Hereditory peripheral neuropathy

1. Hereditory Neuropathy

2. THE BIOLOGY OF INHERITED PERIPHERAL
NEUROPATHIES
A common feature of the majority of genes mutated in CMT
is the role they play in maintaining the structure or function of the two
main cellular components of the peripheral nervous system, Schwann
cells and the axons of peripheral neurons.

3. Charcot-Marie-Tooth disease (CMT)
Charcot-Marie-Tooth (CMT) hereditary neuropathy
‘ a group of disorders characterized by a chronic motor and
sensory polyneuropathy, also known as hereditary motor and
sensory neuropathy (HMSN)’.

4. Clinical Presentation
 prevalence-between 1 in 1213 to 1 in 2500.
 Three common phenotype:
1)The typical phenotype - slowly progressive symmetric distal leg weakness with
sensory loss, usually beginning in the first to third decade and progressing to footdrop
and hand weakness .
O/E distal weakness and sensory loss, DTR -globally suppressed or absent.
At most, these patients require ankle-foot orthoses for ambulation.

5. 2) earlier onset of symptoms with delayed walking (after age 15 months or more), toe
walking, or clumsiness in childhood.
Patients with this phenotype progress to above-the-knee bracing, walkers, or
wheelchairs for ambulation.
3)adult onset (around 40 years) with variable subsequent progression.
Clinical Presentation

6. Classification of Charcot-Marie-Tooth
disease foot deformity.
 A, First stage: flexible cavus foot, reducible.
 B, Second stage: equinus and pronation of first ray (the
column of bones and joints forming the medial border of the
forefoot), possible reducible clawing of great toe.
 C, Third stage: equinus of whole forefoot, varus of the heel,
irreducible clawing of great toe, no osseous structural
abnormalities.
 D, Fourth stage: structural osseous changes, irreducible
clawing of toes, possible tarsal movements.
 E-G, Fifth stage: firmly fixed deformity, pronounced osseous
changes, irreducible clawing of toes with subluxation or
luxation of metatarsophalangeal joints.

7. Classification:(based on electrodiagnostic
features and inheritance pattern).
1. autosomal dominant and a demyelinating - CMT type 1
2.autosomal dominant and an axonal - CMT type 2
3. autosomal recessive , regardless of the electrodiagnostic features-
CMT type 4 .
4. X-linked - CMT type X (CMTX).

10. Electrophysiology:
 NCV- important tools to establish the presence of polyneuropathy, extent of
damage, and demyelinating versus axonal physiology.
 Demyelinating forms of CMT are diagnosed based on uniformly slowed conduction
velocities of 38 meters per second or less in the upper extremities, without evidence
of conduction block or temporal dispersion (the latter two are features associated with acquired
demyelinating neuropathies).
 Diagnosis of axonal forms is based on relatively normal velocities but prominently
reduced sensory nerve action potential (SNAP) amplitudes, reduced CMAP
amplitudes, or both.

11. Electrophysiology
In hereditary neuropathy, the electrophysiological changes are often already notably pronounced in early
adulthood.
CMT disorders can be classified into the following forms, according to the pattern of the damage/injury
1) Demyelinating:
injury to the myelin sheath; CMT1, motor nerve conduction velocity of the nerves in the arm <38 m/s
2)Axonal:
primary injury to the axon; CMT2, motor nerve conduction velocity of the nerves in the arm>38 m/s
3)Intermediate:
mixed forms of injury; motor nerve conduction velocity of the nerves in the arm 25–45 m/s.

12. Further diagnostic evaluation
 Young age at manifestation and a positive familial history should give rise to the
suspicion of a hereditary neuropathy,
but thorough diagnostic evaluation is still required to rule out metabolic, nutritive-
toxic, infectious, and inflammatory or autoimmunological causes.
( CSF, ESR, Sr.creatinine, HbA1c, , ANA, ANCA, and vitamin B12,immunofixation
and protein electrophoresis , Nerve sonography- thickening of the nerves , MRI of
the muscle - distal muscular atrophy )

13. Nerve biopsy
 The indication for a nerve biopsy (sural nerve) should be discussed
especially if non-hereditary neuropathies are considered as a
potentially treatable differential diagnosis.
 These include inflammations such as vasculitis and perineuritis as well
as atypical cases of neuritis (chronic inflammatory demyelinating or
axonal neuropathy, CIDP or CIAP), a lymphoma affecting the nerves,
and amyloid neuropathy.

