Leber’s hereditary optic neuropathy with the 3434, 9011 mitochondrial DNA point mutation

Background  

Leber’s hereditary optic neuropathy (LHON) contains several well-known mitochondrial DNA (mtDNA) point mutations. We report a case with characteristic clinical manifestations of LHON involving a possible new LHON point mutation.     

Glaucoma progression associated with Leber’s hereditary optic neuropathy

The purpose of this article is to describe a case of open-angle glaucoma progression associated with Leber’s hereditary optic neuropathy. Single case analysis method is used. A 53-year-old woman with a previous diagnosis of glaucoma presented with progressive visual field loss. Complete ophthalmological examination and blood tests were negative for other concomitant diseases. Genetic counseling revealed mitochondrial DNA mutation compatible with the diagnosis of Leber’s hereditary optic neuropathy. In conclusion, the case describes the concomitant occurrence of open-angle glaucoma and Leber’s optic neuropathy. We hypothesize that the two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the consequent rapid progression of visual impairment. Screening for mitochondrial DNA mutations may be requested in patients with glaucoma who, despite pharmacologically controlled intraocular pressure, show rapid progression of the disease.     

Pupillary light reflexes in patients with Leber’s hereditary optic neuropathy

 Background: According to a recent pupillographic study, patients with Leber’s hereditary optic neuropathy (LHON) show the same pupillary behaviour as normals. Because this raises many questions concerning the real nature of LHON and challenges our concept of the afferent pupillary system, we tried to verify the results of this study. · Methods: Pupillary function was assessed in 34 normal subjects and 40 patients with LHON. Pupillary light reflexes were recorded by means of the Compact Integrated Pupillograph (CIP, AMTech). Under mesopic conditions 200-ms stimuli were presented at two different stimulus intensities. Latency, constriction amplitude and baseline diameter were defined automatically. Pupil light reflexes were compared between LHON patients and normals and between the better and the worse eye in 20 LHON patients with different visual acuities. · Results: For both stimuli there were significant differences in latency between LHON patients and controls. The latency of the pupil light reflex proved to be about 20 ms longer for LHON patients, and the amplitude was significantly smaller for the bright stimulus. Within LHON patients, the eyes with the worse visual acuity had a significantly smaller constriction amplitude than the eyes with the better visual acuity. · Conclusion: The results of our study confirm that LHON really is an optic nerve disease and that the pupillary light reflexes are not normal. Received: 5 January 1998 Revised version received: 28 February 1998 Accepted: 11 March 1998     

Clinical phenotype and the G11778A mutation of mitochondrial DNA in patients with Leber’s hereditary optic neuropathy in Taiwan

We report the clinical manifestations and mitochondrial DNA (mtDNA) mutations of nine Chinese patients with Leber’s hereditary optic neuropathy from seven families in Taiwan. The nine probands were all males, aged 19 to 43 years at the time of the study and with ages of onset ranging between 13 and 30 years. They were characterized by an acute or subacute onset of visual loss in one eye, which progressed to the other eye within a few weeks. Their visual outcome was poor, although improvement was noted in four patients. A muscle biopsy from one patient showed a decreased activity of cytochrome c oxidase and subsarcolemmal mitochondrial aggregation. All patients and unaffected maternal family members had a homoplasmic G11778A mtDNA mutation regardless of variations in clinical manifestation. High frequencies of environmental factors such as smoking, alcohol consumption, trauma, and/or military training were found in these patients. We conclude that even though a homoplasmic G11778A mtDNA mutation was found in all patients and their maternal family members, this mutation could not account for the presentation of the clinical features. Additional genetic, epigenetic, and/or environmental factors may be important trigger factors in the clinical expression.     

Leber’s hereditary optic neuropathy A report of two unusual cases

Two unusual cases of Leber’s hereditary optic neuropathy (LHON) are reported. The first case was a man with Charcot-Marie-Tooth (CMT) disease since childhood, who was affected with LHON (the 14484 mtDNA mutation) at the age of 45. He had several relatives with CMT, but none with LHON.A genetic interrelationship between these two diseases could not be excluded. The second case was affected with LHON (the 11778 mtDNA mutation) in one eye before the age of 2.5 years and in the other eye at the age of 14. There was no family history of LHON. The early age of onset and long inter-eye delay were remarkable.     

