Inherited Polyneuropathy

00:02 In this talk, we're going to review inherited polyneuropathies.

00:08 When we think about inherited polyneuropathies this is actually one of the three most common causes of neuropathy in the United States.

00:15 In addition to diabetes and alcoholic polyneuropathy, this is a condition we will want to consider in patients presenting with new onset polyneuropathy primarily in adults or adolescents.

00:27 This is a group of conditions that are inherited peripheral neuropathies.

00:31 And they're classified based on a number of criteria, The clinical characteristics that are present in the patient, the mode of inheritance or a family history electrodiagnostic features, metabolic defects that are present, and subsequently upon specific Genes and Loci.

00:48 And so, been in the majority of these patients, genetic testing will be performed and will be critical for ultimate diagnosis.

00:56 First, let's start with an overview of the inherited neuropathies.

00:59 How do we think about them? What are they? and what are they called? Well, we call this group of disorders, the Charcot-Marie-Tooth diseases.

01:07 And this is a spectrum of disorders caused by pathogenic variants and various genes whose protein products are expressed in myelin, gap junctions, axonal structures within the peripheral nerves.

01:21 Problems with the myelin, the axons, or the gap junctions results in the development of neuropathy.

01:27 Major categories of the Charcot-Marie-Tooth are CMT types 1 to 7, as well as an X-linked category or CMTX.

01:37 The initial presentation often begins with distal weakness, atrophy may be present, with foot drop being a common initial sign and symptom in patients.

01:47 And we can see structural changes in the formation of the bones and joints pes cavus is high arching of the feet, which result from the chronicity, the very chronic nature of these inherited poly neuropathies and the presence of pes cavus should warrant the evaluation for an inherited neuropathy.

02:08 Sensory symptoms are often present, but tend to be less prominent than we see with other toxic metabolic or acquired causes of polyneuropathy.

02:17 And genetic testing is key here to confirming the diagnosis, but is often performed after nerve conduction EMG, which can demonstrate supportive findings.

02:27 So as we've said in terms of the typical presentation of the inherited polyneuropathy is this family of disorders presents with distal weakness, atrophy manifesting with early foot drop and pes cavus, this is not uncommon.

02:39 Sensory symptoms are often present but tend to be less prominent and this presentation should warrant further diagnostic investigation.

02:48 We can categorize the inherited polyneuropathies based on the presentation and genetic findings.

02:54 As well as the underlying mutation that is present.

02:57 In CMT1 there is both a CMT1a and 1b.

03:01 CMT1a results from duplication of the PMP22 Gene.

03:06 CMT1b as a result of mutations in MPZ.

03:10 CMT2 in MFN.

03:12 CMT3 is termed Dejerine-Sottas syndrome.

03:16 CMTX results from a problem in the connexin gene.

03:20 And you can see here the typical example of some of the structural changes that can occur in patients with hereditary motor sensory polyneuropathies.

03:29 Pes Planus is flat feet, which can be seen in 11% of patients, but pes cabus, is extremely more common seen an over up to 80% of patients with inherited polyneuropathies in the presence of this high arching of the feet should warrant further diagnostic testing for an inherited polyneuropathy.

03:50 And importantly, when we evaluate the feet in people with CMT, the lack of muscle, high arches and hammertoes are signs that should warrant further diagnostic workup for a genetic cause.

04:06 There are also some other inherited disorders where neuropathy can be present.

04:10 These are more generalized inherited disorders of the nervous system, but neuropathy may be a prominent feature that includes refsum disease, metachromatic leukodystrophy, Krabbe disease, globoid leukodystrophy and adrenoleukodystrophy.

04:27 In addition, we can see neuropathy with amyloid: amyloid neuropathy, as well as other conditions where neuropathy may be a prominent feature.