14. Genetics of Charcot-Marie-Tooth
Disease
 >90% of patients with CMT -mutation in the PMP22, MFN2, MPZ, or GJB1gene.
 Most cases of CMT- autosomal dominant.
 Apprx 80% to 90% of cases of autosomal dominant CMT1 areCMT1A, which is due to
duplication of the PMP22 gene on chromosome 17p11.2, expressed in Schwann cells
 One percent to nine percent are due to a PMP22 deletion, which causes hereditary
neuropathy with liability to pressure palsies (HNPP), presenting with recurrent
pressure palsies.

15. Genetics of Charcot-Marie-Tooth Disease
 Of the autosomal dominant CMT1 cases, 10% are due to CMT1B, caused by
mutations in the MPZ gene, which results in deleterious overexpression of the major
myelin structural protein
 CMT1X is caused by a mutation on the X chromosome in the GJB1 gene, also known
as the connexin 32 gene.
 CMT2A accounts for 20% to 30% of all causes of CMT2 due to mutations in the
MFN2 gene.
 The same CMT gene mutation can present in any of these three ways, demonstrating
the marked phenotypic variability of a single genotype

17. An Approach to Diagnosis and
Genetic Testing
 Obtaining a detailed three generation family pedigree- one of the most
important steps in establishing a possible diagnosis in CMT.
 Patients should specifically be asked about early deaths in the extended family,
consanguinity, and family members with walking problems without a clear diagnosis.
 More specific diagnosis provides the patient with the most accurate
inheritance and risk information, which is important in making reproductive
decisions.
 Different mutations progress at different rates and are associated with

20. PROS & CONS of each genetic testing
Single Gene
Sequencing
(Traditional
genetic
testing)
PMP22, MPZ, GJB1,
MFN2, LITAF, EGR2,
RAB7, GARS, FEFL,
HSPB1, HSPB8,
GDAP1, SH3TC2,
PRX, FIG4, DNM2,
YARS, FGD4,
NDRG1, TRPV4,
MTMR2, SBF2, etc.
Good
historical
database to
track variants
of uncertain
significance;
Quick turn
around time
If testing for more than
one gene, can get
expensive.
If it is easy to
narrow down the
most likely type of
CMT to one to three
genes based on
clinical presentation
and family history.
TEST GENE PROS CONS BEST USE

21. Microarray Testing
(AKA array CGH,
aCGH)
PMP22 duplication/d
eletion
Cheap and
quick
Can only be used to
determine if someone has
CMT1A or HNPP. Can pick
up incidental findings if
there are duplications or
deletions in other parts of
the genome.
If someone has
classical signs of
CMT1A or HNPP, it is
the cheapest way to
determine if the
duplication or
deletion is present.
TEST GENE PROS CONS BEST USE

22. TEST GENE PROS CONS BEST USE
Next Generation
Sequencing
AARS , ATL1; DNM2; DNMT1;
DYNC1H1; EGR2; FGD4; GARS;
GDAP1; GJB1; GLA; HSPB1;
HSPB8; KIF1B; LITAF; LMNA;
LRSAM1; MED25; MFN2; MPZ;
MTMR2; NDRG1; NEFL; PMP22;
PRX; RAB7A; SBF2; SCN9A;
SH3TC2; SPTLC2; TRPV4; TTR;
YARS
Cheap
Many of the genes are only peripherally
associated with CMT – just known to
cause peripheral neuropathy.
Sequencing more genes can lead to
more variants and not necessarily a
clear result. Deletions and duplications
not picked up as well as in traditional
testing or CGH. Turn around time can
be lengthy.
Unusual presentation of CMT.

23. Key messages
 Patients with an AD or sporadic demyelinating neuropathy should be tested using
the PMP22 duplication test.
 Genetic testing for demyelinating Charcot-Marie-Tooth disease is recommended in
therapy refractory CIDP.
 To find further explanations for hereditary neuropathies, a multitude of genes will
have to be considered because of genetic heterogeneity.
 Next generation sequencing (NGS) is an effective testing method for peripheral
neuropathies and should be used early on in the stepwise diagnostic evaluation.
 Integrating the results of NGS into the overall clinical picture requires close
collaboration between clinicians, neuropathologists, and human geneticists.

24. Management
 Currently no disease-modifying treatment exists for CMT.
 Current patient management can be optimized with a multidisciplinary
approach to care.
 An annual evaluation by a neurologist, physiatrist, or both can assess the
patient’s function and continuing needs.
 Physical therapy plays a major role in gait retraining, maintaining core muscle
strength, energy conservation, and use of serial casting and night splinting to
improve range of motion.
 Occupational therapy can improve hand range of motion and provide tools to
improve activities of daily living, such as buttoning clothing, opening bottles,
and using eating utensils.

