Ophthalmic manifestations in patients with Leigh syndrome, French Canadian type.

BACKGROUND: Leigh syndrome, French Canadian type is a rare neurodegenerative disease. To our knowledge, there have been no studies based on ocular findings published for this disease. The purpose of this study is to describe ophthalmic findings in these patients. PATIENTS: Six patients genetically identified as having the syndrome were included in this study. METHODS: Four patients had an ophthalmic examination with an ophthalmologist including evaluation of visual acuity, extraocular motility and lid position, orthoptic workup, evaluation of stereopsis, refraction, evaluation of pupils, color vision, slit-lamp biomicroscopy, measurement of intraocular pressure, and fundoscopy. Two patients had a chart review. RESULTS: Visual acuity ranged from 0.00 logmar to 1.55 logmar. Extraocular motility abnormalities and ptosis were noted in half of the patients. Strabismus was present in the entire cohort, and stereopsis was absent in half of these patients. Amblyopia was noted in 83% of individuals and suppression in 33%. Only one patient had nystagmus. Refraction varied throughout patients. It included severe hyperopia, myopia, astigmatism, and significant anisometropia. Pupils, anterior segment, fundus, and color vision were normal in all patients. Intraocular pressure was slightly elevated in one patient. CONCLUSION: Patients with Leigh syndrome, French Canadian type display a variety of ophthalmic findings, and screening at a young age is recommended.

Novel truncating mutation in CACNA1F in a young male patient diagnosed with optic atrophy.

BACKGROUND: Low vision in children can be accompanied by pallor of the optic disc with little or no characteristic morphologic changes of the retina. A variety of diseases can be the underlying cause, including hereditary optic atrophy, Leber's congenital amaurosis (LCA), achromatopsia, and calcium channel, voltage-dependent, L-type, alpha-1F subunit gene (CACNA1F)-associated retinopathy (most widely known as incomplete congenital stationary night blindness: iCSNB). Differentiation at early age is desirable due to large differences in prognosis, but may be difficult because phenotypes overlap and electrophysiological testing is challenging in young patients. We present the case of a 6-year-old boy with unexplained low vision and pallor of the optic disc who originally had been diagnosed with hereditary optic atrophy in the absence of recordable full-field electroretinography (ERG) due to poor patient cooperation. MATERIALS AND METHODS: Standard Sanger sequencing excluded mutations in the OPA1 gene (autosomal-dominant optic atrophy). To identify the underlying genetic cause, whole-exome sequencing was performed on patient's DNA. Recording of the full-field ERG was successfully performed 6 months later. RESULTS: We identified a novel truncating mutation in CACNA1F gene (NM_001256789: c.3895C > T in exon 33) which led to the correct diagnosis of CACNA1F-associated retinopathy in the young boy. ERG recordings showed a negative scotopic mixed response with preserved oscillatory potentials and a flicker ERG with reduced amplitude and biphasic waveform, compatible with a CACNA1F-asssociated phenotype. CONCLUSIONS: We show that genetic testing may help to differentiate between optic atrophy, LCA, and CACNA1F-associated retinopathy at a much earlier age, in absence of electrophysiological examination and by widely overlapping phenotypes.

OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model.

Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients.

Toll-like receptor 4 (TLR4) gene polymorphisms in giant cell arteritis.

OBJECTIVE: To investigate potential associations between toll-like receptor 4 (TLR4) gene polymorphisms and susceptibility to, and clinical features of giant cell arteritis (GCA). METHODS: A total of 155 patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 210 population-based controls from the same geographical area were genotyped for two coding single nucleotide polymorphisms of TLR4 (Asp299Gly and Thr399Ile) by molecular methods. The patients were subgrouped according to the presence or absence of polymyalgia rheumatica and severe ischemic complications (visual loss and/or cerebrovascular accidents). RESULTS: The distribution of allele and genotype frequencies did not differ significantly between GCA patients and healthy controls. Carriers of the -299 G allele (G/A+ G/G) [odds ratio (OR) 1.78, 95% confidence intervals (CI) 0.90-3.50)] were more frequent among GCA patients than among the controls, but the difference was not statistically significant. No significant associations were found when GCA patients with and without PMR or with and without severe ischemic complications were compared. CONCLUSION: Our data suggest that the TLR4 gene polymorphisms are not associated with susceptibility to, and clinical expression of, GCA in Italian patients.

Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.

OBJECTIVE: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappaB activity predict the Blau syndrome/EOS clinical phenotype. METHODS: Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB activity with muramyldipeptide. RESULTS: All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappaB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappaB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. CONCLUSION: NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.

[Successful treatment of clinical manifestations of Muckle-Wells syndrome with anakinra]. / Erfolgreiche Behandlung der klinischen Manifestationen des Muckle-Wells-Syndroms mit Anakinra.

HISTORY: A 58-year-old woman and her 18-year-old daughter were first seen in our rheumatology centre after having experienced many years of periodic fever, arthralgia and urticaria. Some months ago a diagnosis of Muckle-Wells syndrome (MWS) had been made and confirmed by genetic testing. The mother had developed partial deafness and substantial loss of vision. Her daughter had been suffering mainly from urticaria and fever at least once daily. THERAPY: Because of the established role of interleukin (IL)-1 in this hereditary disease and some positive case reports, we decided to treat these patients with the IL-1 receptor antagonist anakinra. The patients reported a great success of this treatment with virtually complete absence of any acute MWS-associated symptoms. CONCLUSION: Therapy of MWS with anakinra seems to be highly efficacious for several clinical manifestations of this disease, including laboratory markers for inflammation. It is possible that organ destruction may be prevented by this medication.

Etiología de la ceguera y visión subnormal en Colombia: frecuencia de enfermedad genética / Ethiology of blindness and subnormal vision in Colombia: incidence of genetic disease

La Unidad de Genética clínica del Instituto de Genética Humana de la universidad Javeriana y la Fundación oftalmológica Nacional, realizaron un estudio piloto, para determinar las diferentes causas de la ceguera y visión subnormal en población institucionalizada en Colombia. Se evaluaron 1295 personas ciegas o con visión subnormal, adscritos a 23 institutos de 17 ciudades del país. Se realizó una completa evaluación médica general y genética, personal y familiar. Se determinaron las diferentes etiologías de la limitación visual en esta población, clasificándolas en tres grandes grupos : causa genética, causa no genética y causa indeterminada. El 31.3/100 correspondió a causas adquiridas o no genéticas. El 48.5/100 a causas genéticas, mientras que en el 20.2/100 no se pudo determinar la etiología básica de la patología.

Additional case of de novo interstitial deletion del(17)(q21.3q23) and expansion of the phenotype.

A child with multiple congenital abnormalities and a de novo interstitial deletion of the long arm of chromosome 17 is reported. This is the third case reported with this chromosome abnormality. The three cases present a peculiar phenotype, which is probably specific to the deletion.

Estudio genético en limitados visuales: rol del consejo genético / Genetical study of visual limmited: genetic counsil roll

Considerando que aproximadamente el 50% de los casos de ceguera infantil son de orden genético y además la tendencia en los limitados visuales a casarse entre ellos, el consejo genético es muy importante. Con este propósito, se investigan las causas de ceguera en 69 asistentes a la Escuela de la Corporación de Ayuda al Limitado Visual de Concepción. Con el objeto de clasificar y aclarar la etiología de su ceguera, pilar fundamental del consejo genético, se hace valoración dirigida de la historia clínica, antecedentes perinatales, pedigree y examen físico. Del total de limitados visuales, 33(47,8%) son de causa hereditaria; de éstos, 12(36,4%) tienen herencia autosómica dominante; 11(33,3%) autosómica recesiva; 2(6%) recesiva ligada al sexo, y 3(9,1%) probable herencia multifactorial. En 5 casos (15,2%) no se pudo precisar el mecanismo. En 8(11,6%) no se logró precisar etiología. Los 28(40,6%) casos restantes se deben a causa ambiental, siendo la mayoría de tipo postnatal. Se discute la importancia del consejo genético, tanto en el afectado como sus familiares, con la finalidad de evitar la recurrencia de cegueras previsibles