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Jul 15, 2010 - Abstract Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by bilateral painless optic atrophy and blindness.

J Neurol (2010) 257:1999–2003 DOI 10.1007/s00415-010-5649-6


Late-onset Leber hereditary optic neuropathy mimicking Susac’s syndrome Stefano Zoccolella • Vittoria Petruzzella • Francesco Prascina • Lucia Artuso Francesca Pacillo • Rosa Dell’Aglio • Carlo Avolio • Nicola Delle Noci • Marcella Attimonelli • Luigi Maria Specchio

Received: 17 May 2010 / Revised: 22 June 2010 / Accepted: 28 June 2010 / Published online: 15 July 2010 ! Springer-Verlag 2010

Abstract Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by bilateral painless optic atrophy and blindness. It usually occurs in young men in association with three major mutations in the mitochondrial genome (mtDNA). We report a patient with a history of alcohol abuse who developed at age 63 years visual impairment, sensorineural hearing loss, and memory S. Zoccolella and V. Petruzzella equally contributed to the paper.

Electronic supplementary material The online version of this article (doi:10.1007/s00415-010-5649-6) contains supplementary material, which is available to authorized users. S. Zoccolella ! F. Pacillo ! C. Avolio ! L. M. Specchio Clinic of Nervous System Diseases, Department of Medical and Occupational Sciences, University of Foggia, Viale Luigi Pinto, 71100 Foggia, Italy V. Petruzzella (&) ! L. Artuso ! R. Dell’Aglio Department of Medical Biochemistry, Biology and Physics, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy e-mail: [email protected] V. Petruzzella Institute of Biomembranes and Bioenergetics, National Research Council, Bari, Italy F. Prascina ! N. Delle Noci Institute of Ophthalmology, University of Foggia, Viale Luigi Pinto, 71100 Foggia, Italy M. Attimonelli Department of Biochemistry and Molecular Biology, ‘E. Quagliariello’, University of Bari, Bari, Italy Present Address: S. Zoccolella Department of Neurological and Psychiatric Sciences, University of Bari, Ospedale Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy

dysfunction, suggestive of Susac’s syndrome. The patient carried the heteroplasmic mt. 11778G[A mutation on the T2e mtDNA haplogroup. It remains unclear if chronic alcohol abuse combined with the mitochondrial genetic background prompted an aged-related neurodegeneration or deferred the onset of the LHON disease. Keywords Optic neuropathy ! Susac’s syndrome ! Mitochondrial DNA mutation ! Late-onset LHON Introduction Leber hereditary optic neuropathy (LHON) is the most common maternally inherited disorder, and it is characterized by bilateral acute or subacute painless loss of central vision and optic atrophy [1]. There is a sex-skewed distribution in LHON; more than 80% of patients are men, with onset generally in young adulthood and a range between 8 and 60 years [1]. Cardiac arrhythmias and variable involvement of the peripheral and central nervous systems (such as a multiple sclerosis-like illness, dystonia, and extrapyramidal tract involvement) can also manifest in a subset of patients, termed LHON ‘‘plus’’ [2]. Hearing loss is uncommon, as a recent study on auditory dysfunction in a case-series of LHON patients found no evidence of cochlear nerve dysfunction [3]. The rate of visual recovery in LHON is extremely variable ranging from 4 to 50% [1]. The classical LHON phenotype is associated with three, mostly homoplasmic primary mitochondrial DNA (mtDNA) point mutations (3460G[A, 11778G[A, 14484T[C), in genes encoding the ND1, ND4, and ND6 subunits, respectively, of respiratory chain complex I [1]. Only about one-third of individuals harboring one of these three mutations eventually develop LHON, with a high inter- and intra-familial variability, and the penetrance varies among



