Spinal and Bulbar Muscular Atrophy Kennedy Disease

Slide 1 · Spinal and Bulbar Muscular Atrophy

(Kennedy Disease)

Molecular pathology • Motor neuron degeneration • Clinical diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Localize the motor neuron and muscle abnormalities in Kennedy disease

Explain why an AR CAG expansion produces a polyglutamine disorder

Relate bulbar and limb findings to lower motor neuron degeneration

Discriminate SBMA from ALS and 5q spinal muscular atrophy

Interpret genetic testing and the inheritance pattern

Slide 3 · Kennedy disease: Defining clinicopathologic combination

Neurodegeneration

Spinal and brainstem lower motor neurons

Limb amyotrophy and fasciculations

Bulbar weakness, tongue atrophy, dysphagia

Androgen-receptor disease

Expanded CAG repeat in AR exon 1

Intranuclear inclusions of mutant protein

Gynecomastia, testicular atrophy, oligospermia

Slide 4 · Motor neurons are the principal anatomical target

Spinal cord

Brainstem

Anterior horn

Lower motor neurons

Cranial motor

Nuclei

Limb muscles

Tongue / bulbar muscles

Slide 5 · Lower motor neuron loss produces denervation

Motor neuron

Degeneration

Axonal input

Is lost

Muscle fibers

Lose innervation

Weakness and

Atrophy

Fasciculations reflect spontaneous activity within surviving motor units.

Slide 6 · Bulbar involvement is a localization clue

Bulbar means motor systems controlling speech and swallowing

Tongue atrophy and fasciculations indicate hypoglossal motor dysfunction

Dysphagia links anatomical disease to aspiration risk

Bulbar signs coexist with limb lower motor neuron deficits

Slide 7 · A genetic motor neuronopathy, not a primary ALS subtype

Shared phenotype

Progressive limb weakness

Muscle wasting and fasciculations

Bulbar dysfunction can occur

Distinct SBMA biology

X-linked AR trinucleotide expansion

Androgen-insensitivity manifestations

Usually slow evolution rather than classic ALS course

Slide 8 · The X-linked inheritance model

AR resides on the X chromosome

46,XY: One AR allele

46,XX: Two AR alleles

Males with a pathogenic expanded allele are hemizygous.

Slide 9 · Why male phenotypes usually predominate

One X: Mutant AR has

No alternate X-linked copy

Two X chromosomes:

Heterozygotes often mildly affected

Typical symptomatic male

Variable carrier phenotype

Sex-limited severity reflects both X-linkage and androgen-dependent biology.

Slide 10 · AR encodes the androgen receptor

AR gene

On X chromosome

Androgen receptor

Protein

Androgen binding

And signaling

Androgen-responsive

Gene regulation

SBMA involves both abnormal protein toxicity and partial androgen insensitivity.

Slide 11 · Exon 1 contains the disease-associated CAG tract

Exon 1

CAG CAG CAG CAG CAG ...

AR

Repeat expansion increases the polyglutamine segment in AR.

Slide 12 · CAG encodes glutamine: DNA to protein

DNA CAG

Triplet repeat

MRNA CAG

Codons

Glutamine (Q)

Amino acids

Expanded polyQ

AR protein

The mutation alters the protein sequence without being a conventional gene deletion.

Slide 13 · Repeat length requires category-specific interpretation

AR CAG repeats

Interpretation

≤34

Normal range in GeneReviews

35

Uncertain clinical significance

36–37

Interpret with clinical and family context

≥38

Full-penetrance allele category

These categories come from GeneReviews (revised January 2026), not the Robbins paragraph.

Slide 14 · Why a CAG expansion is a polyglutamine disease

Lengthened CAG tract

Expanded Q-rich protein region

Abnormal AR protein behavior

PolyQ-expanded proteins may misfold and accumulate in vulnerable cells.

Slide 15 · Polyglutamine disease does not mean complete AR absence

Toxic gain of function

Mutant AR can disrupt cell homeostasis

Nuclear accumulation / protein misfolding

Neuronal and muscle pathology

Partial androgen insensitivity

Androgen-responsive function is altered

Gynecomastia and reproductive features

Clinical phenotype integrates both mechanisms

Slide 16 · Androgen binding modulates mutant AR localization

Androgen ligand

Binds AR

AR translocates

Toward nucleus

Expanded AR

Becomes toxic

Cellular stress

And dysfunction

Ligand-dependent steps are supported by mechanistic studies; They do not imply proven therapy.