25. Management
 An orthotist may provide ankle-foot orthoses to improve gait and
energy conservation, prevent falls, and reduce long-term damage to
knee and hip joints.
 Orthopedic interventions, such as tendon lengthening and tendon
transfer, can help maintain long-term function, and guidelines are
currently being developed to direct proper timing of interventions to
optimize outcomes.
 Pain management for genetic neuropathies follows the same principles
as for other chronic neuropathies, including encouragement of
movement and activity, maintenance of a healthy body mass index, and
avoidance of narcotics for long-term pain control

27. Agents/Circumstances to Avoid
 Obesity is to be avoided because it makes walking more difficult.
 Medications that are toxic or potentially toxic to persons with CMT
comprise a spectrum of risk ranging from definitehigh risk to negligible
risk.

29. HEREDITARY SENSORY AND
AUTONOMIC NEUROPATHIES
The primary hereditary sensory and autonomic neuropathies (HSANs) predominantly
affect myelinated and unmyelinated sensory nerves but also have motor nerve
involvement.
Classification of Hereditary Sensory and Autonomic Neuropathies
1.HSAN I with autosomal dominant inheritance (the most common form, but genetically
heterogeneous),
2.HSAN II (autosomal recessive inheritance, early onset),
3.HSAN III (familial dysautonomia, also known as Riley-Day syndrome, with AR
inheritance)
4. HSAN IV and

30. Genetics of Hereditary Sensory and
Autonomic Neuropathies
HSAN I - mutations in SPTLC1, SPTLC2, ATL1,DNMT1,
and ATL3 genes.
HSAN II - mutations in the WNK1 gene .
HSAN III -by mutations in the IKBKAP gene and is limited
to children of Ashkenazi Jewish descent.
HSAN IV and HSAN V- NTRK1 gene & NGF gene.

31. Clinical Presentation
 HSAN I - sensory loss and neuropathic pain, sometimes with foot ulceration,while mean age
of presentation is in the mid-twenties & Autonomic and motor involvement can be variable.
Some patients also have sensorineural deafness and dementia. Pes cavus and absent
reflexes can be seen on examination.
 HSAN II, involving both large and small nerve fibers, presents with loss of pain, temperature,
pressure, and touch sensation. It is associated with self-mutilation of fingers and toes and
can come to initial medical attention because of recurrent infections.
 HSAN III presents with sympathetic autonomic dysfunction, including orthostatic
hypotension, excessive salivation, gastrointestinal dysmotility, bladder dysfunction,
decreased or absent tearing, absent fungiform tongue papillae, pupillary dilatation,
hypohidrosis, and episodic hyperhidrosis. Episodes of dysautonomic crises can be triggered
by physical and emotional stress.

32.  Patients with HSAN IV present in infancy with mild to moderate
developmental delay; profound insensitivity to pain; and self-
mutilation of digits, face, and mouth regions.
 HSAN IV differs from HSAN III by preservation of tearing and
tongue papillae.
 Almost 20% of patients with HSAN die from hyperpyrexia
before the age of 3
Clinical Presentation

33. Electrophysiology
 Nerve conduction studies in HSAN are highly variable, reflecting the
genetic heterogeneity.
 HSAN I- axonal sensory more than motor neuropathy; however, motor
nerve conduction slowing into the demyelinating range can be seen.
 HSAN II - axonal neuropathy with absent sensory responses.
 HSAN III, similar to HSAN I, is associated with sensory more than
motor involvement.
 HSAN IV and HSAN V, which predominantly affect small myelinated and
unmyelinated nerve fibers, typically show normal nerve conduction
studies.

34. Diagnosis and Management
 Prominent sensory and autonomic manifestations should raise concern for the diagnosis of
HSAN. The diagnosis of HSAN I secondary to SPTLC1 mutations should be considered in
patients with a motor and sensory neuropathy, even in the presence of demyelinating
features, particularly if the patient has marked sensory involvement and a family history .
 Dietary supplementation with oral L-serine in SPTLC1-mutant mice reduced the
sphingolipid metabolites and improved motor and sensory performance. However, despite
these promising studies, no specific treatment exists for HSAN.
 Chronic sores and infections can lead to osteomyelitis and eventual amputation.
 Management requires protection of the extremities, shoes that fit properly, orthotics for
footdrop, treatment of callus formation, proper dressing of wounds to promote healing, and
avoidance of trauma to the hands and feet.
 Similarly,supportive care and symptomatic therapies are the mainstay of HSAN III
management.

