Familial transthyretin amyloidosis (ATTR) is a rare inherited disorder characterized by the abnormal accumulation of amyloid fibrils in various tissues and organs throughout the body. The amyloid deposits are primarily composed of misfolded transthyretin (TTR) protein.
Familial transthyretin amyloidosis genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
The pathology usually manifests between the third and fifth decade of life. Depending on the variant present in TTR, the peripheral nervous system (PNS), the central nervous system (CNS), or other organs such as the heart may be more affected. There are 3 main phenotypes:
- Amyloid polyneuropathy: sensorimotor neuropathy of the legs, carpal tunnel syndrome, psychomotor impairment, constipation or diarrhea, impotence, cardiomyopathy, vitreous opacities, glaucoma, nephropathy.
- Cerebral and meningeal amyloidosis: dementia, ataxia, tense and rigid muscles, seizures, psychosis, hydrocephalus, hemorrhage, and amyloid deposits in CNS.
- Cardiac amyloidosis: cardiomyopathies, arrhythmias, angina, heart failure.
Familial transthyretin amyloidosis is caused by mutations in the TTR gene, which provides instructions for making transthyretin. The mutated TTR gene produces abnormal transthyretin protein, which forms amyloid deposits in tissues and organs.
The age of onset, specific symptoms, and disease progression can vary widely among individuals and may depend on the particular TTR gene mutation. Some individuals may experience symptoms in early adulthood, while others may not develop symptoms until later in life.
Diagnosis of familial transthyretin amyloidosis involves a combination of clinical evaluation, genetic testing, and imaging studies. Genetic testing can identify the specific TTR gene mutation, confirm the diagnosis, and guide treatment decisions.
Management of familial transthyretin amyloidosis may include supportive care, symptom management, and, in some cases, targeted therapies. Liver transplantation has been used as a treatment option because the liver is the primary source of transthyretin production. In recent years, new medications targeting transthyretin have been developed and approved for the treatment of ATTR amyloidosis.
Given the genetic nature of familial transthyretin amyloidosis, genetic counseling is essential for affected individuals and their families. It can provide information about the inheritance pattern, the risk of passing the condition to future generations, and options for family planning.
Early diagnosis and intervention can help improve outcomes and quality of life for individuals affected by this rare genetic disorder.
Transthyretin (TTR) is an evolutionarily conserved serum and cerebrospinal fluid tetrameric protein transported throughout the body and brain, forming complexes with retinol and thyroxine (T4). It is a protein that tends to form aggregates naturally and in the mutated protein. In addition to its transport function, it is suggested that it may also play a vital role in the preservation of the nervous system (neuroprotective function).
More than 80 pathogenic variants in the TTR gene have been described to date. The disease phenotype varies according to the particular TTR variant and geographic area. Worldwide, c.424G>A (p.Val142Ile or V142I) is the most frequent variant in 3.4% of African Americans. V142I is mainly associated with cardiac amyloidosis. Before 60 years, the variant does not appear to affect mortality or cardiac function. However, after age 60, V142I carriers are at increased risk of mortality and congestive heart failure.
The most common pathogenic variant in Europe is c.148G>A (p.Val50Met or V50M), also known as the "Portuguese mutation," and affects a highly conserved amino acid whose alteration appears to affect the tetramerization capacity of the protein. This variant is usually found in patients with amyloid polyneuropathy. Another variant found mainly in patients in Europe, specifically in northwestern Ireland, is c.238A > G (p.Thr80Ala or T80A). The pathogenic variant c.238A > G is associated with polyneuropathy and cardiomyopathy.
One of the best-known variants related to cerebral and leptomeningeal amyloidosis is c.113A>G (p. Asp38Gly or D38G).
It should be noted that other genetic and environmental factors may contribute to the expression and severity of the disease, and many carriers may not develop symptoms.
Familial transthyretin amyloidosis genetic testing analyzes the 12 most frequent pathogenic mutations of the TTR gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