different families [2, 4]. Several studies have reported that the co-occurrence of two primary LHON mutations, or the association with additional mtDNA variants, may contribute to the clinical expression of LHON and LHON ‘‘plus’’ phenotype [5–7]. Many factors, such as mtDNA background, levels of mutant mitochondrial genomes, environmental factors, and as yet uncharacterized nuclear gene(s), or their various combination, have been suggested to influence the full phenotypic expression of LHON [4, 6, 8]. The onset of LHON disease in the elderly is uncommon, and fewer cases over age 60 have been described [9–13], generally with a poor prognosis as for visual recovery. A mixture of precipitating factors such as acute blood loss [11], chronic anemia [11], high eye pressure [11], and chronic alcohol intake [13] have been invoked in late-onset LHON. Herein, we report a patient with a late-onset LHON phenotype characterized by visual and hearing loss and memory impairment carrying the heteroplasmic 11778/ ND4 on T2e haplogroup as mtDNA background.

Case report A 63-year-old man presented with bilateral visual and hearing loss, and memory complains that had progressively Fig. 1 a MRI of the brain revealing slight increase in the signal of left optic nerve (arrow) and mild cortical atrophy. b Automated static perimetry showing altitudinal superior scotoma. c Fundoscopic examination detecting, in the left eye, temporal optic disc atrophy and mild hyperemic appearance of the nasal portion of the disc with ipsilateral obscuration of the nerve fiber layer and mild peripapillary telangiectasia


J Neurol (2010) 257:1999–2003

worsened in the latest 6 months. Family history was unremarkable for neuromuscular and neurological disorders. The patient referred a 40-year history of alcohol abuse (0.75 l/day) and denied tobacco intake or drug abuse, head injury, middle ear infections, chronic exposure to noise, and the assumption of drugs that may harm the inner ear. Neurological examination at presentation was normal. Mini Mental State Examination score was 28/30 and Alzheimer’s Disease Assessment Scale-Cognitive subscale score was 29. Blood routine examinations were unremarkable. Best-corrected visual acuity was 20/300 in both eyes and the anterior segment examination was normal without relative afferent pupillary defect. Fundoscopy revealed bilateral temporal atrophy of optic disc, more evident in the right eye, and hyperemic appearance of the nasal side of disc with mild tortuosity of the medium-sized peripapillary retinal arterioles in the left eye (Fig. 1b). Automated static perimetry and visual evoked potentials showed altitudinal visual defect involving the superior field and a reduced amplitude of P100 waves with an increase in latency in both eyes, respectively (Fig. 1c). Fluorangiography was normal. Cardiac examination and EKG were normal. Audiological examination revealed moderate sensorineural hearing loss (mean decibel loss: 47 on the right hear, 48 on the left) whereas brainstem auditory evoked

J Neurol (2010) 257:1999–2003 Normalized Melting Curves 100,000 90,000

Relative Signal (%)

Fig. 2 Analysis of patient specimen for the 11778A[G mutation. Melt curves specific for the homoplasmic wild-type and mutant mtDNA molecules as well as for the patient’s heteroplasmic mutant mtDNA are indicated by small circles



80,000 70,000


60,000 50,000 40,000


30,000 20,000 10,000 0,000 81,5









Temperature (°C)

potentials revealed an increase in the III-V waves interpeak latencies (2.4 ms right; 2.25 left). Brain MRI showed mild cortical atrophy and slight increase in the signal of both optic nerves, without contrast enhancement (Fig. 1a, c). The combination of high-resolution melting (HRM) screening (Fig. 2)—run in a Light Cycler 480 instrument and analyzed using the Gene Scanning Software (Roche, Germany)—and direct sequencing of the MT-ND4 gene on an ABI310 automatic sequencer detected the most common LHON-associated mutation (11778A[G) in the patient’s peripheral blood DNA. The mutation was heteroplasmic (75% mutant mtDNAs) in blood when assessed with a SfaNI-specific PCR-restriction fragment length polymorphism (RFLP) method, as reported elsewhere [14]. Whole mtDNA sequencing showed that the patient belongs to T2e haplogroup (see Supplementary Table).

