What is Hereditary Transthyretin Amyloidosis (hATTR)?

 

Transthyretin protein is produced primarily in the liver and the choroid plexus, small intestine, and retinal pigment epithelium and is responsible for transporting vitamin A and thyroxine (T4). Mutations in the TTR gene lead to a loss of the protein’s stable structure, forming insoluble amyloid fibrils. The mutant TTR protein dissociates from its natural tetramer form, gains toxic functionality, and accumulates in various tissues and organs. Hereditary transthyretin amyloidosis (hATTR) is an inherited disease where each child has a 50% chance of inheriting the disease-causing genetic variant if one parent has it. 

There are estimated to be 50,000 hATTR patients worldwide. The average life expectancy after diagnosis is reported to be 4.7 years. 

 

What Are the Clinical Symptoms of Hereditary Transthyretin Amyloidosis (hATTR)? 

 

Hereditary Transthyretin Amyloidosis (hATTR) Clinical Symptoms 

Peripheral Sensorimotor Neuropathy 

• Neuropathic pain 
• Paresthesia 
• Muscle weakness 
• Bilateral Carpal Tunnel Syndrome 
• Walking difficulties 
• Autonomic Neuropathy 

Orthostatic hypotension 

• Urinary retention 
• Recurrent urinary tract infections 
• Sexual dysfunction 
• Abnormal sweating 

Gastrointestinal Symptoms 

• Diarrhea
• Nausea
• Vomiting
• Unexplained weight loss 

Cardiovascular Symptoms 

• Arrhythmias 
• Conduction abnormalities 
• Heart failure 

In the early stages of the disease, classic symptoms include significant sensory loss, paresthesia, and neuropathic pain in the distal lower extremities. However, as the disease progresses, motor and autonomic involvement also appear. 

 

Diagnosis of Hereditary Transthyretin Amyloidosis 

 

Evaluation Tests in Hereditary Transthyretin Amyloidosis: 

• NCS/EMG (Nerve Conduction Studies/Electromyography) 
• NIS Assessment (Neuropathy Impairment Score) 
• QST (Quantitative Sensory Testing) 
• Sweat Gland Test (QSART; Quantitative Sudomotor Axon Reflex Test) 
• Wound and Skin Biopsy 

 

What treatment options are for Hereditary Transthyretin Amyloidosis (hATTR)? 

 

• TTR Tetramer Stabilizers 
• RNA Interference (RNAi) Therapy 

 

Source: 

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2. Hawkins et al. Ann Med 2015;47:625-38;

3. Mohty et al. Arch Cardiovasc Dis 2013;106:528-40;

4. Conceição et al. J Peripher Nerv Syst 2016;21:5-9.

5. Shin, Robinson-Papp. Mt Sinai J Med 2012;79:733-48; 5. Swiecicki et al. Amyloid 2015;22:123-31

6. Gertz MA, et al. Brain Behav. 2019;00:e01371.