Hereditary neuropathies

1. Hereditary
Neuropathies
Dr. Sunil Kr. Sharma
Senior Resident
Dept. of Neurology
GMC Kota

2. Introduction
– Inherited neuropathies are diverse in both genetic
causes and clinical phenotypes.
– They are frequently underdiagnosed or
misdiagnosed.
– Family history –most imp. but difficult to obtain.

3. Introduction
– ≈ 40% of chr. polyneuropathies,
– ≈50% of previously unidentified PN.
– Inherited nature may go unrecognized in a large
percentage of patients
(Klein, 2007).

4. – Insidious onset and indolent course over years to
decades.
– Classification depends on the clinical phenotype,
mode of inheritance, and class of neurons
predominantly affected.
(Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).

5. – Major advances -molecular basis of inherited
neuropathies.
– Gene defect coding for a specific gene product
essential to myelin or axonal function
(Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).

6. Clues to diagnosis
– Long-standing neuromuscular symptoms
– Detailed family histories
– Skeletal abnormalities such as hammer toes, High
arches, or scoliosis
– Neurological evaluations in relatives

7. – Negative F/H cannot rule out an inherited
neuropathy. e.g.
1. Early death of one or both parents
2. Few blood relatives
3. AR dis.
– About 1/3 - de novo gene mutations (Boerkoel
et al., 2002).

8. Acquired vs. Inherited
– Often difficult, especially in the absence of +ve
history.
– An acquired etiology may compound an inherited
neurologic defect.
– Rapid or accelerated neurologic declines -
suggest superimposed acquired etiologies.

9. Acquired vs. Inherited
– More susceptible to injury from metabolic, toxic,
and other nervous system insults e.g. CTx.
– Major deficits with limited toxic or metabolic
exposure.
– HN frequently misdiagnosed as diabetic
neuropathy(less likely in the absence of
retinopathy or nephropathy).
Chaudhry V, Chaudhry M, Crawford TO, Simmons-O’Brien E, Griffin JW. Toxic neuropathy in patients with pre-existing neuropathy. Neurology. 2003; 60:337–340.
[PubMed: 12552058]
Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in
a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993; 43:817–824. [PubMed: 8469345]

10. Historical and Examination
Clues of Inherited Neuro-pathy
History-
– Frequent childhood ankle sprains and toe-
catching falls
– Slowest child in foot races
– Recurrent acral calluses, and ulcers in sensory
predominant forms.

11. Physical examination
– Foot drop
– High arches and hammer toes
– Inverted champagne bottle appearance of the legs
– Recurrent painless foot ulcers
– Thickened nerves in hypertrophic demyelinating
varieties
– Refractory response to the treatment of acquired
disease
– Major sensory loss without positive sensory
symptoms (e.G., Paresthesia, burning, or
lancinating pain).

12. Neurophysiology
– Temporal dispersion and conduction blocks are
often absent Exceptions -CX32 mutations,
temporal dispersion can occur.
– NCV <38 m/s -demyelinating,
– NCV =38– 45 m/s-intermediate.
– NCV >45 m/s -primary axonal process
Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. 1982; 32:592–596. [PubMed:
6283420]
Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, et al. Unusual electrophysiological findings in X-linked dominant Charcot–Marie–Tooth disease.
Muscle Nerve. 2000; 23:182–188. [PubMed: 10639608]

13. – Inheritence may be AD,AR and X linked.
– Can be divided into 3 groups:
(1) Isolated neuropathy involving PNS exclusively
(2) Multisystem neuropathy involving both CNS and
PNS
(3) Neuropathy with multiorgan involvement
affecting nonneurologic organs such as skin,
kidney, heart, and liver

14. Neuropathy with isolated
nerve involvement
– Hereditary motor and sensory neuropathy (HMSN,
or Charcot– Marie–Tooth)
– Hereditary sensory and autonomic neuropathy
(HSAN)
– Hereditary sensory neuropathy (HSN)

15. Neuropathy with isolated
nerve involvement…
– Distal hereditary motor neuropathy (dHMN)
– Hereditary brachial plexus neuropathy (HBPN)
– Hereditary neuropathy with liability to pressure
palsies (HNPP)

