Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Sir, Autosomal dominant optic atrophy (DOA) is the most commonly diagnosed inherited optic neuropathy in clinical practice and the majority of patients harbour pathogenic mutations within the OPA1 gene (3q28-q29, OMIM 165500) (Yu-Wai-Man and Chinnery, 2013). OPA1 is a multifunctional protein located within the mitochondrial inner membrane and it regulates a number of critical cellular functions, including mitochondrial network stability, oxidative phosphorylation and mitochondrial cell death pathways (Lenaers et al., 2009). Until recently, DOA was largely viewed as a limited genetic disorder that preferentially affects retinal ganglion cells resulting in progressive visual failure from early childhood (Carelli et al., 2004; Yu-Wai-Man et al., 2014). It is now abundantly clear that pathogenic OPA1 mutations can have much more severe multisystemic consequences that are detrimental not only to optic nerve function, but also target other tissues that are frequently involved in other well-established mitochondrial syndromes (Amati-Bonneau et al., 2008; Hudson et al., 2008). In a large multicentre study published in Brain, up to 20% of OPA1 mutation carriers developed these so-called DOA plus (DOA + ) phenotypes where the optic atrophy was complicated by a wide range of neuromuscular features that included ataxia, myopathy, peripheral neuropathy, sensorineural deafness, and fascinatingly, chronic progressive external ophthalmoplegia (YuWai-Man et al., 2010). A previous case report in Brain described two brothers diagnosed with classical Behr’s syndrome who were eventually found to carry a single heterozygous pathogenic OPA1 mutation (c.1652G4A, p.Cys551Tyr) within the catalytic GTPase domain (Marelli et al., 2011; Yu-Wai-Man and Chinnery, 2011). In their case series, Bonneau and colleagues extend the association between pathogenic OPA1 mutations and Behr’s syndrome with a detailed account of four unrelated children who developed the typical clinical features of an early-onset progressive optic neuropathy that was further compounded by ataxia, spasticity and peripheral neuropathy (Bonneau et al., 2014). Their most striking observation is the identification of compound heterozygous OPA1 mutations in all four patients with the co-occurrence of a missense GTPase mutation and a truncative nonsense mutation. Interestingly, three of these families harboured the same missense GTPase OPA1 mutation (c.1146A4G, p.Ile382Met) that has been previously reported in another DOA+ family with compound heterozygous mutations (Schaaf et al., 2011). This specific pathogenic variant is clearly highly penetrant for the neurological ‘plus’ features and it does support our earlier observation that misssense GTPase OPA1 mutations seem to have a more potent deleterious impact, possibly via a dominant negative mechanism and increased mitochondrial DNA instability (Yu-Wai-Man et al., 2010; Yu-Wai-Man and Chinnery, 2012). As Bonneau et al. (2014) correctly point out, we did describe two siblings from a non-consanguineous Norwegian family in our original Brain paper, who developed a particularly aggressive disease course characterized by ataxia, spasticity, peripheral neuropathy and myopathy (Yu-Wai-Man et al., 2010). OPA1 sequencing identified two pathogenic variants in both the affected brother and sister: the c.768C4G (p.Ser256Arg) missense mutation in exon 5b and the c.854A4G (p.Gln285Arg) missense mutation in exon 8. Bonneau et al. (2014) rightly queried whether we had actually proven compound heterozygosity in these two affected Norwegian siblings. Although DNA was not available from their deceased parents, we did have access to DNA samples from the brother’s two doi:10.1093/brain/awu187 Brain 2014: 137; 1–3 | e302