Hereditary Transthyretin amyloidosis

By Pr David Adams, Dr Céline Labeyrie, Dr Térésa Antonini, Dr Cécile Cauquil, Dr Antoine Rousseau, Pr Michel Slama – CHU KREMLIN BICETRE / Antoine Beclere Hospital PARIS - FRANCE

What is Hereditary Transthyretin amyloidosis?

Hereditary (also called familial) transthyretin amyloidosis is a rare disease due to an anomaly (mutation) of part of your DNA (gene). This gene produces a protein, transthyretin or TTR. TTR amyloidosis mainly affects the nerves (neuropathy), the heart, but also, more rarely, the eyes and the kidneys.

More than 500 cases have been diagnosed in France, in most of the departments in metropolitan France and in the overseas territories. This disease concerns adults (from 20 to 88 years old). The age when the disease begins is very variable: around 30 in northern Portugal (where many families are affected) or later (around 60 on average) for non-Portuguese patients.

This is a potentially very serious, debilitating disease if the subject does not receive specialized treatment and care.

What are the causes of the disease?

The presence of a mutation on the coding gene for the synthesis of transthyretin is nearly always responsible. Nearly all the transthyretin is synthesized by the liver.

The TTR protein in its normal state usually serves to transport substances in the blood: the thyroid hormone (thyroxine) and the binding protein of retinol. It circulates in the form of a molecule called tetramer with four identical components. When the gene mutates, the protein produced undergoes a modification. Its four components are dislocated and deposited in the form of a toxic amyloid substance in the tissues and organs, thus altering their functions.

What are the manifestations of the disease?

Manifestations linked to a neuropathy (affection of the peripheral nervous system)

These revealing manifestations are very varied, which explains largely why diagnosis is delayed. They indicate a malfunctioning of the peripheral sensory, motor and vegetative nerves.

This can be:

  • A loss of sensitivity in the feet, predominantly on sensibility to temperature and pain; spontaneous and intense pain (like “burning”) or unpleasant sensations (paresthesia) non-perceived or non-healing wound or sore.
  • Weakness in the feet or more rarely the hands making walking or precise gestures difficult. Walking difficulties or loss of balance in older patients.
  • Vegetative disorders may also occur by lesions in the nerves which command the digestive, genital, cardiovascular and urinary systems with respectively: nausea, slow digestion, loss of appetite or more rarely vomiting, constipation, diarrhoea, or alternation between diarrhoea and constipation, erection disorders, dizziness, fainting just after getting up, difficulties in urinating….

As the disease evolves, the sensitivity disorders spread gradually to the knees and then to the hands: the weakness in the limbs is accentuated and the vegetative disorders get worse.

  • Weight loss: involuntary weight loss of more than 5kgs over six months is also usual; it can be inaugural.

Manifestations related to heart disease

A heart condition is very frequent particularly when the disease starts late in life and depending on the type of mutation undergone by the gene responsible for the disease. These manifestations are silent for many years, hence the importance of regular heart check-ups.

These can be:

  • Conductive disorders: a risk of extreme slowing down of the heart beat or even cardiac arrest which may require the implantation of a pacemaker. This proves necessary in nearly one third of cases during the evolution of the disease.
  • Cardiac infiltration by the deposits of amyloidosis leading to increased thickness and rigidity of the heart, breathlessness in case of effort (heart failure).
  • An attack oh the nerves of the cardiovascular system (low blood pressure, juste efter getting up, loss of normal variations of the heartbeat, anomalies on the MIBG scintigraphy.

When the heart starts to be affected by amyloidosis, the patient is not always aware of the problem, so detection of the heart condition is indispensable and requires a thorough initial check-up. Early detection is extremely important because it conditions a rapid treatment as soon as the anomalies have been shown up.

Manifestations concerning the eyes

There are several types of eye condition which depend on where the amyloid deposits are situated in the eye and vary considerably from one patient to another.

