Motor Neuron Disease (ALS, SMA, PLS)

Motor neuron disease (MND) — most often amyotrophic lateral sclerosis (ALS) — is characterized by progressive degeneration of upper and lower motor neurons. The histologic findings include neuronal loss with reactive gliosis in the motor cortex and anterior horn cells, characteristic cytoplasmic inclusions, and a distinctive pattern of selective vulnerability that spares oculomotor neurons and Onuf nucleus. About 50% of ALS patients have cognitive or behavioral features overlapping with frontotemporal dementia (ALS-FTD), and this overlap is now recognized as a spectrum disorder rather than two separate diseases. This page covers MND pathology and the related disorders.

ALS Pathology

Selective Vulnerability

  • Anterior horn motor neurons: progressive loss with reactive gliosis.
  • Betz cells of motor cortex: upper motor neuron involvement.
  • Motor cranial nerve nuclei (V, VII, IX, X, XII): bulbar involvement.
  • Sparing of Onuf nucleus: sacral motor neurons for bladder/bowel (continence) — preserved until late.
  • Sparing of CN III, IV, VI: extraocular muscle motor neurons — preserved.
  • Frontotemporal cortex: in ALS-FTD spectrum.

Histologic Features

  • Motor neuron loss: with reactive astrogliosis in anterior horn and motor cortex.
  • TDP-43 cytoplasmic inclusions: highly characteristic. Phospho-TDP-43 IHC; present in nearly all sporadic ALS and most familial ALS.
  • Bunina bodies: small, eosinophilic intracytoplasmic inclusions in surviving motor neurons; specific for ALS but not present in all cases.
  • Skein-like inclusions: thread-like ubiquitin/TDP-43-positive inclusions.
  • Hyaline conglomerate inclusions: in some SOD1-mutant ALS (less TDP-43 in SOD1 cases).
  • FUS-positive inclusions: in FUS-mutant ALS.
  • Wallerian degeneration of corticospinal tract: pyramidal tract pallor with macrophages and astrogliosis.
  • Skeletal muscle: denervation atrophy, fiber type grouping with reinnervation.

Clinical Features (El Escorial / Awaji Criteria)

  • Progressive upper motor neuron (UMN) findings: hyperreflexia, spasticity, extensor plantar response.
  • Progressive lower motor neuron (LMN) findings: muscle atrophy, fasciculations, weakness.
  • UMN + LMN in same body region: characteristic.
  • Bulbar onset (about 25%): dysarthria, dysphagia.
  • Spinal onset (75%): limb weakness, often asymmetric distal.
  • Spread to adjacent regions over time.
  • Respiratory failure usually fatal within 3-5 years.
  • Sparing of ocular motility, bladder/bowel control, sensation — characteristic.

ALS-FTD Spectrum

  • About 15% of ALS patients meet bvFTD criteria.
  • About 50% have measurable cognitive/behavioral changes.
  • Underlying pathology: FTLD-TDP type B (in C9orf72-mutant) or other.
  • Recognized as continuum: ALS-FTD spectrum.

Genetic ALS

  • About 10% of ALS is familial; gene mutations account for ~70% of familial and ~10% of sporadic cases.

Major Genetic Causes

  • C9orf72: hexanucleotide GGGGCC repeat expansion (>30 repeats); most common cause of ALS and FTD globally. Distinctive RNA foci, dipeptide repeat protein (DPR) inclusions, and TDP-43 pathology.
  • SOD1: superoxide dismutase 1 mutations; ~10-20% of familial ALS; SOD1-positive aggregates rather than TDP-43-predominant pathology.
  • TARDBP (TDP-43): TDP-43 mutations; rare; TDP-43 pathology.
  • FUS: FUS mutations; FUS aggregates; younger onset; aggressive course.
  • UBQLN2, VCP, OPTN, TBK1, ANG, ALS2, SETX, ATXN2 intermediate expansions, MATR3, CCNF, NEK1, KIF5A, DNAJC7, GLT8D1: rarer.

Therapy

  • Riluzole: glutamate modulator; modest survival benefit (~2-3 months).
  • Edaravone: antioxidant; modest benefit in selected patients (early disease, preserved function).
  • Tofersen: antisense oligonucleotide for SOD1-ALS; targets SOD1 mRNA; FDA-approved 2023 for SOD1-positive ALS.
  • Sodium phenylbutyrate-taurursodiol (PB-TURSO): approved in 2022 but mixed efficacy data; subsequently withdrawn from market for some indications.
  • Multidisciplinary care: nutrition, respiratory (NIV), communication, mobility.
  • Anti-C9orf72 ASO and other antisense oligonucleotide therapies in trials.

