Charcot-Marie-Tooth Disease

Question 1

Provide some basic background on CMT/HMSN

Answer 1

• wide range of very similar clinically and genetically heterogenous diseases
• group of disorders make up most common inherited disease of peripheral nervous system
• Include AD, AR and X-linked inheritance
• More than 40 different genes involved

Question 2

What is the prevalence of CMT/HMSN?

Answer 2

1 in 2500/3000

Question 3

What are some common clinical symptoms observed across CMT/HMSN?

Answer 3

• Peripheral motor and sensory nerve function is impaired
• Progressive degeneration of distal muscles of the limbs (muscle weakness and muscle wasting)
• Decreased sensation in hands and feet
• Characteristic deformities often present e.g. Pes cavus (high arched feet)

Question 4

What is the most common form of CMT?

Answer 4

Autosomal dominant demyelinating CMT (CMT Type 1) = ~40-60% in European populations

Question 5

What are the five sub-classifications for CMT Type 1 and what is the major gene involved in each of these?

Answer 5

1. CMT1A (70-80%): PMP22 - mainly dups and point mutations, commonly 1.5Mb dup at 17p11.2-12 (can also cause CMT1E)
2. CMT1B (5-10%): MPZ mutations
3. CMT1C (less than 2%): LITAF mutations
4. CMT1D (less than 2%): EGR2 mutations
5. CMT1F (less than 2%): NEFL mutations

Question 6

In more than 90% of individuals with a CMT1 phenotype a mutation is found in one of three genes. What are they?

Answer 6

• PMP22
• MPZ
• GJB1

Question 7

What genes are involved in the CMT2A subtypes?

Answer 7

• KIF1B and MFN2 genes (CMT2A1 and CMT2A2, respectively)

- Approx 33% of CMT2 mutations are in MFN2

Question 8

Aside from CMT Types 1 and 2, what are the other types of CMT?

Answer 8

• CMT3: dejerine-sottas syndrome (DSS)
• CMT4: autosomal recessive demyelinating CMT
• CMTX: X-linked CMT

Question 9

What is the most common form of CMTX and what is the implicated gene?

Answer 9

• CMTX1: caused by mutations in GJB1 (connexin 32) gene

- 10-15% of CMT cases due to GJB1 mutations

Question 10

Mutations in PRPS1 are associated with what subtype of CMTX?

Answer 10

• CMTX5: CMT2-like with deafness and optic neuropathy

Question 11

What was the historic testing approach for CMT?

Answer 11

• Sequential approach (Sanger seq) based on clinical phenotype/inheritance pattern
• CMT1 patients with known male to male transmission test for PMP22 dup (CMT1A) then MPZ (CMT1B)/point mutations in PMP22 (CMT1E) then LITAF (CMT1C)/EGR2 (CMT1D)

Question 12

What is the current testing approach for CMT?

Answer 12

• PMP22 duplication dosage analysis (initial test in CMT/HNPP patients)
• Gene panel testing of multiple genes

Question 13

Provide details on the 1.5Mb CNV observed in PMP22 in the context of hereditary neuropathy

Answer 13

• Duplication of this region is the most common genetic cause of CMT1
• Deletion of this region leads to another clinical phenotype: hereditary neuropathy with liability to pressure palsies (HNPP)

Question 14

Why is there a high frequency of the 1.5 Mb duplication in PMP22?

Answer 14

Due to NAHR between the repeated regions flanking the PMP22 gene

Question 15

What is the testing method for PMP22 deletion/duplication?

Answer 15

• PMP22 dosage analysis commonly by MLPA

- P033 kit (MRC Holland) detects 70% of CMT1 (98% of CMT1A) and 84% of HNPP mutations

Question 16

What is the role of PMP22 in the nervous system?

Answer 16

• Primarily expressed by Schwann cells of peripheral nerves, making up 2-5% of peripheral nervous system myelin
• thought to stabilise MPZ within myelin
• may have role during Schwann cell growth and differentiation

Question 17

Provide details on the molecular pathogenesis of CMT1A arising through the 1.5 Mb PMP22 duplication

Answer 17

• PMP22 overexpression may disrupt timing and regulation of myelin protein production (including PMP22)
• Result = demyelination of the peripheral nerves which leads to abnormal axon structure and function, slowing of nerve conduction and axonal loss

Question 18

Provide details on the molecular pathogenesis of CMT arising through changes in the MPZ gene

Answer 18

• MPZ is major myelin protein in peripheral nervous system
• MPZ molecules form homotetramers that facilitate cell adhesion and are necessary for normal myelin compaction
• MPZ mutations can cause a demyelinating phenotype (CMT1B) or an axonal phenotype (CMT2I/CMT2J) as well as intermediate forms
• Mutations altering the myelination process and compaction of myelin lead to early onset forms of CMT1

Question 19

Provide details on the molecular pathogenesis of CMT arising through the GJB1 gene

Answer 19

• GJB1 forms gap junctions which are important for cell-cell communication
• Expressed in myelinating Schwann cells and are a means of communications between layers of the myelin sheath
• Loss of function mutations in GJB1 lead to demyelination

Question 20

Provide details on the molecular pathogenesis of CMT arising through the MFN2 gene

Answer 20

• MFN2 is a mitochondrial membrane protein that, via interaction with mitofusin-1, plays major role in mitochondrial fusion
• Abnormalities in mitochondrial dynamics affect mitochondrial energy production in neurons and disrupt axon function

Question 21

What are the clinical features of CMT1?

Answer 21

• Demyelinating
• slow nerve conduction: 5-30m/sec (compared to normal of more than 40-45)
• distal muscle weakness
• sensory loss

Question 22

What are the clinical features of CMT2?

Answer 22

• Axonal
• nerve conduction usually in normal range but may be low normal or mildly abnormal
• similar problems to CMT1 but less disabled and less sensory loss
• Accounts for 10-15% of CMT

Question 23

What are the clinical features of CMTX1?

Answer 23

• Moderate to severe Motor and sensory neuropathy in affected males with mild to no symptoms in females
• deafness and CNS symptoms in some
• other X-linked forms associated with ID, optic neuropathy, spasticity or pyramidal signs