Motor neurone disease

From Ganfyd

Motor neurone disease is a relentless progressive degenerative disease of motor neurons and their associated microglia. It is a disease of motor nerves only, UMN and LMN only, with no sensory symptoms. Also known as also Motor Neuron Disease (MND) or Amyotrophic Lateral Sclerosis (ALS)

Prevalence of about 6/100,000. Most cases are sporadic, but up to 10% of cases are familial (see familial amyotrophic lateral sclerosis). Of the familial variety, about 20% of cases are associated with mutations in the superoxide dismutase 1 (SOD1) gene. Another 2-6% are associated with mutations in the TDP-43 gene. There is also an association with a region of chromosome 9p21.

It is more common in athletes and males. Possible role of excitotoxins including cycad nuts (methylaminoalanine), chickling peas, seaweed and shell fish

Aetiology

In most sporadic cases, the pathogenesis appears to be a TDP-43 proteinopathy. Fragments of this protein become aberrantly hyperphosphorylated and ubiquitinated, resulting in deposition of these fragments and neurodegeneration. The familial form associated with SOD1, however, does not involve TDP-43 and is likely represent a distinct subset.

Mice models reveal that SOD 1 expression in the motor neuron can determine the onset of the disease and the separate issue of how SOD 1 is expressed by the microglia can determine the progression of the disease.^[1]

Increased genetic risk is associated with mutations of:

• Angiogenin at 14q11.2
• Charged multivesicular body protein 2B(CHMP2B) coded for at 2p11.2 - a mutation can also cause familial amyotrophic lateral sclerosis
• Neurofilament protein coded for at 22q12.2
• Survival motor neuron gene 1 (SMN1) - which codes for a protein that functions as an assembly factor for snRNPs and 2(SMN2) at 5q12.2-q13.3
• Vascular endothelial growth factor coded for at 6p12
• Single nucleotide polymorphisms have been mapped to suggest associations with^[2]:
  • LOXHD1 gene on chromosome 18
  • PTPRT gene on chromosome 20 associated with cytosketal regulation
  • MAG12 gene on chromosome 7
  • IL18RAP gene on chromosome 2 associated with neuroinflammation
  • Unknown genes on chromosome 12 and 2.

Classification

Three main types exist, depending on the motor neurone type affected:

• Upper motor neurone - Primary Lateral Sclerosis (very rare - 0.01 per 100,000)
• Lower motor neurone - Progressive Muscle Atrophy, and Spinal Muscle Atrophy
• Mixed upper and lower MN - Amyotrophic Lateral Sclerosis

Symptoms

In the older patient, usually presents with noticeable weakness or increasing clumsiness. Other variants, exist. These include those evident around birth, with floppy infant, or failure to thrive.

• SMA types I to IV

Signs

Different clinical patterns all of which can coexist

• Progressive muscle atrophy
• Weakness
• Wasting
• Fasiculations
• Progressive bulbar palsy
• Dysphagia
• Nasal regurgitation
• Altered speech
• Aspiration
• Wasted fasiculating tongue
• Amyotrophic lateral sclerosis

Diagnosis

• Presence of each of the following:
  1. LMN signs in at least 2 limbs
  2. UMN signs in at least one region
  3. Progression of disease as increasing symptomatic impairment by history
  4. Absence of:
  • Sensory signs
  • Neurogenic sphincter abnormalities
  • Other CNS disease
  • Other PNS disease

• Role of EMG in diagnosis:
  • Extension of clinical examination
  • Strict electrophysiological criteria - "El Escorial" criteria

• Blood tests:
  • CK
  • Lyme serology
  • Serum electrophoresis
  • Porhyria screen
  • Anti-ACh antibodies
  • HIV test
• Imaging:
  • MRI brain and/or cervical spine
• Muscle biopsy:
  • No role in diagnosis, other than exclusion of primary muscle disorder.
  • Lyme serology

Differentials

• Progressive muscle atrophy
• Primary lateral sclerosis
• Brainstem syndromes
• Cervical disc disease
• Paraneoplastic neuropathy
• Lyme disease
• Tay-Sachs disease
• GM2 ganglioside disease
• Primary muscle disease
• LEMS/Myasthenia gravis
• HIV related disease

Mimic syndromes

• Bulbospinal muscular atrophy (Kennedy's syndrome)
• Multifocal motor neuropathy

Treatment

• Supportive
• Education and counselling
• Hydration
• Skin care
• PEG feeding
• Riluzole - glutamate release inhibitor
  • Inactivates voltage dependent sodium channels
  • In SOD1 defective mice, delays median time to death
  • Two trials may demonstrate delay in time to tracheostomy or death on riluzole
    • This is not statistically significant
  • Does produce early increase in survival
• Non-invasive ventilation is beneficial and increases survival by about 7 months with good bulbar function^[3].

References