Other Motor Neuron Diseases

Primary Lateral Sclerosis (PLS)

  • Pure upper motor neuron syndrome.
  • Slowly progressive spastic paraparesis/quadriparesis.
  • Pathology: corticospinal tract degeneration, motor cortex (Betz cell) loss, gliosis, sparing of anterior horn.
  • Often eventually develops LMN features (transition to ALS).

Progressive Muscular Atrophy (PMA)

  • Pure lower motor neuron syndrome.
  • Anterior horn cell loss.
  • Usually eventually develops UMN signs (transition to ALS).

Spinal Muscular Atrophy (SMA)

  • Autosomal recessive; SMN1 deletion or mutation.
  • Anterior horn cell loss; LMN syndrome.
  • Types I-IV by severity (infantile to adult).
  • Nusinersen, onasemnogene abeparvovec (Zolgensma), risdiplam: disease-modifying therapies that have transformed prognosis.

Bulbospinal Muscular Atrophy (Kennedy Disease)

  • X-linked; androgen receptor CAG repeat expansion.
  • Adult-onset; men only.
  • Bulbar + limb LMN weakness + gynecomastia + sometimes diabetes.
  • Sensory neuropathy in many patients.
  • Slowly progressive.

Hereditary Spastic Paraplegia (HSP)

  • Genetically heterogeneous (many SPG genes); pure or complicated forms.
  • Progressive spastic paraplegia with corticospinal tract degeneration.
  • Some forms with additional features (thin corpus callosum, ataxia, neuropathy, retinopathy).

Poliomyelitis / Post-Polio Syndrome

  • Acute poliovirus destruction of anterior horn cells.
  • Post-polio syndrome: late progressive weakness years after recovery.

🔍 Did You Know?

The 2011 discovery that a hexanucleotide GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD revolutionized our understanding of these diseases. Before C9orf72, the connection between ALS and FTD was clinical — many ALS patients had cognitive or behavioral changes, and some FTD patients developed motor neuron disease — but the genetic and molecular link was elusive. C9orf72 unified them: a single mutation causes ALS, FTD, or ALS-FTD, with variable clinical phenotype within affected families. The molecular pathology is unique: the expanded repeat produces (1) RNA foci that sequester RNA-binding proteins, (2) dipeptide repeat proteins (DPRs) produced by repeat-associated non-ATG (RAN) translation in all six reading frames, and (3) haploinsufficiency of normal C9orf72 protein. Plus standard TDP-43 pathology. The discovery has opened therapeutic targets: antisense oligonucleotides targeting the expanded RNA are in clinical trials. The lesson: the genetic architecture of neurodegenerative disease often reveals connections between previously distinct entities. ALS, FTD, and ALS-FTD form a continuum, and the unifying genetic discovery has implications for clinical management (family history, genetic counseling), prognosis, and therapeutic development. Looking for C9orf72 expansion is now standard in any patient with familial ALS or familial FTD.

Pitfalls and Pearls

  • ALS: UMN + LMN findings in same region; progressive; respiratory failure.
  • TDP-43 cytoplasmic inclusions: hallmark of sporadic and most familial ALS.
  • SOD1-ALS: SOD1 aggregates, NOT TDP-43 predominant.
  • FUS-ALS: FUS aggregates; younger onset.
  • C9orf72 expansion: most common genetic cause of ALS and FTD; RNA foci + DPRs + TDP-43.
  • Bunina bodies: small eosinophilic inclusions in ALS motor neurons; specific.
  • Anterior horn cell loss + corticospinal tract pallor: ALS.
  • Sparing of Onuf and ocular motor: characteristic ALS pattern.
  • ALS-FTD spectrum: 15% bvFTD criteria; 50% measurable cognitive change.
  • Tofersen: ASO for SOD1-ALS; approved 2023.
  • SMA: SMN1 deletion; nusinersen, Zolgensma, risdiplam transform prognosis.
  • Kennedy disease: X-linked; androgen receptor CAG expansion; gynecomastia; sensory + motor.
  • Primary lateral sclerosis (PLS): pure UMN; can transition to ALS.
  • Hereditary spastic paraplegia: multiple genes; corticospinal tract degeneration.
  • Riluzole + edaravone + multidisciplinary care standard.

References

  1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
  2. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245-256.
  3. Brown RH Jr, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162-172.
  4. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-133.
  5. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110.
  6. Mercuri E, Sumner CJ, Muntoni F, Darras BT, Finkel RS. Spinal muscular atrophy. Nat Rev Dis Primers. 2022;8(1):52.