Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?

Abstract

Introduction: Charcot-Marie-Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur.

Methods: We studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision.

Results: Patients harbored a PMP22 gene alteration (n = 28) or a mutation in MPZ (n = 11), GJB1 (n = 4), LITAF (n = 2), MFN2 (n = 2), INF2 (n = 1), NEFL (n = 1). We identified four novel mutations (3 MPZ, 1 GJB1). A total of 88% presented at least one additional feature. In MPZ patients, we detected hypertrophic nerve roots in 3/4 cases that underwent spinal MRI, and pupillary abnormalities in 27%. In our cohort, restless legs syndrome (RLS) was present in 18%. We describe for the first time RLS associated with LITAF or MFN2 and predominant upper limb involvement with LITAF. Cold-induced hand cramps occurred in 10% (PMP22,MPZ,MFN2), and autonomous nervous system involvement in 18% (PMP22,MPZ, LITAF,MFN2). RLS and respiratory insufficiency were mostly associated with severe neuropathy, and pupillary abnormalities with mild to moderate neuropathy.

Conclusions: In CMT patients, additional features occur frequently. Some of them might be helpful in orienting genetic diagnosis. Our data broaden the clinical spectrum and genotype-phenotype associations with CMT.

Keywords: Additional symptoms; HMSN; RLS; hereditary motor and sensory neuropathy; pupillary abnormalities.

Figure 1

Thoraco‐lumbo‐sacral MRI and sural nerve biopsies in three CMT1B patients with MPZ‐mutation and hypertrophic cauda equina/nerve roots. (A–C) T2‐weighted sagittal sections of the thoracal, lumbar, and sacral spinal column in patients 6 (A), 4 (B), and 2 (C), indicating the thickened nerve roots of the cauda equina (arrows). This is also shown for patient 2 at a T1‐weighted sagittal section (D) and a T1‐weighted coronal section (E). Arrow heads show congested intraspinal vessels. (F–H) T2‐weighted axial sections at the level of the fourth lumbar vertebral body (L4) of patients 6 (F), 4 (G) and 2 (H), showing extensive hypertrophic nerve roots of the cauda equina inside the spinal column. (I–K) Nerve Biopsy pictures of patients 6 (I, J) and 2 (K) with (J) being a magnification of (I). Arrow heads show onion bulb formations, the arrow points toward a remaining hypomyelinated nerve fiber. Notice the extensive loss of the large myelinated fibers.