Hereditary polyneuropathy

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The peripheral nervous system is affected by a diverse range of diseases known as hereditary polyneuropathies.

The disorders affecting the peripheral motor, sensory, and autonomic nerves are collectively referred to as peripheral neuropathies or polyneuropathies (PNP). These disorders have varying causes, including infections, immune-mediated reactions, metabolic imbalances, toxic exposure, vascular issues, genetic factors, and unknown origins. The clinical manifestations of these disorders often share similarities, and they may also coexist with other disease mechanisms.

There are several types of hereditary peripheral neuropathies, including Charcot-Marie-Tooth disease (CMT), also known as hereditary motor sensory neuropathy (HMSN), hereditary sensory and autonomic neuropathies (HSAN), also known as hereditary sensory neuropathy (HSN), hereditary motor neuropathies (HMN), and small fiber neuropathies (SFN). Over 100 genes have been identified as the cause of hereditary neuropathies and related disorders, with distinctions made between autosomal dominant, autosomal recessive, and X-chromosome linked inherited forms. Additionally, hereditary mitochondriopathies can also manifest as peripheral neuropathies.

HNPP, which results from a deletion in PMP22, typically manifests as acute and recurring nerve sensory and motor neuropathy affecting one or multiple nerves. This condition usually begins during adolescence or young adulthood and is characterized by local conduction abnormalities at nerve entrapment sites, as well as reduced SNAPs. HNPP exhibits a wide range of phenotypical variability, and some patients may experience symptoms similar to those of CMT1, multiple mononeuropathies with focal conduction slowing, vasculitic neuropathy, or leprosy.

In the Caucasian population, the SH3TC2 gene is the most commonly implicated gene in recessive demyelinating CMT disease, with a prevalence of approximately 18% [34]. Early signs of the disease include scoliosis, as well as cranial nerve and proximal limb involvement. ENMG studies typically reveal an intermediate or demyelinating neuropathy, often accompanied by conduction blocks and temporal dispersion.

GDAP1, PLEKHG5, MTMR2, SBF2, NDRG1, EGR2, PRX, FGD4, and FIG4 are genes that cause recessive demyelinating CMT disease, but they occur much less frequently.

Certain genes associated with demyelinating CMT, including LITAF, PMP22, MPZ, PLEKHG5, FIG4, GJB1, and SH3TC2, can imitate inflammatory neuropathies like CIDP and exhibit conduction blocks on ENMG. Research has indicated that CMT disease is often misdiagnosed as CIDP when patients experience an early onset of symptoms (before 40 years old), have a family history of the disease, exhibit muscle weakness and wasting at the onset of the disease, have a normal plexus MRI, normal CSF protein content, hearing loss, and do not respond to intravenous immunoglobulin treatment.

Mutations in GJB1 are inherited through the X chromosome. Typically, males will experience symptoms such as progressive distal muscle weakness, early involvement of the hands, loss of deep tendon reflexes, and sensory loss by their second decade. In some cases, stroke-like manifestations indicating CNS dysfunction may occur, with brain MRI revealing subcortical and corpus callosum white matter lesions. Hemizygous women may experience mild symptoms.

Late-onset axonal CMT disease is commonly the type of CMT disease that remains genetically undiagnosed in middle-aged and elderly individuals, particularly in cases that are not familial. Some of the genes that could potentially be linked to this form of CMT disease include MPZ, MME, LRSAM1, HSPB1, and TTR.

A diverse range of diseases fall under the category of genetic neuropathies, varying from the prevalent CMT disease to more intricate inherited conditions. Over the past decade, the rapid progress in molecular genetics and the utilization of NGS have facilitated the identification of numerous genes and expanded the clinical range of certain previously recognized genes.

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SNP polymorphisms related to the topic Polyneuropathy: