Hereditary neuropathies

HEREDITARY

NEUROPATHIES

Classification & Diagnosis

BY

AMR HASAN ELHASANY

Ass. Lecturer of Neurology –Cairo University

2008

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:








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


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

http://www.neuro.wustl.edu/neuromuscular/time/hmsn.html








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


(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

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
















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





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








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









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



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



Type 3 :


↓ NCV < 10 m/sec

Biopsy: Prominent Onion bulb appearance



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;



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

http://www.neuro.wustl.edu/neuromuscular/time/child.html









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


Hereditary Motor & Sensory Neuropathy (CMT) Type 4 :


↓ 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


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


CMT 5: HMSN + Pyramidal signs

CMT 6: HMSN + Optic atrophy

CMT 7: HMSN + Retinitis Pigmentosa




Charcoat (left) & Babinski

at the Salpêtrière clinic

http://www.whonamedit.com/doctor.cfm/370.html








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

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








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

http://www.neuro.wustl.edu/neuromuscular/sensory-small.html

http://www.neuro.wustl.edu/neuromuscular/sensory-large+small.html

http://www.neuro.wustl.edu/neuromuscular/autonomic.html


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)


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.


(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


SNAP Amplitude ↓

Biopsy: Sural N biopsy : loss of large & small axons


(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


(HSAN)

Hereditary Sensory & Autonomic Neuropathies (HSAN) type III =Familial Dysautonomia = Riley Day Syndrome


SNAP Amplitude ↓

Biopsy:

Sural N biopsy : loss of small & large axons

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

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

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

http://www.neuro.wustl.edu/neuromuscular/time/hsn.htm





http://www.neuro.wustl.edu/neuromuscular/sensory-pain.html

http://www.neuro.wustl.edu/neuromuscular/sensory-large.html

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=210300







Other Hereditary Sensory Neuropathies

Sensory PN + Hearing loss: Connexin-31; 1p35

Sensory PN + Deafness: Xq23

HSMN + Ataxia: 7q22

HSN + Cough & GE reflux












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








B) Syndromic Hereditary Neuropathies

1) Demyelinating Dominant

Disorder Gene / Locus Associated

features

Wardeenburg

type IV

22q13;

SOX10

CNS & PNS

dysmyelination

Hirschsprung

disease


2) Demyelinating Recessive

Disorder Gene / Locus Associated features

Metachromatic

leukodystrophy

22q13;

(ArylsulfataseA)

Optic atrophy

Mental retardation

Hypotonia

Globoid cell

leukodystrophy

(Krabbe's)

14q31;(Galactosyl

ceramide -

galactosidease)

Spasiticity,

Optic atrophy

Mental retardation


2) Demyelinating Recessive


Refsum's disease 10 pter-p11.2

PAHX (Phytanoyl-

CoA hydroxylase)

& 7q21-22; PEX7

(Peroxin-1)

Deafness

Retinting pigmentosa,

Ichthyosis

heart failure

Merosin

deficiency

6q 22; LAMA2

(laminin-2)

Neuropathy and

muscular dystrophy


3) Axonal dominant


Familial

Amyloidotic

Neuropathy

(FAP-I &

FAP-II

18q21; TTR

(Transthyretin)

Painful axonal neuropathy;

other organs involved;

FAP-II also causes carpal

tunnel syndrome

FAP-III"lowa" 11q23; ApoAl

(Apoliporotein

A1)

Nephropathy, liver disease

FAP- IV

"Finnish"

9q32-q34; AGel

(Gelsolin)

Corneal dystrophy, cranial

neuropathies


3) Axonal dominant


Acute

Intermittent

Porphyria

11q23.3; PBGD

(Porphobillino

gen deaminase

Acute neuropathy follows

abdominal crises;

psychosis; depression;

dementia; seizures

Coproporphyria 3q12;CPO

(Copropophrin

ogen 3

oxidease)

Skin photosensitivity,

psychosis, crises of acute

neuropathy and

abdominal pain

Variegate

Porphyria

3q12;CPO

(Coproporphur

inogen 3

oxidease)

South Africa; similar to

acute intermittent

prophyria


3) Axonal dominant Disorder Gene / Locus Associated

features

Fabry's disease Xq22;GLA

(galactosidase)

Angiokeratoma

Pain

Stroke

Renal failure

Cardiomyopathy

Hereditary

Neuralgic

Amyotrophy

17q25 Painful episodes of

brachial palsy,

dysmorphic features


4) Axonal Recessive

Disorder Gene /

Locus

Associated

features

Hereditary

tyrosinemia

type 1

15q23-q25;

FAH

(Fumaryl-

Acetoacetase)

Hepatic and Renal

disease,

Cardiomyopathy

Giant axonal

neuropathy

16q24; GANI

(Gigaxonin)

Kinky/curly hair

CNS features

UMNL, Optic atrophy,

Nystagmus,Ataxia

Mental retardation,


4) Axonal Recessive

Disorder Gene / Locus Associated

features

Abetalipoproteinemia 4q24; MTP

(microsomal

triglyceride

transfer protein)

Ataxia,

Acanthocytosis

Analphalipoproteinemia

(Tangier's disease)

9q31; ABC1

(AtP- binding

cassette

transporter)

Orange tonsils,

Organomegaly

Atherosclerosis

, Painless

ulcerations


4) Axonal Recessive Disorder Gene / Locus Associated features

Cowchock's

syndrome

Xq24-26 Mental retardation

(60%)

Deafness

Congenital

Catarcts, Facial

Dysmophism

Neuropathy

(CCFDN;

18 q23-qter; CTDP1

(intron 6)