16. Neuropathy with brain and/or
spinal cord involvements
– Spinocerebellar atrophy (SCA)
– Friedreich ataxia (FA)
– Hereditary spastic paraplegia neuropathy
(i.e., complicated HSP, HMSN 5)

17. Neuropathy with non-
neurologic organ involvement
– Familial amyloid (transthyretin, gelsolin, ApoA1)
– Leukodystrophy
– Peroxisomal
– Lipoprotein deficiency
– Porphyrias
– Defective DNA maintenance
– Mitochondrial defects

18. Miscellaneous
– Giant axonal neuropathy
– Neurofibromatosis type 1
– Neurofibromatosis type 2
– Others

19. Charcot–Marie–Tooth
Disease(HMSN) and Related
Disorders

20. Charcot–Marie–Tooth
Disease (Hereditary Motor
and Sensory Neuropathy)
– First described in 1886 by Charcot and Marie in
Paris and Tooth in London (Charcot and Marie,
1886; Tooth, 1886).
– Most common inherited neuropathy
– Prevalence of 10 to 41 per 100,000 (Martyn and
Hughes, 1997).

21. – two main groups:
1. CMT1 [HMSN-I]- chara. By motor NCVs (<38
m/sec in forearm) and nerve biopsy findings of
demyelination and onion bulb formation
2. CMT2 [HMSN-II]- chara. By - normal or near
normal motor NCVs , and nerve biopsy reveals
axonal loss without prominent demyelination
(Harding, 1995).

22. – Hereditary distal spinal muscular atrophy- The
peroneal muscular atrophy phenotype without
sensory involvement on either clinical or
electrophysiological examination .
– Dejerine-Sottas disease (or syndrome, DSS) – A
severe form of demyelinating neuropathy with onset
occurring in early childhood .

23. – CMT1 and the vast majority of subtypes of
CMT2 display autosomal dominant inheritance.
– A minority of cases occur sporadically or in
siblings only -attributed to AR inheritance or to
de novo gene mutations.

24. – CMT may be classified by-
1. Mode of inheritance (AD, X linked and rarely
AR)
2. Chromosomal locus
3. Causative genes

28. A, CMT 1,HNPP,CMTX, DSS,CMT4-inherited disorders of myelin. CMT2 is a primary axonal disorder.
B, Point mutations of these genes (connexin-32 [Cx32], myelin protein zero [MPZ, P0], PMP22, EGR2,
periaxin) result in CMTX, CMT1B, CMT1A, DSS, and CMT4. Mutations of the LITAF gene result in
CMT1C.
C, Point mutations of the KIF1B and NFL genes and specific MPZ missense mutations result in CMT2.

29. Charcot–Marie–Tooth
Disease Type 1
– Onset- first or second decade .
– Chara. By slowly progressive weakness, muscular
wasting, and sensory impairment predominantly
involving the distal legs.
– Symmetrical weakness and wasting in the intrinsic
foot, peroneal, and anterior tibial muscles.

30. CMT-1
– In 2/3 rd Pt., the UL are involved later in life.
– Foot deformities
1. Pes cavus and hammer toes ≈3/4 of adult pt.
2. Mild kyphosis ≈ 10%
3. Palpably enlarged hypertrophic peripheral
nerves ≈ 1/4

31. CMT-1…
– Absent ankle reflexes are universal - frequently
a/w absent or reduced knee and UL reflexes.
– Some degree of distal sensory impairment (↓
vibration and light touch)
– Rarely - positive sensory symptoms.
– Occasionally, a/w essential or postural upper-limb
tremor-referred to as roussy-lévy syndrome-not a
separate clinical or genetic entity

32. CMT-1…
– Severity varies considerably.
– ≈10% Pt. with slowed NCVs -asymptomatic.
– May exacerbate during pregnancy-temporary in ≈
1/3rd of pt. , becomes progressive in the
remainder.

