CMT - Part 1A and 1B Flashcards Preview

Genetics of Neuromuscular Disorders > CMT - Part 1A and 1B > Flashcards

Flashcards in CMT - Part 1A and 1B Deck (28)
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1
Q

Give a brief introduction to Charcot-Marie-Tooth disease.

A
  • Charcot-Marie Tooth disease (CMT), or Hereditary Motor and Sensory Neuropathy (HMSN) encompasses a wide range of very similar clinically and genetically heterogeneous diseases.
  • Includes autosomal dominant, autosomal recessive and X-linked inheritance; >40 different genes involved.
  • This group of disorders make up the most common inherited disease of the peripheral nervous system.
  • Prevalence is approximately 1 in 2500 - 1 in 3000.
  • Peripheral motor and sensory nerve function is impaired.
  • Progressive degeneration of the distal muscles and limbs leading to muscle weakness and muscle wasting.
  • Decreased sensation in the hands and feet.
  • Characteristic deformities are also often present. For example pes cavus, high-arched feet.
2
Q

What is the prevalence of CMT?

A

Prevalence is approximately 1 in 2500 - 1 in 3000.

3
Q

Describe the classification of CMT and the features of the different types of CMT.

A
  • Since the initial description of CMT the disease has been further classified based initially on electrophysiological findings, and later on molecular inheritance patterns and molecular genetics.
  • Historically, CMT1 was described as a demyelinating neuropathy. This classification was based on motor nerve conduction velocities (MCVs) below 38m/s. Normally, CMT1 shows autosomal dominant inheritance but autosomal recessive forms have also been reported.
  • In comparison, CMT2 was classed as a neuronal neuropathy. CMT type 2 patients show higher nerve conduction velocities (MCVs) >38m/s. CMT2 is also normally autosomal dominant but autosomal recessive forms have been documented.
  • CMT type 4 (CMT4) is a demyelinating neuropathy. CMT4 was initially used to describe autosomal recessive forms of CMT1 but this class of CMT is now usually referred to as autosomal recessive CMT1 or AR CMT1.
  • CMTX - X-linked forms of CMT also occur with mixed demyelinating and axonal phenotypes.
  • Intermediate CMT / Dominant Intermediate CMT (DI-CMT) - There are also some forms of CMT that show intermediate motor nerve conduction velocities between about 25 and 45m/s. These forms often involve a mixed clinical picture of demyelinating and axonal neuropathy in a single individual.
  • Other classifications of inherited peripheral neuropathies include Hereditary Sensory and Autonomic Neuropathies (HSAN) and Distal Hereditary Motor Neuropathy (dHMN). HSAN shows fewer motor signs and dHMN has no sensory signs.
  • The various classes of CMT show overlapping clinical phenotypes and also show some clinical similarity with isolated sensory or motor neuropathies (i.e. overlaps with HSAN and dHMN).
  • HMSN V may be used to refer to CMT/HMSN with pyramidal features.
  • HMSN VI may be used to refer to hereditary neuropathy with optic atrophy.
4
Q

What are the main ways in which the following peripheral neuropathies differ from CMT/HMSN?

i) . Hereditary Sensory and Autonomic Neuropathies (HSAN).
ii) . Distal Hereditary Motor Neuropathy (dHMN).

A

i) . Hereditary Sensory and Autonomic Neuropathies (HSAN) show fewer motor signs.
ii) . Distal Hereditary Motor Neuropathy (dHMN) has no sensory signs.

5
Q

What type of CMT/HMSN does HMSN V refer to?

A
  • HMSN V may be used to refer to CMT/HMSN with pyramidal features.
6
Q

What type of CMT/HMSN does HMSN VI refer to?

A
  • HMSN VI may be used to refer to hereditary neuropathy with optic atrophy.
7
Q

Describe the subtypes of CMT Type 1.

A
  • AD CMT1 (Autosomal dominant demyelinating CMT1) is the most common form of CMT making up about 40-60% of the CMT found in European populations.
  • CMT1A - This is the most common form of CMT type 1. This makes up approximately 70-80% of all CMT1 cases. The vast majority of CMT1A (98%) is caused by a 1.5Mb duplication of 17p11.2-12 including PMP22, the peripheral myelin protein 22 gene. Studies have demonstrated that the CMT phenotype is caused by duplications in the PMP22 gene rather than the other genes in the duplicated region. CMT1A has also been reported to result from point mutations in the PMP22 gene and these have also been reported to cause CMT type 1E.
  • CMT1B - This is the next most common subtype of CMT1. This is caused by mutations in the Myelin Protein Zero (MPZ) gene and accounts for around 5-10% of CMT1 cases.
  • CMT1C - Lipopolysaccharide-induced tumour necrosis factor alpha (LITAF) mutations (<2%).
  • CMT1D - Early Growth Response Protein 2 (EGRP2) mutations (<2%).
  • CMT1F - Neurofilament Light Peptide (NLP) mutations (<2%).
8
Q

What is the most common form of CMT?

A

AD CMT1 (Autosomal dominant demyelinating CMT1) is the most common form of CMT making up about 40-60% of the CMT found in European populations.

9
Q

Describe the most common form of CMT1?

A
  • CMT1A - This is the most common form of CMT type 1. This makes up approximately 70-80% of all CMT1 cases. The vast majority of CMT1A (98%) is caused by a 1.5Mb duplication of 17p11.2-12 including PMP22, the peripheral myelin protein 22 gene. Studies have demonstrated that the CMT phenotype is caused by duplications in the PMP22 gene rather than the other genes in the duplicated region. CMT1A has also been reported to result from point mutations in the PMP22 gene and these have also been reported to cause CMT type 1E.
10
Q

What gene mutation causes CMT1A?