Is there alteration in aortic stiffness in Leber hereditary optic neuropathy?

PURPOSE: Leber hereditary optic neuropathy (LHON) is recognized as the most common cause of isolated blindness in young men. The current study was designed to test whether LHON as a mitochondrial disease is associated with vascular functional alterations characterized by aortic elastic properties during echocardiography. METHODS: A total of 19 patients with typical features of LHON aged 42+/-13 years (10 males) were included. Their results were compared to 19 age- and gender-matched healthy controls. Aortic stiffness index was calculated from the echocardiographically derived aortic diameters and the clinical blood pressure data. RESULTS: In this patient population, the point mutation was present in 3460G>A position in five cases, in 11778G>A position in five cases, and in 14484T>C position in nine patients. Diastolic aortic diameter (26.0+/-2.5 mm vs 28.4+/-4.1 mm, p<0.05) and aortic stiffness index (5.1+/-2.6 vs 12.0+/-7.9, p<0.05) were significantly increased in LHON patients compared to controls. CONCLUSIONS: Aortic stiffness can be increased in LHON disease, but further studies are warranted to confirm these findings in a larger LHON patient population with a more reliable method focusing on the pathophysiologic background.     

Visual prognosis of Leber’s hereditary optic neuropathy with 14484/ND6 mutation in Koreans

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA)is one of the three primary mutations of Leber’s hereditary optic neuropathy (LHON). It shows a better visual prognosis than either the 11778 or the 3460 mutation. In order to determine if there is any difference in visual prognosis according to race,we evaluated 12 Korean LHON patients with this mutation who were negative for eight proposed secondary mutations. Two of the 12 patients had a family history of optic neuropathy. Four of the 12 patients (33%) showed an improvement in visual acuity of up to 20/50 or better in both eyes. Four of the remaining eight patients showed an improvement in visual acuity of up to 20/50 or better in one eye. The visual acuity of the remaining four patients, however, did not improve, even though they were were under 25 years of age and none of them were heavy alcohol drinkers or heavy tobacco users. These findings indicate that Korean patients with the 14484 mutation may have a visual prognosis similar to that of Caucasian or Japanese patients with the same mutation.     

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. Received: 24 July 1998 Revised version received: 22 January 1999 Accepted: 10 February 1999     

Genotypic and phenotypic characteristics of Korean children with childhood-onset Leber’s hereditary optic neuropathy

Graefe's Archive for Clinical and Experimental Ophthalmology - We sought to identify the phenotypic and genotypic characteristics of Korean children with genetically confirmed Leber’s...     

Genetic screening of Leber’s hereditary optic neuropathy by PCR with whole blood cell lysate

Leber’s hereditary optic neuropathy (LHON) is accompanied by a mitochondrial DNA (mtDNA) mutation. The G to A substitution at nucleotide position 11,778 (11,202) of mtDNA is most common in Japanese LHON patients. Whole blood cell lysate, not purified DNA, was used as a template of the polymerase chain reaction (PCR) for the analysis of the G11,778 (11,202)A point mutation. The amplified DNA fragment was concentrated and desalted with a centrifuge device, SUPREC TM -02, and digested by SfaNI and MaeIII. This method does not need purified DNA from blood and avoids the phenol/chloroform treatments for PCR products prior to the restriction enzyme digestion. Therefore, it is convenient and safe for the genetic screening of LHON.     

Leber hereditary optic neuropathy – Therapeutic challenges and early promise

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the general population. It is an important cause of severe, usually irreversible, visual loss among young adults with a peak age of onset in the second and third decades of life. Management is currently mostly supportive but recent developments in LHON research are pointing the way towards more effective treatments for this blinding mitochondrial disorder.     

Leber hereditary optic neuropathy—new insights and old challenges

Graefe's Archive for Clinical and Experimental Ophthalmology - Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder with the majority of...     

Leber’s hereditary optic neuropathy: course of disease in consideration of idebenone treatment and type of mutation

Graefe's Archive for Clinical and Experimental Ophthalmology - In September 2015, the first and so far only medication for treatment of Leber’s hereditary optic neuropathy (LHON) was...     

