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Congenital glaucoma, a true hydrocephalus of the eye, is defined by ocular hypertension resulting in buphthalmos in children up to three years old, the elasticity of the eye wall allowing its expansion. Juvenile glaucoma in teenagers and chronic glaucoma in adults do not alter the external aspect of the eye, as the eyeball has lost its elasticity. However, chronic ocular hypertension always causes ischemic excavation of the optic nerve head, leading to insidious amputation of the visual field and, potentially, blindness. Like most ophthalmological disorders, the different types of glaucoma have been shown to be genetically determined, and alterations in several genes have been identified. These altered genes can be expressed more or less early in life, suggesting a role of modifier genes. The role of CYP1B1 alterations in classic primary congenital glaucoma is well known, as is the role of PITX2, FOXC1, PAX6 and LOXC1 alterations in secondary congenital glaucoma due to iridogoniodysgenesis, and of MYOC alterations in the genesis of chronic glaucoma in adulthood. An outbred family carrying CYP1B1 mutations in the compound heterozygous state includes two sibs with primary congenital glaucoma and two others who developed chronic glaucoma in adulthood.

Leber congenital amaurosis (LCA) is a the earliest and most severe form of retinal dystrophy responsible for congenital blindness. LCA has genetic heterogeneity and the study of this disease is elucidating the genetics and molecular interactions involved in the development of the retina. To date, 11 LCA genes have been mapped, ten of which have been identified. The CEP290 gene has been shown to account for Joubert and Senior-Loken syndromes and to be a frequent cause of nonsyndromic LCA. We report here the first Arab patient, born to consanguineous parents, with Leber congenital amaurosis attributable to mutation of the CEP290 gene., (Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.)

Age-related macular degeneration (ARMD) is a multifactorial and polygenic disease and is the main cause of vision loss in developed countries. The environmental factors of ARMD can modify prevalence and incidence of this disease. This article is a review of the main environmental factors currently recognized as at risk or protective factor for ARMD. Modification of these factors is of crucial importance because it could delay the onset of exudative or atrophic forms of the disease.

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium, but they are involved in strikingly different physiologic pathways, resulting in an unforeseeable pathophysiologic variety. This broad genetic and physiologic heterogeneity, which could greatly increase in the coming years, hinders molecular diagnosis in LCA patients. Genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here we report a comprehensive mutational analysis of all the known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% of patients. GUCY2D accounted for by far the largest part of the LCA cases in our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%) and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited in the search for phenotype variations. Genotype-phenotype correlations were found that made it possible to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rod-cone dystrophy. In addition, objective ophthalmologic data subdivided each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the onerous task of genotyping new patients, but only if the most precise clinical history since birth is available.

Hereditary macular dystrophies are degenerative diseases of the central area of the retina associating primary anomalies of the retinal pigment epithelium and sensory retina. These conditions, whose hallmark is a loss of visual acuity, are a major cause of blindness and affect patients at all ages. Macular dystrophies group diseases that are heterogenous at the genetic level, as well as at the clinical, histological and physiopathological levels. Monogenic macular dystrophies are rare autosomal dominant conditions, with the exception of Stargardt disease in its typical form, which is not only relatively frequent but is also inherited as an autosomal recessive trait. During the last few years, the molecular bases of these conditions have begun to be elucidated with the identification of several responsible genes. For some macular dystrophies, this new information has confirmed pre-existing hypotheses on their pathophysiology, but for others, the discovery of the disease gene has added further complexity to the disease process. Two contradictory concepts were particularly highlighted by these genetic studies. Several phenotypes previously described as different clinical entities were brought together by the identification of mutations in the same gene, and converselyome conditions that were clinically assigned the same name, often heterogeneous at the clinical level, appeared genetically and physiopathologically heterogeneous. In addition, it is worth noting that the monogenic macular dystrophy genes were often regarded as potential factors for susceptibility to age-related macular degenerations. However, to date, only ABCA4 mutations have been associated with a minority of this frequent multifactorial condition. The aim of this article is to give a progress report on the monogenic macular dystrophy genes and to review current knowledge concerning the pathophysiology of these conditions.

Macular dystrophies are a group of hereditary disorders of the macula occurring in children or young adults. The most frequent in France will be presented in detail: Best disease, Stargardt macular dystrophy, cone dystrophy, X-linked retinoschisis, pattern dystrophy, and malattia leventinese. Molecular biology studies have now mapped and identified the genes involved in these macular dystrophies. Analysis of the features of fundus examination will lead to further examinations such as fluorescein angiography, indocyanine green angiography, optical coherent tomography, electroretinography, or electrooculography, in order to confirm the diagnosis. We will also present the differential diagnosis of each of these macular dystrophies.

