2. HEREDITARY NEUROPATHIES
A) Non Syndromic Hereditary Neuropathies:
1- Hereditary Motor & Sensory Neuropathies (CMT).
2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
3-Hereditary Sensory & Autonomic Neuropathies
(HSAN).
4- Distal Hereditary Motor Neuropathies (HMN).
B) Syndromic Hereditary Neuropathies:
3. HEREDITARY NEUROPATHIES
A) Non Syndromic Hereditary Neuropathies:
1- Hereditary Motor & Sensory Neuropathies (CMT).
2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
3-Hereditary Sensory & Autonomic Neuropathies
(HSAN).
4- Distal Hereditary Motor Neuropathies (HMN).
B) Syndromic Hereditary Neuropathies:
4. 1) Hereditary Motor & Sensory Neuropathies
=CMT
CMT Type 1
CMT Type 2
CMT Type 3
CMT Type 4
CMT Type 5
CMT Type 6
CMT Type 7
XL CMT
5. 1) Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy (CMT)
Type1:
Subtypes
Disorder
Pattern of
inheritance
Protein Location
CMT 1A AD PMP-22 17p11
CMT 1B AD P0 1q22
CMT 1C AD LITAF 16p13
CMT 1D AD EGR2 10q21
CMT 1E
AD
P0 protein;
1q22
CMT 1F
AD Neurofilament light
chain
8p21
6. 1) Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy (CMT)
Type 1:
Clinical Picture
(CMT) Type 1A:
1st or 2nd decade.
Symmetrical distal LL weakness (intrinsic foot, peroneal & ant tibial
muscles) Champaign bottle shape
UL involvement in 2/3 of cases.
↓ Reflexes
Hypertrophic nerves
± UL Tremors = (Rousy lévy syndrome)
Retain ambulance for life
7. 1) Hereditary Motor & Sensory Neuropathies
(CMT) Type 1B, 1C, 1D,1E & 1F:
Clinically similar to 1A with varying severity
Electrophysiology: Demyelinating
↓ NCV ( Cut off between CMT 1 & 2 38 m/sec)
Biopsy: Onion bulb appearance
8. 1)Hereditary Motor & SensoryNeuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type 2 :
Subtypes
Disorder Pattern of inheritance Gene Location
CMT 2A AD KIF1Bβ 1p36
CMT 2B AD RAB7 3q13
CMT 2C AD 12q23-q24
CMT 2D AD GARS 7p15
CMT 2E AD NF-68 8p21
CMT 2F AD HSPB1 (HSP 27) 7q11
CMT 2G AD 12q12
CMT 2L AD HSPB8 12q24
AR-CMT2A AR Lamin A/C 1q21
AR-CMT2B AR 19q13
Andermann AR KCC3 15q13
9. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type 2 :
Clinical picture
Disorder Clinical picture
CMT 2A
Onset of neuropathy by 10yr of age;
progresses to distal weakness and atrophy
in legs; mild sensory disturbance
CMT 2B
Onset 2nd- 3rd decade; severe sensory
loss with distal ulcerations.
CMT 2C
Vocal cord and diaphragmatic
weakness
10. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type
2 :
Clinical picture
CMT 2D
Arm>leg weakness; onset in 2nd-3rd
decade.
CMT 2E
Variable onset and severity; ranging from
DSS-like to CMT-2 phenotype
CMT 2F Severe distal weakness & Fasciculations
CMT 2G Proximal >distal weakness
CMT 2L Onset 15 to 33 years , Distal weakness
11. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type
2 :
Clinical picture
AR-CMT2A
Onset of neuropathy in 2nd decade;
progresses to severe distal weakness and
atrophy
AR-CMT2B 3rd & 4th decade,Distal weakness
Andermann 1st decade,Hypotonia
12. 1) Hereditary Motor & Sensory Neuropathies
b- Hereditary Motor & Sensory Neuropathy (CMT)
Type 2:
Electrophysiology: Axonal
SNAP: ↓ Amplitude or even absent
Biopsy: Preferential loss of large myelinated fibers without
significant demyelination, there may be clusters of of regenerating
myelinated fibers
13. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type
3 :
Subtypes & Clinical picture
Disorder Locus;Gene Clinical picture
DSS=Dejerene-
Sottas
syndrome
PMP22,MPZ,GJB
DGR2,NEFL
(dominant)
PRX. MTMR2
(recessive)
Onset before 3yr age
with delayed motor
development, severe
Weakness, atrophy,
and sensory loss
Congenital
Hypomyelinating
Neuropathy
(CHN)
PMP22, MPZ
(dominant); EGR2
(recessive)
Hypotonic at birth,
developing into
clinical picture often
similar to DSS
14. 1) Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy (CMT)
Type 3 :
Electrophysiology: Demyelinating
↓ NCV < 10 m/sec
Biopsy: Prominent Onion bulb appearance
15. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type