Atypical Leber’s hereditary optic neuropathy: a case with five different episodes of visual disturbance

We report an unusual case of Leber’s hereditary optic neuropathy (LHON) with recurrent episodes of visual disturbance. The patient, a 53-year-old male, was a heavy smoker and alcohol drinker. At the age of 38, he was diagnosed as having bilateral optic neuropathy. After corticosteroid therapy, visual function recovered. By the age of 40, this condition had recurred five times. At the age of 51, he demonstrated decreased visual acuity in both eyes and Goldmann perimetry revealed bilateral cecocentral scotoma. Both optic nerves had blurred margins, a hyperemic appearance, and microangiopathy. A peripheral blood specimen showed a point mutation in mitochondrial DNA at np11778, indicating LHON. The patient was hospitalized for corticosteroid (methylprednisolone) therapy to help him cease smoking and drinking alcohol. After this treatment, his visual acuity recovered. We speculate that the mechanism involved the ATP deficiency theory in which visual disturbance is caused by an ATP deficiency due to a gene defect. The induced stress caused by smoking and drinking diminished during hospitalization due to the cessation of these activities by the patient.     

Visual evoked potentials findings in non-affected subjects from a large Brazilian pedigree of 11778 Leber’s hereditary optic neuropathy

To investigate pattern-reversal visual evoked potentials (PRVEP) in asymptomatic maternally and non-maternally related members from a large Brazilian 11778/ND4 LHON pedigree. Transient PRVEP for check sizes 15′ and 60′ were recorded from asymptomatic mutation carriers and non-mutant descendants of affected/non-affected males, all with best-corrected visual acuity of 20/20. A control group of spouses (off-pedigree) was also included. Parameters of N75, P100 and N135 latencies (ms) and N75-P100 peak-to-peak amplitude (μV) as well as temporal dispersion (latency of N135-latency of N75) were determined. Longitudinal testing was obtained in a subseries of carriers in three annual consecutive visits. We tested 48 asymptomatic mutation carriers, 19 descendants of affected males, 9 descendants of non-affected males and 27 off-pedigrees, all of the latter being non-mutant. All non-mutant male descendants did not differ from off-pedigree controls. Statistically prolonged P100 latencies were found in mutation carriers (P = 0.0143) when compared with off-pedigrees for check sizes 15′, as well as significantly larger temporal dispersions for both check size 15′ (P = 0.0012) and check size 60′ (P = 0.0271). Serial testing in 15 mutation carriers disclosed prolonged P100 latencies and larger temporal dispersion that did not change over time. Subclinical PRVEP abnormalities were detected in this large group of asymptomatic carriers of the 11778/ND4 LHON mutation from the same family, confirming and extending previous psychophysical and structural findings of a selective involvement of the parvocellular pathway. PRVEP is a useful test to characterize and monitor visual dysfunction in this devastating disease.     

Foveal pit morphological changes in asymptomatic carriers of the G11778A mutation with Leber’s hereditary optic neuropathy

AIM: To investigate the foveal pit morphology changes in unaffected carriers and affected Leber’s hereditary optic neuropathy (LHON) patients with the G11778A mutation from one family. METHODS: This study was a prospective cross-sectional study. Both eyes from 16 family members (age from 9 to 47y) with the G11778A mutation were analyzed and compared with 1 eye from 20 normal control subjects. Eleven family members with the G11778A mutation but without optic neuropathy were classified as unaffected carriers (n=22 eyes). Five family members (n=10 eyes) expressed the LHON phenotype and were classified as affected patients. Retinal images of all the subjects were taken by optical coherence tomography (OCT), and an automatic algorithm was used to segment the retina to eight layers. Horizontal and vertical OCT images centered on the fovea were used to measure intra-retinal layer thicknesses and foveal morphometry. RESULTS: Thicker foveal thickness, thinner foveal pit depth, and flatter foveal slopes were observed in unaffected carriers and affected LHON patients (all P<0.001). Further, the slopes of all four sectors in the LHON were flatter than those in the unaffected carriers (all P<0.001). Compared with the control group, affected LHON patients had a thinner retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer (GCL+IPL), and total retina (all P<0.01). The retinal nerve fiber layer (RNFL) of affected patients was 38.0% thinner than that of controls while the GCL+IPL was 40.1% thinner. CONCLUSION: The foveal pit morphology shows changes in both unaffected carriers and affects patients. RNFL and GCL+IPL are thinner in affected LHON patients but not in unaffected carriers.     

