[Leber optic neuropathy with clinical improvement]. / Lebersche Optikusneuropathie mit klinischer Besserung.

BACKGROUND: Spontaneous recovery in Leber's hereditary optic neuropathy is rare. Does the clinical course of Leber's hereditary optic neuropathy (LHON) differ between patients with and without spontaneous recovery? MATERIALS AND METHODS: We compared the clinical and molecular genetic characteristics of 12 visually symptomatic patients having the classical clinical course of LHON who recovered spontaneously with those of 60 who did not. RESULTS: Classical fundus findings and typical visual field defects were comparable in the two groups; vision improved within 18 months in all cases. The worst visual acuity during the acute stage of LHON was 0.03 in the recovery group. Patients with the 3460 and especially the 14484 mutation had a better chance of recovery. No patient with the 11778 mutation who recovered had secondary mutations. Among patients who recovered women were underrepresented and heteroplasmy was more common. Some families showed a raised rate of clinically affected members with recovery. CONCLUSIONS: The clinical picture of LHON remains the same regardless of whether the patient recovers spontaneously. A higher rate of spontaneous recovery characterizes some families. Spontaneous recovery is rare in women. Heteroplasmy is frequent in patients with recovery. Our results show a better clinical course of LHON in patients with the 11778 mutation without secondary mutations. Prognosis is better if the peripapillary microangiopathy is seen for a relatively long period, and there is only partial optic atrophy.

A pedigree of Leber's hereditary optic neuropathy with visual loss in childhood, primarily in girls.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) mostly affects young males. In patients carrying one of the primary mutations the risk to develop LHON is 50% for males and 10% for females. We report a family with predominantly young girls affected. METHODS: In a family with 14 known maternal relatives (11 females, 3 males) 9 patients in 4 generations developed LHON. Eight of the 9 patients were females. Three affected females could be examined and followed. RESULTS: The only affected male showed the typical course of LHON with acute visual loss in both eyes (20/400-20/800) within 6 weeks at 20 years of age. Eight of 9 females developed signs of LHON. In these females acute visual loss occurred at about 10 years of age. Final visual acuity was about 20/200. Central or paracentral scotomata, color vision defects and delayed P100 latencies in the VEP were seen. Ophthalmoscopy showed hyperemic discs in the acute stage and optic atrophy in later stages. Molecular genetic analysis revealed the presence of the mtDNA ND4/np11778 mutation in this family. Specific clinical or additional molecular genetic risk factors could not be detected. CONCLUSION: Families with LHON may show considerable variations of the clinical course and the gender- or age-specific risk. We present a family with a high disease penetrance of 64% and a 2 times higher risk for young females than for males. Furthermore, early visual loss in this family is permanent.

[Leber optic neuropathy in women and children]. / Lebersche Optikusneuropathie (LHON) bei Frauen und Kindern.

BACKGROUND: Leber's hereditary optic neuropathy is associated with point mutations in the mitochondrial DNA (mtDNA) that appear to be pathogenetic for this disease. These mutations affect nucleotide positions 3460, 11778 and 14484. Does the clinical course of LHON differ between men, women and children? MATERIALS AND METHODS: We reviewed the clinical and molecular genetic characteristics of 15 visually symptomatic patients with the clinical diagnosis of LHON (11 women and 4 male children) and compared them with 66 men with LHON. RESULTS: LHON was confirmed clinically and with molecular genetic methods in all cases. Men, women and children showed no differences: Classic fundus findings and typical visual field defects were equally found in both sexes. However, age at the beginning of the disease, severity of LHON and rate of spontaneous recovery differed between groups. Women were older (19-55 years, average 31.3 years) than men (15-53 years, average 24.3 years) at the beginning of the disease. Women suffered more severely from LHON. Spontaneous recovery of vision in women was extremely rare. Many more women had a LHON-affected mother than men. All the affected children (9-14, average 11.7 years at the beginning of the disease) did not have a good visual outcome. CONCLUSIONS: There are some differences in the course of LHON between men and women, concerning age, severity of LHON and rate of spontaneous recovery. Children may also have an unfavorable prognosis.