Age related macular degeneration (AMD) is the main cause of blindness after age 55 in western countries. These last past years, several lines of evidence such as familial aggregation or twin studies suggested a genetic component in AMD. However, the late onset of the disease and the fact that AMD is a polygenic and multifactorial disease are the main limiting factors for linkage studies. Gene candidate strategy allowed the exclusion of several genes (VMD2, RDS, TIMP3) and lead to the implication of two genetic factors: the apoE gene (involved in the transport of lipids) and the ABCR gene (involved in Stargardt macular dystrophy). Concerning the apoE gene, a lower frequency of the epsilon 4 alleles carriers was observed in the exudative AMD population compared with controls, supporting the idea of a role of the apoE gene in exudative AMD with drusen. These results, together with ultrastructural studies, suggest that allele epsilon 4 is a protective factor for drusen and thus for AMD. For the ABCR gene, several studies and a large multicentric study definitively show that some heterozygous mutations are predisposing factors for AMD, in a polygenic and multifactorial model.

Purpose: We have previously identified rhodopsin gene mutations in France in autosomal dominant (ADRP) retinitis pigmentosa in France, using a combination of SSCP (single-strand conformation polymorphism) and direct sequence analysis. The aim of this study was to perform a more rapid tool to identify a mutation in a ADRP family, when this mutation has been identified for one affected member of this family., Methods: We looked for a restriction site, created or abolished by a mutation in the rhodopsin gene. We performed in vitro DNA amplification using PCR (polymerase chain reaction), enzymatic digestion, and migration on agarose gel., Results: Abnormal patterns of migration were observed for affected ADRP members., Discussion: This technique is useful and rapid (less than 5 hours) to recognize a previously identified mutation. However, previous precise identification of the mutation in one member of the family is needed.

Duchenne and Becker muscular dystrophies (DMD and BMD) are two allelic recessive X-linked disorders. Molecular deletions of various regions of the dystrophin gene are the main mutations detected in DMD and BMD patients. Molecular study of DMD and BMD DNA are instrumental to understand the pathological molecular mechanisms and the function of the protein. We describe here dystrophin and its interaction with a glycoprotein complex and we then focus on two particular patients with partial deletions of the dystrophin gene: 1) a typical Becker patient, who shows an intragenic deletion disrupting the reading frame. We describe in this case alternative splicings restoring the reading frame, which might explain the mild clinical phenotype of this patient, 2) a deletion of the distal part of the DMD gene coding for the carboxyterminal domain of the dystrophin in a young patient. The normal localization of dystrophin at the inner face of the plasma membrane in the muscle of this patient suggests that the last domain of this protein is not sufficient to anchor dystrophin at the membrane.

In 1988, by using the powerful cDNA/PCR technique, it was demonstrated that there are very low levels of dystrophin mRNA in a variety of non-muscle tissues, including cultured fibroblasts and lymphoblastoid cell lines. The phenomenon was also shown for a number of other tissue-specific gene, including beta-globin, factors VIIIc and IX, anti-müllerian hormone, L-pyruvate kinase, retinal blue pigment, phenylalanine hydroxylase. The level of transcript in inappropriate cells is exceedingly low, perhaps one mRNA per 100-1,000 cells. This low-level ubiquitous transcription of tissue-specific genes was called "illegitimate" or "ectopic" transcription, and has been proven to occur for 17 gene transcripts to date. The mechanism and biological significance of illegitimate transcription are still obscure, but, since illegitimate transcripts exhibit the same pathology as legitimate transcripts, they have been useful tool in the study of already 9 inherited diseases. This strategy will be applied widely for diseases where samples from the appropriate tissue for study is difficult to obtain, or where an mRNA is easier or more informative to study than a genomic DNA (as for large genes, or where alternative splicings is involved).

The authors first give an account of the work undertaken jointly by two Canadian and one American groups, which lead to the cloning and identification of the cystic fibrosis gene. To achieve this aim, it was necessary to clone a large region amounting to 500 kb, using chromosome walking and jumping. The gene was located from a cross-hybridization signal with two probes from the cloned region and bovine cDNA. The CF gene is made of 24 exons giving a messenger of 6,500 nucleotides and a protein of about 1,500 aminoacids. The protein structure has been deduced from its composition in aminoacids. However, the localization of the protein in the cell and its true function remain an open question. At the same time workers from those groups identified the prevalent mutation in CF. These outstanding achievements will help unravelling the physiopathology of the disease. They increase the possibilities of prevention, but it is fanciful to think that they can lead to its eradication.

The availability of more and more reliable obstetrical echographies makes now possible to screen fetuses for microphtalmies and anophtalmies. More over, by mean of linkage studies with DNA markers within a family, we can identify the women who will transmit X-linked diseases, and realize a prenatal diagnosis. This technology can be applied to the following ophthalmological diseases: the X-linked retinoschisis, the choroideremia, the ocular albinism, the Noorie disease, and recently the retinoblastoma. From now on, the use of such a technology which makes it possible to detect ophthalmological diseases in the fetuses, is posing ethical problems especially in case of diseases without any survival prognosis involvement.

