.2299delG variant reach blindness (BCVA <20/400) at 42.3 years old instead of 79.8 years for other USH2A pathogenic variants. CONCLUSIONS: We conclude that c.2299delG is associated with a more severe phenotype of the Usher type 2, in homozygotes and in compound heterozygotes.

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

OBJECTIVE: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. METHODS: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. RESULTS: We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported. CONCLUSIONS: Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

Functional characterization of a novel non-coding mutation "Ghent +49A > G" in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare disorder usually caused by heterozygous mutations in the iron-responsive element (IRE) in the 5' untranslated region (5'UTR) of the L-ferritin gene (FTL), disturbing the binding of iron regulatory proteins (IRPs) and the post-transcriptional regulation of ferritin expression. Here, the proband of a consanguineous family displayed moderate bilateral cataracts and elevated serum ferritin in the absence of iron overload. The parents and siblings showed variable degrees of mild bilateral cataracts combined with elevated levels of circulating ferritin. Sequencing of FTL identified a novel 5'UTR mutation c.-151A > G, also named "Ghent +49A > G". The zygosity of the mutation, occurring in homozygous and heterozygous state in the proband and other affected family members respectively, correlated well with severity of ophthalmological and hematological manifestations. The substitution is expected to impair the secondary structure of the upper IRE stem. Functional characterization of +49A > G by electrophoretic mobility shift assays demonstrated a reduced binding affinity for IRP1 compared to the wild-type IRE of FTL. Overall, we have expanded the repertoire of deleterious biallelic FTL IRE mutations in HHCS with this novel +49A > G mutation, the zygosity of which correlated well with the disease expression.

Management of congenital and posttraumatic splenic cysts in children.

Splenic cysts are rarely observed in young patients. We report three cases of splenic cysts. The management and the surgical procedure, if needed, are discussed. If the splenic cyst is symptomatic or if its size reaches a diameter of 4-6cm, it requires surgical management. This treatment would be performed by laparoscopic approach and is intended to spare splenic tissue as much as possible. A prophylactic anti-pneumococcal vaccination is recommended before surgical treatment.