Slide 17 · Mutant AR forms intranuclear inclusions

Conceptual normal motor neuron

Expanded AR: Nuclear inclusion

Red nuclear dot depicts a schematic inclusion—not microscopy.

Slide 18 · Inclusion bodies are a pathologic signature

Intranuclear inclusions containing the involved protein

Inclusions support an abnormal protein-accumulation mechanism

Their presence alone does not prove that visible aggregates are the toxic species

Pathologic interpretation must distinguish association from causation

Slide 19 · Selective motor neuron vulnerability remains unresolved

Established observations

Spinal lower motor neurons degenerate

Brainstem motor neurons degenerate

Expanded AR accumulates in nuclei

Mechanistic uncertainty

Why particular neurons are vulnerable is not settled

Inclusions may mark—not fully explain—toxicity

Contributions from muscle are under investigation

Slide 20 · Motor neurons and skeletal muscle can both be involved

Motor neuron compartment

Skeletal muscle compartment

Muscle fiber: Myopathic

And denervation changes

Convergent muscle weakness

Both neurogenic and primary muscle contributions appear in contemporary literature.

Slide 21 · From molecular change to functional disability

Expanded AR

PolyQ tract

Neuronal / muscle

Dysfunction

Motor-unit loss

And remodeling

Limb and bulbar

Weakness

A mechanistic framework; Individual intermediate steps are still being studied.

Slide 22 · Spinal cord pathology: Anterior horn neuron loss

Anterior spinal gray matter

SBMA: Reduced motor neuron pool

Schematic cell counts are illustrative only—not measured tissue densities.

Slide 23 · Brainstem pathology explains lingual weakness

Brainstem lower motor neurons

Hypoglossal motor nucleus

Other bulbar motor nuclei

Tongue atrophy / fasciculations

Speech / swallowing abnormalities

Slide 24 · Denervation leads to neurogenic muscle atrophy

Intact innervation

Motor-unit loss

Equal-sized fibers (schematic)

Atrophic fiber subsets (schematic)

Slide 25 · Neurogenic versus primary myopathic components

Neurogenic pathology

Reduced motor-neuron input

Denervation-driven muscle fiber atrophy

Motor-unit remodeling

Myopathic contribution

Muscle is also an AR-expressing tissue

Myopathic changes can coexist

Muscle pathology is not solely secondary in all models

Slide 26 · Androgen insensitivity is part of the disease

Expanded AR

Impaired androgen

Responsiveness

Endocrine / genital

Manifestations

Recognizable diagnostic

Constellation

Motor-neuron disease plus androgen-insensitivity signs is a major diagnostic clue.

Slide 27 · Gynecomastia has specific diagnostic value

Breast enlargement can predate clinically obvious motor symptoms

It reflects altered androgen signaling, not motor denervation

The finding gains diagnostic value when paired with fasciculations or weakness

Absence of gynecomastia does not exclude a pathogenic AR expansion

Slide 28 · Testicular atrophy and reproductive features

Testicular atrophy and oligospermia

Reduced fertility may accompany partial androgen insensitivity

Severity varies among affected individuals

Reproductive history helps interpret the motor-neuron phenotype

Slide 29 · Limb weakness usually evolves gradually

Cramps / tremor

Or subtle weakness

Limb motor-unit

Loss progresses

Gait / hand

Function declines

Assistive devices

May be needed

Slide 30 · Early presenting symptoms may be nonspecific

Muscle cramps and fine tremor may precede overt weakness

Fasciculations are often noticed by patients

Weakness may emerge in proximal limb groups and impair activities

A long history of endocrine clues can shorten diagnostic delay

Slide 31 · Limb amyotrophy reflects ongoing motor-unit loss

Reduced effective

Motor-unit output

Weakness • visible wasting • reduced endurance

Slide 32 · Bulbar disease produces dysarthria and dysphagia

Motor speech deficits

Weakness changes articulation

Tongue and facial muscles contribute

Speech-language assessment is relevant

Swallowing deficits

Bulbar weakness impairs bolus handling

Aspiration and nutrition become concerns

Clinical swallowing evaluation guides care

Slide 33 · Tongue findings help localize lower motor neuron injury

Hypoglossal lower motor neuron degeneration

Loss of tongue muscle bulk

Tongue fasciculations

A combination of atrophy and spontaneous contractions points to LMN pathology.

