Prof. Tarnev, approximately how many rare neurological diseases exist, and how many of them are treatable?
Rare diseases are over 7000; regrettably, there is a treatment for not more than 7% of them.
Do rare disease patients in Bulgaria have access to treatment? How quickly are new medications approved in Bulgaria?
The majority of the patients affected by a rare disease for which there is a treatment receive modern therapy such as DNA- and RNA-based therapies, enzyme replacement therapy, etc. However, the registration procedure for those therapies takes longer than in other European countries. It takes approximately two years more to register a new drug in Bulgaria after the drug has been approved by the European Medicines Agency. While in many countries a drug’s approval by the European Medicines Agency automatically means that the drug must also be registered in the respective country, the process in Bulgaria is different. That is why some families of patients with a rare disease emigrate to these countries, so they can receive the new treatments sooner. For example, two drugs for treatment of hereditary amyloidogenic transthyretin amyloidosis that were registered in 2018, were available for Bulgarian patients in 2021 and 2022 respectively.
And what care is available to patients with rare diseases without any existing treatment?
For a very large number of the rare disease patients who are under follow-up with our Expert Center for Genetic Nervous and Metabolic Disorders there is no treatment currently available. These are various muscular dystrophies, hereditary motor and sensory neuropathies, hereditary spastic paraplegia, hereditary cerebellar ataxias, etc. Such patients receive symptomatic treatment and kinesiotherapy. We aim to provide them with a better quality of life and to postpone the progression of their disease.
What is hereditary amyloidogenic transthyretin amyloidosis?
Hereditary amyloidogenic transthyretin amyloidosis (hATTR) is the most common hereditary peripheral neuropathy in Bulgaria. This is a life-threatening, hereditary disease which is inherited in an autosomal dominant manner. It is caused by the buildup of amyloid deposits in all tissues, but mostly in the peripheral nerves, the heart and the gastrointestinal tract. This disease was first described by the Portuguese neurologist Mário Corino de Andrade in 1952 and was first identified in the endemic area of Northern Portugal. The gene that is responsible for the disease codes for a plasma protein called transthyretin, which circulates as a tetramer composed of 4 identical monomer subunits. It is produced primarily in the liver and serves as a transport protein for thyroxine (it binds 20% of it) and retinol (vitamin A). Hereditary amyloidogenic transthyretin amyloidosis (hATTR) has large genetic and clinical heterogeneity worldwide. Over 130 mutations have been described. Five different mutations have been described in the Bulgarian population, which lead to a mixed clinical phenotype with high variability with regard to the onset and the clinical course of the disease. The age at onset may vary between 18 and 78 years depending on the mutation that causes the disease.
What are the symptoms of the disease and the difficulties in diagnosing it?
A more complete clinical picture of the disease includes late-onset axonal neuropathy, restrictive cardiomyopathy or conduction disturbances, as well as gastrointestinal and autonomous manifestations. Peripheral nerve impairment with evolving sensorimotor polyneuropathy is often an initial symptom of the disease. Increased sensitivity to pain and impaired temperature sensation are also typical. Autonomic nervous system disfunctions such as bladder or sexual disfunctions are also common. The accumulation of amyloid in the subendothelium of peripheral blood vessels leads to severe orthostatic hypotension (low blood pressure). Patients with accumulation of amyloid in the heart tissue have symptoms such as congestive heart failure (dyspnea on exertion, peripheral edema) and/or arrhythmia (tachycardia, dizziness, transient loss of consciousness). Patients with amyloid buildup in the gastrointestinal tract complain of diarrhea and/or constipation. They can also have nausea and vomiting, heaviness in the abdomen; and rarely pain. In the advance stages we observe malabsorption syndrome, significant weight loss, asthenia and cachexia (extreme physical wasting of the body). The carpal tunnel syndrome, which sometimes may precede the other clinical manifestations with more than 20 years, is also common. In one-third of the cases kidney impairment occurs during the progression of the disease, including nephrotic syndrome and progressive kidney failure. Ocular presentations involving accumulation of amyloid in the vitreous body and the retina may also be observed.
In most cases the process to get an accurate diagnosis is long. Patients often tell us about their frustrations after the numerous futile visits to doctors and hospitals. Their frustration is a result of the great number of different misdiagnoses, the progression of the disease, and the lack of response to the therapy they are receiving. This disease quickly impairs patients’ overall health and quality of life, and takes away their ability to function independently.
How many Bulgarians are affected by hATTR and do all of them receive treatment?
This disease is endemic to the southwestern region of Bulgaria (in particular, Blagoevgrad and Kyustendil districts); nevertheless, cases have been identified in 21 other districts of the country. To date, we have found 127 affected families with 231 patients and 111 asymptomatic carriers, who are subject to regular follow-up.
What is the prognosis for people who are misdiagnosed and do not receive any treatment?
If left untreated, hATTR continually progresses. Late-stage hATTR patients suffer from severe disability, malnutrition, cachexia, urinary and fecal incontinence, are bedridden or wheelchair-bound, and are unable to take care of themselves. hATTR staging is done according to the criteria for sensory/motor impairment, mobility and the degree of impairment, and there are three stages of the disease progression.
What is your advice to the patients with hATTR?
Our team has developed a guide for patients with hereditary amyloidogenic transthyretin amyloidosis. This guide is given to each newly-diagnosed patient. It includes important guidelines for the patients, contact information of the medical specialists who are familiar with this disease and can be contacted directly, if needed.
All patients undergo regular follow-ups every six months at the Expert Center at Alexandrovska Hospital. Their health status is evaluated and they are prescribed treatment.
At present, the most important advice I can give those patients is to get vaccinated against COVID-19 with an mRNA vaccine because COVID-19 poses big risks for patients with hATTR.