ATTR Monitoring Tools

NAC/Gilmore staging system for cardiac ATTR

NAC/Gilmore staging system for cardiac ATTR

NYHA Functional classification

Table 1. Neurologic and Cardiac Monitoring of Asymptomatic carriers of ATTRv gene mutations

* Cardiac amyloid bone scintigraphy is insensitive to TTR amyloid Type B TTR fragments. The amyloid fibril in hereditary transthyretin (TTR) Val30Met (pVal50Met) amyloid (ATTR Val30Met) amyloidosis is composed of either a mixture of full-length and TTR fragments (Type A) or of only full-length TTR (Type B). ATTR fibrils consisting entirely of uncleaved TTR (Type B) have so far have been found solely in patients with the TTR Val30Met (p. Val50Met), Phe64Leu (p. Phe84Leu), Glu74Asp (p. Glu94Asp), and Tyr114Cys (p. Tyr134 Cys) mutations.

Peripheral Nerve Amyloidosis

• Systemic amyloid deposition can frequently involve the peripheral nerves causing:
  • Small fibre neuropathy
  • Autonomic neuropathy
  • Sensory or sensorimotor large fibre neuropathies
• Neurological manifestations can also result from tenosynovial amyloid deposition leading to:
  • Carpal tunnel syndrome – causing a median neuropathy at the wrist.
    • This is frequently experienced as pain and tingling in the thumb, index and middle fingers, increasing with activity and flexed or extended wrist positions. Symptoms often wake individuals at night needing to shake the hand to reduce symptoms.
  • Spinal canal stenosis – causing neurogenic claudication
    • This is frequently experienced as numbness, leg and back pain, cramping, or legs giving way with walking, that is relieved by sitting or leaning forwards.
• Hereditary ATTR amyloidosis and AL amyloidosis most frequently result in neurological manifestations.
  • Typically small fibre and autonomic nerve fibres are involved first and then there is progression to involve sensory large fibre nerves and then motor large fibre nerves.
• Small fibre neuropathies involve damage to the smallest, unmyelinated nerve fibres in the skin.
  • Involvement of these nerves cause neuropathic pain, tingling, burning, numbness electric shock sensations, inability to recognise temperature or pain.
  • Small fibres are of a similar calibre to autonomic nerves, and so these systems can be affected at similar times.
  • Nerve conduction studies do not evaluate these small fibres, and so can not exclude this form of neuropathy. Specialised testing is required.
• Autonomic neuropathies involve damage to the nerves controlling the autonomic nervous system which controls involuntary bodily functions such as heart rate, blood pressure, pupillary function, sweating, gastric motility, bladder, bowel and genital functions.
  • Common symptoms of autonomic neuropathy include:
    • Postural or orthostatic hypotension, pre-syncope, syncope, palpitations, exercise intolerance
    • Early fullness, bloating, nausea and vomiting regurgitation after eating
    • Diarrhoea, constipation, rapidly alternating diarrhoea and constipation, faecal incontinence, weight loss.
    • Urinary urgency, frequency, nocturia, urinary incontinence, incomplete emptying and retention
    • Erectile dysfunction
    • Abnormal sweating
    • Dry eyes and mouth, difficulty adjusting to different lighting conditions and focal distances.
• Sensory and Sensorimotor large fibre neuropathies involve damage to the larger calibre myelinated nerves.
  • Involvement of the sensory large-fibre nerves results in numbness, tingling, loss of vibration and proprioception causing imbalance, ataxia and falls, and pain.
    • Patients are at risk of foot ulcers and need podiatry monitoring for foot and nail care.
  • Involvement of the motor large fibre nerves results in loss of strength, muscle mass, reflexes, dexterity and increasing falls.
    • Foot drops may occur requiring orthoses and physiotherapy input is necessary.
  • Nerve conduction studies evaluate these large fibre nerve components and is the investigation typically used to confirm a sensory or sensorimotor large-fibre neuropathy.
• These neuropathies are commonly length-dependent, affecting the feet and spreading up the legs, before developing in the hands.
• The symptoms of amyloid neuropathies can be very disabling for patients. Optimal supportive care (Link) is essential to improve function and quality of life for individuals with these symptoms.

Neurological Monitoring tools

Neurological monitoring tools are necessary to assess the small and large fibre nerve functions. In amyloidosis the following tools are typically used in both clinical practice and research studies:

• Postural blood pressures:
  • Lying blood pressure after 2-3 minutes of rest
  • Immediate standing blood pressure
  • Blood pressure after 1,3,5 minutes of standing
• PND and FAP staging
  • Assessment of these scores are required for PBS prescription of Patisiran in ATTRv amyloidosis.
• Medical Research Council (MRC) score to assess motor weakness:
  • The Neuropathy Impairment Score (NIS) is a similar measure of motor strength often used in clinical trials in amyloidosis. NOTE: The scoring is different to the MRC score, and practitioners needs to be trained in the use of the NIS.
• Familial Amyloid Polyneuropathy- Rasch- build Overall Disability scale (FAP-RODS): questionnaire evaluating the ability for patients to engage with activities of daily living and perform social activities.
  • Further information about this score
• Norfolk Quality of Life – Diabetic Neuropathy (NOFOLK QOL-DN) questionnaire is a tool used to evaluate quality of life in diabetic polyneuropathy. This has been validated in amyloidosis and is commonly used in clinical trials.
  • Further information about this score
• COMPASS-31 is an easy to use composite autonomic symptom score
  • Further information about this score

Further details about amyloid neuropathies, including information about symptoms and management can be found in the Amyloidosis Research  Consortium’s booklet Neuropathy and Amyloidosis available here.