Slide 34 · Upper motor neuron signs are not typical

Expected SBMA pattern

Atrophy and fasciculations

Reduced or absent tendon reflexes

No classic pyramidal pattern

Consider ALS / alternative if

Spasticity dominates

Pathologic hyperreflexia

Extensor plantar responses

Rapid mixed UMN–LMN decline

Slide 35 · Sensory abnormalities may accompany SBMA

Some patients have sensory symptoms or abnormal sensory nerve studies

This does not make SBMA a purely sensory neuropathy

Sensory features can help distinguish it from classic ALS

Interpret with motor findings and confirmatory AR repeat analysis

Slide 36 · A clinical timeline has prognostic implications

Adolescent

Androgen signs

Adult-onset

Neuromuscular symptoms

Gradual limb and

Bulbar progression

Late mobility and

Swallowing challenges

Age at onset and course vary; This is not a fixed patient trajectory.

Slide 37 · Laboratory and electrophysiology: Supportive, not defining

Useful supportive findings

Elevated serum creatine kinase may occur

EMG supports chronic denervation

Nerve conduction can show sensory involvement

Diagnostic caution

None of these is SBMA-specific

Typical studies do not identify an AR expansion

Genetic testing supplies molecular confirmation

Slide 38 · The molecular test interrogates the CAG repeat

Clinical suspicion

Targeted AR CAG

Repeat-size analysis

Allele-size

Interpretation

Clinical / family

Correlation

Routine sequencing panels may not characterize repeat expansions reliably without an appropriate assay.

Slide 39 · Interpret borderline AR repeat sizes cautiously

Observed repeat

Clinical interpretation

≤34

Not in pathogenic repeat range

35

Questionable significance

36–37

Borderline: Clinical / family correlation

≥38

Full-penetrance category in GeneReviews

GeneReviews also notes that >35 repeats establishes molecular diagnosis in an appropriate male proband.

Slide 40 · Diagnosis integrates genotype and phenotype

LMN + bulbar

Clinical syndrome

Endocrine signs /

X-linked pedigree

AR repeat testing

Integrated

SBMA diagnosis

History and examination direct testing; The repeat expansion confirms the molecular diagnosis.

Slide 41 · ALS is the most important mimic

Feature

SBMA

Typical ALS

Inheritance

X-linked AR expansion

Usually sporadic; Varied familial genes

Upper motor signs

Generally absent

Often present

Androgen signs

May be present

Not a defining feature

Progression

Usually gradual

Often more rapid

Slide 42 · SBMA differs genetically from 5q-SMA

Question

SBMA (Kennedy)

5q-SMA

Main gene

AR

SMN1

Variant class

Expanded CAG repeat

Usually loss-of-function / deletion

Typical context

Adult male onset

Often childhood onset

Androgen signs

May occur

Not a defining feature

Slide 43 · Other neuromuscular differentials

Adult-onset inherited motor neuropathies and spinal muscular atrophy

Charcot–Marie–Tooth phenotypes with prominent distal weakness

Endocrine causes of gynecomastia without motor neuron disease

Mixed presentations require localization, electrophysiology, and genetics

Slide 44 · When is AR testing especially high yield?

Adult male with slowly progressive lower motor neuron weakness

Tongue fasciculations or dysphagia with absent UMN findings

Gynecomastia, testicular atrophy, or reduced fertility

Pedigree compatible with X-linkage—even if family history is negative

Slide 45 · Course: Slow progression, variable disability

Slow progression and prolonged preservation of ambulation

Daily function may decline from combined limb and bulbar symptoms

Clinical severity is heterogeneous even within families

Life span is normal; Complications still require monitoring

Slide 46 · Why swallowing surveillance matters

Bulbar weakness

Dysphagia

And impaired airway protection

Aspiration /

Nutritional risk

Targeted assessment

And intervention

Dysphagia management is a functional safety priority even in slowly progressive disease.

Slide 47 · Rehabilitation addresses functional consequences

Mobility / ADLs

Strength and functional evaluations

Physical and occupational therapy

Braces, walkers, and fall prevention

Communication / swallowing

Speech-language evaluation

Diet and swallowing strategy assessment

Follow-up as bulbar symptoms progress

Slide 48 · Surveillance is system based

Domain

Recommended monitoring

Mobility / ADLs

Strength and rehabilitation evaluation

Speech / swallowing

Speech-language and feeding assessment

Advanced disease

Pulmonary function assessment

Cardiometabolic

Lipids, liver evaluation when indicated, cardiac review

GeneReviews (2026) suggests annual review or more frequently if clinically needed.

Slide 49 · Endocrine and cardiometabolic care

Assess bothersome gynecomastia and reproductive health concerns

Individualize endocrine evaluation and supportive interventions

Consider lipid profile and cardiovascular health monitoring

Psychosocial and family support are longitudinal care needs

Slide 50 · Affected fathers: X-linked transmission

Affected father: X* Y

Unaffected mother: X X

Sons: Paternal Y

(no father–son X transmission)

Daughters: Paternal X*

(typically carriers)

Assumes an unaffected mother and conventional sex-chromosome transmission.