Discussion In the case presented here, the late-onset occurrence of visual manifestations with an abnormal visual field as seen in anterior ischemic optic neuropathy [15] in combination with moderate deafness and short-term memory impairment resembled Susac’s syndrome, a microvasculopathy usually characterized by a triad including encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss [16]. However, no sign of microangiopathy was observed on both fluorangiography and brain MRI. Differential diagnosis also ruled out nutritional and toxic optic encephalopathy, and ischemic optic neuropathy, as well as other more common causes of hearing loss. Conversely, the combination of painless symmetric vision loss with poor visual acuity, optic disc pallor, nerve fiber layer drop-out, and auditory deficit in an otherwise healthy man with ethanol abuse made possible the diagnosis of LHON [13],

which was later confirmed by the identification of the 11778 mtDNA mutation. Interestingly, complete mtDNA sequencing also revealed that the patient harbored an adjunctive change at nucleotide 4136 converting the moderately conserved tyrosine at amino acid 277 to a cysteine (T277C), a known ‘‘secondary’’ LHON mutation in MT-ND1 [2] falling within the mtDNA haplogroup T. MtDNA haplogroups tend to be restricted to specific geographic areas and/or ethnic groups [17] but have also been claimed as key players in disease expression [18]. Haplogroups J, K, and H have been shown to influence the clinical expression in European patients harboring primary LHON mutations [19] probably because they confer a number of faulty properties to oxidative phosphorylation (OXPHOS) including generation of reactive oxygen species (ROS) [20] or impairment of OXPHOS capacity and assembly kinetics [21]. Individuals carrying haplogroup T are believed to be more vulnerable to oxidative damage [22], in part because of the rare 4136/ND1 variant that appears to be possibly deleterious for complex I activity. Co-occurrence of the 4136/ND1 with the ‘‘common’’ 11778/ND4 mutation could further impair complex I function, as suggested in other LHON families, one of which also belongs to the haplogroup T [2]. Although the patient had formally denied a positive family history for LHON, reconstruction of his haplotype (Supplementary Table) revealed a common geographic origin—if not an undisclosed familial relationship through the maternal lineage—with cases reported elsewhere (family 1 in [2]) presenting LHON ‘‘plus’’. The full mitochondrial sequence of that family is available on the Web. However, clinical manifestations, disease severity, and age at onset among those cases and our proband varied greatly and lend further support to the notion of heterogeneity in LHON. The issue of heteroplasmy in LHON mutation is quite contradictory in literature. A lower prevalence of heteroplasmy in



families carrying the 11778 mutation as opposed to the 3460 or 14484 LHON mutations has been documented [24]. Analyses of four large Thai LHON pedigrees spanning four to six generations strongly suggested that the transmission of the heteroplasmic G11778A mutation is under selective pressure in favor of the mutated allele and that heteroplasmy influences the disease expression [25]. Other groups have reported that that there is no selection for either mtDNA genotype but the segregation of the wildtype mtDNAs and those carrying LHON mutations is a stochastic process governed by random genetic drift. In this respect, LHON mutations seem to behave like neutral polymorphisms [26]. The heteroplasmic condition of the 11778 mutation in blood of the presented patient may have act as protective factor delaying the onset of visual symptoms. In an earlier report [27], it was suggested that the clinical features of heteroplasmic patients with at least 76% mutant mtDNA are similar to those of homoplasmic mutant patients once visual symptoms had occurred and that a progression toward homoplasmy in peripheral blood tended to increase in subsequent generations. We can speculate that in the case of the patient presented here, a progression toward a higher mutation load may have occurred during his lifespan. Whether the genetic background with the heteroplasmic status of the 11778A[G mutation and the long-term alcohol intake [23] might have modulated the onset and characteristics of clinical presentation in the present case remains uncertain. Acknowledgments This work was supported in part by grants from the Italian Ministry of Health (Ricerca Corrente e Finalizzata), MIUR-PRIN ‘‘Molecular mechanisms, physiology and pathology of membrane bioenergetics system ’’, Project No. 2005052128_001 and Research Foundation Cassa di Risparmio di Puglia.

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