Divergent phenotypes of Charcot-Marie-Tooth disease: demyelinating with childhood onset and axonal with late onset and slow pupillary reaction, resulting from different myelin protein zero (MPZ, P0) gene mutations
Abstract
Background: Mutations of the peripheral myelin protein zero (MPZ, PO) gene have been for 10 years one of the known causes of the demyelination type of Charcot-Marie-Tooth (CMT) disease, which in addition to the classical CMTl form also includes the early onset and severe form of Déjerine-Sottas neuropathy (DSS) and yet earlier onset and more severe congenital hypomyelinating neuropathy (CHN). PO protein is the main component of peripheral myelin and plays a crucial role in the process of peripheral myelination.
In the last few years, families with axonal type of CMT due to PO gene mutations have been described. Patients and Results: We describe 3 Czech families with proven PO gene mutations and completely different times of onset, clinical courses and forms of the CMT disease.
The mutations found have been reported previously in other countries. Arg98Cys was found in two families with three affected members, once in 2 generations, with a severe demyelinating form, childhood onset and stable course and with extremplv low nerinheral nerve conduction velocity, and next, Thrl24Met ''lutation in a female patient with late onset of axonal form of CMT disease at the end of the fourth decade, abnormal pupillary reaction and relatively rapid progression of disease.
Arg98Cys mutation occurred in both families de novo, in the Thrl24Met mutation, patient's parents could not be investigated but the patient's mother has a history compatible with CMT disease. Both son and daughter of the patient have presently no clinical signs of polyneuropathy but have abnormal pupillary reaction.
The son has the same mutation, daughter has not been investigated yet. Conclusions: Severe demyelinating hereditary neuiopathy with childhood onset (DSS) and axonal late-onset CMT2 represent the opposite ends of the spectrum of myelination disorder caused by PO gene mutations.
The 98 Arg codon of the PO gene is a locus of repeated occurrence of mutations found also in Czech families. Elucidation of the reason why some PO gene mutations lead to very early-onset demyelinating neuropathy and other mutations of the same gene lead to late-onset axonal neuropathy could offer a clue to molecular interactions between the axon and the Schwann cell.