Absence of OLIG2 mutations in patients presenting with a severe Pelizaeus‐Merzbacher‐like leukodystrophy associated with motor neuron dysfunction

Abstract

The absence of mutations in the OLIG1 and OLIG2 transcription factor genes in 13 patients presenting with a Pelizaeus-Merzbacher Like (PMLD) phenotype has been recently reported [Ruf et al., 2007]. We would like to complement this observation by reporting also the absence of OLIG2 mutation in three PMLD patients presenting with a phenotype characterized by severe hypomyelination and motor neuron dysfunction.OLIG1 and OLIG2 are oligodendroglial transcription factors that regulate key stages of early oligodendrocyte development. Persistence of Olig gene expression throughout oligodendrocyte lifetime suggests later roles in oligodendrocyte maturation and/or survival. Moreover, in the spinal cord, Olig2 has been shown to be necessary not only for oligodendrocyte development but also for development of motor neurons from the motor neuron progenitor (pMN) domain [Lu et al., 2002;Takebayashi et al., 2002;Zhou and Anderson, 2002]. Whereas Olig1-null mutant mice display only a delay in oligodendrocyte maturation, analysis of Olig2-null mutants demonstrated an absence of oligodendrocyte precursors (OLPs) in the spinal cord and a small number of OLPs in the different brain areas as well as a total absence of somatic motor neurons [Lu et al., 2002]. Additionally, loss-of-function studies in zebrafish indicated that the fish Olig2 homolog has a conserved role in development of both oligodendrocytes and motor neurons [Park et al., 2002].In order to test the potential involvement of OLIG2 in hypomyelinating leukoencephalopathies of unknown etiology, we selected three patients (from three independent families) from our large cohort of PMLD patients [Vaurs-Barrière et al., 2006]. These three patients all present with a severe and diffuse hypomyelination on brain MRI unexpectedly associated with a lower motor neuron involvement on electromyography (EMG) analysis. Extensive metabolic analyses in serum, lymphocytes, urine, and cerebrospinal fluid were negative and in the three cases, skin or brain histological analysis ruled out neuroaxonal dystrophy. Patient G83 presented with connatal hypotonia, epilepsy, and severe hypomyelination on brain MRI, leading to death at 1 month of age. Post-mortem brain histological analyses confirmed the severe CNS hypomyelination with quantitative and qualitative myelin abnormalities. Patient G392 manifested a mild delay in its motor development since birth. A psychomotor regression was observed at 14 months, which led to a neuropaediatric evaluation at 20 months. A severe hypomyelination on cerebral MRI associated with an axonal lower motoneuron involvement on EMG were found. At 6 years of age, head control was lost with spastic quadriplegia and optic atrophy whereas white matter abnormalities and cortical atrophy remained stable. The third patient G812 presents a severe form 0 of PMLD [Cailloux et al., 2000] with neonatal onset and absence of motor milestones acquisition. Febrile epileptic seizures occurred at 9 months. Neuropaediatric evaluation performed at 3 years of age showed a severe hypomyel...