Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.

Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil.

OBJECTIVE: Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, CLN 3, Batten Disease) (OMIM #204200) belongs to the most common group of neurodegenerative disorders of childhood. We report the clinical data and molecular analysis of a large Brazilian family. METHOD: Family composed of two consanguineous couples and thirty-two children. Clinical data of ten JNCL patients and molecular analyses on 13 participants were obtained. RESULTS: The large 1.02 kb deletion was detected. The most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-year-old male. Nyctalopia was the first symptom in one deceased child. The visual loss of six patients has been first observed in the school and not at home. CONCLUSION: The report highlights the phenotypical intrafamily variation in 10 affected children of this family. The molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling.

Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil / Lipofuscinose ceróide neuronal juvenil: investigação clínica e molecular em uma família grande no Brasil

OBJECTIVE: Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, CLN 3, Batten Disease) (OMIM #204200) belongs to the most common group of neurodegenerative disorders of childhood. We report the clinical data and molecular analysis of a large Brazilian family. METHOD: Family composed of two consanguineous couples and thirty-two children. Clinical data of ten JNCL patients and molecular analyses on 13 participants were obtained. RESULTS: The large 1.02 kb deletion was detected. The most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-year-old male. Nyctalopia was the first symptom in one deceased child. The visual loss of six patients has been first observed in the school and not at home. CONCLUSION: The report highlights the phenotypical intrafamily variation in 10 affected children of this family. The molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling.

OBJETIVO: Lipofuscinose Ceróide Neuronal Juvenil (JNCL, CLN 3, Doença de Batten) (OMIM # 204200) pertence ao grupo mais comum de doenças neurodegenerativas na infância. É causada por mutações no gene CLN3, com padrão de herança recessiva. A deleção de 1,02 kb é a mutação mais comum. Relatamos os dados clínicos e análise molecular de uma família consanguínea numerosa. MÉTODO: Família composta por dois casais consanguíneos e trinta e duas crianças. Foram obtidos dados clínicos de dez pacientes e análises moleculares de 13 participantes. RESULTADOS: Foi detectada deleção de 1,02 kb. O fenótipo mais grave, com comportamento autista, tiques e parkinsonismo foi visto em uma paciente do sexo feminino de 12 anos e o fenótipo mais leve em um paciente do sexo masculino de 14 anos. Nictalopia foi o primeiro sintoma de uma criança falecida. A perda visual de seis pacientes foi observada pela primeira vez na escola e não em casa. CONCLUSÃO: Destaca-se a variação fenotípica intrafamiliar em 10 pacientes. A investigação molecular desta família numerosa tornou possível o diagnóstico, a abordagem correta e aconselhamento genético.

Calcium channelopathies.

Intracellular calcium ([Ca2+]i) is highly regulated in eukaryotic cells. The free [Ca2+]i is approximately four orders of magnitude less than that in the extracellular environment. It is, therefore, an electrochemical gradient favoring Ca2+ entry, and transient cellular activation increasing Ca2+ permeability will lead to a transient increase in [Ca2+]i. These transient rises of [Ca2+]i trigger or regulate diverse intracellular events, including metabolic processes, muscle contraction, secretion of hormones and neurotransmitters, cell differentiation, and gene expression. Hence, changes in [Ca2+]i act as a second messenger system coordinating modifications in the external environment with intracellular processes. Notably, information on the molecular genetics of the membrane channels responsible for the influx of Ca2+ ions has led to the discovery that mutations in these proteins are linked to human disease. Ca2+ channel dysfunction is now known to be the basis for several neurological and muscle disorders such as migraine, ataxia, and periodic paralysis. In contrast to other types of genetic diseases, Ca2+ channelopathies can be studied with precision by electrophysiological methods, and in some cases, the results have been highly rewarding with a biophysical phenotype that correlates with the ultimate clinical phenotype. This review outlines recent advances in genetic, molecular, and pathophysiological aspects of human Ca2+ channelopathies.

Síndrome de Goldmann Favré: estudio clínico de una familia / Goldmann: favre syndrome clinical study of one family

Se presenta el estudio clínico y genético de una familia (cinco casos) con Síndrome de Goldmann-Favé. Cuatro pacientes son del sexo femenino y uno masculino: Todos con disminución de la agudeza visual bilateral, con nictalopia reportada desde la primera década de la vida, presencia de catarata subcapsular posterior en algunos de ellos; así como desprendimiento de retina en tres pacientes. En la exploración al fondo de ojo se encontró licuefacción vítrea y datos de retinosis pigmentaria.