A

CMT1A - This is the most common form of CMT type 1. This makes up approximately 70-80% of all CMT1 cases. The vast majority of CMT1A (98%) is caused by a 1.5Mb duplication of 17p11.2-12 including PMP22, the peripheral myelin protein 22 gene. Studies have demonstrated that the CMT phenotype is caused by duplications in the PMP22 gene rather than the other genes in the duplicated region. CMT1A has also been reported to result from point mutations in the PMP22 gene and these have also been reported to cause CMT type 1E.

11
Q

What gene mutation causes CMT1B?

A

CMT1B - This is the next most common subtype of CMT1. This is caused by mutations in the Myelin Protein Zero (MPZ) gene and accounts for around 5-10% of CMT1 cases.

12
Q

What gene mutation causes CMT1C?

A

CMT1C - Lipopolysaccharide-induced tumour necrosis factor alpha (LITAF) mutations (<2%).

13
Q

What gene mutation causes CMT1D?

A

CMT1D - Early Growth Response Protein 2 (EGRP2) mutations (<2%).

14
Q

What gene mutation causes CMT1F?

A

CMT1F - Neurofilament Light Peptide (NLP) mutations (<2%).

15
Q

Describe the subtypes of CMT Type 2.

A
  • CMT type 2 has been reported to make up about 10-15% of CMT cases but as genes have only been identified for approximately 40% of cases of CMT2 prevalence may be higher.
  • CMT2 shows extensive clinical overlap with CMT1; however, in general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1.
  • CMT2A is the most common axonal variant of CMT.
  • The locus for CMT2A is on chromosome 1p35-36 and contains the genes KIF1B (CMT2A1) and MFN2 (Mitofusin 2) (CMT2A2).
  • Approximately 33% of CMT type 2 mutations are in MFN2. The other CMT2 cases are split between multiple genes.
  • Other CMT2 causing loci have been identified but the causative genes have not been determined in all cases.
16
Q

What is the most common axonal variant of CMT?

A

CMT2A is the most common axonal variant of CMT.

17
Q

What locus has been linked to CMT2?

A

The locus for CMT2A is on chromosome 1p35-36 and contains the genes KIF1B (CMT2A1) and MFN2 (Mitofusin 2) (CMT2A2).

18
Q

What genes are CMT2 mutations linked with?

A

Approximately 33% of CMT type 2 mutations are in MFN2. The other CMT2 cases are split between multiple genes.

19
Q

Describe the form of CMT sometimes referred to as CMT3.

A
  • CMT3 / Dejerine-Sottas Syndrome (DSS) is sometimes used to describe a phenotype of severe motor and sensory neuropathy with onset in early infancy.
  • CMT3 can be AD (de novo mutations) or recessive depending on the genes involved and mutation types.
  • CMT3 can be due to mutations in PMP22, MPZ, EGR2 and PRX (Periaxin).
  • Now usually classed as severe phenotypic form of CMT type 1 (or CMT type 4).
20
Q

Describe AR-CMT1/CMT4.

A
  • Autosomal recessive CMT1, also termed CMT4 in the literature, is less frequent than CMT1 in European populations but may be more common in other populations.
  • The severity of the phenotype of CMT4 varies within and between the subtypes depending on the mutations involved.
  • CMT4 loci A-J have been identified and include the genes GDAP1, EGR2 and PRX.
  • CMT4A caused by mutations in GDAP1 is the most common form of AR CMT in most populations.
  • CMT4E caused by ERG2 mutations has also been termed congenital hypomyelinating neuropathy.
21
Q

What is the most common form of autosomal recessive CMT in most populations?

A

CMT4A caused by mutations in GDAP1 is the most common form of AR CMT in most populations.

22
Q

What gene mutations are known to cause CMT4E?

A

ERG2 mutation.

23
Q

What CMT type is also known as congenital hypomyelinating neuropathy?

A

CMT4E caused by ERG2 mutations has also been termed congenital hypomyelinating neuropathy (CHN).

24
Q

What is the most common form of X-linked CMT?

A

CMTX1.

25
Q

Describe X-linked CMT.

A
  • The most common form of X-linked CMT, CMTX1, is caused by mutations in the GJBJ1 (conexin 32) gene on Xq13.1.
  • This is the second most common form of CMT in most populations making up approximately 10-15% of CMT in Europeans.
  • The phenotype of CMTX1 is normally more severe in males. Females can show later onset/mild progression or can be unaffected. The phenotype in females may be affected by skewed X-inactivation.
  • Phenotypes can demonstrate characteristics of either CMT1 or CMT2. E.g. MCVs are not always reduced, especially in females.
  • Another form of X-linked CMT, CMTX5, has been reported. This shows a CMT2-like phenotype with deafness and optic neuropathy.
  • CMTX5 results from mutations in the PRPS1 (Ribose-phosphate pyrophosphokinase 1) gene and shows an X-linked recessive inheritance.
  • There are other X-linked forms of CMT but they have not yet had genes identified.
26
Q

What is CMTX1 caused by?

A

The most common form of X-linked CMT, CMTX1, is caused by mutations in the GJBJ1 (conexin 32) gene on Xq13.1.

27
Q

What kind of phenotype does CMTX5 usually show?

A

This shows a CMT2-like phenotype with deafness and optic neuropathy.

28
Q

CMTX5 results from mutations in what gene?

A

CMTX5 results from mutations in the PRPS1 (Ribose-phosphate pyrophosphokinase 1) gene and shows an X-linked recessive inheritance.