Everything You Need to Know About hATTR Amyloidosis!
Familial transthyretin amyloidosis or hATTR is caused by a mutation in the transthyretin gene. Historically, hATTR has been characterized on the basis of its predominant clinical presentation. However, it is important to note that hATTR often presents as a mixed phenotype, with some patients primarily suffering from neuropathy (formerly known as familial amyloid polyneuropathy or FAP), and others exhibiting predominantly cardiac symptoms (previously referred to as familial amyloid cardiomyopathy or FAC).
These clinical presentations are now further described under the respective names of hATTR amyloidosis with polyneuropathy (hATTR-PN) and hATTR amyloidosis with cardiomyopathy (hATTR-CM). In practice, there is a range of overlapping clinical phenotypes in which the majority of TTR gene mutations lead to a mixed clinical phenotype with both neurological and cardiological symptoms. Even in patients of the same family who carry the same mutation, the clinical presentation may be different.
There are at least 100 variants of hATTR amyloidosis, each with a specific clinical presentation. The most common mutation is V30M. The condition can manifest itself with a variety of symptoms, mainly of a neurological, cardiac and/or gastrointestinal nature. The most characteristic neurological manifestation is length-dependent axonal degeneration, which causes neurological dysfunction. Heart problems are mainly heart failure and conduction disturbances. Autonomic disorders can also occur, for example erectile dysfunction or kidney problems. Kidney problems are, however, less common with hATTR than with other forms of amyloidosis.
PREVALENCE RATE & TRENDS OF hATTR
HATTR amyloidosis is a rare disease. It is not known exactly how many people suffer from it, but it is estimated that there are 50,000 in the world.
HATTR amyloidosis with polyneuropathy (hATTR-PN) is quite common in some countries like Portugal, Sweden, Cyprus, Mallorca and Japan. In northern Portugal, for example, it is even estimated that 1 in 538 people have the disease.
HATTR amyloidosis with cardiomyopathy (hATTR-CM) is more common among the African American population.
HATTR amyloidosis is an autosomal dominant disease that is progressive and irreversible. If one of the two partners has a mutated gene, then the children will have a 50% risk of developing the disease as well. This is why the disease is now relatively concentrated in certain regions. However, the current trend towards migration should force doctors to be vigilant, and a thorough family history is certainly not an unnecessary luxury in making the diagnosis. Considering the irreversible evolutionary character of the affection, an early diagnosis is extremely important to be able to hope to stabilize the disease somewhat. But the very many symptoms are usually responsible for referral from one doctor to another, which can sometimes last for several years, leading to errors in diagnosis and treatment. This can have important consequences since the median age of the patient at the time of diagnosis is 63 years and his life expectancy is 2 to 15 years from the onset of symptoms.
WHAT ARE THE THERAPEUTIC OPTIONS WITH hATTR?
It goes without saying that, given the wide range of possible symptoms, a multidisciplinary approach to this pathology is the only right choice. Initially, therapy should be targeted to prevent further production and deposition of amyloid fibrils. Until a few years ago, only a high-risk liver transplant was eligible for this. However, in recent decades, a continuous search has been made for drug alternatives such as the treatment of hATTR in adult patients suffering from polyneuropathy (hATTR-PN)
● Tafamidis is a transthyretin-specific stabilizer (TTR) that slows down the evolution of hATTR amyloidosis by re-stabilizing the transthyretin protein (TTR). This makes it possible to prevent the dissociation of the tetramer into monomers and toxic metabolites causing amyloid. Tafamidis has also been shown to be active with mutations other than V30M and is a potential treatment for most patients with hATTR. Tafamidis also benefits from 5.5 years of efficacy data as a treatment against ATTR-PN. 21 Tafamidis is administered orally once a day, at an early stage of the disease.
● Patisiran is a small double-stranded interfering ribonucleic acid (pARNi) that causes catalytic degradation of mutated and wild (normal) TTR mRNA in the liver. This causes a decrease in serum TTR protein levels. Partisiran is administered by intravenous infusion once every 3 weeks.
● Inotersen is an antisense oligonucleotide (ASO) that promotes the degradation of the mRNA of the mutated and wild-type TTR gene (normal), and prevents the synthesis of the TTR protein in the liver and thus its secretion into the bloodstream. Inotersen is administered once weekly by subcutaneous injection.
In addition to these drug treatments, the various complaints must be treated symptomatically with painkillers, anti-diarrhea, treatments for orthostatic hypotension and diuretics or aldosterone antagonists in case of heart failure. A pacemaker may be required for conduction disturbances. A major concern in the management of cardiac amyloidosis is to avoid the use of beta blockers and calcium channel blockers; these can exacerbate hypotension and decrease myocardial contractility due to their negative inotropic effect. Also, ACE inhibitors and sartans should be administered with caution as they too may aggravate hypotension.
Not sure whether you are at risk for hATTR amyloidosis or not? Take this short survey by hATTR.ca to find out if you are at risk for this severe disease.
