Early nerve damage seen in woman with rare TTR mutation
Neuropathy followed by heart damage points to hATTR
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A rare mutation in the TTR gene — mutations in which are the cause of hereditary transthyretin amyloidosis (hATTR) — resulted in early, progressive neurological symptoms that were followed by heart damage manifestations in a 54-year-old woman, a study showed.
The findings suggest that “progressive neuropathy [nerve damage] followed by cardiomyopathy [heart damage] may represent key clinical features associated with p.Asp58Val hereditary transthyretin amyloidosis,” a particularly rare mutation, the researchers wrote.
The study, “p.Asp58Val Hereditary Transthyretin Amyloidosis: A Case Report and Literature Review,” was published in Cureus.
In hATTR, mutations in the TTR gene result in the production of an abnormal form of the transthyretin protein, which tends to misfold and clump, forming toxic aggregates that accumulate in various parts of the body.
In hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), these toxic aggregates, called amyloid deposits, tend to build mainly in the nerves outside the brain and spinal cord, causing polyneuropathy, or damage to multiple nerves. When these clumps mainly accumulate in the heart, the disease is classified as hereditary transthyretin amyloidosis with cardiomyopathy (hATTR-CM). Most hATTR patients experience both polyneuropathy and cardiomyopathy.
Rare mutation changes amino acid
More than 100 hATTR-causing mutations have been identified. The p.Asp58Val mutation changes a single amino acid, a protein’s building block, in the transthyretin protein. Only seven hATTR cases caused by this mutation had been reported in medical literature, according to the trio of researchers in Australia who described the case in the study.
The 54-year-old woman’s medical history included numbness and tingling in her lower limbs that progressed up her body, as well as mild swelling in her limbs. She later started to have sudden, rapid heartbeats (palpitations), episodes of fainting associated with changes in blood pressure, and frequent falls.
Polyneuropathy can affect both sensory nerves, which detect touch and pain, and autonomic nerves, which control involuntary functions such as heart rate and blood pressure. The woman’s symptoms suggested damage in both sensory and autonomic nerves.
Because of recurrent fainting, the woman had undergone surgery to implant a cardioverter-defibrillator, a small, battery-powered device implanted under the skin to continuously monitor the heart’s rhythm and correct life-threatening irregular heartbeats.
She also had a family history of heart disease. Her father had hypertrophic cardiomyopathy, a disease in which the heart muscle thickens and stiffens, limiting how well the heart pumps blood. He died from a heart attack at age 69, as did her maternal half-brother at 63. Her mother and older sister had experienced non-fatal heart attacks.
Multidisciplinary assessments focused on both polyneuropathy and cardiomyopathy. Electromyography, which assesses the health of muscles and the nerves controlling them, showed signs of damage to peripheral nerves, which likely contributed to her falls, and unstable blood pressure and heartbeat.
Heart imaging revealed thickened heart walls and signs suggestive of amyloidosis. New analyses of biopsies from prior colonoscopy samples confirmed the presence of amyloid deposits. Genetic testing revealed the presence of the rare p.Asp58Val mutation.
How this mutation manifests “remains variable,” the researchers wrote. “Of the seven previously reported cases, all affected individuals exhibited varying degrees of neurologic and [heart] sequelae.”
Many of these cases were characterized by predominant neurological symptoms, including those related to damage to autonomic nerves, followed by cardiomyopathy. Genetic counseling was offered to the woman’s relatives, though she refused testing for her children.
The woman was treated with epigallocatechin-3-gallate (EGCG; a molecule present in green tea), doxycycline, and diflunisal; all have shown potential to reduce the accumulation of toxic transthyretin clumps.
She stopped taking EGCG due to excessive sweating. She was given pregabalin and amitriptyline to target the onset of painful leg symptoms related to peripheral neuropathy, “with good effect,” the researchers wrote. She was also on a daily fluid restriction and other medications to control progressive heart failure.
After a year, she had fewer symptoms related to posture changes, a lower tendency to fall, and improved functional status and quality of life. While she had not returned to her full previous activity level, her neurological symptoms stabilized, highlighting the importance of early detection and treatment of polyneuropathy in hereditary transthyretin amyloidosis.
At the time the report was written, a multidisciplinary team was closely following the woman to continue to monitor her for disease progression.
“Progressive neuropathy and cardiomyopathy may be characteristic clinical features of [hATTR] involving the p.Asp58Val mutation,” the researchers wrote. “Vigilance for these symptoms, especially amongst patients with familial cardiomyopathy, may improve detection of this rare disease.”
