Inherited Peripheral Neuropathies

Slide 1 · Inherited Peripheral Neuropathies

Genetic mechanisms, nerve pathology, and clinicopathologic patterns

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Differentiate axonal, demyelinating, and neuronopathic mechanisms in peripheral nerves.

Classify major inherited neuropathies by phenotype, inheritance, and primary injury pattern.

Link PMP22, MPZ, GJB1, and MFN2 abnormalities to characteristic CMT subtypes.

Recognize the morphology and clinical implications of sensory and amyloid neuropathies.

Slide 3 · Inherited neuropathy may appear sporadic

Adult presentation does not exclude an inherited disorder.

De novo mutations may occur without an affected family member.

Overlapping phenotypes mean the same presenting symptom can reflect different genetic causes.

Inherited disease remains part of the differential diagnosis for unexplained peripheral neuropathy.

Slide 4 · Four broad groups of inherited neuropathy

Hereditary motor + sensory (CMT)

Hereditary motor neuropathy

Hereditary sensory ± autonomic

Other inherited causes

Other inherited causes explicitly include familial amyloidosis and inherited metabolic diseases.

Slide 5 · Historical and genetic classification serve different purposes

Historical classification used the inheritance pattern and clinical presentation.

Modern molecular assessment identifies defects in numerous unrelated genes.

More than 100 genes linked to inherited neuropathies.

No single molecular pathway explains all inherited neuropathy phenotypes.

Slide 6 · Three complementary descriptors of neuropathy

Clinical phenotype

Inheritance

Injury pattern

Motor + sensory

Autosomal dominant

Demyelinating

Motor-predominant

X-linked

Axonal

Sensory ± autonomic

Other / variable

Mixed injury may occur

Slide 7 · What can fail within a peripheral nerve?

The axon conducts impulses from the neuronal cell body to its target.

Schwann cells form and maintain peripheral myelin.

Peripheral nerve dysfunction may begin in the axon, myelin, or neuronal cell body.

The location of primary injury influences morphology and nerve-conduction findings.

Slide 8 · Functional organization of a motor unit

Anterior-horn motor neuron

Peripheral motor axon

Neuromuscular junction

Innervated muscle fibers

In hereditary neuropathy, axonal/myelin damage compromises conduction to the distal motor unit.

Slide 9 · Functional organization of somatic sensation

Distal sensory ending

Peripheral sensory axon

Dorsal root ganglion

Central axon + spinal synapse

Sensory disturbances may reflect the peripheral axon or the primary sensory neuron.

Slide 10 · Myelin thickness and functional specialization

Large myelinated fiber

Fast conduction: Motor, light touch, proprioception

Thin unmyelinated fiber

Slow conduction: Autonomic signals and some pain/temperature

Slide 11 · Segmental myelin loss interrupts internodal continuity

Intact myelinated axon

Axon with segmental myelin injury

Exposed axonal segment

Segmental loss of myelin may leave the axon relatively intact.

Schematic

Slide 12 · A Schwann cell establishes one myelinated internode

Each myelinating Schwann cell wraps a single axonal segment.

The internodes are separated by nodes of Ranvier.

Saltatory conduction depends on intact myelin and appropriately spaced nodes.

Myelin abnormalities therefore impair conduction even if axons persist.

Slide 13 · Peripheral nerve compartments and their significance

Component

Anatomic role

Why it matters

Axon

Long neuronal process

Primary target in axonal neuropathy

Myelin / Schwann cell

Insulation around axon

Primary target in demyelination

Endoneurium

Around individual nerve fibers

Contains nerve-fiber microenvironment

Perineurium

Encloses nerve fascicles

Organizes groups of axons

Epineurium

Covers entire nerve

Fibrovascular outer support

Slide 14 · Distinct gene defects converge on peripheral neuropathy

PMP22

Myelin protein dosage

MPZ

Major myelin protein

GJB1

Schwann-cell gap junction

MFN2

Mitochondrial fusion

Disturbance of axon and/or myelin homeostasis

Slide 15 · Axonal versus demyelinating neuropathy

Axonal injury

Demyelinating injury

Primary reduction or degeneration of axons

Injury can progress despite attempted axonal regeneration

Nerve response loses signal amplitude as axons drop out

Primary injury to Schwann cells or myelin

Repeated segmental loss with remyelination

Conduction slowing from impaired saltatory transmission

Slide 16 · Axonal neuropathy: The functional deficit reflects fiber loss

Axons may fragment and their myelin disintegrates after severe injury.

