Analysis of Inherited Optic Neuropathies

Abstract

Background Inherited optic neuropathies (IONs) cover a spectrum of clinically and genetically heterogenic conditions. Genetic evaluation of patients with IONs may enable their better clinico-diagnostic assessment and management of the disease. The aim of the present study was to determine the genetic condition related to the phenotype in patients with diverse inherited optic neuropathies.

Patients and Methods A retrospective study was performed in 12 adults and 8 children of 8 non-related families. Clinical phenotyping, supported by color fundus, FAF, and OCT imaging, was performed. Genetic testing was obtained for all family members suspected for ION.

Results Identification of pathogenic mutations in eight non-related families helped to confirm the diagnosis of ION. Affected from ION were ten patients (eight adults and two children; four women and six men). Bilateral Leberʼs hereditary optic neuropathy (LHON) was linked to the m.11778G>A mutation in two families (two affected and five carriers). Secondary homoplasmic LHON mutations in MT-ND1 (m.4216T>C) and MT-CO3 genes (m.9804G>A) were confirmed in two families (each one subject, three eyes affected), without detection of a primary LHON mutation. One member presented a picture of right-sited optic neuropathy associated with a c.220C>G mutation in the ACO2 gene and a heterozygous c.185C>T mutation in the LDLR gene. Autosomal dominant optic atrophy was confirmed in three non-related families (five subjects with bilateral ION), where molecular genetic analyses confirmed four different heterozygous mutations in OPA1: c.1847+1G>T; c.2497-1G>A, 297A>G and c.(2983+1_2984-1)_(c.*3211) (2 splicing mutations, 1 missense mutation, and 1 gross deletion encompassing exons 30 and 31).

Conclusions Combining clinics and molecular genetics when evaluating patients with IONs helps in characterizing disease and, therefore, is strongly recommended for such patients.

Zusammenfassung

Hintergrund Hereditäre Optikusneuropathien umfassen ein breites Spektrum von klinisch und genetisch heterogenen Krankheitsbildern. Die genetische Untersuchung von Patienten mit hereditären Optikusneuropathien ist ein wichtiger Bestandteil zur Optimierung der klinischen und genetischen Krankheitsdiagnostik sowie entscheidender Punkt bei der Therapieplanung. Das Ziel dieser Studie ist eine Bestimmung von genetischen Pathologien, welche den möglichen klinischen Varianten der hereditären Optikusneuropathien zugeordnet werden können.

Patienten und Methodik Eine retrospektive Studie an 8 Kindern und 12 Erwachsenen aus 8 nicht miteinander verwandten betroffenen Familien. Der klinische Phänotyp wurde mithilfe einer klinischen Untersuchung sowie der Fundusautofluoreszenzaufnahmen, Farbfotodokumentation und OCT-Bildgebung bestimmt und mit der genetischen Abklärung aller teilnehmenden Familienmitglieder ergänzt.

Ergebnisse Die Identifikation von pathogenen Genmutationen wurde bei den Familienmitgliedern der 8 nicht miteinander verwandten Familien durchgeführt und konnte somit eine hereditäre Optikusneuropathie bestätigen. Die hereditäre Optikusneuropathie konnte bei insgesamt 10 Patienten (8 Erwachsenen und 2 Kindern, 6 Männern und 4 Frauen) bestätigt werden. Eine bilaterale LHON zeigte einen Zusammenhang mit einer m.11778G>A-Mutation in 2 Familien (2 betroffene Patienten und 5 Träger). Sekundäre homoplasmische LHON-Mutationen der MT-ND1-Gene (m.4216T>C) und MT-CO3-Gene (m.9804G>A) wurden in 2 Familien festgestellt (3 Augen von 2 betroffenen Patienten), ohne eine primäre LHON-Mutation zu identifizieren. Bei einem Mitglied der weiteren untersuchten Familie mit einer rechtsseitigen Optikusneuropathie konnten eine assoziierte c.220C>G-Mutation im ACO2-Gen und eine heterozygote c.185C>T-Mutation im LDLR-Gen bestätigt werden. Autosomal-dominante Optikusatrophie wurde in insgesamt 3 nicht miteinander verwandten Familien festgestellt (5 Patienten mit bilateraler Optikusneuropathie), welche die Assoziation mit 4 verschiedenen heterozygoten Mutationen im OPA1-Gen zeigte [c.1847+1G>T; c.2497-1G>A; c.297A>G and (c.2983+1_2984-1)_(c.*3211_?)].

Schlussfolgerungen Kombiniertes klinisches und genetisches Vorgehen bei Evaluation der Patienten mit hereditären Optikusneuropathien kann zur präzisen Krankheitsdiagnostik und deren Optimierung angewendet werden.

Key words

novel mutation - inherited optic neuropathy - genetics - Leberʼs hereditary optic neuropathy (LHON) - autosomal dominant optic atrophy

Schlüsselwörter

neue Mutation - hereditäre Optikusneuropathie - Genetik - Leberʼsche hereditäre Optikusneuropathie - autosomal-dominante Optikusneuropathie

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