Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases

Abstract

A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 duplication. 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 the lower limbs. None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients. Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss. Needle electromyography recruitment was reduced in distal muscles for all patients. MNCV slowing was fully consistent with the presence of duplication even in clinically asymptomatic individuals or in children, confirming the complete electrophysiological penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional disability was mild. Ninety-six percent of patients were autonomous; 25% were asymptomatic and diagnosed by systematic family investigation especially on the basis of median nerve MNCV reduction. Early age at onset and greatly reduced median nerve MNCV were predictive of a more severe disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be after an equivalent disease duration. Cross-sectional analysis of neurological deficit, functional deficit and MNCV according to disease duration showed that, regardless of age at onset, CMT1A disease with 17p11.2 duplication is a clinically progressive disorder. Neurological deficit and functional disability increased, whereas median nerve MNCV and compound muscle action potential (CMAP) amplitude did not change with disease course. Intrafamilial phenotype variation between parents and children and between siblings was studied in large families. Functional disability and neurological deficit differed widely and the highest range of median nerve MNCV within a family reached 23 m/s. Clinical and electrophysiological data were compared with those of CMT1B patients with peripheral myelin P0 protein point mutation. CMT1A patients were found to be more severely affected with more prolonged distal motor latency and more reduced CMAP amplitude, whereas MNCV did not significantly differ, indicating that peripheral myelin P0 protein point mutation is not always associated with a severe phenotype. The same genetic defect (17p11.2 duplication) results in variable expression within the phenotype, even in siblings with variations in age at onset, clinical severity and MNCV slowing. This phenotypic variation could be due to additional genetic factors related to peripheral myelin protein 22 expression as well as to other endogenous or environmental factors.

Wide phenotypic variations in Charcot-Marie-Tooth 1A neuropathy with rare copy number variations on 17p12

“…A diameter histogram of myelinated fibers showed a unimodal distribution pattern and confirmed the hypertrophic or demyelinating changes. Those clinical, electrophysiological, and histopathological features were similar to the CMT1A patients with common duplication (Birouk et al 1997;Lee and Choi 2006). The exact duplication regions were different among the three families; however, the PMP22 gene was included in all the duplications.…”

Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells

“…However, despite the large number of different mutations, the clinical severity caused by different mutations appears to be relatively uniform in affected men, including those with a deleted gene. Some mutations appear to cause exceptionally severe phenotypes, typically with early onset: R22stop Birouk et al, 1997), the double-mutation R22Q and V63I (Silander et al, 1998), V136A (Choi et al, 2004), 147 frameshift (Meggouh et al, 1998), C201R (Sillen et al, 1998), F235C (Lin et al, 1999), and the deletion nucleotides 265-273 deletion/frameshift . E102G, N175D, and T191A have been reported to be associated with a milder phenotype (Silander et al, 1998;Kobari et al, 2000;Abrams et al, 2003).…”

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31–q33: exclusion of candidate genes including EGR1

“…Foot and spine deformities, which were also reported in families BOU-001 and ABD-210, were observed in three or four patients in three new families where the stage of disability ranged from 1 to 4. 21 The values for MNCV were homogeneous, ranging from 20 to 30 m/s in 14/16 patients including those from two of the three new families. The sural nerve biopsy in patient TER-162-004 showed severe loss of axons and of myelinated fibres with signs of Schwann cell proliferation in surviving nerve fibres.…”