4 :
Subtypes
Disorder Pattern of
inheritance
Gene; Location
CMT-4A AR GDAPI 8q13-q21;
CMT-4B1 AR MTMR2 11q22;
CMT-4B2 AR SBF2 11p15;
CMT-4C AR KIAA1985 5q23-33;
CMT-4D AR NDRG1 8q24;
16. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type
4 :
Disorder Pattern of
inheritance
Gene; Location
CMT 4E AR EGR2 10q21
CMT 4F AR Periaxin 19q13
HMSN-Russe
(4G)
AR 10q23
CMT 4H AR FGD4 12q12
CMT 4J AR FIG4 6q21
17. 1)Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy(CMT)Type
4 :
Subtypes
Disorder Clinical Picture
CMT-4A Early-childhood onset, progression to wheelchair
dependency; both demyelinating and axonal phenotypes
CMT-4B1 Early-childhood onset, may progress to wheelchair
dependency; focally folded myelin sheaths
CMT-4B2 Childhood onset; progressive; focally folded myelin
sheaths; glaucoma
CMT-4C Infantile to childhood onset; progressing to wheelchair
dependency
CMT-4D Childhood onset; severe disability by 50yr; hearing loss,
dysmorphic features
18. 1) Hereditary Motor & Sensory Neuropathies
Hereditary Motor & Sensory Neuropathy (CMT) Type 4 :
Electrophysiology: Demyelinating
↓ NCV 20-30 m/sec
Biopsy:
focally folded myelin sheaths (tomacula) in type CMT-4B1
CMT-4B2
Segmental demyelination
Onion bulb appearance
Myelinated axon loss: Large > Small
19. 1) Hereditary Motor & Sensory Neuropathies
XL Hereditary motor & sensory neuropathy (CMT)
Xq13.1; CJB1 (Connexin 32)
Clinically:
Phenotypically similar to CMT 1
Males are more severely affected
Affected females -- mild or asymptomatic
Transient ataxia ,dysarthria
CNS white matter abnormalities on MRI studies
Electrophysiology:
↓ NCV in males
↓ NCV & amplitudes in females
Abnormal BAEP
22. HEREDITARY NEUROPATHIES
A) Non Syndromic Hereditary Neuropathies:
1- Hereditary Motor & Sensory Neuropathies (CMT).
2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
3-Hereditary Sensory & Autonomic Neuropathies
(HSAN).
4- Distal Hereditary Motor Neuropathies (HMN).
B) Syndromic Hereditary Neuropathies:
23. 2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
Genetics
AD , 17P11.2 ,PMP 22
Clinically:
2nd or 3rd decade
↑ susceptibilityof PN to mechanical traction ,compression or minor trauma
Recurrent sudden painless episodes of isolated mononueropathy commonly
affecting
Common peroneal, brachial plexus,radial& median nerves
Complete recovery in days or weeks
Less common presentations
-Progressive monoeuropathy
-Chronic sensory polyneuropathy
-Chronic sensory motor neuropathy
-Transient positional sensory symptoms
24. 2- Hereditary Neuropathy with liability to
Pressure Palsy (HNPP)
Electrophysiology:
Prolonged distal motor latencies with focal slowing of
ulnar & fibular nerve at the compression sites
Diffuse reduction of sensory nerve action potential
amplitudes
Biopsy:
Focal sausage-like thickening of myelin termed Tomacula
due to redundant myelin loop as a result of overgrowth
of myelin spiral
25. HEREDITARY NEUROPATHIES
A) Non Syndromic Hereditary Neuropathies:
1- Hereditary Motor & Sensory Neuropathies (CMT).
2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
3-Hereditary Sensory & Autonomic Neuropathies
(HSAN).
4- Distal Hereditary Motor Neuropathies (HMN).
B) Syndromic Hereditary Neuropathies:
26. 3- Hereditary Sensory & Autonomic
Neuropathies (HSAN)
Subtypes
Disorder
Pattern of
inheritance Gene Location
I AD SPTLC1 9q22
II AR HSN2 12p13
III AR IKBKAP 9q31
IV
AR TRKA/ NGF
receptor
1q21
V AR
27. 3- Hereditary Sensory & Autonomic Neuropathies
(HSAN)
Hereditary Sensory & Autonomic Neuropathies (HSAN) type I
Clinically:
2nd 4th decade
Superficial & deep sensory loss affecting feet & legs acrodystrophic neuropathy=
Acromutilation
Lancinating or shooting pain
± Distal muscle weakness ( D.D. CMT type 2B)
Electrophysiology: Axonal
SNAP Amplitude ↓
Motor CV NL but CMAP Amplitude may ↓ in late stages
Biopsy: Sural N biopsy : Severe loss of unmyelinted & small myelinated axons and to lesser
degree loss of large myelinated fibers.