33. CMT-1…
– Slow deterioration in strength and decline in
axonal function continues throughout adulthood
(Verhamme et al., 2009).
– Motor nerve conduction studies show uniform
slowing to less than 75% of the lower limits of
normal in all nerves

34. CMT-1…
– Motor conduction of upper-limb nerves proves
more useful than studies of lower-extremity nerves
because distal denervation in the feet is often
severe and virtually complete.
– A motor NCV <38 m/sec in the forearm segment of
the median nerve -as a cutoff value to distinguish
between CMT1 and CMT2.
– SNAPs are usually absent with surface recordings
– Uniform conduction slowing

35. CMT-1…
– Neurological deficits correlate with reductions in
CMAP and SNAP amplitudes rather than conduction
velocity.
– Uniform conduction slowing
1. CMT1A with PMP22 dupli. or pm.
2. CMT1B with MPZ pm
3. DSS, including PMP22, MPZ, and EGR2 gene
mutations
4. Metachromatic leukodystrophy
5. Cockayne disease
(Lewis et al., 2000).

36. CMT-1…
– Routine hematological and biochemical studies and
CSF are normal(D/W CIDP)
– Sural nerve biopsy-onion bulb formation.
A, Semi-thin transverse section of sural nerve showing numerous onion bulbs. (Toluidine blue; bar =
20 μm.) B, Electron micrograph of an onion bulb formation; two small myelinated fibers are
surrounded by multiple layers of Schwann cell processes.

37. CMT-1…
– Gene mutations-account for about 3/4th CMT1 .
– CMT1A is the most common CMT subtype-70%–
80% of CMT1 cases and more than 50% of all
CMT cases.
– The disease is caused by duplication in the
17p11.2-12 -PMP22,rarely by PMP22 point
mutation.

38. CMT-1…
– PMP22 -membrane glycoprotein of myelin sheath.
– Deletion of the same 1.5-Mb region on
chromosome 17p11.2 results in a single copy of the
normal PMP22 gene-observed in 85% of patients
with HNPP
– CMT1B is clinically indistinguishable from
CMT1A accounts- for 10–20% of all CMT cases.

39. CMT-1…
– CMT-1B-mutations(pm) in MPZ gene- 1q22-23.
MPZ –
1. major peripheral myelin glycoprotein
2. adhesion molecule
3. member of the immunoglobulin superfamilywith
extracellular, transmembrane and intracellular
domains.
– Mutations in MPZ -also a/w DSS, and congenital
hypomyelination neuropathy.

40. CMT-1…
– Different MPZ mutations - uncompacting of
myelin or focal myelin foldings (Gabreëls-Festen
et al., 1996).
– Motor conduction block -rarely in CMT1B (Street
et al., 2002).
– Specific MPZ missense mutations in CMT2
phenotype- only mild slowing of NCVs (Marrosu
et al., 1998).

41. CMT-1…
– CMT1C -mutation in lipopolysaccharide-induced
TNF-alpha (LITAF/SIMPLE) gene, chr.16p13-12 .
– Encodes a lysosomal protein - protein degradation
pathways (Street et al., 2003).
– CMT1C used to be reserved for autosomal
dominant CMT1 families not linked to either
CMT1A or CMT1B
– Manifest characteristic CMT1 symptoms.

42. CMT-1…
– CMT1D -mutation of the early growth response 2
gene (EGR2) -chro. 10q21-q22 .
– Regulates the expression of myelin proteins
including PMP22, P0, Cx32, and periaxin
(Kamholz et al., 2000).
– Respiratory compromise and cranial nerve
dysfunction a/w EGR2 mutations.
– Other rare CMT1 subtypes include CMT1E and
CMT1F
Szigeti et al., 2007.

43. Charcot–Marie–Tooth
Disease Type 2
– CMT2-1/3rd of all AD CMT disease.
– A/W mutations in genes affecting intracellular
processes such as axonal transport, membrane
trafficking, and translation.
– Onset later than in CMT1, MC 2nd decade,-may be
delayed until middle age or beyond.

44. CMT-2
– Foot and spinal deformities -less prominent than
in CMT1.
– Peripheral nerves are not enlarged
– Upper limb involvement, tremor, and general
areflexia - less frequent.
– 20% -asymptomatic.

