Study Describes Characteristics of Autonomic Symptoms in Hereditary Amyloidosis

Ana Pena, PhD avatar

by Ana Pena, PhD |

Share this article:

Share article via email
clinical trials in FAP

Autonomic symptoms are common among patients with hereditary ATTR amyloidosis, usually accompany the progression of peripheral neuropathy, and are more prevalent in carriers of Val30Met mutations, a review of studies concluded.

The research, “Characteristics and natural history of autonomic involvement in hereditary ATTR amyloidosis: a systematic review,” was published in the journal Clinical Autonomic Research.

Hereditary ATTR amyloidosis is a rare genetic disease caused by mutations in the transthyretin gene (TTR) that lead to deposits of abnormally shaped transthyretin protein, or amyloids, which damage nerves and other tissues.

Familial amyloid polyneuropathy (FAP), or transthyretin (TTR) amyloid polyneuropathy, is a common form of hereditary ATTR.

Autonomic neuropathy is a hallmark of the condition, caused by damage to the nerves that control involuntary bodily functions such as heart rhythm, blood pressure, temperature control, digestion, bladder function, blood glucose regulation, or the reflexive ability of the eyes’ pupils to adjust to light and darkness.

Autonomic symptoms emerge at very early stages of the disease and pose a strong burden to patients. However, they often are overlooked because they can be masked by other, more pronounced symptoms of the disease.

In a bid to better characterize the autonomic dysfunctions of people with hereditary ATTR amyloidosis, researchers in this study reviewed the natural history studies and clinical trials that have been published about the disease.

They selected 10 reviews, 10 clinical studies and clinical trial extension studies, and eight clinical cases or series in different patient populations, for the final analysis.

This joint analysis revealed that autonomic symptoms were present in 50%–80% of the patients. The most common symptoms were orthostatic hypotension (OH,, which is a decrease in blood pressure after standing up), diarrhea, constipation, erectile dysfunction, urinary incontinence, and xerostomia (dry mouth).

Gastrointestinal symptoms and OH usually were felt earlier than urogenital complications.

Such manifestations were more common in patients with the Val30Met mutation, the most common cause of FAP. They were the first to experience symptoms after the onset of disease (on average 2.7 years after).

Conversely, patients carrying cardiac mutations were less likely to develop autonomic symptoms. Prevalence also seemed to be more common in younger patients, and in those with early-onset disease.

Reports often illustrated that autonomic symptoms are overlooked and masked by other non-autonomic symptoms. These mistakes can limit therapeutic options, researchers noted.

Symptom progression often matches that of motor and sensory peripheral neuropathy — a progressive loss of nerve function in the periphery of the body, including the feet, legs, hands, and arms.

In most clinical trials, nutritional status and autonomic components in the quality-of-life questionnaire of the Norfolk QOL-DM questionnaire were the most common measures to assess the indirect progression of autonomic dysfunction. COMPASS-31 questionnaire — a patient-reported score of autonomic symptoms — was used in one trial and showed “good results,” researchers wrote.

The use of more complex measurements is challenging given the involvement of multiple organs in the disease. Checking for heart rate variability, for instance, is of limited value for patients with irregular heartbeats (arrhythmias).

“Better biomarkers to assess the onset and progression of the autonomic dysfunction are needed,” the authors said.

Another aspect emerging from studies was the impact of autonomic dysfunction over patients’ health and quality of life. Autonomic symptoms had a significant impact on disease complications, progression, and mortality.

Researchers cautioned that available studies are still insufficient to understand clearly the features and how autonomic manifestations evolve over time in patients. Better outcome measures also are needed, they said.

The progression of autonomic symptoms is still poorly characterized and there is a lack “of robust, objective indicators” for its course. The gap exists, in part, to the fact that hereditary ATTR is a very rare disease, and also because most of the published literature are case reports or case studies looking at only one or a few patients.

The team calls attention to the fact that assessing autonomic symptoms should be done carefully. This “will help the clinician to better understand the multisystemic complaints of patients … and will facilitate the treatment of certain conditions,” the wrote.