Hereditary ATTR presents with more severe nerve damage
Study notes distinct symptom patterns between hereditary and wild-type
Polyneuropathy, or widespread nerve damage, occurs in both hereditary and wild-type transthyretin amyloidosis (ATTR), but the hereditary form, which includes familial amyloid polyneuropathy (FAP), tends to cause more severe nerve impairment.
Hereditary ATTR was also more often associated with gastrointestinal symptoms and less often connected to carpal tunnel syndrome, a condition affecting nerves in the wrist, than wild-type ATTR.
That’s according to a prospective, single-center study of 72 patients evaluated at their first neurological presentation in Germany.
“Our findings underscore a high [frequency] of polyneuropathy in patients with transthyretin amyloidosis, irrespective of its origin,” the researchers wrote. “Differences in the severity of polyneuropathy as well as in red flags indicate different underlying mechanisms of damage.”
The study, “Polyneuropathy in hereditary and wildtype transthyretin amyloidosis, comparison of key clinical features and red flags,” was published in Scientific Reports.
What causes nerve damage in different forms of ATTR
ATTR includes a group of conditions in which a faulty transthyretin protein folds incorrectly and forms toxic clumps called amyloid fibrils, which are damaging to tissues.
The disease can be hereditary (ATTRv), caused by an inherited mutation in the TTR gene, or wild-type (ATTRwt), which develops sporadically with aging, typically in older adults and more often in men.
In FAP, also called hereditary ATTR with polyneuropathy (hATTR-PN), amyloid fibrils mainly accumulate in the peripheral nerves that run from the spinal cord to the hands and feet. This buildup leads to widespread nerve damage and neurological symptoms.
“Despite being one of the commonest manifestations in ATTRv, the presence of polyneuropathy has long been underestimated in ATTRwt patients,” the researchers wrote.
How researchers compared hereditary and wild-type ATTR
To better understand how nerve damage differs between the two forms, the researchers in Germany evaluated 72 people diagnosed with either hereditary or wild-type ATTR at their first neurological visit.
All participants were followed at the Amyloidosis Center Lower Saxony, in Germany, a center supported by the German subsidiary of Alnylam Pharmaceuticals, which develops and markets treatments for hATTR-PN and other forms of ATTR.
Of the 72 participants, 11 had ATTRv and 61 had ATTRwt. People with ATTRv had a lower median age (74 vs. 78 years) and less often men (64% vs. 90%).
All but two of the ATTRv patients carried the Val50Met mutation — the most common cause of hATTR-PN. The remaining two carried other disease-causing mutations (Cys30Arg and Ile104Thr).
All participants with hereditary ATTR had polyneuropathy. Most ATTRwt patients did as well (84%). In total, 64% of ATTRv patients and 67% of those with ATTRwt had no other identifiable cause of polyneuropathy.
The most common neurological symptoms were numbness and sensory discomfort, reported by 73% of ATTRv patients and 43% of those with ATTRwt. Walking difficulties were the next most frequent (55% vs. 31%, respectively).
The red flag manifestations commonly used to diagnose [hereditary ATTR] were also prevalent in the majority of [wild-type ATTR] patients, making it challenging to differentiate between the two groups.
During neurological exams, doctors found more signs of nerve damage than patients reported. For example, muscle weakness was detected in 55% of ATTRv patients and 23% of those with wild-type ATTR — even though only 27% and 8%, respectively, reported feeling weak. Similar gaps appeared with sensory symptoms and walking difficulties.
Nerve conduction studies, tests that measure how well electrical signals move through nerves, showed that 82% of ATTRv patients had symmetric sensorimotor large-fiber polyneuropathy, meaning nerves controlling both movement and sensation were affected on both sides of the body.
Among ATTRwt patients who underwent nerve testing, 81% showed signs of large-fiber polyneuropathy. Most had sensorimotor involvement, while a few had motor-only nerve damage. A small number had findings limited to a single nerve or to carpal tunnel syndrome alone. Only two ATTRwt patients had normal results.
Disability scores also showed more severe nerve-related impairment in hereditary ATTR. For example, 45% of ATTRv patients scored four or higher on the Inflammatory Neuropathy Cause and Treatment scale, indicating more limitations in daily life activities involving the arms and legs, compared with 16% of those with ATTRwt.
Blood tests also showed nerve-damage biomarkers. All tested participants had detectable levels of neurofilament light chain (NfL). Median levels were nearly twice as high in hereditary ATTR (76 vs. 40 picograms/ml). In addition, 55% of ATTRv patients, compared with 10% of those with ATTRwt, had NfL levels above the 95th percentile for their age group.
Key symptom clues that help distinguish the two forms
When looking at common “red flag” symptoms used to diagnose ATTRv, polyneuropathy, autonomic dysfunction (issues with blood pressure, digestion, or sweating), and heart involvement were common in both hereditary and wild-type ATTR.
However, gastrointestinal symptoms, including diarrhea and constipation, were significantly more common in hereditary ATTR. In contrast, carpal tunnel syndrome was significantly more frequent in wild-type ATTR, affecting nerves in the wrist and causing pain, tingling, numbness, or weakness.
“The red flag manifestations commonly used to diagnose [hereditary ATTR] were also prevalent in the majority of [wild-type ATTR] patients, making it challenging to differentiate between the two groups,” the researchers wrote. “However, a notable discrepancy in the severity of polyneuropathy was observed … which may aid in the initial clinical diagnosis before a genetic diagnosis is established.”
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