1. Approach to Inherited Neuropathies
Jodi Warman Chardon, MD, MSc
Neuromuscular Fellow, McGill University
Neurogenetics Fellow, University of Ottawa

2. Objectives Develop approach to inherited neuropathies
Appropriate history
Relevant physical exam
Review of electrodiagnostic testing
Develop appreciation for benefits and erroneous conclusions due to genetic testing
At the end, discussion of career or fellowship options if you would like
Please provide feedback: written or oral, positive and especially negative

3. Disclosures
No disclosures

4. Quiz
HMSN patients usually have primarily positive sensory symptoms at onset T/F
With ROS on focused exam, it is necessary to review symptoms of visual changes, hearing loss, dysphagia and hoarseness T/F
GJB1 is most common mutation causing inherited neuropathy T/F
Patients with HMSN most often have decreased amplitudes and preserved conduction velocities and latencies on NCS T/F

5. Case X 65 year old man, diabetic, smoker, alcoholic
4 year history of sensory loss in his feet
Exam: MS, CN N
Motor: pes cavus, distal weakness, length dependent
Sensory: distal pp decreased to ankles, vibration decreased to MM
Reflexes: 1+ symm reflexes except absent Achilles
What other information do you need?

6. Clinical approach to any neuropathy
Hx:
Negative motor symptoms weakness, fatigue and wasting
Positive motor symptoms include cramps, twitching and myokymia
Negative sensory symptoms: hypesthesia and gait abnormalities such as ataxia
Positive sensory symptoms include burning or lancinating pain, paresthesias, “buzzing,” “tingling”
Alport and Sander, Continuum, 2012

7. Clinical-assess for acquired causes
Exposures with
occupation (possibility of toxic exposures to solvents, glues, fertilizers, oils, and lubricants)
sexual history
recreational drug use
excessive alcohol intake
dietary habits
smoking
Alport and Sander, Continuum, 2012

8. General PMHx (r/o acquired)
Medical (FHx) neuropathy focus: endocrinopathy (DM, hypothyroidism), renal insufficiency, hepatic dysfunction, CTD, and cancer.
Surgical history: bariatric surgery, multiple orthopedic procedures, and multiple surgeries for ‘‘entrapped nerves’’
Medication list: (temporal) HAART, chemotherapy, Abx, herbal, etc
ROS: rash/skin changes, arthralgias, dry eyes and mucous membranes, orthostasis, GI, and constitutional symptoms (fever, weight loss, night sweats).
Alport and Sander, Continuum, 2012

9. Family History
Not just “no neuromuscular conditions…” unless clearly acquired cause
Draw pedigree 3

10. Clinical-Clues to Inherited Neuropathy
Any symmetric, generalized polyneuropathy (+HNPP)
….Family history
Symptoms less obvious to patient
Lack of positive sensory symptoms
Early age at onset, delayed milestones/ development
Ankle weakness (difficulty skating), stumble, running difficulties, balance difficulties vs later adult onset *
Associated skeletal abnormalities
Foot deformities
Scoliosis
Very slowly progressive
Lower, 10 years delay upper extremities (vs CMT1D)
Siskind and Shy, Seminars in Neurology, 2011
Alport and Sander, Continuum, 2012

11. Causes of Negative Family History
Family data are frequently not available, incomplete, or unknown, a genetic cause is not ruled out:
initial sporadic mutation
expression can be variable
penetrance incomplete
late-onset disease
family members available for study may be pre-symptomatic
older relatives may have other comorbidities that confound the phenotype
older relatives may also pass away before evaluation
Lawson & Gharibshahi, Seminars in Neurology, 2010

12. Pathophysiological Approach
Suter and Scherer. Nature Reviews Neuroscience, 2003

13. Neuropathy is the sole or primary part of the disorder
Charcot–Marie–Tooth disease (CMT)= Hereditary Motor Sensory Neuropathy (HMSN)
Hereditary neuropathy with liability to pressure palsies (HNPP)
Hereditary sensory and autonomic neuropathies/hereditary sensory neuropathies (HSAN/HSN)
Distal hereditary motor neuropathies (dHMN)
Hereditary neuralgic amyotrophy (HNA)
Reilly and Shy, J Neurol Neurosurg Psychiatry, 2009