Chronic injury may show both degenerating and regenerating axons.

Ongoing injury can outpace regeneration, progressively reducing the axonal population.

The source describes reduced nerve-signal amplitude with relative preservation of conduction velocity.

Slide 17 · Demyelination can spare the underlying axon

Myelin sheath damage may involve discontinuous internodal segments.

Schwann-cell proliferation contributes to attempted repair.

Remyelinated internodes are typically shorter and thinner than their predecessors.

Marked slowing of nerve conduction is the classic physiologic signature.

Slide 18 · Segmental demyelination: Loss of internodes

Intact myelinated axon

Axon with segmental myelin injury

Exposed axonal segment

Segmental loss of myelin may leave the axon relatively intact.

Schematic

Slide 19 · Remyelination produces shorter, thinner sheaths

Intact myelinated axon

After demyelination and remyelination

Replacement internodes are shorter and thinner.

Schematic

Slide 20 · Length dependence helps explain distal symptoms

Peripheral axon disorders frequently affect the longest axons first.

Weakness or sensory loss therefore often begins in the feet.

Distal involvement can extend proximally and eventually involve the hands.

This principle helps explain the stocking–glove pattern of many polyneuropathies.

Slide 21 · Anatomic patterns guide localization

Pattern

Distribution

Illustrative cause in Robbins

Mononeuropathy

Single named nerve

Trauma or compression

Mononeuritis multiplex

Patchy individual nerves

Vasculitis

Polyneuropathy

Multiple nerves, usually symmetric

Metabolic or inherited disease

Polyradiculoneuropathy

Roots and peripheral nerves

Immune-mediated disease

Slide 22 · CMT is the largest hereditary motor-sensory group

Charcot–Marie–Tooth (CMT) denotes hereditary motor and sensory neuropathies.

Prevalence of up to 1 in 2500 people.

The classic presentation links distal muscle atrophy, sensory loss, and foot deformities.

Multiple molecular mechanisms can converge on this shared clinical phenotype.

Slide 23 · CMT phenotype is not a single genetic diagnosis

Mutations in more than 50 genes can produce CMT phenotypes.

Gene products participate in peripheral axonal or myelin structure and function.

Inheritance and injury pattern help divide this heterogeneous clinical group.

Phenotypic resemblance does not establish a specific pathogenic variant.

Slide 24 · Motor and sensory abnormalities in CMT

Motor emphasis

Sensory emphasis

Distal muscle atrophy

Progressive distal motor impairment

Foot deformities can accompany chronic motor neuropathy

Sensory deficits may coexist with weakness

Axonal and myelin disease both impair peripheral signaling

The relative balance varies among genetic subtypes

Slide 25 · Why distal motor neuropathy alters foot architecture

Chronic distal motor impairment

Imbalance of intrinsic/extrinsic muscle forces

Progressive foot deformity

Conceptual clinicopathologic sequence based on the textbook-described association of distal muscle atrophy with deformity.

Slide 26 · Major CMT subtypes at a glance

Group

Inheritance

Primary injury

Representative gene

CMT1

Autosomal dominant

Demyelinating

PMP22, MPZ

CMT1X / CMTX

X-linked

Peripheral nerve dysfunction

GJB1

CMT2

Autosomal dominant

Axonal

MFN2

Slide 27 · CMT1 is the dominant demyelinating category

CMT1 encompasses autosomal dominant demyelinating neuropathies.

The CMT1 group is the most common hereditary motor-sensory subtype.

Characteristic histology includes recurrent demyelination and remyelination.

CMT1A and CMT1B are important defined molecular examples.

Slide 28 · CMT1A: The gene-dosage lesion

Chromosome 17 segment duplication

PMP22 gene included

Demyelinating motor–sensory neuropathy

This chromosome-17 duplication as the cause of CMT1A.

Slide 29 · CMT1A: Expected clinical course

Presentation usually occurs in the first or early second decade of life.

Peripheral motor and sensory dysfunction progresses slowly.

Demyelination is the dominant injury pattern.

Motor manifestations are generally more conspicuous than sensory manifestations.

Slide 30 · CMT1A frequency requires an explicit denominator

Approximately 55% of genetically defined CMT as CMT1A.

This figure concerns CMT cases with molecular characterization.