The authors, from their personal experience arising from 766 consultations, show that the percentages of marriages or procreations in subjects themselves suffering from a disorder, or with affected relatives, are independent of the risk estimated for their offspring. The procreation rate in couples with affected children is lower in high risk cases and depends also on the family composition. It appears that this procreation is voluntary in the great majority of cases because there were very few terminations of pregnancy among the couples seen before procreation. The estimated risks correspond to the risks observed but the authors insist that there is a relatively high proportion (4.4 per cent) of children born with a disorder different from that which motivated the consultation.

Ornithine transcarbamylase (OTC) deficiency is an inborn error of urea cycle metabolism, responsible for lethal hyperammonemia in males and for severe symptoms in at least 20% of heterozygous females. The authors provide here additional data on the informativity of the protein loading test (PLT) for the detection of heterozygotes. They show that the risk of being a carrier for the mother of an affected boy falls from 2/3 a priori to only 1/8 if her PLT is negative. The risk for the mother of heterozygote girl falls from 1/2 a priori to 1/16 if her PLT is negative.

The fears concerning potential hazards of man made recombinant DNA have been dismissed and the burden of compelling unnecessary safety regulations has been cleared away. The deciphering of the entire human genome at the nucleotide level is no longer an impossible task. It is based upon the utilization of cloned fragments of DNA used as specific probes. The present catalogue of cloned human genes is still small, but it will expand rapidly in the near future. There are two categories of probes: those corresponding to know genes, and those consisting of random "anonymous" DNA sequences present in genomic libraries. The increasing number of cloned probes will allow us to saturate progressively the entire genome. Medicine will benefit from this progress, first of all with regard to pre-natal and post-natal diagnosis of some genetic diseases and in the field of cancer research.

The authors give a summing up of ten years of genetic counselling concerning 1271 requests and single out two equally important categories of consultants. The first might require premarital counselling (in cases of consanguineous unions, or when one of the partners or relatives are affected) but, in fact, come to consultation, four times out of ten, after marriage and even after procreation. The consultants of the second group need prenatal counselling either because a child suffers from a hereditary disorder, or because earlier pregnancies did not come to term. Whichever the type, one consultation out of seven concerned a pregnant woman. A classification by type disorder and by mode of transmission is given.

Data are tabulated on the number of nomenclature current abbreviations, the occurence of multiple gene loci and corresponding polypeptide chains, and chromosomal assignment of 114 enzymes. Gene dose effect measurement is dependent upon several properties of the enzyme which are also listed: tissue and subcellular distribution, subunit number, interloci hybrids, genetic polymorphism, qualitative and quantitative methods of detection. The possibilities and limits of the concept of a gene-dose relationship, for the detection of carriers of chromosomal aberrations, and also for chromosomal assignment are discussed.

Among 924 consultations for definite or probable genetic disorders, two persons out of five seeking counselling run a high risk (10% or more) of having an affected child, one in five a risk varying between 1% and 9%, and two out of five a negligeable risk (less than 1%). In most cases (three out of four) individuals with affected relatives could be completely reassured, whilst one out of two affected persons seeking counselling ran a high risk of having a child who would suffer the same handicap. Among the normal parents with affected children, one out of three could be completely reassured, but on the other hand the same proportion ran a high risk of having another affected child. The calculated risks were compared in prenuptial, pre-pregnancy and prenatal counselling. The evaluation of the risk is only the first step in the counselling and certain special situations were chosen to demonstrate the factors which can modify the risk. The authors stress that genetic counselling, which is rarely simply indicative, should often be directive. In some cases, the prenatal diagnosis converts the theoretical risk into a certainty.

Nucleoside phosphorylase activity was assayed in two previously reported patients with trisomy for the proximal portion of 14q. A sesquialter dosage effect was demonstrated in erythrocytes as well as in leucocytes. These results are in favor of an ubiquitous expression of the gene and confirm its assignment to 14q13.

A case of severe lead poisoning with haemolytic anemia, extensive polyneuropathy and arterial hypertension is reported in a patient for whom G-6-P-D deficiency and renal tubular acidosis were discovered. Both traits were present in his family. Incomplete regression of paralysis and persistant biological abnormalities after chelating treatment were demonstrative of heavy saturnine load even though the toxic exposure was brief. The role of the two deficiencies in the mechanism of intoxication is discussed: facilitation of haemolysis by enzymopathy and bone lead redistribution resulting from osteolysis probably due to the tubulopathy. The authors emphasize the fact that thorough and serial biological investigation is essential in the discovery of factors which may precipitate lead poisoning, as well as in the determination of follow-up criteria of efficient toxic epuration with sufficient delay. Typing of the enzyme has led to the identification of a new variant of glucose-6-phosphate dehydrogenase deficiency.