In the mild form of retinitis pigmetosa a significant increase of mean paternal age 38.8 years which is suggestive of new mutations

Josseline Kaplan1 , Dominique Bonneau1, Jean Frézal1, Arnold Munnich1 and Jean-Louis Dufier2

(1) Clinique de Génétique Médicale, Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U.12, Hôpital des Enfants-Malades, 149, Rue de Sèvres, 15 Paris Cedex, France
(2) Consultation d'Ophtalmologie, Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U.12, Hôpital des Enfants-Malades, 149, Rue de Sèvres, 15 Paris Cedex, France

Received: 12 December 1989 Revised: 14 March 1990

Summary The clinical course of defective vision and blindness has been investigated in relation to different modes of genetic transmission in a large series of 93 families with retinitis pigmentosa (RP). For autosomal dominant RP, two clinical subtypes could be distinguished according to the delay in macular involvement. In the severe form, macular involvement occurred within 10 years, while in the mild form, macular involvement occurred after 20 years. Interestingly, a significant increase of mean paternal age (38.8 years, mean controls in France = 29.1 years, P < 0.001) was found in this form of RP, a feature which is suggestive of new mutations. For autosomal recessive RP, four significantly different clinical subtypes could be recognized, according to both age of onset and the pattern of development (P < 0.001), namely cone-rod dystrophy and early-onset severe forms on the one hand (mean age of onset = 7.6 years), late-onset mild forms and senile forms on the other. Similarly, two significantly different clinical subtypes could be recognized in X-linked RP, according to both mode and age of onset, which were either myopia (mean age = 3.5±0.5 years) or night blindness (mean age = 10.6±4.1 years, P < 0.001). By contrast, no difference was noted regarding the clinical course of the disease, which was remarkably severe whatever the clinical subtype (blindness before 25 years). In addition, all obligate carriers in our series were found to have either severe myopia or pigment deposits in their peripheral retina. Finally, sporadic RP represented the majority of cases in our series (42%). There was a considerable heterogeneity in this group, and at least three clinical forms could be recognized, namely cone-rod dystrophy, early onset-severe forms and late onset moderate forms. At the beginning of the disease, the hereditary nature of the sporadic forms was very difficult to ascertain (especially between 7–10 years) and only the clinical course could possibly provide information regarding the mode of inheritance. However, the high level of consanguinity, and the high sex ratio in early onset and severe sporadic forms (including cone-rod dystrophy), was suggestive of an autosomal or X-linked recessive inheritance, while increased paternal age in late onset forms was suggestive of autosomal dominant mutations.

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Hum Genet. 2005 Jul;117(2-3):288-90.



Parents of children with autosomal recessive diseases are not always carriers of the respective mutant alleles.

Zlotogora J.

Department of Community Genetics, Public Health Services, Ministry of Health, Tel Aviv, Israel. joelz@cc.huji.ac.il

Classically, each parent of a child with an autosomal recessive disease has been considered to carry at least one copy of the abnormal allele. However, with the increasing ability to characterise the molecular basis of genetic diseases, several exceptions have been reported. The most frequent situation is that only one parent is a carrier of the mutation that is present in the patient in two copies either because of uniparental disomy or because of a de-novo mutation on the gene transmitted by the non-carrier parent. In order to give accurate genetic counselling, in particular when prenatal diagnosis is envisaged, molecular analysis of each of the parents of a child affected with an autosomal recessive disease must be routinely performed.

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