Anna Maria De Negri

Idebenone Treatment In Leber's Hereditary Optic Neuropathy

Sir, We have read with great interest the results presented by Klopstock et al. (2011) concerning the RHODOS study on a clinical trial with idebenone in Lebers hereditary optic neuropathy (LHON) and we would like to share our own experience of idebenone therapy in LHON. Idebenone has been an approved drug (Mnesis®, Takeda Italia Farmaceutici) in Italy since the early 1990s and, after the initial report by Mashima et al . (1992) on its possible efficacy in LHON, we offered this therapeutic option to all of our new consecutive patients with LHON, almost all of whom accepted treatment. Idebenone was given after informed consent following the regulation for ‘off-label’ drug administration and was provided for free by the National Health Service, under the legislation for certified rare disorders. Patients were initially treated with 270 mg/day (Cortelli et al ., 1997; Carelli et al ., 1998 a , b ), but following the reports on idebenone treatment in Friedreich ataxia, the dosages were increased to 540–675 mg/day (Rustin et al ., 1999; Kearney et al ., 2009). To evaluate retrospectively the efficacy of idebenone therapy, we reviewed all of our patients with LHON, idebenone treated and untreated, after approval of the institutional Internal Review Board. Inclusion criteria for treated patients were the initiation of therapy within 1 year after visual loss in the second eye, and for all patients (treated and untreated) age at onset of at least 10 years and a follow-up of at least 5 years. We included only patients treated within 1 year after onset because this is the time frame to reach the nadir of the visual loss and the probability of spontaneous recovery of vision is highest in the following 5 years (Nikoskelainen et al ., 1983; Barboni et al ., 2005, 2010; …

Association of Optic Disc Size with Development and Prognosis of Leber’s Hereditary Optic Neuropathy

PURPOSE To study the optic nerve head (ONH) morphology of patients with Lebers hereditary optic neuropathy (LHON) in a large family from Brazil carrying the 11778/ND4 mutation and in a case series of unrelated Italian families bearing different mitochondrial DNA (mtDNA) pathogenic mutations. METHODS Enrolled in the study were 15 LHON-affected patients (LHON-affected) and 45 LHON unaffected mutation carriers (LHON carriers) belonging to the previously reported Brazilian SOA-BR LHON pedigree and 56 LHON-affected and 101 LHON carriers from 45 unrelated LHON Italian pedigrees molecularly defined. The LHON-affected were subgrouped according to the extent of visual recovery. All individuals underwent optic nerve head (ONH) analysis by optical coherence tomography. RESULTS In the Brazilian sample, the mean optic disc area was significantly larger in LHON carriers than in the control group (P=0.002). In the Italian sample, the mean optic disc area and vertical disc diameter were significantly higher in LHON carriers than in both LHON-affected (respectively, P=0.008 and P<0.001) and control subjects (P<0.001 in both cases). The LHON-affected with visual recovery had a significantly larger vertical disc diameter when compared with those without visual recovery (P=0.03). CONCLUSIONS The results, revealing that the ONH size is larger in LHON carriers than in LHON-affected, suggest a protective role for this anatomic trait. Such a hypothesis is reinforced by the observation that, among the LHON-affected, larger discs correlated with visual recovery and better visual outcome. The findings may be relevant for prognosis and provide a mechanism for identifying nuclear-modifying genes implicated in the variability of penetrance in LHON.

Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Leber's Hereditary Optic Neuropathy

Background Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. Methodology/Principal Findings In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. Conclusions/Significance Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.

Childhood leber’s hereditary optic neuropathy (ND1/3460) with visual recovery

The authors report the clinical features and the results of genetic and biochemical studies of a child affected by ND1/3460 Lebers hereditary optic neuropathy, who demonstrates a persistent visual recovery after protracted monitoring. A 10-year-old male suffered from a severe right visual impairment that was incidentally detected. Within 2 months the left eye was also seriously involved, and visual acuity worsened to 20/300 in both eyes, associated with bilateral cecocentral scotomas and dyschromatopsia. During the following months a progressive visual improvement occurred, and 2 years later the visual acuity was 20/20 OU. After 9 years of follow-up the clinical status is unchanged. The mutation at np ND1/3460 was found to be virtually homoplasmic in the probands mtDNA, which was extracted either from platelets or leukocytes, whereas the mother and the sister tested heteroplasmic for the same mutation. The specific activity of complex I in platelets was reduced in the proband and normal in his relatives. An abnormal resistance of NADH:ubiquinone reductase to the inhibitory effect of rotenone was found in platelet mitochondria from the proband and family members and was consistent with the degree of heteroplasmy. This pattern of biochemical abnormalities suggests a cumulative effect of the increasing percentage of mutated mtDNA on complex I function, which involves the interaction between complex I and its substrate ubiquinone in the heteroplasmic condition (asymptomatic state), and the catalytic function of complex I, as mutated mDNA turns toward the homoplasmic condition (symptomatic state).

Bilateral trochlear nerve palsy associated with cryptococcal meningitis in human immunodeficiency virus infection

This is the report of a case of bilateral trochlear nerve palsy secondary to cryptococcal meningitis in a 34-year-old woman with acquired immune deficiency syndrome. Based on clinical and neuroradiologic findings, it is concluded that in the present case, a postinflammatory shrinking of the arachnoid has stretched the fourth cranial nerves at their point of emergence from the dorsal surface of the brainstem.

Mitochondrial DNA mutation in an Italian family with Leber hereditary optic neuropathy

SummaryMitochondrial (mt) DNA from a Southern Italian family with Leber hereditary optic neuropathy was analyzed for the presence of the reported mutation at position 11778 of the ND4 subunit gene. The point mutation was found in mt DNA extracted from peripheral blood in all members of the family with the exclusion of the father, and was present in a homoplasmic fashion, despite the phenotypic heterogeneity of disease presentation among family members.