14. Neuropathy part of a widespread neurological or multisystem disorder
Familial amyloid polyneuropathy
Disturbances of lipid metabolism
Porphyrias
Disorders with defective DNA
Neuropathies associated with mitochondrial diseases
Neuropathies associated with hereditary ataxias
Reilly and Shy, J Neurol Neurosurg Psychiatry, 2009

15. CMT
Charcot-Marie-Tooth disease (CMT) disease = Hereditary Motor Sensory Neuropathy (HMSN)
encompasses inherited neuropathies that demonstrate both genetic and phenotypic heterogeneity
i.e. PMP-22 [CMT1a, CMT1e, HNPP, early onset CMT (~CMT3 (previously known as Dejerine-Sottas) Congenital Hypomyelinating  Neuropathy]
CMT results from mutations in more than 50 genes expressed in Schwann cells and neurons causing overlapping phenotypes
Choi et al. Human Mutation, 2012

16. Complex CMT Genetics 60% of all CMT=CMT1
(80-90% is CMT1A with PMP 22 duplication> point mutation

17. CMT
“Classic”clinical phenotype: length-dependent degeneration characterized by
distal sensory loss and weakness
deep tendon reflex abnormalities
and skeletal deformities (foot, scoliosis)
Vs. “CMT-Plus” syndromes:
Optic atrophy, cataracts, glaucoma, deafness, dysphagia, respiratory, UMN etc

18. Patzkó and Shy. Curr Neurol Neurosci Rep. 2011

19. Patzkó and Shy. Curr Neurol Neurosci Rep. 2011

20. Electrodiagnostic studies (Classic)
Demyelinating
Decreased conduction velocity {<38 M/s}
Conduction velocities
Uniformly slow in all nerves (Mean 17 to 20 M/s)
Onset before clinical signs appear
Usually NO abnormal temporal dispersion or conduction block (≠ HNPP)
i.e. CMT 1 (AD) and 4 (AR)
Intermediate
(much less common)
NCS velocities between M/s
=Dominant or recessive Intermediate CMT
Axonal
Electrodiagnostic: Usually Axonopathy
Median NCV
Velocity: Slightly decreased; > 38 M/s
CMAP amplitude: Reduced
SNAP amplitude: Reduced
EMG: Denervation in distal muscles
i.e. CMT 2 (AD) and 4 (AR)
Shy M. Inherited Peripheral Neuropathies. Continuum. 2011
accessed September 15th, 2012

21. Current Organization of CMT
CMT1=AD demyelinating <38 M/s
CMT2=AD axonal >38 M/s
CMT3=no longer used
Previously Dejerine-Sottas
CMT4=AR demyelinating or axonal
(Previously Refsum disease, but now Refsum not considered part of CMT)
X-linked
Dominant Intermediate (meaning CV between M/s
Patzko and Shy, Continuum 2012
Shy M. Inherited Peripheral Neuropathies. Continuum. 2011

22. Demyelinating Nerve Pathology

23. Approach to CMT Genetic Testing
> 80% PMP22, MPZ, GJB1, MFN2
Siskind and Shy, Seminars in Neurology, 2011
Patzko and Shy, Continuum 2012

24. Approach to CMT Testing
Siskind and Shy, Seminars in Neurology, 2011

25. Hereditary neuropathy with liability to pressure palsies (HNPP)
Usually due to PMP 22 deletion (vs duplication with CMT1a)
Clinical features:
transient and recurrent motor and sensory mononeuropathies, usually at entrapment sites, such as the carpal tunnel, ulnar groove, and fibular head
duration: last hours, days or weeks or occasionally longer
HNPP can progress to long-term peripheral neuropathy phenotypically indistinguishable from CMT1
Siskind and Shy, Seminars in Neurology, 2011

26. Hereditary sensory and autonomic neuropathies/hereditary sensory neuropathies (HSAN/HSN)
Distribution: Distal > proximal; Symmetric; Legs > Arms
Sensory Loss
Pain & Temperature (Small fiber)
Large fiber loss also occurs
Progressive
Spontaneous sensations
Lancinating pains, burning
Autonomic & reflex loss
Edx studies usually only useful later in disease
accessed Sept 13th, 2012

27. Patzko and Shy, Continuum, 2012

28. Distal hereditary motor neuropathies (dHMN)
Heterogeneous group of diseases with length-dependent predominantly motor neuropathy.
+/- minor sensory abnormalities and/or a significant upper-motor-neuron component,
often an overlap with CMT2 and with juvenile forms of ALS and HSP.
Rossor et al., Neuromuscular disorders, 2012

