Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases¶
Chapter 448 | Part 13: Neurologic Disorders
KEY CLINICAL POINTS¶
- ALS is the most common progressive motor neuron disease, characterized by degeneration of both upper and lower motor neurons.
- Genetic mutations in C9orf72 (45–50% of familial ALS), SOD1 (20%), TDP43 (5%), and FUS/TLS (5%) are major causes of inherited ALS.
- Diagnosis requires simultaneous upper and lower motor neuron involvement with exclusion of other causes; biomarkers like elevated neurofilament light chains (Nfl) correlate with disease severity.
- Riluzole and edaravone are FDA-approved treatments that modestly prolong survival, while antisense oligonucleotides (ASO) target specific genetic mutations.
- Functional neurological symptom disorders (FND) mimic ALS but are nonorganic, with features like variable tremor frequency and placebo responsiveness.
1. DEFINITION & OVERVIEW¶
Amyotrophic lateral sclerosis (ALS) is the most common progressive motor neuron disease, characterized by degeneration of both upper and lower motor neurons. It is a prime example of a neurodegenerative disease with devastating clinical consequences. Other motor neuron diseases include bulbar palsy, spinal muscular atrophy (SMA), and primary lateral sclerosis (PLS). Functional neurological symptom disorders (FND) may mimic ALS but are nonorganic in origin.
Table 448-1: Etiology of Motor Neuron Disorders¶
| DIAGNOSTIC CATEGORY | INVESTIGATION |
|---|---|
| Structural lesions | MRI scan of head (including foramen magnum and cervical spine) |
| Infections | CSF exam, culture |
| Intoxications, physical agents | 24-h urine for heavy metals |
| Immunologic mechanisms | Complete blood count, sedimentation rate |
| Metabolic | Fasting blood sugar, PTH, thyroid function |
| Hereditary disorders | WBC DNA for mutational analysis |
Table 448-2: Sporadic Motor Neuron Diseases¶
| CHRONIC | ENTITY |
|---|---|
| Upper and lower motor neuron | Amyotrophic lateral sclerosis |
| Predominantly lower motor neuron | Multifocal motor neuropathy with conduction block |
| CHRONIC | ENTITY |
|---|---|
| Motor neuropathy with conduction block | Motor neuropathy with paraproteinemia or cancer |
| Motor predominant peripheral neuropathies | Other |
1.1 Motor Neuron Disease Classification¶
ALS is classified as a chronic, progressive motor neuron disease. Other motor neuron diseases include: (1) bulbar palsy and SMA (predominantly lower motor neuron involvement), (2) pseudobulbar palsy, PLS, and hereditary spastic paraplegia (HSP) (upper motor neuron involvement), and (3) multifocal motor neuropathy with conduction block (MMCB).
1.2 Functional Neurological Symptom Disorders (FND)¶
FND (formerly psychogenic disorder) presents with nonorganic motor symptoms like tremor, dystonia, or myoclonus. Diagnosis requires exclusion of organic causes and identification of nonorganic features such as variable tremor frequency, entrainment with external stimuli, and placebo responsiveness.
2. EPIDEMIOLOGY¶
ALS has an incidence of 1–3 per 100,000 and prevalence of 3–5 per 100,000. Men are more frequently affected than women. Risk factors include exposure to pesticides, silica, smoking, and military service. Familial ALS accounts for ~10% of cases, with autosomal dominant inheritance. Endemic foci exist in Guam and Papua New Guinea.
2.1 Demographics¶
Median survival is 3–5 years. ALS is more common in men than women. Age of onset varies, with familial ALS typically presenting in adulthood and juvenile-onset variants (e.g., Fazio-Londe syndrome) in childhood.
2.2 Risk Factors¶
Environmental risk factors include pesticide exposure, silica, smoking, and military service. Genetic factors include mutations in C9orf72, SOD1, TDP43, and FUS/TLS. Familial ALS accounts for ~10% of cases.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
ALS is caused by genetic mutations (C9orf72, SOD1, TDP43, FUS/TLS) or sporadic factors. Pathogenesis involves protein aggregation (TDP43, SOD1), RNA processing defects, and neuroinflammation. Mutant proteins disrupt axonal transport and cause excitotoxicity.
Table 448-3: Genetic Motor Neuron Diseases¶
| DISEASE | GENE SYMBOL | GENE NAME | INHERITA NCE | % FALS | USUAL ONSET | PROTEIN FUNCTION | UNUSUAL FEATURE S |
|---|---|---|---|---|---|---|---|
| ALS/ALS-F TD | C9ORF72 | Chromoso me 9 open reading frame 72 | AD | 45% (6–10% SALS) | Adult | Regulates vesicle trafficking | May also be associated with parkins onism, PLS |
| DISEASE | GENE SYMBOL | GENE NAME | INHERITA NCE | % FALS | USUAL ONSET | PROTEIN FUNCTION | UNUSUAL FEATURE S |
|---|---|---|---|---|---|---|---|
| ALS | SOD1 | Cu/Zn superoxide dismutase 1 | AD | 20% (2% SALS) | Adult | Protein antioxidant | |
| ALS/ALS-F TD | TARDBP | TAR DNA binding protein | AD | 5% | Adult | DNA, RNA binding | |
| ALS/ALS-F TD | FUS/TLS | Fused in sa rcoma/trans located in li posarcoma | AD | 5% | Adult | DNA, RNA binding | |
| ALS | NEK1 | NMA-relate d kinase | AR | 2% | Adult | Microtubule s, nuclear transport | |
| ALS | TBK1 | Tank binding kinase 1 | AD | 2% | Adult | Regulates autophagy, inflammatio n | |
| ALS | KIF5A | Kinesin family member 5A | AD | 1–2% | Early adult | Microtubule motor | CMT |
| ALS | PFN1 | Profilin 1 | AD | ~1% | Adult | Involved in actin polym erization | |
| ALS/ALS-F TD | OPTN | Optineurin | AD/AR | ~1% | Adult | Attenuates NF-kB | |
| ALS | SPG11 | Spastic paraplegia 11 | AR | ~1% | Adult | Vesicle trafficking | Spastic paraplegia |
| ALS | SETX | Senataxin | AD | ~1% | Late juvenile | DNA helicase | Late childhood onset |
| ALS-FTD | UBQLN2 | Ubiquilin 2 | XR | <1% | Adult or juvenile | Protein degradation | |
| ALS-FTD | CHMP2B | Chromatin modifying protein 2B | AD | <1% | Adult | Chromatin binding protein | |
| ALS-FTD | MAPT | Microtubule Associated Protein Tau | AD | <1% | Adult | Cytoskeleta l protein | Usually causes only FTD |
| ALS2 | ALS2 | Alsin | AR | <1% | Juvenile | GEF signaling | May mimic PLS |
| Spinal muscular atrophies | SMN | Survival motor neuron | AR | 1/10,000 live births | Infancy | RNA metabolism | |
| X-linked spinobulbar muscular atrophy | AR | Androgen receptor | XR | Adult | Nuclear signaling |
3.1 Genetic Causes¶
Familial ALS is autosomal dominant with mutations in C9orf72 (45–50%), SOD1 (20%), TDP43 (5%), and FUS/TLS (5%). C9orf72 mutations cause hexanucleotide repeat expansions (-GGGGCC-).
3.2 Molecular Mechanisms¶
Pathogenesis includes: (1) protein misfolding and aggregation (TDP43, SOD1), (2) RNA processing defects (C9orf72, FUS/TLS), (3) impaired axonal transport, and (4) neuroinflammation via microglial activation.
4. CLINICAL FEATURES¶
ALS presents with asymmetric weakness, fasciculations, spasticity, and bulbar symptoms. Early denervation leads to muscle atrophy and reflex hyperactivity. Progression is typically symmetric, with preserved sensory function and cognitive abilities. Functional disorders may mimic ALS but lack organic pathology.
4.1 Early Symptoms¶
Initial symptoms include asymmetric weakness, cramping with volitional movements, and fasciculations. Bulbar involvement may present with dysphagia, dysarthria, and respiratory insufficiency.