Juvenile open-angle Glaucoma associated with Leber’s hereditary optic neuropathy: a case report and literature review

Background

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited recessive disease rarely complicated with glaucoma. We conducted a clinical and genetic retrospective case series to describe three cases of juvenile open-angle glaucoma (JOAG) and an ND4 m11778G?>?A mitochondrial DNA (mtDNA) mutation, which is pathognomonic for LHON.

Case presentation

Patient 1 was a 16-year-old boy diagnosed with bilateral JOAG and high myopia. His intraocular pressure (IOP) was poorly controlled with the use of full topical anti-glaucoma medications. His best-corrected visual acuity (BCVA) decreased gradually over 5?years. Fundoscopic examination revealed bilateral enlarged disc cupping of the optic nerves with sectorial excavation and reduction of the neural rim in the left eye. His visual field (VF) was characterized by bilateral progressive central scotoma. Pattern visual evoked potentials (VEPs) and pattern electroretinograms (ERGs) showed extinguished responses in both eyes. Because of the non-specific visual field findings and the optic neuropathy disclosed by the pattern VEPs and pattern ERGs, we arranged a genetic test for the patient, which revealed an m11778G?>?A mtDNA mutation. Patient 2, the younger brother of Patient 1, was a 15-year-old boy who had been diagnosed with bilateral JOAG in 2010. The BCVA of both eyes remained at 1.0 during the follow-up period. Fundoscopic examination revealed bilateral mildly paled optic disc with enlarged cupping and reduction of the neural rim. The pattern ERG revealed a decreased N95 amplitude bilaterally. The genetic test revealed an m11778G?>?A mtDNA mutation. Patient 3 was a 35-year-old man with bilateral JOAG. His BCVA decreased gradually over 10?years. Fundoscopic examination revealed paled optic disc with enlarged disc cupping and reduction of the neural rim in both eyes. The pattern ERG revealed a decreased N95 amplitude bilaterally. The genetic test revealed an m11778G?>?A mtDNA mutation.

Conclusions

This case series describes three patients with concomitant occurrence of JOAG and LHON. These two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the rapid deterioration of vision, which may occur during adolescence.

     

Leber’s hereditary optic neuropathy: clinical and molecular genetic findings in a patient with a new mutation in the ND6 gene

Background: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited ocular disease associated with mutations in the mitochondrial DNA (mtDNA). We describe the clinical and molecular genetic findings in a LHON patient and his family with a new mtDNA mutation at np14568 in the ND6 gene. · Methods: Ophthalmological examination was performed in one affected male and two maternal relatives. Direct sequence analysis of the complete mtDNA protein coding region was initiated in the affected patient. Four unaffected maternal relatives also underwent molecular genetic evaluation. · Results: Clinical examination of the affected male showed typical features of LHON. In his unaffected mother slight peripapillary microangiopathy was found. Molecular analysis did not show any of the common LHON mutations. A nucleotide exchange was detected at position 14568 replacing a glycine by serine in the ND6 gene. This mutation was the only new mutation found within the entire protein and tRNA coding region of the patient’s mitochondrial genome. This novel mutation was also present in four non-affected maternal family members, but absent in 60 other LHON lineages and 175 unrelated controls. · Conclusion: The new mutation at nucleotide position 14568 lies in the close vicinity of other LHON-related mutations (np14459, np14484, np14498, np14596) within the evolutionarily most conserved region of the ND6 gene. Since no other mutation was detected throughout the mtDNA coding region and the new alteration was excluded in controls, our clinical and molecular genetic findings suggest that the novel point mutation at np14568 is responsible for LHON in this family. Received: 3 February 1998 Revised version received: 11 August 1998 Accepted: 13 August 1998