Monograph: Hereditary Motor and Sensory Neuropathies (HMSNs) With Conduction Block-Article

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This 2025 AANEM Monograph by Hebatallah R. Rashed provides a comprehensive review of hereditary motor and sensory neuropathies (HMSNs) exhibiting conduction block (CB) and non-uniform slowing of nerve conduction, which mimic acquired demyelinating neuropathies. Traditionally, HMSNs, particularly dysmyelinating forms (e.g., CMT type 1), are characterized by uniform conduction slowing. However, advances in genetic understanding reveal novel mutations causing segmental conduction abnormalities such as conduction block and excessive temporal dispersion (TD), complicating diagnosis and often leading to misclassification as inflammatory neuropathies like CIDP, resulting in inappropriate immunotherapy.<br /><br />Key HMSN subtypes associated with conduction block include:<br /><br />- Hereditary Neuropathy with Liability to Pressure Palsies (HNPP), caused mainly by PMP22 deletion, features focal, persistent conduction blocks at common nerve compression sites without abnormal temporal dispersion.<br /><br />- CMT1X, due to GJB1 (connexin 32) mutations, shows intermediate or variable conduction slowing and non-uniform slowing with conduction block and TD, more severe in males. CNS involvement and stroke-like episodes can occur.<br /><br />- CMT1B (MPZ gene mutations) exhibits mild to severe demyelinating neuropathy with occasional conduction block, sometimes mimicking CIDP; segmental demyelination and myelin irregularities contribute to pathology.<br /><br />- CMT1C (LITAF/SIMPLE mutations) presents mild demyelinating neuropathy with slow conduction velocities, occasional conduction block, and temporal dispersion.<br /><br />- CMT4J (FIG4 mutations) is a severe, often asymmetric demyelinating neuropathy with very slow conduction velocities and conduction blocks, frequently misdiagnosed as CIDP.<br /><br />Electrophysiologically, there are no standardized criteria for defining conduction block and temporal dispersion in inherited neuropathies, leading to inconsistent reporting. Studies suggest conduction block cutoffs vary from 30% to 50% reduction in CMAP amplitude/area, and temporal dispersion definitions differ by nerve and study.<br /><br />Pathologically, conduction block is linked to paranodal abnormalities, segmental demyelination, and tomacula (focal myelin thickening) in diseases like HNPP. In CMT1B and CMT1C, myelin infoldings and paranodal damage are postulated mechanisms. In CMT1X, Schwann cell abnormalities and regenerating fibers contribute to non-uniform conduction.<br /><br />The monograph emphasizes that careful clinical evaluation and recognition of these electrophysiological patterns are crucial to avoid misdiagnosis and unnecessary immunotherapy. It calls for establishing standardized electrophysiological criteria for conduction block and temporal dispersion in inherited neuropathies and underscores the importance of genetic diagnosis in guiding care, particularly as gene therapy and novel treatments evolve.

Keywords

Hereditary motor and sensory neuropathies

Conduction block

Non-uniform nerve conduction slowing

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

Charcot-Marie-Tooth disease type 1X (CMT1X)

Charcot-Marie-Tooth disease type 1B (CMT1B)

Charcot-Marie-Tooth disease type 1C (CMT1C)

Charcot-Marie-Tooth disease type 4J (CMT4J)

Temporal dispersion

Misdiagnosis as chronic inflammatory demyelinating polyneuropathy (CIDP)