28. 3- Hereditary Sensory & Autonomic Neuropathies
(HSAN)
Hereditary Sensory & Autonomic Neuropathies (HSAN) type II
Clinically:
Started in infancy
Panmodal sensory affection -> Acromutilation
Dysautonomia
Variable features : spastic para , retinitis pigmentosa ,motor weakness or keratitis
Electrophysiology: Axonal
SNAP Amplitude ↓
Biopsy: Sural N biopsy : loss of large & small axons
29. 3- Hereditary Sensory & Autonomic Neuropathies
(HSAN)
Hereditary Sensory & Autonomic Neuropathies (HSAN) type III
=Familial Dysautonomia = Riley Day Syndrome
Clinically:
Childern of Ashkenazi Jewish ethnicity
Autonomic > sensory
Begin at birth ( poor feeding, esophageal dysmotility ,vomiting ,recuurent
fever & chest infection)
Emotional stimuli provoke episodic hypertension, profuse sweating
&marked skin blotching due to defective autonomic control
Defective lacrimation ,absence of tongue papillae
Hypotonia delayed motor milestones, gait ataxia, stunted growth &
scoliosis
Potentially life threatening condition due to aspiration pneuomonia,
autonomic crises
30. 3- Hereditary Sensory & Autonomic Neuropathies
(HSAN)
Hereditary Sensory & Autonomic Neuropathies (HSAN)
type III =Familial Dysautonomia = Riley Day
Syndrome
Electrophysiology: Axonal
SNAP Amplitude ↓
Biopsy:
Sural N biopsy : loss of small & large axons
31. Hereditary Sensory & Autonomic Neuropathies
(HSAN)
Hereditary Sensory & Autonomic Neuropathies (HSAN) type IV
Clinically:
Congenital insensitivity to pain
Anhidrosis
Recurrent fever
Self mutilating behaviour
Mild MR
Loss of C axons
Electrophysiology:
SNAP are preserved
Biopsy: Sural N biopsy : loss of myelinted & unmyelinated axons
32. Hereditary Sensory & Autonomic Neuropathies
(HSAN)
Hereditary Sensory & Autonomic Neuropathies (HSAN) typeV
Clinically:
Congenital, or Early childhood
Absence of pain
No anhidrosis
Loss of Aδ-axons
Electrophysiology:
SNAP are preserved
Biopsy: Sural N biopsy : SELECTIVE loss of small myelinted
fibers
33. Other Hereditary Sensory Neuropathies
Disorder gene locus inheritance onset clinical
Absent pain NGF-b 1p13 Recessive
Early childhood
to Adult
Absence of
pain
No anhidrosis
Inability to
experience pain
SCN
9A
2q24 Recessive Congenital
Absence of
pain
No anhidrosis
Erythromelalgia
SCN
9A
2q24 Dominant Childhood
Pain, distal
Episodic
Biemond ataxia Dominant 19 to 30 years Sensory loss
Ulcero-mutilation Dominant 5 to 30 years Acromutilation
Spastic
paraparesis
5p15 Recessive 1 to 5 years Acromutilation
35. HEREDITARY NEUROPATHIES
A) Non Syndromic Hereditary Neuropathies:
1- Hereditary Motor & Sensory Neuropathies (CMT).
2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
3-Hereditary Sensory & Autonomic Neuropathies
(HSAN).
4- Distal Hereditary Motor Neuropathies (HMN).
B) Syndromic Hereditary Neuropathies:
36. 4- Distal Hereditary Motor Neuropathies
(HMN)= Distal Spinal Muscular Atropthy (SMA).
Subtypes &Clinical picture:
Disorder Gene/Locus Clinical picture
HMN-5 7p; GARS
Arm> leg weakness; onset in 2nd- 3rd
decade; no sensory involvement
HMN 7 2q14 Vocal cord involvement
HMARD 11q13;
Distal infantile SMA with diaphragm
paralysis
HMNJ 9p21; 1-p12 Childhood-onset distal weakness (Jerash type)
HMN
2p13;
DCTNl
Progressive hand >leg weakness and atrophy,
vocal fold paralysis & facial weakness
37. HEREDITARY NEUROPATHIES
A) Non Syndromic Hereditary Neuropathies:
1- Hereditary Motor & Sensory Neuropathies (CMT).
2- Hereditary Neuropathy with liability to Pressure
Palsy (HNPP)
3-Hereditary Sensory & Autonomic Neuropathies
(HSAN).
4- Distal Hereditary Motor Neuropathies (HMN).
B) Syndromic Hereditary Neuropathies:
38. B) Syndromic Hereditary Neuropathies
1) Demyelinating Dominant
Disorder Gene / Locus Associated
features
Wardeenburg
type IV
22q13;
SOX10
CNS & PNS
dysmyelination
Hirschsprung
disease
49. Diagnosis Of Hereditary Neuropathies
History taking (hereditary cause is suggested)
Examination
Lab work to exclude causes of acquired neuropathies
Neurophysiological study
Biopsy
Genetic study
63. Clinical Case
40ys old female patient presenting with gradual progressive
weakness both UL & LL, D>P, UL>LL associated with distal
wasting
NC study showed axonal motor affection with no sensory
affection
keywords
UL involvement
Pure motor
Axonal