30. Why would you perform genetic testing in CMT?
Family planning and counselling
Diagnostic certainty
Relevance of unusual clinical features
Avoidance of potential iatrogenic toxicities
Scientific study
Lawson & Gharibshahi, Seminars in Neurology , 2010

31. To choose no genetic testing
Identification of a mutation in a presymptomatic or mildly affected individual
Social stigmatization
Selection of appropriate and rational testing
Cost
Genetic heterogeneity
Lawson & Gharibshahi, Seminars in Neurology 2010

32. Causes of Negative Genetic Testing
Disease may be heterogeneous and the wrong gene has been tested
Techniques used may be insufficiently sensitive to detect the causative mutation in that individual/family
Mutation of unclear pathogenic significance may be found
Eccles, Practical Guide to Neurogenetics, 2008

33. Inheritance Pattern?
45 year old male with large fibre sensory loss, with myoclonus and hearing loss

34. Mitochondrial
Mitochondria are almost always inherited from the mother.
If a female has a mitochondrial trait, all of her offspring inherit it.
If a male has a mitochondrial trait, none of his offspring inherit it.
Complex phenotype, heteroplasmy
Mitochondrial inheritance not followed if nuclear mutations cause mitochondrial dysfunction

35. Inheritance Pattern?
12 year old female with with slowly progressive sensory loss in feet>hands with 5- weakness in l/e, palpable peroneal nerves
Demyelination pattern in EDx

36. Autosomal Recessive
Affected offspring are usually born to unaffected parents
Appears in both sexes with equal frequency
Trait tend to skip generations
When both parents are hetrozygous, approx. 1/4 of the progeny will be affected
Appears more frequently among the children of consanguinous marriages

37. Inheritance Pattern?
5 year old boy with progressive, length dependent sensory and motor signs with NCS demonstrating demyelination

38. Autosomal Dominant Appears in both sexes with equal frequency
Both sexes transmit the trait to their offspring
Does not skip generations (but penetrance may not be 100%
Affected offspring must have an affected parent unless they posses a new mutation
When one parent is affected (het.) and the other parent is unaffected, approx. 1/2 of the offspring will be affected
Unaffected parents do not transmit the trait

39. Inheritance Pattern?
18 year old boy with demyelination in S/M nerves on biopsy and progressive weakness and sensory loss; sisters and female cousins less affected

40. X-Linked Dominant
Both males and females are affected; often more females than males are affected
Does not skip generations.
Affected sons must have an affected mother;
Affected daughters must have either an affected mother or an affected father
Affected fathers will pass the trait on to all their daughters
Affected mothers if heterozygous will pass the trait on to 1/2 of their sons and 1/2 of their daughters

41. Inheritance Pattern?
30 year old male with 18 year history of progressive distal l/e weakness, now complaining of more hand weakness; mother has high arches and no weakness

42. X-Linked Recessive More males than females are affected
Affected sons are usually born to unaffected mothers, thus the trait skips generations
Approximately 1/2 of carrier mothers’ sons are affected
It is never passed from father to son
All daughters of affected fathers are carriers

43. Inheritance Pattern? For the sake of completeness:
30 year old male, thought he was in the urology clinic (mistake with neurology clinic by the clerk) due to infertility

44. Y-linked dominant Only males are affected
It is passed from father to all sons
It does not skip generations
Traits on the Y chromosome are only found in males, never in females.
The father’s traits are passed to all sons.
Dominance is irrelevant: there is only 1 copy of each Y-linked gene (hemizygous).

45. Quiz
HMSN patients usually have primarily positive sensory symptoms at onset F
With ROS on focused exam, it is necessary to review symptoms of dysphagia and hoarseness, etc T
GJB1 is most common mutation causing inherited neuropathy F
Patients with HMSN most often have decreased amplitudes and preserved conduction velocities and latencies on NCS F

46. Summary
Hereditary neuropathies can easily be misdiagnosed as acquired due to negative or incomplete family history
Hereditary neuropathies exhibit both genetic and phenotypic heterogeneity
Hereditary neuropathies have important consequences for prognosis, familial consequences (…and future molecular therapies)

47. Questions? jwarman@cheo.on.ca
Merci
Questions?