It must not be presented automatically as 55% of all clinically suspected neuropathies.

Frequency is a classification aid, not a substitute for establishing the causal duplication.

Slide 31 · CMT1B: MPZ and the myelin scaffold

Pathogenic MPZ gene variant

Altered myelin protein zero biology

Demyelinating neuropathy

MPZ encodes a major structural peripheral-myelin protein; CMT1B with MPZ mutations.

Slide 32 · CMT1B spans multiple ages of onset

CMT1B has markedly variable timing of clinical presentation.

Onset may occur in infancy, childhood, or adulthood.

Approximately 9% of genetically defined CMT.

Age at onset alone cannot reliably exclude MPZ-associated CMT.

Slide 33 · CMT1A versus CMT1B

CMT1A (PMP22)

CMT1B (MPZ)

Chromosome-17 duplication containing PMP22

Typically early onset with slow progression

Motor-predominant demyelinating presentation

Pathogenic variants of the MPZ structural gene

Highly variable onset, including adulthood

Demyelinating presentation

Slide 34 · CMTX is defined by X-linked inheritance

CMTX includes multiple X-linked Charcot–Marie–Tooth syndromes.

CMT1X is the most common X-linked subtype.

Its pathogenic variants involve the GJB1 gene.

Inheritance context aids interpretation but does not replace molecular identification.

Slide 35 · GJB1: A Schwann-cell gap-junction gene

GJB1 pathogenic variant

Connexin 32 dysfunction

Peripheral nerve disease

GJB1 encodes connexin 32 (gap-junction protein β1), which is expressed in Schwann cells.

Slide 36 · CMT1X differs between males and females

Males typically experience more severe manifestations.

Females may also have clinically significant disease.

Variable X-chromosome inactivation contributes to the range of severity in females.

The text reports around 15% of genetically defined CMT cases as CMT1X.

Slide 37 · Interpreting the X-linked phenotype

Male with GJB1-related disease

Female with GJB1-related disease

Usually more severely affected description

May show motor–sensory CMT manifestations

Inheritance history can be informative

Can be symptomatic

Severity is variable

X-inactivation contributes to phenotypic variation

Slide 38 · CMT2 is defined by predominantly axonal injury

CMT2 encompasses autosomal dominant hereditary motor-sensory neuropathies.

Its primary lesion is axonal, rather than demyelinating.

Affected nerves may show axonal loss rather than conspicuous primary myelin injury.

CMT2A is the most common CMT2 subtype described in this Robbins section.

Slide 39 · CMT2A: A mitochondrial mechanism

MFN2 pathogenic variant

Disrupted mitofusin 2 function

Axonal neuropathy

Mitofusin 2 is required for normal mitochondrial fusion; The CMT2A phenotype is axonal.

Slide 40 · CMT2A: Clinically severe early presentation

The typical phenotype begins in early childhood.

The disease course is usually severe.

Sensory manifestations often predominate.

CMT2A at about 4% of all CMT disease (not specifically genetically defined cases).

Slide 41 · Do not mix denominators in CMT frequencies

Entity

Reported estimate

Population denominator

CMT1A

≈55%

Genetically defined CMT

CMT1B

≈9%

Genetically defined CMT

CMT1X

≈15%

Genetically defined CMT

CMT2A

≈4%

All CMT disease

Slide 42 · Four principal CMT gene–phenotype associations

Subtype

Gene / lesion

Physiologic or pathologic emphasis

CMT1A

PMP22 duplication

Demyelination; slowly progressive distal motor > sensory

CMT1B

MPZ variants

Demyelination; onset from infancy to adulthood

CMT1X

GJB1 variants

Schwann-cell connexin 32; X-linked severity variation

CMT2A

MFN2 variants

Axonal disease; early, often severe sensory symptoms

Slide 43 · Onion bulbs are a morphologic clue to repeated injury

Demyelinating CMT can produce repeated cycles of myelin loss and replacement.

Schwann-cell proliferation accumulates around nerve fibers.

Concentric layered Schwann-cell structures are called onion bulbs.

The finding indicates a chronic demyelinating–remyelinating process, not a specific gene by itself.

Slide 44 · Onion bulbs: Repetitive Schwann-cell proliferation

Axon

Recurrent demyelination and remyelination

Concentric Schwann-cell processes around nerve fibers

May produce marked nerve enlargement in CMT

Cross-sectional schematic — not a histologic image

Slide 45 · In some CMT nerves, onion bulbs become extensive

Pronounced Schwann-cell hyperplasia can expand the affected nerve.

