Genetic Screening for Mutations May Help in Early Diagnosis, Treatment
A seven-year genetic screening program in Bulgaria involving people at high risk of hereditary transthyretin amyloidosis — a group of conditions that also includes familial amyloid polyneuropathy (FAP) — found patients showed mixed symptoms, with some clinical peculiarities related to specific disease-causing mutations.
According to researchers, such genetic screening is a “potent tool for early diagnostic and timely treatment” of these high-risk individuals and those from regions in the country with a high incidence of the disease.
The study, “Seven Years of Selective Genetic Screening Program and Follow-Up of Asymptomatic Carriers With Hereditary Transthyretin Amyloidosis in Bulgaria,” was published in the journal Frontiers in Neurology.
FAP is an inherited form of transthyretin amyloidosis, or ATTR amyloidosis. This group of conditions is triggered by the abnormal deposits and buildup, in different parts of the body, of a protein called transthyretin.
These transthyretin deposits — also known as amyloid fibrils — cause nerve damage in FAP, resulting in limb numbness, tingling, and weakness. In other forms of ATTR amyloidosis, amyloid fibrils can affect heart function and the digestive tract.
Most cases are caused by mutations in the TTR gene that encodes transthyretin. When inherited, these defects are passed down in an autosomal dominant pattern, meaning that a single mutated copy of the gene is sufficient to trigger the disease.
Bulgaria, a country in southeastern Europe, has a high number of ATTR amyloidosis cases. Given that, the Alexandrovska University Hospital, in the nation’s capital, Sofia, established the ATTR Amyloidosis Centre.
The multidisciplinary center now has been performing genetic screening for any mutation causing ATTR amyloidosis in high-risk populations for the past seven years.
In a new report, the center’s researchers described their experiences with the testing program. In it, the team also follows up on asymptomatic individuals — those who carry TTR mutations but did not initially show disease-related symptoms.
Since 2014, 954 people underwent genetic screening, and 340 carriers — 179 males and 161 females — were identified as having a TTR mutation. This included both affected and asymptomatic individuals, who belonged to a total of 127 families.
The most common disease-associated mutation in the TTR gene was Glu89Gln, occurring in 78.53% of the cases. Of note, like all proteins, transthyretin is made up of a chain of amino acid building blocks. The Glu89Gln mutation causes one of these amino acids, called glutamate (Glu), to be replaced by another amino acid called glutamine (Gln), at position 89 of the amino acid chain sequence.
The second most common mutation, as seen in the genetic screening, was Val30Met — a valine replaced by methionine at position 30 — found in 8.24% of the cases. This is the most common disease-associated mutation in FAP patients, especially in those living in some parts of Portugal, Japan, and Sweden.
A total of 470 individuals from the 127 families did not carry TTR mutations. In the remaining 144 individuals who neither belonged to a carrier family nor had a TTR mutation, 134 were patients with late-onset nerve damage, and 10 had heart problems.
The mean age of onset was significantly lower for males compared with females (48.33 vs. 54.09 years), with overall survival ranging between three and 20 years. The predominant initial symptom was consistent with damage to multiple areas of the nervous system, or polyneuropathy. Digestive system involvement at onset was found in seven affected patients.
Reported symptoms included carpal tunnel syndrome and sensory, motor, and autonomic impairment with painful itching and burning sensations more pronounced in the feet. Patients also reported the loss of vibration and temperature sensation, a lack of coordination, muscle weakness, eye impairment, and heart problems. Constipation/diarrhea and weight loss also were reported by patients.
Of note, autonomic impairment results from damage to nerves that control bodily functions that do not require conscious thought, such as digestion and blood pressure.
Generally, the clinical characteristics (phenotypes) of those with the Glu89Gln mutation were mixed, with involvement of peripheral nerves — those found outside the brain and spinal cord — the heart, and the digestive system.
The Val30Met mutation occurred in 14 affected Bulgarian families and was associated with late-onset disease. Specifically, the mean age of onset was about 65 years old. All of these patients had neuropathy affecting sensory, motor, and autonomic systems associated with left heart enlargement. Clinically, this mutation led to “milder” symptoms compared with other mutations found in Bulgaria.
Over three years, the team followed 65 asymptomatic carriers of TTR mutations. Among these, 56 had the Glu89Gln mutation. During this period, 39 individuals became symptomatic and were diagnosed with FAP stage 1, with 38 showing abnormalities in neurological examinations. Heart involvement was seen in 19 of those who developed symptoms.
A total of 150 patients with FAP stage 1 were treated with oral Vyndaqel (tafamidis), which acts as a transthyretin stabilizer. During seven years, 84 affected individuals remained in stable condition and continued treatment, while 66 stopped the medication due to disease progression or death.
Researchers reported that all patients were frustrated with the delay in diagnosis and treatment. Moreover, patients did not always share the emotional impact of the diagnosis with family members. Therefore, “psychological support is needed and directed to the patients, carriers, and their families,” they wrote.
“Bulgarian [ATTR amyloidosis] patients display a mixed phenotype with some clinical peculiarities for each mutation that should be considered when treating the affected and the follow-up of the asymptomatic carriers of a specific gene defect,” the scientists concluded.
About the Author