[Diagnostic error in Leber's optic neuropathy. Value of clinical and molecular genetic studies]. / Fehldiagnose Lebersche Optikusneuropathie (LHON). Stellenwert klinischer und molekulargenetischer Untersuchungen.

BACKGROUND: Leber's hereditary optic neuropathy is associated with point mutations in the mitochondrial DNA (mtDNA) that appear to be pathogenic for this disease. These mutations affect nucleotide positions 3460, 11,778 and 14,484. MATERIALS AND METHODS: We reviewed the clinical and molecular genetic characteristics of 29 visually symptomatic patients with the clinical diagnosis of LHON. RESULTS: Nine patients really suffered from LHON, but in 20 patients other ocular diseases could be proven. Degeneration of the retina and choroid was most common (seven patients), followed by vascular optic disease (six patients). Three patients suffered from tobacco-alcohol amblyopia, two from optic neuritis and two from autosomal dominant optic neuropathy. CONCLUSIONS: The clinical diagnosis of LHON is strengthened by a proven maternal inheritance and clinical signs such as a severe decrease in visual acuity, central or centrocecal scotomas in the perimetry and pseudoedema of the optic disc, followed by optic atrophy. Pathognomonic clinical signs of LHON are twisted vessels and ectatic capillaries in the fundus of these patients and their relatives of the maternal line, i.e., peripapillary microangiopathy. A careful analysis of the patients' pedigrees, anamnesis and the functional and morphological results of the clinical examinations helps to avoid misdiagnosis of the disease. However, the expensive and time-consuming molecular genetic analysis is always necessary to confirm or exclude the diagnosis of LHON.

RDS/peripherin gene mutations are frequent causes of central retinal dystrophies.

Patients from 76 independent families with various forms of mostly central retinal dystrophies were screened for mutations in the RDS/peripherin gene by means of SSCP analysis and direct DNA sequencing. Two nonsense mutations (Gln239ter, Tyr285ter), five missense mutations (Arg172Trp, Lys197Glu, Gly208Asp, Trp246Arg, Ser289Leu), and one single base insertion (Gly208insG), heterozygous in all cases, were detected. Only one of these mutations, Arg172Trp, has been reported previously. Cosegregation of the mutation with the disease phenotype could be established in selected families. Other missense mutations were excluded from a panel of 55-75 control subjects. The patients showed remarkable variation in phenotype and disease expression not only between cases with different mutations but also between affected members of the same family. This study indicates that RDS/peripherin mutations are a frequent cause of various types of central retinal dystrophies and that the RDS/peripherin gene exhibits a broad spectrum of allelic mutations. Comparative analysis of known mutations allowed us to hypothesise that the deleterious effect of RDS/peripherin gene mutations is the result of different molecular mechanisms.

Mutation analysis of the ND6 gene in patients with Lebers hereditary optic neuropathy.

DNA sequence analysis of the gene encoding subunit 6 of the NADH-ubiquinone-oxidoreductase complex (ND6) in human mitochondria was performed in 25 independent patients who suffer from Lebers hereditary optic neuropathy (LHON). In 10 cases the well-known LHON mutation at nucleotide position (np) 14484 was detected. Furthermore, silent substitutions at np14167 and np14527 and missense mutations at np14498, np14564, np14568, and np14582 were found in individual patients. The np14498 and np14568 mutations were found in patients who present a typical clinical picture and course of LHON but lack any of the canonical mtDNA mutations. The np14568 mutation, which replaces a moderately conserved glycine by a serine residue, was observed in a single male patient and subsequently excluded in 175 independent controls. The mutation at np14498, which replaces an evolutionarily highly conserved tyrosine with a cysteine, was found in a multigeneration family with four affected members, the eldest carrying a heteroplasmic mixture of mutated and wildtype mtDNA molecules. None of 170 analyzed control subjects carried this mutation. These findings provide evidence that several allelic ND6 gene mutations may be involved in Lebers hereditary optic neuropathy.

Leber's hereditary optic neuropathy: clinical and molecular genetic results obtained in a family with a new point mutation at nucleotide position 14498 in the ND 6 gene.

