Researchers suggest that guidelines and standardized protocols are needed to evaluate the autonomic nervous system — which regulates certain body processes such as such as breathing, heartbeat, and digestion — in the development of familial amyloid polyneuropathy (FAP).
FAP, also known as hereditary transthyretin amyloidosis (hATTR), is a progressive disorder characterized by the accumulation of faulty TTR protein in the form of amyloid aggregates. These have been recognized as the cause of adult-onset nerve cell degeneration affecting the sensory and motor systems.
But TTR deposits can also affect the autonomic nervous system, controling regular bodily activities that aren’t consciously directed, including eye and renal functions.
In the study, “Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis),” Alejandra Gonzalez‑Duarte, MD, a neurologist at the Salvador Zubirán National Institute of Medical Sciences and Nutrition in Mexico City, reviewed the features of autonomic symptoms in FAP patients.
The review study was published in the journal Clinical Autonomic Research.
Previous reports have noted that damage to the peripheral autonomic nerves often happens before motor nerve impairment. Also, an increase in the accumulation of amyloid deposits has been detected in nerve regions that control the autonomic functions, rather than those regulating motor functions.
Autonomic nervous system involvement consists of low blood pressure, sexual impotence, erectile dysfunction, altered gastrointestinal motility, skin blistering in the hands and feet (dyshidrosis), and abnormal bladder control.
Although all these symptoms can severely affect patients’ quality of life, loss of control of the cardiovascular system can lead to life-threatening events such as arrhythmias and sudden death.
“Since autonomic disturbances affect patient survival, an understanding and recognition of these disturbances are important,” Gonzalez‑Duarte said. “Several methods of assessment of the autonomic function have been used for describing the natural history and outcomes of [FAP].”
Determining heart rate variability has been shown to be a good marker for autonomic dysfunction. A reduced heart rate variation upon stimulus has been reported in patients, and was found to be proportional to the severity of neurologic disability.
Also, the use of imaging techniques with adequate imaging contrast agents can detect nerve cell damage at early asymptomatic stages of the disease.
Low blood pressure in a resting position (called orthostatic hypotension) has also been shown to be an early manifestation of autonomic dysfunction. However, FAP patients may not be aware of this symptom because it progresses so gradually.
In addition to these methods, clinicians can use previously validated questionnaires that provide useful information on autonomic involvement. These include the Composite Autonomic Symptom Score (COMPASS-31), the Norfolk QoL-DN, and the Modified Neuropathy Impairment Score Plus 7 (mNIS+7).
The accumulation of TTR amyloid aggregates in the skin is an early event in the course of the disease, so it can be used as a biomarker of disease severity and progression. However, only a few studies have evaluated whether this finding can be linked to autonomic symptoms, and their results have been inconclusive.
Several therapies have been developed to promote TTR protein stability and prevent the formation of amyloid aggregates as strategies to treat FAP. Among these emerging treatments are Vyndaqel (tafamidis), Dolobid (diflunisal), Patisiran, and Inotersen.
Results from clinical trials have shown that some of these medications could improve at least a few of the symptoms of system dysfunction. But the results are still controversial; some patients seem to benefit from the treatment, while others developed new autonomic symptoms while they were taking the therapies.
“There is not one standardized current approach to evaluate dysautonomia in [FAP],” the researcher said, which could affect the results obtained in an ongoing clinical trial.
She believes a better understanding of the significance of the signs and symptoms may help in the evaluation of available therapies, and improve knowledge about the disease’s natural course.