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

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 hypomyelinated brain on cerebral MRI and typical neurogenic spikes on EMG without alteration of motor and sensitive nerve conductions. Muscle biopsy confirmed the lower motoneuron dysfunction and assessed normal respiratory chain activities. Presently aged 8 years, little cognitive and motor progress have been noticed despite good control of seizures. Quadriplegia with absence of head control and tendon reflexes, progressive scoliosis, lingual fasciculations are observed. MRI remains unchanged with a persistent severe diffuse hypomyelination of the cerebral hemispheres (Fig. 1). Peripheral nerves analysis demonstrate the progression of the motor axonopathy with a severe alteration of motor potentials amplitudes predominant in the lower limbs (<800mV) and a mild decrease of motor nerve conduction velocities (27–32 m/sec in respectively the lower and upper limbs) contrasting with the relative preservation of sensitive conductions (58 to 50 m/sec in respectively the lower and upper limbs). We postulated that mutation in the OLIG2 gene may lead to a primary defect both in oligodendrocyte and motor neuron development and could explain this peculiar phenotype. Duplication and point mutation in the PLP1 gene as well as mutations in the GJA12 gene were ruled out by DNA analysis. The whole exon 2 of OLIG2, containing the coding region as well as part of the 50UTR and the full 30UTR, have been analyzed by direct sequencing of overlapping PCR products. Except for the presence of four previously described single nucleotide polymorphisms (G/A rs762178, G/T rs9982080, C/A rs1059004, and T/G rs13046814), no mutation was detected. These results suggest that mutations in the OLIG2 gene are Grant sponsor: Institut National de la Santé et de la Recherche Médicale (INSERM); European Leucodystrophy Association (ELA) Foundation; Jean-Pierre and Nancy Boespflug myopathic research foundation.