The nerve may become palpably enlarged in severe demyelinating CMT.

Enlargement therefore reflects chronic structural remodeling as well as functional impairment.

Morphology should be interpreted together with phenotype and inheritance pattern.

Slide 46 · Mechanism predicts the electrodiagnostic tendency

Primary process

Structural effect

Electrophysiologic hallmark

Axonal injury

Axon dropout

Reduced amplitude; relatively maintained velocity

Demyelination

Disrupted myelin internodes

Slowed conduction velocity; amplitude relatively preserved

Slide 47 · The clinical classification remains provisional

Similar distal weakness and sensory loss can result from numerous pathogenic genes.

Inheritance pattern, injury type, and clinical course narrow the possibilities.

An apparently negative pedigree cannot exclude inherited neuropathy.

Molecular identification provides etiologic specificity beyond the shared CMT phenotype.

Slide 48 · Hereditary motor neuropathies are a distinct group

Hereditary motor neuropathies separately from the motor–sensory CMT syndromes.

The category emphasizes predominantly motor dysfunction.

Its molecular subtypes are not developed in detail in this textbook section.

It should not be merged automatically with a sensory or autonomic phenotype.

Slide 49 · Hereditary sensory neuropathy: Loss of protective perception

Sensory loss dominates, with motor strength generally preserved.

Pain and temperature deficits are especially characteristic.

Many cases have predominantly axonal neuropathic injury.

Autonomic dysfunction may or may not accompany the sensory deficit.

Slide 50 · Why sensory loss causes tissue damage

Impaired pain + temperature detection

Unrecognized mechanical or thermal injury

Trauma to hands and feet

Damage arises because the protective warning function of pain is lost.

Slide 51 · Sensory/autonomic neuropathy versus CMT

Hereditary sensory ± autonomic

Charcot–Marie–Tooth

Predominantly sensory deficit

Preserved motor strength

Traumatic injury from impaired protective sensation

Combined motor and sensory dysfunction

Distal muscle atrophy may be prominent

Foot deformity is a classic manifestation

Slide 52 · Autonomic involvement varies across inherited syndromes

Hereditary sensory neuropathies may be accompanied by autonomic dysfunction.

Not every hereditary sensory phenotype has important autonomic symptoms.

Predominant sensory loss with spared motor strength is the defining pattern emphasized.

Peripheral autonomic and sensory fibers can be affected together in selected genetic neuropathies.

Slide 53 · Familial amyloid polyneuropathy: Protein deposition in nerve

This inherited group is characterized by amyloid within peripheral nerves.

Most familial amyloid polyneuropathies are linked to germline TTR mutations.

Abnormal transthyretin is prone to assemble into extracellular amyloid fibrils.

Peripheral nerve is one of several tissues in which the abnormal protein may deposit.

Slide 54 · TTR mutation to amyloid-associated nerve dysfunction

Germline TTR mutation

Amyloid-prone transthyretin

Peripheral nerve amyloid deposits

Sensory ± autonomic deficits

Clinical overlap with hereditary sensory and autonomic neuropathies.

Slide 55 · Transthyretin has a physiological transport role

The TTR gene encodes transthyretin.

Thyroid hormone binding and transport among its normal functions.

Hereditary pathogenic variants can render the protein susceptible to amyloid fibril deposition.

Hereditary protein misfolding translates a systemic molecular disorder into nerve pathology.

Slide 56 · Familial amyloid disease may mimic a sensory neuropathy

Clinical symptoms can resemble hereditary sensory/autonomic neuropathies.

A family history may support inherited disease, but its absence does not eliminate a genetic explanation.

Histopathologic demonstration of amyloid can distinguish the deposition mechanism.

TTR-associated disease represents a different pathology from primary inherited myelin disorders.

Slide 57 · Congo red is the key amyloid histochemical method

Congo red staining as a method for detecting peripheral nerve amyloid.

Polarized-light examination provides characteristic optical findings in amyloid-positive deposits.

Electron microscopy can provide additional characteristic evidence of fibrillar material.

This presentation uses a schematic explanation; No specimen image is represented as authentic.