  • Deposits in the vitreous body occur in 20 to 30% of cases during the disease. They are manifested most often by the perception of “floating bodies” or “flying flies”. If the deposits are dense, they can cause sight impairment.
  • Glaucoma is secondary to amyloid deposits in the evacuation mechanism of the aqueous humour. This obstacle to resorption of the aqueous humour is accompanied by gradual increased pressure inside the eye which cannot be felt by the patient. However, it causes irreversible damage to the optic nerve causing disorders of the visual field. Without adapted treatment, glaucoma leads to permanent sight loss. Glaucoma concerns about 20% of the patients affected with amyloidosis.
  • Dryness of the eye is very frequent in the case of amyloidosis patients. This is manifested by a stinging feeling or foreign body sensation. This is due to a malfunctioning of the tear glands infiltrated by amyloidosis.

For all these reasons, it is indispensable for the patient to have a systematic eye test followed by regular check-ups of the vitreous disorders (visual acuity and eye fundus), glaucoma (ocular tension and if there is the slightest doubt the visual field and an analysis of the fibres in the optic nerve by OCT) and dryness of the eye.

Less common manifestations

Kidneys condition (proteinuria, kidney failure) or in exceptional cases damage to the meninges with headaches and confusion.

How is an amyloid neuropathy diagnosed?

The diagnosis of amyloid neuropathy can be difficult and is often delayed, bearing in mind that the disorders are irreversible. It is easier among patients of Portuguese origin where there is a quasi- constant medical history, providing there is genetic screening and regular follow-up care. It is more difficult in all the other patients for whom there is no family history of the disease in over half the cases. Delay in diagnosis can vary from 3 to 6 years as a cause of neuropathy other than amyloidosis is initially suspected as causing the patient’s health problems.

Diagnosis relies currently on three elements: 

  • Information collected during medical consultations with a neurologist trained for this rare disease. All this information can be put together thanks to questioning to detect neurological manifestations, by a neurological clinical examination to look for certain particularly distinctive signs or by data from an electromyogram.

Other elements will bring arguments in the cardiological field thanks to an electrocardiogram and a cardiac ultrasound scan.

A similar family history found in one of the parents is not a reliable indication as it is to be found in fewer than 50% of patients of non-Portuguese origin.

  • A genetic test – after a simple blood test- indispensable for asserting the presence of a mutation of the transthyretin gene responsible for amyloidosis. The blood sample is sent to the molecular biology laboratory of Kremlin Bicêtre university hospital.
  • A biopsy to demonstrate the presence of abnormal deposits of amyloid substances.

From what moment is a patient detected as carrying a mutated transthyretin gene actually considered to be ill? 

This subject is of major importance for several reasons.

Indeed, the disorders caused by the disease are usually irreversible and the earlier anti-amyloid treatments are administered, the more effective they are. However, the disease takes hold insidiously, making it difficult to put a precise date to it and we know that most carriers of the mutated transthyretin gene will develop the disease one day.

To identify this moment, there consequently needs to be a concerted effort on the part of patients carrying the mutation, specialised doctors trained for this disease and certain complementary examinations if necessary to confirm the presence of amyloidosis, hence the importance for carriers of mutations to take stock of the situation regularly by means of an annual check-up. If all the conditions together lead to the assertion that the disease has started, then an anti-amyloid treatment is initiated by the specialised medical doctor.

We still see the children of patients who had an amyloid neuropathy twenty years ago arriving in specialised consultation units. They even arrive at a very advanced stage of the disease whereas they were diagnosed as being positive during genetic tests performed several years before.

Familial transmission and genetic counseling

Screening in families with amyloid neuropathy is fundamental in the detection and monitoring carriers of genetic mutation likely to develop the disease later in life.

The genetic anomaly responsible for amyloidosis is transmitted in the family from parents to children. Each child has a one-in-two risk of receiving the abnormal gene from the parent who is affected (autosomal, dominant transmission) and therefore of developing the disease later in life. The disease will develop in a large majority of people with the genetic anomaly as the risk increases with age.

Treatment of familial amyloid neuropathy

The treatment of a patient suffering from hereditary amyloid neuropathy requires specialist care from a pluri-disciplinary team composed of a minimum of a neurologist, a cardiologist, an ophthalmologist and a geneticist.

The treatment includes anti-amyloid treatment if possible, treatment of the manifestations of the disease, medico-social care and genetic advice for the detection and care for carriers of a mutation of the TTR gene.

