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

Sir, The Behr syndrome (MIM#210000) is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay (Behr, 1909). Although the disorder is believed to be inherited in an autosomal recessive manner, it may be clinically heterogeneous, encompassing several genetic aetiologies and patterns of inheritance. Recently, an adult-onset Behr-like syndrome, including optic atrophy and ataxia, was reported in two brothers carrying a heterozygous mutation in the optic atrophy type 1 gene ( OPA1 , p.Cys551Tyr) (Marelli et al. , 2011). Heterozygous mutations in OPA1 , a gene encoding for a dynamin-related GTPase involved in mitochondrial dynamics and mtDNA maintenance, are the main causes of autosomal dominant optic atrophy (DOA). In DOA, the optic neuropathy occurs insidiously in the first decade of life leading to various levels of visual impairment. As many as 20% of patients with DOA exhibit extra-ocular neuromuscular signs including deafness (Amati-Bonneau et al., 2005), chronic progressive external ophthalmoplegia, ataxia, peripheral neuropathy and mitochondrial myopathy with multiple mtDNA deletions, also called the ‘DOA plus’ phenotype (Amati-Bonneau et al. , 2008; Yu-Wai-Man et al. , 2010). The ‘DOA plus’ phenotype, which is similar to that observed in multi-systemic mitochondrial disorders (Amati-Bonneau et al. , 2005), is often associated with missense mutations in OPA1 (Yu-Wai-Man et al. , 2010). Apart from these autosomal dominant forms, only a few syndromic cases have so far been reported with compound heterozygous OPA1 mutations suggestive of either recessive or semi-dominant patterns of inheritance (Pesch et al. , 2001; Yu-Wai-Man et al. , 2010; Schaaf et al. , 2011). However, the clinical spectrum of these emerging double-mutant OPA1 -related disorders remains to be characterized. We here report four cases of children affected by the Behr syndrome associated with compound heterozygous OPA1 mutations. This …