Interpreting diagnostic genetic Tests Flashcards
Why is it relevant - just send for a panel
- pathogenic
- likely pathogenic
- variant of uncertain significance
- likely benign
- benign
Pitfalls:
- in some countries VUS are not reported
- poor coverage of duplication and deletions/ repeat expansions
- wrong panel
Probability of a VUS being disease causing
Hot - 81%
Warm - 67.5%
Tepid - 50%
Cool - 32.5%
Clinical presentation of CMT
Length dependent weakness or sensory loss
Slow progression
Onset varies from childhood to late adult
Often but not always a family history:
- de novo mutations
- non paternity
- late onset
Neurophysiology
Is there a neuropathy
- sometimes only detected on EMG
Is there involvement of motor and sensory nerve fibres
- hereditary motor AND sensory neuropathy (CMT) vs HMN or HSN
Is the neuropathy demyelinating or axonal?
- <38m/s upper limb CV
Nomenclature of hereditary neuropathies
Hereditary weakness or numbness
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Neurophysiology
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Demyelinating - CMT1
Axonal
- sensory predominant HSN
- mixed motor and sensory CMT2
- motor predominant HMN
CMT1A = chromosome 17p duplication
Childhood onset
Disability from foot deformity
Variable disease severity
- neurophysiology always abnormal (slow NCV)
- some asymptomatic adults
Charcot Marie tooth
- duplication of 17p
X linked CMT (CMTX1)
- mutations in GJB1 encoding connexin 32 (channel protein)
- 2nd commonest form of CMT
CMT (X)
- clinically similar to CMT1
- no male to male transmission
- males more severe than females
- males demyelinating/ females axonal
- patchy clinically (may mimic CIDP on NCS)
- sometimes upper limb dominant
- CNS
Split hand in CMTX
- weakness and wasting of APB> ADM or FDIO
CMT2
Mutations in the MFN2 are the commonest cause of axonal CMT (10-20%)
Majority autosomal dominant
- can be recessive
- associated with optic atrophy in a minority
Traditionally severe
For CMT2, hereditary sensory neuropathy and hereditary motor neuropathy, most patients do not have a genetic diagnosis (~50%)
Non-length dependent CMT2
Autosomal dominant
Neurofilament heavy chain NEFH
- onset 2/3rd decade
- distal/proximal weakness
HMSN-proximal (Okinawa type)
-TFG mutations
- onset 4th decade
- proximal > distal weakness
- Death by 7th decade
Autosomal recessive
Membrane metalloendopeptidase MME
- onset 5th decade
- distal = proximal
Often require wheelchair
May mimic CIDP (no slowing)
What is a complex genetic disease
Disease in which peripheral neuropathy is part of a clinical syndrome
- usually neurological - spasticity, ataxia, developmental delay
- other organ involvement e.g cardiac
Disease in which peripheral neuropathy is a significant feature of the syndrome
May present with peripheral neuropathy
Global developmental delay and peripheral neuropathy
- large number of diseases including metabolic leukodystophies
- commonly linked to mutations in microtubule transport based on motor proteins (diseases of cortical migration)
Global developmental delay and peripheral neuropathy
- large number of diseases including metabolic leukodystophies
- commonly linked to mutations in microtubule transport based on motor proteins (diseases of cortical migration)
Lower limb spasticity and upper limb motor neuropathy
- upper limb > lower limb denervation
- wrist extensor weakness with SIGMAR1
BSCL2 - misfolds in ER (dominant)
(Silver syndrome)
REEP1 - ER protein (dominant)
RTN2 - ER protein (recessive)
SIGMAR1 - ER protein (recessive)
May need to request HSP panel