Anti- amyloid treatments

Their purpose is to prevent the formation of new deposits of amyloidosis by stabilising Transthyretin and blocking its production. The treatments available so far are only able to slow down the progression and even to stop it but not to get rid of the symptoms already present.

a) Liver transplant 

The purpose of a liver transplant is to remove the main organ producing abnormal TTR protein even if the liver is functioning perfectly well otherwise. A liver transplant is a complicated operation that needs to be performed in a specialized centre.

This treatment has been offered to over 2000 patients worldwide. It has been effective in stopping the progression of the disease in a large majority of cases (70%) treated in their early stages. It is not advised for patients who developed the disease late in life or for carriers of a certain type of mutation. It cannot be performed on patients over 70 years old.

In spite of the transplant, the disease sometimes continues to develop in the nervous system and the heart. This deterioration can be explained by an accumulation of non-mutated (wild) TTR after a liver transplant in subjects over 50.

b) “Anti-amyloid” medication

Tafamidis ® (Vindaqel ®) is the only medication currently authorized by the French authorities. It is a stabilizer of mutated transthyretin which slows down the progression of the disease. It is a tablet which is taken daily. It is well tolerated and must be prescribed by a neurologist who is familiar with the disease. Other medicines are currently being developed and tested for patients who are not candidates fot a liver transplant. They aim at inhibiting the production of both the mutated transthyretin protein and normal TTR protein by blocking its production by the cells of the liver.

c) Medication repressing the expression of the TTR gene

Medication has been developed to control and reduce the expression of the Transthyretin gene. These molecules are administered by repeated intravenous or subcutaneous injections. They block most of the mutated and wild transthyretin by the cells of the liver. Two important international studies are being carried out currently to test the effectiveness of these medicines on the progression of the neuropathy.

Treatment of the manifestations of the disease

It is very important to correct the manifestations of the disease to ensure everyday comfort and improve the patients’ quality of life.

Neurological manifestations

Nervous (neuropathic) pain is treated by specific painkillers. Recently, local treatments have been developed using a patch to be applied to painful areas. Special precautions need to be taken to protect insensitive legs and feet from burns and wounds.

For vegetative disorders, there exist corrective treatments, mainly in the form of diets and medication.

For motor disorders, physiotherapy is indispensable.

Cardiac manifestations

It may be necessary to implant a pacemaker to protect the patient from sudden cardiac arrest.

Ophtalmological manifestations

When it is responsible for impaired vision, vitreous damage may be treated by a surgical ablation of the vitreous body (vitrectomy) which will remove the amyloid deposits and recover the patient’s sight. It is most often combined with ablation of the lens. Glaucoma is treated with eye drops which lower ocular tension. When the latter are ineffective, it is possible to use laser treatment or glaucoma surgery (trabeculectomy) to lower ocular tension. Dryness of the eye is treated with drops which replace tears (lachrymal substitutes).

Monitoring and evolution of hereditary amyloidosis

Hereditary transthyretin amyloidosis is a chronic disease. Regular monitoring of the disease by a multi-disciplinary team including a neurologist, a cardiologist and a hepatologist in case of a liver transplant, as well as other specialists depending on each case, is indispensable. It is necessary for the patient to have a neurological check-up every six to twelve months to monitor the evolution of the neuropathy. Depending on the associated vegetative disorders, other specialists may also be consulted (gastroenterologist, urologist). A heart check-up including at least one clinical examination, an ECG, a cardiac ultrasound scan, a dosing of BNP and troponin and possibly a 24-hour ECG recording in outpatients is carried out every year and, if necessary, a check on the functioning of the pacemaker every six months. The check-up may be completed at varying intervals according to the gravity of the heart condition and its evolution. In case of a liver transplant, a close watch will be kept by the transplant physicians Concerning the reference centre (NNERF), sessions with a psychologist are organised both at CHB Paul Brousse and in the Neurology Department, if necessary completed by social assistance, ergo-therapy or physiotherapy.

How does familial amyloid neuropathy develop?

Without treatment the disease evolves inexorably towards the worsening of sensory and motor deficiencies, vegetative disorders and often a heart condition, which all cause disabilities. Death occurs within approximately ten years. A liver transplant can halt the disease, especially if it is carried out early in the development of the disorders. It has doubled the survival rate among subjects affected with Met30 mutation and younger people (under 50) at an early stage. Available “anti-amyloid” medication has slowed down the progression of the disease; we do not yet have any information concerning their impact on the survival rate.