Cataracts, microcornea,

Facial dysmorphism

Skeletal deformities

Other Syndromic Hereditary Axonal

Neuropathies

Ataxia telangectasia

Cerebrotendinous xanthomatosis

Chediak-Higashi

Friedreich Ataxia

Glycogenosis, Type 3

Mitochondrial: MNGIE; NARP; Leigh; Other

Neuroacanthcytosis

Brachial Plexopathy

http://www.neuro.wustl.edu/neuromuscular/ataxia/dnarep.html

http://www.neuro.wustl.edu/neuromuscular/ataxia/metatax.html




http://www.neuro.wustl.edu/neuromuscular/ataxia/recatax.html

http://www.neuro.wustl.edu/neuromuscular/msys/glycogen.html

http://www.neuro.wustl.edu/neuromuscular/mitosyn.html





http://www.neuro.wustl.edu/neuromuscular/nanatomy/proxmot.html

Diagnosis Of Hereditary

Neuropathies

Based on Clinical Presentation and

Electrophysiological Findings

Diagnosis Of Hereditary Neuropathies

History taking (hereditary cause is suggested)

Examination

Lab work to exclude causes of acquired neuropathies

Neurophysiological study

Biopsy

Genetic study

Recurrent Hereditary Neuropathies

Hereditary Neuropathies Liability to Pressure

Palsy

Brachial Plexopathy

Refsum

Porphyria





http://www.neuro.wustl.edu/neuromuscular/nanatomy/proxmot.html


http://www.neuro.wustl.edu/neuromuscular/nother/porph.htm

Hereditary Neuropathies affecting UL>LL

HMN 5A

CMT 2D

HMN 5B

Amyloidosis (Carpal

tunnel syndrome)

http://www.neuro.wustl.edu/neuromuscular/synmot.html



http://www.neuro.wustl.edu/neuromuscular/nother/amyloid.htm

http://www.neuro.wustl.edu/neuromuscular/nanatomy/median.htm


Hereditary Neuropathies Affecting Motor

Neurones

HMN-5A

HMN 7

HMARD

HMNJ

HMN

Hereditary Neuropathies associated with skin

manifestations

Amyloidosis :Petechiae or purpura

Refsum: Ichthyosis

Sensory neuronopathies: Ulcers

Coproporphyria: Skin photosensitivity,

Fabry: Angiokeratoma



Hereditary Neuropathies Affecting eye

CMT-4B2 : Glaucoma

CMT 6 : optic atrophy

CMT 7 : RP

Mitochondrial disorders

Leukodystrophies: optic atrophy

Refsum: RP

FAP- IV: Corneal dystrophy

Congenital Catarcts, Facial Dysmophism Neuropathy (CCFDN) : Cataract

Ataxia Telangectasia


Hereditary Neuropathies associated with

Hearing Loss

X-linked

Cowchock

HMSN X (Connexin 32)

Recessive

CMT 4D (Lom)

Refsum

Xeroderma Pigmentosum

CEDNIK

Dominant

CMT 1A

CMT 1B

CMT 2E

CMT-4D

Dejerine-Sottas (Dominant)














thickened nerves

Demyelinating

HMSN I & III

Refsum

Neurofibromatosis




http://www.neuro.wustl.edu/neuromuscular/nanatomy/pntumor.htm


Hereditary Neuropathies associated with GIT

troubles

HSN + Cough & GE reflux

Mitochondrial: MNGIE & Variants

Riley-Day (HSAN3)








Facial Nerve palsy

Amyloid: Gelsolin

Tangier disease


http://www.neuro.wustl.edu/neuromuscular/nanatomy/proxsens.html


Dysmorphic Features

CMT-4D

Hereditary Neuralgic Amyotrophy

Congenital Catarcts, Facial Dysmophism

Neuropathy (CCFDN;


Vocal cord affection

HMSN II C

HMN 7

Hereditary Axonal Neuropathies

HMSN: II ,V ,VI

HSAN

Spinal muscular atrophy: Proximal; Distal

Amyloidosis

Porphyria

Fabry's

Hereditary tyrosinemia type 1

Giant Axonal Neuropathy

A-beta-lipoproteinemia

An-α-lipoproteinemia (Tangier's)

Cowchock's syndrome

Congenital Catarcts, Facial Dysmophism Neuropathy (CCFDN;



Chediak-Higashi Friedreich Ataxia




























Hereditary Demyelinating Neuropathies

HMSN type I, III, IV, XL

HNNP

Leukodystrophies

Refsum

Wardeenburg type IV


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

Hereditary Neuropathies Affecting Motor

Neurones

HMN-5A

HMN 7

HMARD

HMNJ

HMN

Hereditary Neuropathies affecting UL>LL

HMN-5A

CMT 2D

HMN 5B

Amyloidosis (Carpal tunnel syndrome)





Hereditary Axonal Neuropathies

HMSN: II

HSAN

HMN =Spinal muscular atrophy: Proximal; Distal

Amyloidosis

Porphyria

Fabry's

Hereditary tyrosinemia type 1

Giant Axonal Neuropathy

A-beta-lipoproteinemia

An-α-lipoproteinemia (Tangier's)

Cowchock's syndrome

Congenital Catarcts, Facial Dysmophism Neuropathy (CCFDN;



Chediak-Higashi Friedreich Ataxia




























Online Mendelain Inheritance in Man

(OMIM):

www.ncbi.nlm.nih.gov/Omim/

Neuromuscular:

www.neuro.wustl.edu/neuromuscular/

http://www.ncbi.nlm.nih.gov/Omim/Online

http://www.ncbi.nlm.nih.gov/Omim/Neuromuscular:www.neuro.wustl.edu/neuromuscular/







THANK YOU

Health & Medicine

Hereditary neuropathies