4.2 Disease Progression¶
Progression is typically symmetric, with loss of both upper and lower motor neurons. Sensory, cognitive, and autonomic functions are preserved. Late-stage features include respiratory failure and muscle atrophy.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include multifocal motor neuropathy with conduction block (MMCB), lead poisoning, thyrotoxicosis, and functional neurological disorders. ALS must be distinguished from other motor neuron diseases and mimics like chronic traumatic encephalopathy.
5.1 Mimicking Conditions¶
MMCB presents with lower motor neuron weakness and elevated GM1 antibodies. Lead poisoning and thyrotoxicosis may mimic ALS but are treatable with environmental or hormonal interventions.
5.2 Functional Disorders¶
FND presents with nonorganic motor symptoms, variable tremor frequency, and placebo responsiveness. Diagnosis requires exclusion of organic causes and identification of nonorganic features.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis requires MRI, EMG, CSF analysis, and genetic testing. ALS is diagnosed when upper and lower motor neuron signs are present with exclusion of other causes. Biomarkers like elevated Nfl in CSF correlate with disease severity.
6.1 Diagnostic Criteria¶
Definite ALS requires involvement of bulbar, cervical, thoracic, and lumbosacral motor neurons. Probable ALS involves two sites, while possible ALS involves one site. Genetic testing is critical for familial cases.
6.2 Imaging and Biomarkers¶
MRI shows corticospinal tract abnormalities. CSF biomarkers like elevated Nfl and phosphorylated neurofilament heavy chains correlate with disease progression. EMG reveals motor unit potentials and conduction block.
7. MANAGEMENT & TREATMENT¶
Riluzole and edaravone are FDA-approved treatments that modestly prolong survival. ASO therapies target specific genetic mutations. Supportive care includes respiratory support, gastrostomy, and speech aids. Physical therapy and psychological support are essential.
7.1 Pharmacologic Therapies¶
Riluzole (100 mg/d) reduces excitotoxicity. Edaravone (antioxidant) slows disease progression. ASO therapies (e.g., tofersen, nusinersen) target SOD1 and SMN mutations.
7.2 Supportive Care¶
Respiratory support via tracheostomy or ventilator, gastrostomy for nutrition, and speech aids (e.g., synthesizers) improve quality of life. Physical therapy and psychological counseling are critical.
8. PROGNOSIS & COMPLICATIONS¶
Median survival is 3–5 years. Complications include respiratory failure, aspiration pneumonia, and cachexia. ALS is associated with increased risk of frontotemporal dementia in C9orf72 carriers.
8.1 Survival¶
Median survival is 3–5 years. Riluzole and edaravone modestly extend survival. Prognosis is poor for patients with early bulbar involvement or rapid progression.
8.2 Complications¶
Respiratory failure is the leading cause of death. Aspiration pneumonia, cachexia, and autonomic dysfunction are common. C9orf72 carriers have increased risk of frontotemporal dementia.
9. SPECIAL CONSIDERATIONS¶
Pregnancy, pediatrics, and elderly patients require tailored management. ALS in children (e.g., SMA, Fazio-Londe syndrome) has distinct presentations and treatments. Functional disorders may mimic ALS but require nonorganic diagnosis.
9.1 Pediatric and Juvenile Cases¶
Juvenile-onset ALS (e.g., Fazio-Londe syndrome) presents with bulbar and limb weakness. Spinal muscular atrophy (SMA) is a distinct lower motor neuron disease with early-onset muscle atrophy.
9.2 Functional Disorders¶
FND may mimic ALS but lacks organic pathology. Diagnosis requires exclusion of other causes and identification of nonorganic features like variable tremor frequency.
10. KEY POINTS & CLINICAL PEARLS¶
- ALS is diagnosed with upper and lower motor neuron signs and exclusion of other causes. 2. Genetic testing is critical for familial ALS. 3. Riluzole and edaravone modestly prolong survival. 4. ASO therapies target specific mutations. 5. Functional disorders mimic ALS but lack organic pathology.