Compensating for central nervous system dysmyelination: Females with a proteolipid protein gene duplication and sustained clinical improvement

A submicroscopic duplication that contains the entire proteolipid protein g ene is the major cause of Pelizaeus-Merzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that carrier females for the duplication are usually asymptomatic. We desc ribe 2 unrelated female patients who present with mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The other patient , who presented with spastic diplegia and was initially diagnosed with cere bral palsy, has also shown clinical improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in bot h patients. Interphase fluorescent in situ hybridization analyses of the fa mily members indicated that the duplication in both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocyt es nor proteolipid protein gene coding alterations were identified in eithe r patient. These findings indicate that, occasionally, females with a prote olipid protein gene duplication can manifest an early-onset neurological ph enotype. We hypothesize that the remarkable clinical improvement is a resul t of myelin compensation by oligodendrocytes expressing one copy of proteol ipid protein gene secondary to selection for a favorable X inactivation pat tern. These findings indicate plasticity of oligodendrocytes in the formati on of central nervous system myelin and suggest a potential role for stem c ell transplantation therapies.