Mitochondrial DNA mutations at nucleotide position (np) 3460 in the ND 1 gene, np 11778 in the ND 4 gene, and np 14484 in the ND 6 gene are commonly considered to be associated with the clinical features of Leber's hereditary optic neuropathy (LHON) and account for the majority of LHON cases. Recently, a further mutation in the mtDNA at np 14459 was detected. Herein we report the clinical and the most relevant molecular genetic findings obtained in a LHON family with a new mitochondrial DNA mutations at np 14498 in the ND 6 gene. Clinical and historical data were collected over four generations on three affected and five yet unaffected relatives of the maternal line in this family. All three patients and four of their relatives underwent molecular genetic examination. Two patients and five relatives were also studied clinically. All patients exhibited typical clinical features of LHON. In all yet unaffected relatives, various degrees of peripapillary microangiopathy were found. Molecular analysis did not reveal any of the common LHON mutations. Sequence analysis of the mtDNA of one patient was performed and showed a thymine-to-cytosine exchange at np 14498 in the ND 6 gene, leading to the replacement of an evolutionary highly conserved tyrosine by a cysteine residue. The mutation was not found among 70 other LHON lineages and 180 controls. The new mutation at np 14498 lies in the vicinity of the LHON-related mutations at np 14484 and of the recently described mutation at np 14459, in a region constituting the most evolutionarily conserved part of this polypeptide. That the new mutation at np 14498 is found within this highly conserved region and was not present in any controls implies that this mutation is responsible for LHON in this family.

[Correlation between clinical and molecular genetic findings in Leber's optic atrophy]. / Korrelation klinischer und molekulargenetischer Befunde bei Leberscher Optikusneuropathie (LHON).

Leber's hereditary optic neuropathy (LHON) is associated with point mutations of mitochondrial DNA (mtDNA) that appear to be pathogenetic for this disease. These mutations affect nucleotide positions 3460, 4160, 11,778, 14,484, and possibly 15,257. The pathogenetic significance of other mtDNA point mutations (secondary mutations) is less clear. We reviewed the clinical and molecular genetic characteristics of 29 visually symptomatic patients from 26 families. In addition, we studied 54 relatives of the maternal line of these patients. Sixteen of them underwent clinical and molecular genetic examination; 38 underwent only molecular genetic examination. The 29 affected individuals showed a male predominance of 93.1% (27/29) and ages of onset of visual loss ranging from 15 to 55 years. The time interval between affected eyes was never longer than 1 year. Tobacco and/or alcohol abuse was common. Peripapillary microangiopathy was found in 20.7% (6/29) of our patients. The number of patients with peripapillary microangiopathy seems to be small, but we could not examine all patients early after onset of the disease: the time of first examination is critical for the diagnosis of peripapillary microangiopathy. From the 16 relatives who underwent clinical examination, 62.5% (10/16) also had peripapillary microangiopathy. Eighteen patients were analyzed by brain computed tomography or magnetic resonance imaging. Four definitely pathological results seem remarkably high in comparison with the results of other authors. Our LHON patients and their relatives invariably had an identical pattern of point mutations, both primary as well as secondary. Of the LHON patients, 79.3% had the primary mutation at position 11,778, 20.7% at position 3460. Different numbers and combinations of secondary mutations were observed in a large portion of both groups. Three patients with the 11,778 mutation noticed remarkable visual recovery. There was no clear correlation between the type and number of point mutations in the individual and the severity of the disease.

Effect of K(+) and Cl (-) ion gradients upon apex regeneration in Acetabularia mediterranea.

Regeneration of a new apex and electrical activity by anucleate posterior stalk segments (PSS) of Acetabularia mediterranea under imposed transcellular concentration gradients of K(+) and Cl(-) has been studied. In a 3 vs. 30 mM K(+) and in a 26 vs. 545 mM Cl(-) gradient, respectively, the PSS preferably regenerate at that end exposed to the low K(+) (replaced by Na(+)) and low Cl(-) (replaced by SO 4 (2-) ), respectively. The effect of the K(+) gradient confirms previous work where voltage-clamped PSS regenerated at the electrically hyperpolarized end (Novák and Bentrup, Planta 108, 227, 1972). The stimulation of regeneration by low Cl(-), that is, at the depolarized end of the PSS, might be mediated by the electrical impulses arising at this end.