[MIM 105 210] 

(hereditary amyloidosis, portuguese amyloidosis)

Rare, but greater prevalence in Portugal, Sweden, Japan, Brazil and Majorca. Autosomal dominant transmission with  variable penetrance of a mutation of the TTR gene (on 18q21.1) which codes for transthyretin (formerly prealbumin), the carrier protein of thyroxine and retinol. The most common mutation is Val30Met; some mutations (Val122Ile, Ile68Leu etc) are more often associated with a cardiomyopathy.

The mutation causes an abnormality of configuration of the protein which accumulates gradually in the extracellular tissues in the form of amyloid fibrils.

Neurological damage consists in is a progressive axonal neuropathy of the small myelinated and non-myelinated fibres: the longest fibers are affected first, which explains the appearance of the first signs in the lower limbs. The average duration of the disease between the appearance of the first clinical signs and death is ten years.

There are different clinical presentations :

Mainly neurological form : onset before the age of 40 years in the high prevalence countries, later in other countries.

-        neuropathic pain: burnings, paresthesia, disorders of sensitivity (risk of injury to the feet)

-        motor weakness in the feet progressing to then legs and finally unability le to walk (wheelchair bound)

-        autonomic disorders: hypotension, gastroparesis, constipation or diarrhea, neurogenic bladder,

-        the heart is affected in about 50% of the cases: conduction disorders, sometimes total atrioventricular block

-        eye disorders: vitreous opacity, glaucoma

-        renal impairment : generally paucisymptomatic.

Mainly cardiac form: conduction disorders and cardiomyopathy by infiltration: ventricular hypertrophy at echography but absence of LVH at ECG and restrictive type physiology, especially at the end of evolution

Leptomeningeal form: very rare: transthyretin is also produced in the choroid plexus which can result in a cerebral amyloidosis and amyloid angiopathy of the cerebral vessels. This can cause: cerebral hemorrhage or thrombosis, hydrocephalus, dementia, spasticity.

Treatments:

-        the only curative treatment is liver transplantation because transthyretin is mainly produced in the liver; it should, however, be performed early in the disease because transplantation only stabilizes the lesions already present

-        experimental treatments: tafamidis, diflunisal [a NSAIDs] or the association doxycycline- tauroursodeoxycholic acid that prevents the abnormal transthyretin from forming fibrillar deposits and thus slows the progression of the disease.

-        gene therapy: weekly subcutaneous administration of eplontersen to reduce transthyretin synthesis: reduction in blood transthyretin levels and improvement in neuropathy

The liver transplantation is generally the opportunity to realize a domino transplantation, where the patient liver is transplanted to another patient, generally older, the pathology of which needs a long time to be symptomatic. However, a few cases of "acquired" amyloid polyneuropathy have been described in recipients having received such hepatic grafts.

Anesthetic implications:

risk of cardiac complications: ECG and preoperative cardiac echography. Vasoplegia in case of bradycardia and or A-V block,  poor or absent hemodynamic  response to atropine but the response to isoprenaline is  preserved; in case of major surgery, it may be useful to place a temporary pacemaker. Delayed gastric emptying. Locoregional anesthesia: risk of major hypotension during a neuraxial block.

References : 

-        Ando Y, Coelho T, Berk JL, Waddington-Cruz M, Ericzon BG et al. 
Guideline of transthyretin-related hereditary amyloidosis for clinicians. 
Orphanet J Rare Dis 2013; 8: 31, 18 p.

-         Eriksson P, Boman B, Jacobsson B, Oloffson BO. 
Cardiac arrhythmias in familial amyloid polyneuropathy during anaesthesia. 
Acta Anaesthesiol Scand 1986; 30: 317-20.

-         Neelakanta G, Mahajan A, Antin C. 
Systemic vasodilation is a predominant cause of hypotension in a patient with familial amyloid neuropathy during liver transplantation. 
J Clin Anesth 2005; 17: 202-4. 

-        Coelho T, Marques W Jr, Dasgupta, Chao C-C, Parman Y, Cavalcante Franca M Jr, Guo Y-C et al.
Eplontersen for Hereditary TransthyretinAmyloidosis with polyneuropathy.
JAMA 2023 ; doi:10.1001/jama.2023.18688

Updated: October 2023