RESUMO
Sorsby fundus dystrophy (SFD) originally was characterized as an autosomal dominant disorder in which patients lose central vision during the 4th or 5th decade of life. Since Sorsby's initial description, interfamilial phenotypic variations have been noted and have given rise to controversy as to whether SFD constitutes more than one nosologic entity. In addition, several reports have proposed the existence of a recessively inherited form of SFD. The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3) as the disease-causing gene in SFD has made it possible to address the questions of clinical and genetic heterogeneity. In this study, we reinvestigated a large, highly consanguineous Finnish family previously diagnosed as having early-onset autosomal recessive SFD. We identified a novel heterozygous Gly166Cys mutation in TIMP3 in all affected individuals and provide strong evidence for an autosomal dominant inheritance of the SFD phenotype in this family. Our results, in conjunction with a critical review of the reported cases, render the existence of a recessive mode of inheritance in SFD questionable. Considering all available data, we suggest that SFD is a genetically homogeneous, autosomal dominant condition.
Assuntos
Fundo de Olho , Genes Dominantes , Genes Recessivos , Degeneração Macular/genética , Proteínas/genética , Adulto , Idade de Início , Consanguinidade , Análise Mutacional de DNA , Feminino , Finlândia , Seguimentos , Haplótipos , Humanos , Masculino , Linhagem , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Inibidor Tecidual de Metaloproteinase-3RESUMO
On the Aland Islands, a 1-month-old girl was diagnosed as having Wolman disease. The diagnosis was confirmed neurochemically; a decreased activity of acid lipase was noted in the proband and her parents had typical carrier values. This is the first Scandinavian case reported. The skin biopsy revealed cytoplasmic accumulations identical to those noted in two sibs who highly probably had Wolman disease during the 1950s. Both these sibs died at the age of about 3 months and presented a heavy accumulation of lipid material in lymph nodes, spleen, adrenal glands, liver, gut, and also some pathological alterations in other organs. Electron microscopic findings from deparaffinized samples showed cytoplasmic accumulation of lipid material similar to that noted in Wolman disease. Genealogical analyses revealed that the index families had ancestors from the same restricted area and also common ancestors during the 17th century. The parents of the two affected sibs were born on a small island and were related in many different ways. On the basis of genealogical studies and other genetic investigations performed, the importance of founder and drift effect for manifestations of rare hereditary disorder in isolates is stressed.
Assuntos
Doença de Wolman/genética , Doença de Wolman/patologia , Consanguinidade , Erros de Diagnóstico , Feminino , Finlândia , Doença de Gaucher/diagnóstico , Humanos , Lactente , Lipase/sangue , Masculino , LinhagemRESUMO
We have performed a reinvestigation of a family with a presumably autosomal recessive form of pseudoinflammatory dystrophy, which we have followed for 25 years. The symptoms in this family are subretinal haemorrhages appearing at age 13-40 years in the central fundus, resulting in glial cicatrication in the outer retinal layers, progressive myopia and profound choroidal atrophy in the advanced stages of the disease. During the follow-up study, a new affected subject was found in the younger generation, and two collateral cases, who had earlier been considered as probably affected subjects, were now considered to have other fundus affections. The new case is the daughter of an affected female. The possibilities of an autosomal dominant mode of inheritance or pseudodominance are discussed. Extended genealogical studies showed that the parents of all the affected subjects, with the exception of the new case, have their origin in an area which was isolated until recently and have several common ancestors within the last 8-10 generations. Recessive inheritance also logically explains the appearance of the disease in so few other members in the vertical line of the family. To this fundus dystrophy, the rule of Lenz seems to apply: If more or less the same phenotype can be caused by both a recessive and a dominant gene, the phenotype caused by the recessive gene is generally manifested earlier and by more severe symptoms.
Assuntos
Distrofias Hereditárias da Córnea/genética , Fundo de Olho , Adolescente , Adulto , Fatores Etários , Consanguinidade , Distrofias Hereditárias da Córnea/complicações , Distrofias Hereditárias da Córnea/epidemiologia , Feminino , Finlândia , Seguimentos , Genes Recessivos , Humanos , Masculino , Miopia/etiologia , Linhagem , Refração Ocular , Acuidade VisualRESUMO
Electrophysiological studies showed that a patient with Aland eye disease had no misrouting of the optic pathways which is always found in all forms of albinism as a consequence of the retino-geniculate anomaly. Also the spontaneous and optokinetic nystagmus did not resemble that of the large majority of human albinos. The marked asymmetry found in this patient seems to be typical for humans with a defective development of foveal binocular vision. These findings are in agreement with clinical, nystagmographic and EM findings that Aland eye disease is distinct from the Nettleship-Falls type of X-linked ocular albinism. Furthermore, Aland eye disease is different from X-chromosomal congenital stationary night blindness with myopia by the fact that the scotopic functions are only moderately affected and there is no restriction of the peripheral photopic visual fields. In addition, there is latent nystagmus of extraocular type that appears also in female carriers. There is no ophthalmoplegia, there is a progression of the myopia and the dyschromatopsia is of secondary type.
Assuntos
Albinismo/genética , Ligação Genética , Cromossomo X , Adulto , Albinismo/complicações , Albinismo/fisiopatologia , Eletronistagmografia , Potenciais Evocados Visuais , Oftalmopatias/genética , Oftalmopatias/fisiopatologia , Fundo de Olho , Humanos , Masculino , Nistagmo Patológico/complicações , Nistagmo Patológico/genética , Nistagmo Patológico/fisiopatologia , Síndrome , Campos VisuaisRESUMO
A family in southwest Finland with bilateral hemorrhagic degeneration of the retina and choroid was followed up for more than 16 years. The maculas showed subretinal hemorrhages, glial cicatrization of the outer retinal layers, and profound choroidal atrophy, particularly in the advanced stages of the disease. Fluorescein angiography demonstrated leakage through the pigment layer in the retinal tissue. The age of onset varied from the second to the fourth decade. The clinical pattern was similar to Sorsby's pseudoinflammatory dominant fundus dystrophy, except that the disorder appeared earlier in this Finnish family, the members of which show secondary dyschromatopsia, many deep hyaloid bodies in the retina, disturbed dark adaptation (1 to 4 log units), subnormal light-peak/dark-trough ratios, progressive myopia, and a mode of inheritance which is probably autosomal recessive. The affected parents are consanguineous in many ways and each of their eight children is affected.