35. POLYNEUROPATHIES ASSOCIATED WITH
GENETIC DISORDERS THAT HAVE SYSTEMIC
NEUROLOGIC MANIFESTATIONS
 Many systemic disorders caused by genetic mutations have
a coexisting neuropathy.
 Often the neuropathy is overshadowed by the systemic
manifestations of the disease.
 An overview of selected disorders having CMT-like features
and specific treatment options are described in the following
sections

36. Other Hereditary Neuropathies

37. Other Hereditary Neuropathies

38. THANK YOU

39.  The classic picture of advanced polyneuropathy with distal wasting and
weakness, absent tendon reflexes, and glove and stocking sensory loss
should be easy to recognise.
-acute symmetrical peripheral neuropathy
-chronic symmetrical peripheral neuropathy
-multiple mononeuropathy
Peripheral neuropathy

40. 1.Acute symmetrical peripheral
neuropathy
 commonest cause is Guillain Barré syndrome-Common early
symptoms are distal paraesthesiae and proximal or distal weakness
occurring one to two weeks after a respiratory or gastrointestinal
infection

41. CAUSE Predominantly motor Mixed Predominantly sensory
GBS + + -
Vasculitis - + -
DM - + +
Drugs - + +
Porphyria + - -
Diphtheria - + -
Paraneoplastic neuropathy - + +
Acute idiopathic sensory
neuropathy
- - +
Critical illness + + -

42. 2.Multiple mononeuropathy
 Acute multiple mononeuropathy is also a neurological emergency
because commonest cause is vasculitis
 If multiple mono neuropathy develops in a patient with an established
connective tissue disorder ( RA, SLE ) it is reasonable to conclude
that vasculitis is the cause.
 Steroids are the main treatment, with cyclophosphamide being
added depending on the severity and general medical condition.
 Sometimes peripheral neuropathy is the presenting or sole feature of
vasculitis. In this case, vasculitis can be diagnosed only by nerve

43. 3.Chronic symmetrical peripheral
neuropathy
 Most peripheral neuropathies are chronic and usually develop over severa
months.
 Any history of a general medical disorder could be relevant.
 Patients should always be asked about alcohol consumption, toxin
exposure (insecticides, solvents), and drugs.
 They should also have a full examination, including breasts and genitalia,
to exclude underlying carcinoma.
 The commonest causes of neuropathy can be identified from the history,
examination, and simple investigations

44. Predominantly Demyelinating
Polyneuropathies/Polyradiculoneuropathie
s
 Charcot-Marie-Tooth disease type 1, 3, 4
 Hereditary neuropathy with liability to pressure palsies (HNPP)
 Krabbe disease
 Metachromatic leukodystrophy
 Refsum disease
 Cockayne syndrome
 Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
 Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome
 Multifocal motor neuropathy (MMN)
 Multifocal acquired demyelinating sensory and motor neuropathy(MADSAM)
 Distal acquired demyelinating symmetric neuropathy (DADS)
 Toxins (diphtheria, buckthorn, amiodarone, n-hexane, arsenic)

45. Chronic inflammatory demyelinating
polyradiculo neuropathy
 commonest form of acquired demyelinating neuropathy and
affects about 2 per 100 000 of the population.
 predominantly motor, and a proximal as well as distal
pattern of weakness; the condition may be relapsing and
remitting.
 diagnosed by exclusion of the other causes and from
neurophysiological testing, which shows multifocal
abnormalities with partial conduction block.
 It is thought to be an autoimmune disease because of the

46. Chronic axonal neuropathy
 Axonal polyneuropathy can be sensory or sensory and motor.
 Loss of pain and temperature sensation and spontaneous neuropathic pain, described as burning or pricking, can
be prominent symptoms of axonal neuropathy. They are due to degeneration of thinly myelinated and unmyelinated
nerve fibres. Occasionally small fibre neuropathy occurs without the thicker myelinated nerve fibres being affected
and the nerve conduction test results remain normal. The diagnosis in such cases usually relies on the clinical
symptoms and signs alone.
 After exhaustive investigation no clear cause is found in about 25% of patients. Such chronic idiopathic axonal
neuropathy usually occurs in elderly people and is often indolent, predominantly sensory, and length dependent.
Proof of the diagnosis would require skin biopsy or enumeration of unmyelinated nerve fibres in electron
micrographs of a nerve biopsy specimen.
 Chronic axonal neuropathy occurs in patients with many multisystem hereditary disorders
 Patients can be reassured that, although their condition may progress, it will usually do so only slowly and is
unlikely to become seriously disabling.