45. CMT-2
– CMT2A -MC of CMT2 cases- 30%.
– CMT2A1-chro. 1p35, -mutation in kinesin protein
involved in axonal transport of synaptic vesicles
(Saito et al., 1997; Zhao et al., 2001).
– CMT2A2- most CMT2 families, similar to
CMT2A1 but has an earlier onset and is more
severe.
– May be a/w optic atrophy.

46. CMT-2…
– Mutations in the mitofusin 2 (MFN2) gene-chro.
1p36-p35.
– MFN2 -mitochondrial fusion protein ubiquitously
expressed in many tissues including PN.
– CMT2B-chro. 3q13-22- RAB7 gene - prominent
sensory loss with foot ulcerations.
– Clinically very similar to HSN1 but lacks
spontaneous lancinating pain

47. CMT-2…
– CMT2C –chromo.12q24-vocal cord, intercostal,
and diaphragmatic muscle weakness (Klein et al.,
2003).
– Life expectancy -shortened.
– CMT2D- chromo . 7p14, is chara. by weakness
and atrophy - more severe in the hands than in
the feet (Ionasescu et al., 1996b).
(De Jonghe et al., 1997 & Verhoeven et al., 2003).

48. CMT-2…
– CMT2E- typical CMT2 phenotype with slowed
motor nerve conduction that is < 38 m/sec
– More severe clinical phenotype.
– Mutations in genes that encode neurofilament light
(NEFL) subunit.
– May have axonal swelling (giant axons) and signi.
sec. demyelination on sural nerve biopsies
(Fabrizi et al., 2006; Jordanova et al., 2003)

49. CMT-2…
– CMT2F- heat shock protein 27 (Hsp27)-
unstable neurofilament network .
– Chara. by later onset (35–60 years), mild sensory
impairment, and moderate to severely slowed
NCVs of lower limbs but normal or mildly
reduced velocities in the upper limbs.
– CMT2G- Spanish family chromo. 12q12-q13.3,
with the age onset from 9 to 76 years.

50. CMT-2…
– CMT2J- also designated as CMT2 with MPZ
(myelin protein zero) gene mutation, is
associated with pupillary abnormalities (Adie
pupil) and hearing loss.
– CMT2L -HSPB8 gene muta. with typical
features of the CMT2 phenotype.

51. CMT-2…
– Motor NCV may be normal or mildly reduced.
– SNAPs - either absent or reduced in amplitude.
– Sural nerve biopsy -preferential loss of large
myelinated fibers, without signi. demyelination.
– There may be clusters of regenerating myelinated
fibers, a hallmark of axonal regeneration.

52. X-Linked Charcot–Marie–
Tooth Disease
– Phenotypically similar to CMT1.
– male -more severely affected, and females -mild
neuropathy or be asymptomatic.
– No male-to-male transmission occurs.
– 7% to 16% of all forms of CMT-second most
common form of CMT (following CMT1A).

53. CMTX…
– Mutations in GJB1-connexin 32 (Cx32) -
channel-forming proteins - gap junction protein
found in - Schwann cell cytoplasm chromo. Xq.
– Most missense mutations -mild clinical
phenotype
– Nonsense and frameshift muta.- more severe
phenotypes (Ionasescu et al., 1996a).
– Some mutations of Cx32 - CNS involvement
with white-matter MRI and MR spectroscopy
abnormalities, abnormal BAER, and deafness
(Murru et al., 2006).

54. CMTX…
– Significant slowing in NCV in male
– BAER responses are often abnormal.
– Nerve biopsy - both axonal loss and
demyelination.
– NCV- near normal to intermediate slowing in the
30- to 40-m/sec range.
– CMTX - primary axonal or demyelinating
disorder- debated (Birouk et al., 1998).

55. CMTX…
– Nonuniform conduction slowing consistent with
demyelination (Gutierrez et al., 2000; Lewis, 2000).
– NC slowing paralleling the loss of CMAP
amplitude.
– No male-to-male transmission, the presence of
intermediate conduction velocities (>42 m/sec) in
female carriers and delayed brainstem auditory
evoked response latencies in affected men is highly
suggestive of Cx32 mutations (Nicholson et al.,
1998).

