Mitochondrial DNA analysis as a diagnostic tool in singleton cases of Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is characterized by subacute loss of central vision due to bilateral optic nerve atrophy accompanied by several nonspecific clinical findings. The only pathognomonic feature is its strictly maternal inheritance. It was therefore impossible to establish the diagnosis in patients with no known affected matrilinear sibs, until several mutations in the mitochondrial DNA (mtDNA) were discovered in relation to LHON. The authors describe the case histories and the occurrence of six mtDNA mutations in eight presumed singleton LHON patients and discuss the clinical and genetic implications of the result

The importance of DNA analysis in sporadic aniridia

Total aniridia was found in a 2-month-old baby boy. Otherwise the baby was healthy. Ophthalmological examination of the elder sister, parents and paternal grandparents revealed no abnormalities. There was no consanguinity between the parents. Hence, the aniridia was considered sporadic, and the possibility of Wilms' tumour had to be taken into consideration. The chromosomes of the baby were normal, as judged by conventional cytogenetic analysis. In addition, DNA analysis demonstrated that there was no subchromosomal deletion in band 11p13, spanning the aniridia-Wilms' tumour region. Therefore, we conclude that the genetic defect leading to aniridia is confined to the aniridia locus and that the child has no increased risk of developing Wilms' tumou

A retrospective study of registered retinitis pigmentosa patients in The Netherlands

A retrospective study was performed of patients with retinitis pigmentosa (RP) registered at the Department of Ophthalmogenetics of the Netherlands Ophthalmic Research Institute. The aim was to establish the relative frequencies of the genetic modes and to attempt a clinical subclassification. Of the 575 RP patients, 10.4% were X-linked, 22.4% autosomal dominant, 30.1% autosomal recessive, and 37.1% simplex cases. Clinical classification was inconclusive, and consequently correlation of phenotype to genotype impossible in most cases. One exception was the occurrence of a tapetal reflex, which seemed to differentiate between RP2 and RP3. Gene defects have not been detected so far in Dutch families with either autosomal dominant or autosomal recessive RP. In the future, simplex cases will have to be classified according to their genetic defects. It is probable that results of DNA studies may prove a better basis for classification of RP than clinical dat

No evidence for 'skewed' inactivation of the X-chromosome as cause of Leber's hereditary optic neuropathy in female carriers

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder of the optic nerves. It has been proposed that the specific mutations in the mitochondrial DNA (mtDNA) that are associated with LHON require and X-chromosomally encoded permissive factor in order to become expressed. This would explain both the preponderance of male patients and the fact that most carriers of specific mtDNA mutations remain unaffected. Although linkage studies have been negative so far, the existence of such a factor has not been ruled out. We investigated the genealogical data of 24 large LHON pedigrees and concluded that the presumed X-linked factor would be recessively inherited and that at least 57% of the affected females would be heterozygous. Therefore, these females must be the victim of nonrandom X-chromosomal inactivation (skewed lyonization). However, analysis of X-chromosomal methylation patterns in 16 LHON-affected females revealed substantial skewing in only 15%-20% of cases, which is not significantly different from the patterns in 49 controls. Moreover, we found the frequency of LHON in daughters of affected heterozygous females to be twice to three times as high as in daughters of unaffected heterozygous females, which cannot be explained by an X-chromosomally inherited factor. We concluded that the results of our investigations do not support the hypothesis that LHON is a digenic disease with an X-linked factor being the main cause of loss of vision in the presence of relevant mtDNA mutation

Leber-opticusatrofie; een mitochondriaal overervende ziekte

Leber hereditary optic neuropathy (LHON) is a heritable disorder, clinically characterized by rapidly progressive loss of central vision due to severe bilateral optic atrophy. The disease predominantly occurs in men. The clinical picture shows marked interpersonal variation. Recently it has been established that LHON is associated with at least three specific mutations in the mitochondrial DNA, which explains the non-Mendelian, strictly maternal inheritance. The presence of different mutations implies that there is not only clinical but also genetical heterogeneity. Since all matrilinear family members carry the mtDNA mutation involved, but only 30-50% of males and 5-15% of the females develop LHON, other etiological factors, hereditary or exogenous, remain to be discovered. Identification of these factors is of major importance to understand the pathogenesis and to explore the possibilities for therapy and prevention of LHO

Long term survival of a patient with the cerebro-hepato-renal (Zellweger) syndrome

A 13-year-old girl with severe mental retardation, tapetoretinal degeneration, an extinguished electroretinogram and sensoneurinal hearing loss is described. In early life the diagnosis of Zellweger (cerebro-hepato-renal) syndrome was considered because of hypotonia, craniofacial dysmorphia, abnormal liver functions and pipecolic aciduria. Biochemical studies in fibroblasts from the patient revealed a general peroxisomal dysfunction comparable to the findings in Zellweger Syndrome. As the clinical presentation of this patient is essentially different from that in classical Zellweger patients, who usually die early in life, we recommend the study of peroxisomal functions in all patients with severe mental retardation, tapetoretinal degeneration and sensoneurinal hearing los

DNA diagnosis in a family with autosomal dominant aniridia

A large family with autosomal dominant aniridia is described. One of the family members presented with reduced visual acuity, nystagmus, slightly distorted macular reflex, but normal irides and clear media. Because of the high variability in expression of aniridia, even within family, a diagnosis of aniridia could not be excluded. However linkage analysis using tightly linked chromosome 11p13 markers flanking the aniridia locus (catalase, D11S151, and D11S325) made it highly unlikely that this patient inherited the aniridia gene from his affected mothe

Multipoint linkage analysis in X-linked juvenile retinoschisis

Thirteen families with X-linked juvenile retinoschisis (XLRS) were studied in order to evaluate the linkage relationship between the XLRS locus (RS) and seven X-chromosomal DNA markers. Linkage was found between RS and DXS9 (theta max = 0.11, Zmax = 4.17), DXS16 (theta max = 0.06, Zmax = 7.72), DXS41 (theta max = 0.06, Zmax = 8.13) and DXS43 (theta max = 0.03, Zmax = 6.11). Recombinants were found between RS and all loci studied. Multipoint linkage analysis and recombination analysis significantly favour the order of Xpter-(DXS9, (DXS16-DXS43))-RS-DXS41-Xce