In medicine, two approaches are canon in improving clinical outcomes: the early detection of a disease and the early initiation of relevant therapies. Combined, they almost always improve prognosis and health-related quality of life.
Granted, certain diseases are easier to diagnose than others; cancers such as cholangiocarcinoma, for example, is notoriously difficult to detect in the early stages of the disease, and once symptoms do become apparent, it is usually an indication that the disease has already progressed significantly.
Let’s take a look at hereditary transthyretin amyloidosis (hATTR) and how a diagnosis is usually made. hATTR is a disease in which transthyretin amyloid fibrils accumulate pathologically in various organs and tissues, causing problems only as time progresses. In addition, when manifestations of the disease arise, they are typically multisystemic in nature; this may occasionally lead physicians to believe that they are dealing with separate issues.
“hATTR is often overlooked or misdiagnosed in patients, at least early in its course, due to the non-specific, heterogeneous, multisystemic presentation of the disease,” Nativi-Nicolau and colleagues wrote in Heart Failure Reviews.
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hATTR has a tendency to mimic the symptoms of other illnesses. Thus, misdiagnosis often occurs initially, leading to the prescription of therapies that have no biological effect on the underlying condition. Misdiagnosis can have far-reaching consequences, given the significant morbidity and mortality associated with this disease. It is therefore imperative that diagnostic mistakes are minimized, and that a careful examination of a patient’s clinical history and symptoms is carried out.
A Constellation of Symptoms
Physicians should recognize that hATTR is best characterized as a constellation of symptoms most prominently affecting the cardiovascular and neurological systems. Aside from cardiac pathology, the accumulation of transthyretin protein in the neurological system can lead to amyloid polyneuropathy. This may manifest as numbness, a burning sensation, or muscular weakness.
“As the disease progresses through each stage, the pattern of progression and class of nerve fiber impacted is reflected through heterogeneous clinical manifestations experienced by the patient with ATTR-polyneuropathy,” Nativi-Nicolau et al wrote.
Sensorimotor neuropathy and autonomic dysfunction are often observed at some point of the disease. Motor deterioration may become more pronounced if the patient is inadequately treated. The challenge for physicians is to ensure that questions related to the possible neurological manifestations of hATTR are asked in detail, including those about dizziness when standing (orthostatic hypotension) and erectile dysfunction, among others.
Studies indicate that musculoskeletal pathology becomes most prominent around 5 years to a decade into the disease. Many patients with hATTR will experience carpal tunnel syndrome, lumbar spinal stenosis, and/or Popeye sign (the rupture of the distal biceps tendon).
If physicians are initially puzzled by the various symptoms possible in hATTR, growing evidence of multisystemic involvement should point them toward suspicions of an underlying condition that can account for the symptomatic spread observed. Of course, the diagnosis of a rare disease is always going to be a challenge because physicians are trained to believe that “common things are common,” which is an axiom that proves true more often than not. This remains one of the great challenges of being a clinician: ensuring that the list of differentials is in the right order and that it is dynamic enough to be changed around according to best available evidence.
“Recognition of the heterogeneous clinical presentations of amyloidosis and diagnostic strategies is essential for all clinicians, with the potential to greatly impact patient outcomes,” Carroll and colleagues wrote in the Journal of Neurology, Neurosurgery, and Psychiatry.
Approaches to Diagnosis and Treatment
In the same journal, Carroll and colleagues reviewed a number of important approaches to diagnosing hATTR.
Genetic studies, for example, are an excellent investigative step should the threshold for clinical suspicion be reached. A total of 114 TTR mutations have been reported in existing literature; the Val30Met variant is among the most commonly found among patients with hATTR, and the Thr60Ala TTR variant is more commonly found in northwest Ireland. The Val30Met mutations are typically associated with peripheral neuropathy, whereas the Thr60Ala variants often have mixed neuropathic/cardiomyopathic phenotypes.
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Gene therapies are also among the most promising approaches to treating hATTR. TTR antisense oligonucleotides, for example, bind to complementary RNA, resulting in the cessation of TTR protein production by hepatocytes. One such therapeutic is inotersen. Various studies have reached the conclusion that it is safe and effective in ameliorating the neurological manifestations of the disease (sensory, motor, and autonomic). In addition, it has been found to stabilize cardiac performance and improve functional parameters such as the 6-minute walk test.
Small interfering RNAs are another class of drug that show significant therapeutic potential. Patisiran, for example, is one such therapeutic that works by targeting the 3’ untranslated region of TTR mRNA, resulting in a drastic reduction in TTR production. This reduction results in tangible effects, such as reducing overall disability and improving quality of life. Patisiran has been shown to improve functional status and reduce neuropathic symptoms such as pain perception.
In conclusion, while arriving at a timely diagnosis of hATTR may prove challenging to even seasoned physicians, there are a plethora of therapies, some approved and others experimental, that may be useful in treating this condition.
Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678. doi:10.1136/jnnp-2021-327909
Nativi-Nicolau JN, Karam C, Khella S, Maurer MS. Screening for ATTR amyloidosis in the clinic: overlapping disorders, misdiagnosis, and multiorgan awareness. Heart Fail Rev. 2022;27(3):785-793. doi:10.1007/s10741-021-10080-2