56. Charcot–Marie–Tooth
Disease Type 3, or
Dejerine-Sottas Disease
– Uncommon progressive hypertrophic neuropathy
with onset in childhood.
– Motor development is delayed; proximal
weakness, global areflexia, enlarged peripheral
nerves, and severe disability are the rule.
– Originally thought to be AR, most cases are
sporadic and in some AD.
– Motor conduction velocities are severely slowed,
often to less than 10 m/sec.

57. CMT-3…
– Temporal dispersion and amplitude reduction on
proximal stimulation may be found in such cases.
– CSF protein ↑.
– Defective myelination is confirmed by an
increased axon-to-fiber diameter ratio.
– Cases of congenital hypomyelination neuropathy
probably represent a variant of CMT3.
– DSS is genetically heterogeneous .

58. Charcot–Marie–Tooth
Disease Type 4
– AR ,<10% of all CMT cases.
– Onset in early childhood and progressive weakness
leading to inability to walk in adolescence.
– Both demyelinating and axonal types have been
identified (Dubourg et al., 2006).
– Disturbance in normal myelination of the axons.
– Clinical and electrophysiological features are similar
iwith CMT3.
– Conduction velocities are slowed (20–30 m/sec).

59. – CSF protein N.
– Nerve Bx -loss of myelinated fibers,
hypomyelination, and onion bulbs.
– Sev. subgroups: CMT4A, CMT4B1 and 2,
CMT4C, CMT4D, CMT4E, CMT4F, and
CMT4H.

60. Complex Forms of Charcot–
Marie-Tooth Disease
– AD -features intermediate between CMT1 and
CMT2, with conduction velocities between 38
m/sec and normal.
– classified separately as dominant intermediate
CMT (DI-CMT) and include types A, B, C, and D.
– DI-CMTA -Chromo. 10q24-25, -gene defect -not
discovered.
– DI-CMTB -dynamin 2 (DNM2) gene ,chromo.
19p12-13.

61. Complex Forms of Charcot–
Marie-Tooth Disease
– Mild to moderately severe CMT phenotype.
– May have neutropenia and early cataracts (Claeys
et al., 2009).
– DI-CMT- tyrosyl-tRNA synthetase gene chromo.
1p34-35
– Mild, very slowly progressive course (Jordanova
et al., 2006).
– DI-CMTD maps to chromosome 1q22 MPZ gene
mutations.

62. Hereditary Neuropathy with
Liability to Pressure Palsies
– AD-chara. by increased susceptibility to mechanical
traction or compression.
– 2nd -3rd decade.
– Prevalence -16 per 100,000 population.
– Recurrent episodes of sudden onset ,painless,
isolated mononeuropathies
– Provoked by compression, slight traction, or other
minor trauma.
– Nerve inv.-Order of decreasing freq- PUB RuM.
– Painless brachial plexopathy -1/3 pt.

63. HNPP…
– Less-common presentations
1. transient positionally induced sensory symptoms,
2. progressive mononeuropathy,
3. chronic sensory polyneuropathy,
4. CMT phenotype with pes cavus
5. diffuse chronic sensorimotor neuropathy
resembling CIDP
(Mouton et al., 1999).

64. HNPP…
– NCV in pt. with PMP22 deletion -prolonged DL and
mild slowing in forearm segments of median and
ulnar nerves.
– Focal slowing and conduction blocks at compr. sites,
and diffuse reduction of SNAP amplitudes
– The median forearm motor NCV >38 m/sec
– Sensory studies demonstrate velocities in the
demyelinating range and reduced or absent SNAPs.
– Asymptomatic carriers- Prolonged median DL and
abnormal sensory conduction .
(Dubourg et al., 2000; Mouton et al., 1999, Infante et al., 2001).

