CMT 1X in Females

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CMT 1X in Females

ANN Poster Session Seattle Wednesday, April 29, 2009 3:45 PM

[s37.001] Females with Charcot-Marie-Tooth Disease Type 1X Display Two Distinct

Phenotypes

Hyman, Sottile, Sindhu Ramchandren, E. Shy, Carly E.

Siskind, Chappaqua, NY, Detroit, MI

OBJECTIVE: Describing the female Charcot Marie Tooth disease type 1X (CMT1X)

phenotypic spectrum.

BACKGROUND: CMT1X is a hereditary demyelinating neuropathy caused by GJB1

mutations encoding the gap junction protein connexin 32 (Cx32). Because this

condition is X-linked, males and females typically exhibit different phenotypes,

with males more severely affected than females. Prior work has documented the

natural history for CMT1X males. Here, we document the phenotypic spectrum for

CMT1X females.

DESIGN/METHODS: Patients (26 females; 54 males) were evaluated in the CMT Clinic

at Wayne State University. Disability was assessed using the validated CMT

Neuropathy Score (CMTNS) and correlated with age and mutation. To estimate

progression, retrospective analysis (by decade) using the CMT Symptom Score

(CMTSS) was performed.

RESULTS: Females had lower CMTNS than males (p < 0.001). CMTSS increased by

decade in females but did not correlate with particular mutations. Females with

CMT1X fell into two groups. The first, consisting of 17 females, had mild

disability (CMTNS 10; mean = 3.6). CMTSS in these females were 2 or less

(maximum 12) and remained nearly constant through the decades. Four genetically

determined affected females had a CMTNS of 0 (ages 7, 36, 36, 47). Nine females

exhibited moderate disability (CMTNS 10 < x 20; mean = 15). In these females,

CMTSS increased/decade in a linear pattern similar to that of CMT1X males.

CONCLUSIONS/RELEVANCE: CMT1X females fall into two groups. One group displays

minimal signs, symptoms, or abnormal electrophysiology as would be predicted

based on random-X-inactivation. In the second group, X-inactivation appears

skewed towards the mutant GJB1 allele since this group presents similarly to

CMT1X males. Four females, including three adults, with a CMTNS of 0 suggests

that in some cases X-inactivation may be skewed towards the wild type allele as

these females have no evidence of neuropathy despite harboring a disease causing

mutation.