47. Nodopathies or channelopathies
 it is recognized that some toxic, immune mediated, and hereditary disorders target proteins
and ion channels in the nodal region.
 The best example is the acute motor axonal neuropathy (AMAN) variant of the GBS which
characterized by rapid decline of CMAP, suggesting motor axon loss. The rapid resolution of
clinical and nerve conduction study changes, however, is not compatible with expected
recovery from that mechanism of injury. Conduction block produced by impaired ion channel function
unassociated with anatomic myelin or axonal injuryprovides a more likely explanation for the rapidly reversible conduction
failure seen in this disorder.
 Like demyelination, nodopathies are not necessarily limited to disrupted conduction and may
be associated with subsequent axon loss. Impairment of sodium-calcium pump function is
hypothesized to lead to intracellular calcium accumulation contributing to eventual axonal
degeneration.

48. Nodopathies
 Acute motor axonal variant of Guillain-Barre´ syndrome
 Guillain-Barre´ syndrome with autoantibodies associated with nodal antigens
 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated with autoantibodies to nodal
antigens
 Miller Fisher syndrome
 Multifocal motor neuropathy (MMN)
 Marine toxins (saxitoxin, ciguatoxin, tetrodotoxin)
 Drugs with ion channel blocking properties (phenytoin)
 Possibly critical illness polyneuropathy
 Possibly ischemic monomelic neuropathy
 Possibly thiamine deficiency

49. Classification:
 Neuropathies that appear to originate in motor or sensory cell bodies are
referred to as neuronopathies. These disorders have clinical and
electrodiagnostic features that suggest axonal degeneration.
 Sensory neuronopathies are presumed to result from selective damage
to dorsal root ganglia.
 Motor neuronopathies (motor neuron diseases) preferentially target
anterior horn cells as a result of a select group of infectious, hereditary,
and degenerative conditions

50. Sensory Neuronopathies
 1. Inflammatory/immune mediated-
Sjo¨ gren syndrome ,Paraneoplastic sensory neuronopathy(anti-Hu positive), Autoimmune hepatitis
 2. Toxic –
Pyridoxine toxicity ,Platin chemotherapy
 3.Infectious-
Herpes zoster ,Epstein-Barr virus,HTLV-1,HIV
 4. Hereditary/degenerative-
Mitochondrial: polymerase + (POLG), sensory ataxic neuropathy, dysarthria, and ophthalmoplegia
(SANDO),Cerebellar ataxia, neuronopathy, vestibular ataxia syndrome (CANVAS) Spinocerebellar
degeneration Facial-onset sensory and motor neuropathy

51. Motor Neuropathies/Neuronopathies
1. Length-dependent pure motor- Hereditary motor neuropathy, hereditary spastic
paraparesis (some genotypes)
2. Length-dependent motor predominant - Charcot-Marie-Tooth disease, toxins
(arsenic, lead)
3. Monomelic- Benign focal amyotrophy/monomelic amyotrophy
4. Monomelic progressing to generalized- Amyotrophic lateral sclerosis/progressive
muscular atrophy, infectious (polio), paraneoplastic (rare)
5. Proximal symmetric/ generalized- Spinal muscular atrophy, AMAN, hexosaminidase
deficiency
6. Multifocal - multifocal motor neuropathy (MMN)

52. Causes of multiple mononeuropathy
Vasculitis
 Primary systemic vasculitis:
 Polyarteritis nodosa
 ChurgStrauss syndrome
 Systemic vasculitis associated with
connective tissue diseases:
 Rheumatoid arthritis
 Sjögren's syndrome
 Vasculitis confined to peripheral
nerves
Other causes
 Sarcoidosis
 Lymphoma
 Carcinoma
 Amyloid
Multiple compression
palsies
 Associated with metabolic or toxic
neuropathy
 Hereditary neuropathy with liability to

53. Summary points:
 Peripheral neuropathy can be into divided into acute and chronic forms,
symmetrical polyneuropathy, and multiple mononeuropathy
 Acute neuropathies are diagnostic emergencies
 Neuropathy due to diabetes mellitus and alcohol misuse can be diagnosed in
primary care
 Neurophysiological tests distinguish axonal from demyelinating neuropathies
 Demyelinating neuropathies are commonly inflammatory and treatable
 Axonal neuropathies have multiple causes
 Generic management includes foot care, ankle supports, and treatment of
neuropathic pain