65. HNPP…
– Sural nerve bx- focal sausagelike thickenings of
myelin termed tomacula .
– Segmental demyelination, and axonal loss.
– Deletion of pmp22 gene chromo. 17p11.2-12
(duplicated region in CMT1A) in 85% .
– Other mutations in PMP22 - frameshift or
nonsense mutations (lenssen et al., 1998; van de
wetering et al., 2002).

66. HNPP…
– Exactly how the deletion of PMP22 causes HNPP
remains unclear.
– Molecular diagnosis has replaced nerve biopsy.
– Testing should be considered - painless multiple
mononeuropathies, brachial plexopathy, or
recurrent demyelinating neuropathy, regardless of
family history (Tyson et al., 1996).
– The primary treatment strategy is to prevent nerve
injury by avoiding pressure damage.

67. Hereditary Neuralgic
Amyotrophy
– AD
– Recurrent brachial plexopathy, often preceded by
severe ipsilateral limb pain-hallmark .
– Recovery over weeks to a few months, with
accumulating evidence of residual neurologic
deficit over time.
– Dysmorphic features- hypotelorism, epicanthal
folds, microstomia, and dysmorphic ears.
– Chromo. 17q25 - SEPT9 gene (Kuhlenbäumer et
al., 2005).

68. Practical Molecular Diagnostic
Testing for Patients with CMT
and Related Disorders
– Samples of peripheral blood .
– Avoid the “battery” of available genetic tests.
– Population studies confirmed that CMT1A
(PMP22 duplication or PMP22 deletion),
CMT1X (Cx32 mutation), CMT1B (MPZ
mutation), and CMT2A (MFN2 mutation)
account for about 65%–70% of all CMT cases
(Bassam, 2014; Boerkoel et al., 2002).

69. 1. ≥2 generations
2. male-to –male transmi.
3. <38 m/sec
CMT1A.
PMP22 duplication
PMP22 sequencing
Normal
If normal
MPZ DNA sequencing to excluded CMT1B

70. – CMT1A should be considered even in the absence of a
positive family history.
– Childhood severe demyelinating neuropathy -
DSS/congenital hypomyelination -the PMP22 dupli.Test f/b
DNA sequencing of PMP22, MPZ, EGR2, and periaxin.
– Severe reactions to vincristine and other chemotherapeutic
neurotoxic drugs in CMT1A –best to rule out .
No PMP22 duplication
No male-to-male transmission
Screen for CMTX -Cx32 muta.
Axonal pattern MFN2 muta. –MC CMT2
(England et al., 2009).

71. Treatment and
Management
– CMT1 and CMT2 are slowly progressive, disability
occurs relatively late, and lifespan may be normal.
– Mx- symptomatic.
– Proper foot care and advised to wear broad, well-fitting
shoes, insole.
– Ankle-foot braces or orthopedic procedures -footdrop.
– Warned to avoid neurotoxic drugs.
– CMT may worsen during pregnancy -associated with
higher risk for complication during delivery (Hoff et al.,
2005).

72. Treatment and
Management…
– Still no effective treatment .
– Rat model with PMP 22-progesterone antagonists
for CMT1A-potentially unacceptable side effects
prevented such trials.
– Ascorbic acid 1 or 3 g/day -no signi. benefit at 12
months (Micallef et al., 2009).
– Possibly beneficial role of neurotrophin 3 (NT3), in
CMT1A -in a small pilot study (sahenk et al., 2005).
– Some CMT2 pt. with MPZ muta. may respond to
steroids (Donaghy et al., 2000).

73. Thank
you

74. References
– Bradley’s ;Neurology in clinical practice;7th edition.
– Inherited Neuropathies: Clinical Overview And
Update Christopher J. Klein, MD et al; Muscle Nerve.
2013 October ; 48(4): 604–622.
doi:10.1002/mus.23775.
– CharcotMarieTooth and Other Hereditary Motor and
Sensory Neuropathies Clinical Presentation; Timothy
C Parsons, MD et al ;Updated: Apr 12, 2017 .
– Overview of hereditary neuropathies UpToDate;
;Peter B Kang, MD, FAAP, FAAN. et ;last updated:
Mar 23, 2016.