CHARCOT-MARIE-TOOTH DISEASE TYPE-1A WITH 17P11.2 DUPLICATION - CLINICAL AND ELECTROPHYSIOLOGICAL PHENOTYPE STUDY AND INFLUENCING DISEASE SEVERITY IN 119 CASES

A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 dupl ication. Onset of the first functional manifestations was in the first decade in 50% of cases and before the age of 20 years in 70% of cases . The predominant clinical signs were muscle weakness and wasting in t he lower limbs. None of the patients was normal on clinical examinatio n and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was less than or equal to 33 m/s in the median nerve for all patie nts. Sensory potentials were abnormal in all cases, even where there w as no clinical sensory loss. Needle electromyography recruitment was r educed in distal muscles for all patients. MNCV slowing was fully cons istent with the presence of duplication even in clinically asymptomati c individuals or in children, confirming the complete electrophysiolog ical penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional d isability was mild. Ninety-six percent of patients were autonomous; 25 % were asymptomatic and diagnosed by systematic family investigation e specially on the basis of median nerve MNCV reduction. Early age at on set and greatly reduced median nerve MNCV were predictive of a more se vere disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be afte r an equivalent disease duration. Cross-sectional analysis of neurolog ical deficit, functional deficit and MNCV according to disease duratio n showed that, regardless of age at onset, CMT1A disease with 17p12.2 duplication is a clinically progressive disorder Neurological deficit and functional disability increased, whereas median nerve MNCV and com pound muscle action potential (CMAP) amplitude did not change with dis ease course. Intrafamilial phenotype variation between parents and chi ldren and between siblings was studied in large families. Functional d isability and neurological deficit differed widely and the highest ran ge of median nerve MNCV within a family reached 23 m/s. Clinical and e lectrophysiological data were compared with those of CMT1B patients wi th peripheral myelin Po protein point mutation. CMT1A patients were fo und to be more severely affected with move prolonged distal motor late ncy and more reduced CMAP amplitude, whereas MNCV did not significantl y differ indicating that peripheral myelin Po protein point mutation i s not always associated with a severe phenotype. The same genetic defe ct (17p11.2 duplication) results in variable expression within the phe notype, even in siblings with variations in age at onset, clinical sev erity and MNCV slowing. This phenotypic variation could be due to addi tional genetic factors related to peripheral myelin protein 22 express ion as well as to other endogenous or environmental factors.