Slide 58 · CMT demyelination versus amyloid deposition

Demyelinating CMT

Familial amyloid polyneuropathy

Altered peripheral myelin and Schwann-cell homeostasis

Onion bulbs may develop after repeated injury

Molecular examples: PMP22 and MPZ

Protein fibrils deposited in peripheral nerve

Congo red / polarized light; Electron microscopy

Frequent genetic mechanism: Pathogenic TTR variant

Slide 59 · A pathology-focused framework for inherited neuropathy

Define dominant deficit

Localize axon / myelin / neuron

Assess inheritance + onset

Relate morphology to gene

The phenotype and morphology guide classification; Neither by itself proves a particular molecular genotype.

Slide 60 · Case: Early distal motor–sensory neuropathy

Clinical presentation

Interpretation task

First-decade onset

Slowly progressive distal weakness and sensory loss

Motor symptoms more prominent than sensory symptoms

Demyelinating injury pattern

Which CMT subtype and lesion are most compatible?

Slide 61 · Case interpretation: Recognize the CMT1A pattern

Early onset and slow progression are consistent with CMT1A.

Predominant motor involvement and demyelination strengthen the pattern match.

The genetic lesion specified by Robbins is duplication of the segment including PMP22.

Clinical pattern supports a hypothesis; Identification of the duplication establishes the specific cause.

Slide 62 · Case: Variable severity in an X-linked family

Clinical presentation

Interpretation task

Several affected relatives across the family

Male relatives show more severe motor–sensory symptoms

A female relative is mildly but clearly affected

Molecular result implicates a Schwann-cell gap-junction gene

Which gene and principle explain the variability?

Slide 63 · Case interpretation: Female carriers can be symptomatic

GJB1-related CMT1X commonly affects males more severely.

Females are not necessarily asymptomatic.

Variable X-inactivation provides a mechanism for variable female severity.

Connexin 32 localization links the genotype to Schwann-cell function.

Slide 64 · Case: Painful injury without protective sensation

Clinical presentation

Interpretation task

Marked loss of pain and temperature sensation

Repeated unrecognized injury of hands or feet

No substantial motor strength reduction

Variable autonomic complaints

Which inherited neuropathy group fits best?

Slide 65 · Case interpretation: Preserved strength is discriminating

Predominant pain/temperature sensory loss points to a sensory neuropathy.

Repeated injury is explained by loss of protective nociception.

Preserved muscle strength argues against the classic motor-predominant CMT pattern.

Autonomic involvement is variable and need not be present.

Slide 66 · Case: Inherited deposition neuropathy

Clinical presentation

Interpretation task

Progressive neuropathy with sensory/autonomic features

Clinical resemblance to hereditary sensory neuropathy

Amyloid deposits seen within peripheral nerve

A pathogenic TTR germline alteration is detected

What is the causal tissue-pathology mechanism?

Slide 67 · Case interpretation: Prove the protein-deposition mechanism

TTR mutation provides a heritable protein-based cause.

Extracellular amyloid within peripheral nerve explains the distinctive pathology.

Congo red with polarized light or characteristic electron microscopy supports amyloid identification.

This should not be conflated with inherited primary demyelinating CMT.

Slide 68 · Integrated classification: Lesion, phenotype, exemplar

Category

Dominant clinical finding

Pathology or molecular exemplar

CMT1

Distal motor + sensory

Demyelination; PMP22 or MPZ

CMT1X

Motor + sensory, X-linked

GJB1 / connexin32

CMT2

Motor + sensory, axonal

MFN2 mitochondrial fusion

Hereditary sensory ± autonomic

Pain/temp loss, motor preserved

Usually axonal

Familial amyloid

Sensory ± autonomic

TTR amyloid in nerve

Slide 69 · Final synthesis: What to remember

Inherited neuropathies are clinically overlapping, genetically heterogeneous, and may present in adulthood.

CMT classification uses phenotype, inheritance, and axonal versus demyelinating injury.

PMP22, MPZ, GJB1, and MFN2 connect distinct molecular lesions to characteristic CMT groups.

Sensory injury with preserved strength and TTR-related amyloid deposition represent important alternative inherited patterns.

Slide 70 · Primary textbook reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Source emphasis: inherited neuropathy phenotypes, gene associations, and nerve morphology.

Peripheral nerve anatomy and patterns of axonal versus demyelinating injury supply the explanatory foundation.

Diagrams in this lecture are original, editable schematics; they are not replacements for genuine clinical or histopathologic specimens.