Slide 51 · Carrier mothers: Probability per pregnancy

Carrier mother: X* X

Unaffected father: X Y

Each child has a 50% chance of inheriting the expanded maternal X.

Affected sons if X* inherited

Carrier daughters if X* inherited

Slide 52 · Female heterozygotes: Usually asymptomatic

Most women carrying one expanded AR allele do not develop the male phenotype

Mild cramps, tremor, or subtle symptoms can occur

Carrier identification has reproductive and family implications

Counseling should avoid asserting uniformly absent manifestations

Slide 53 · Genetic counseling follows molecular confirmation

Confirm AR

Repeat expansion

Construct a

Three-generation pedigree

Discuss sex-linked

Transmission

Offer appropriate

Family counseling

Counseling and testing decisions should account for autonomy and informed consent.

Slide 54 · No established disease-modifying therapy

Current care emphasizes symptoms, mobility, swallowing, and complications

Androgen-pathway modulation has been investigated

Reducing androgen signaling has not established a universally effective disease-modifying approach

Experimental agents should not be presented as standard treatment

Slide 55 · Research strategies target mutant AR toxicity

Mutant polyQ-expanded AR

Reduce AR expression

Modulate ligand signaling

Improve protein handling

Investigational concepts; No efficacy or clinical availability is implied.

Slide 56 · The neuroprotective mechanism remains an active question

Established target

One pathogenic AR repeat-expansion class

Lower motor neuron and muscle abnormalities

Ligand-associated mutant AR toxicity

Open questions

How cellular toxicity is initiated

Relative importance of neuron vs muscle

Which interventions preserve motor function

Slide 57 · Case discussion: Adult-onset LMN syndrome

A 49-year-old man reports years of cramps and progressive difficulty climbing stairs

Examination: Tongue fasciculations, limb atrophy, reduced tendon reflexes

No clear spasticity or other pyramidal signs

History reveals longstanding gynecomastia

Slide 58 · Case resolution: Combine localization and genetics

Adult male

LMN + bulbar signs

Androgen

Insensitivity clue

Order targeted

AR CAG analysis

Confirm or exclude

SBMA

Electrophysiology helps characterize denervation but does not replace molecular testing.

Slide 59 · Case discussion: Ambiguous repeat length

An adult male has slowly progressive limb weakness and an AR result of 36 repeats

His family history is uninformative; Endocrine findings are subtle

Which result category applies?

What clinical and familial evidence should accompany interpretation?

Slide 60 · Borderline alleles should not be oversimplified

What is established

GeneReviews places 36–37 in an intermediate interpretation range

History and phenotype influence interpretation

Within-family genotype data may assist

What not to conclude

Do not equate every borderline allele with full penetrance

Do not dismiss a phenotype without follow-up

Do not use a single CK/EMG result as proof

Slide 61 · Teaching synthesis: Molecular and anatomical axis

AR exon 1

CAG expansion

Polyglutamine

Protein abnormality

LMN and muscle

Pathology

Bulbar + limb

Weakness

Partial androgen insensitivity supplies a parallel endocrine diagnostic clue.

Slide 62 · Teaching synthesis: Discriminating features

Recognize

Adult-onset, slowly progressive LMN syndrome

Tongue atrophy / fasciculations and dysphagia

Gynecomastia or reproductive features

Verify / monitor

Confirm AR repeat expansion

Distinguish from ALS and 5q-SMA

Evaluate swallowing, mobility, respiratory status

Slide 63 · Essential references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 28, p. 1173.

La Spada A. Spinal and Bulbar Muscular Atrophy. GeneReviews; Revised 8 January 2026.

Grunseich C, Fischbeck KH. Spinal and Bulbar Muscular Atrophy. Neurol Clin. 2015;33:847–854.

MedlinePlus Genetics: Spinal and bulbar muscular atrophy. National Library of Medicine.

Slide 64 · Further mechanistic reading

Grunseich C, Fischbeck KH. Pathogenesis and clinical management (2014), PMC4284073.

Grunseich C, Fischbeck KH. Neurol Clin. 2015;33:847–854. doi:10.1016/j.ncl.2015.07.002.

Therapeutic targeting of the polyglutamine androgen receptor. Expert Opin Ther Targets. 2025. doi:10.1080/14728222.2025.2464173.

Research models inform mechanism; only validated patient outcomes establish treatment benefit.