Hereditary transthyretin amyloidosis (hATTR) is a progressive, debilitating disorder that often leads to early death. It is characterized by mutations in the transthyretin gene and is inherited in an autosomally dominant manner. Because amyloids are deposited across the body, this disease is best characterized as a multisystem disorder, most commonly affecting the nervous system and cardiac health. 

Some scientists classify the disease into 2 broad categories: early-onset and late-onset, with the latter being the most frequent mutation of the disorder and known as Val30Met. Patients with early-onset hATTR tend to first experience neuropathic pain and algothermal sensory loss at the distal limbs, with motor involvement and touch/deep sensory loss occurring later as the disease progresses. Individuals with early-onset disease often have an informative family history. 

In late-onset hATTR, patients usually experience early muscle wasting that starts distally, as well as general sensory loss. Cardiac dysfunction becomes more apparent as the disease progresses. If left untreated, patients have a life expectancy of about a decade from the time of diagnosis. Family history in this form of the disease is often negative. 

Key Characteristics of hATTR 

It must be stressed that hATTR is a multisystem disorder—its phenotype range is wide with significant clinical heterogeneity. However, in general, the most pressing complaint in hATTR is peripheral nervous system involvement. This is an important point to note because recognition of peripheral nervous system symptoms as a primary manifestation of hATTR can lead to early diagnosis, which is of utmost importance during the early stages of the disease. 

“The main challenge for clinicians in evaluating a neuropathic patient is when to suspect hATTR in order to catch the diagnosis early,” Manganelli and colleagues wrote in Neurological Sciences. “In regions where hATTR is non-endemic, diagnosis can be delayed by 3-4 years.” 

Read more about hATTR etiology 

According to Manganelli et al, the primary symptoms of hATTR that should raise clinical suspicion of the disease include progressive sensory length-dependent axonal polyneuropathy and dysautonomia in early-onset hATTR, as well as progressive idiopathic sensory/sensory-motor length-dependent axonal polyneuropathy or atypical chronic inflammatory demyelinating polyneuropathy (CIDP) in late-onset hATTR. 

Upon diagnosis, physicians should carry out a comprehensive health assessment involving various organs in the body. For example, clinicians should investigate cardiac serum biomarkers such as brain natriuretic peptide and cardiac troponin to assess the possibility of amyloid cardiomyopathy. Physicians should also focus on renal health by measuring renal biomarkers such as serum creatinine and proteinuria. 

In addition, Manganelli and colleagues stressed the importance of an ophthalmological assessment, given that ocular manifestations of the disease are common. There is significant heterogeneity in terms of eye involvement among patients with hATTR; should serious oculopathy be discovered, treatment should be initiated and the patient be kept under close follow-up.

Ocular Manifestations of hATTR 

Ophthalmologists usually conduct a number of tests in individuals with hATTR to assess the extent of ocular disease, such as measuring visual acuity and intraocular pressure, the Schirmer test, and slit-lamp examination. 

Around one-tenth of patients with hATTR experience some form of ocular involvement, usually late into the disease. The primary reason that the eyes require special monitoring in hATTR is because the eye can synthesize mutant transthyretin locally, especially via the retinal pigment epithelium. 

“Intraocular transthyretin synthesis accounts for the progression of vitreous amyloid formation post-liver transplant, resulting from the local production of mutated transthyretin in the eye,” Minnella and colleagues wrote in Molecular Mechanisms of Neuromuscular Disorders. “Not only do ocular manifestations in hATTR continue to occur after liver transplant, but their development may even speed up after the surgical procedure.” 

The fact that liver transplantation is not curative of ocular disease is well-documented in the medical literature. Scientists have observed that ocular disease continues to progress over time postoperatively; thus, an organized ophthalmological follow-up is critical. A possible ocular manifestation of the disease is glaucoma, which may first appear benign but may eventually result in irreversible harm, including blindness. Ironically, liver transplantation allows patients to live longer, giving more time for ocular disease to develop and mature. 

Read more about hATTR treatment 

Because the eyes can produce transthyretin locally, the severity of ocular pathology may not correlate with the severity of systemic disease. Nevertheless, some eye disease is driven by circulating pathological transthyretin (as opposed to that produced locally). This commonly gives rise to vascular conjunctival abnormalities. 

Like most pathologies related to hATTR, it is always better for treatment to be initiated early. Add to this the sight-threatening nature of ocular disease associated with hATTR, it is crucial for ophthalmologists to initiate eye assessments as soon as possible and administer treatment according to eye disease findings. 

“Moreover, ophthalmologists may play a key role by prompting additional investigations to search for systemic manifestations that may deserve early treatment interventions,” Minnella et al wrote. 

In summary, hATTR is a complex disease involving multiple systems in the body and therefore multidisciplinary care. Ocular disease is merely one of many possible symptoms of the disorder, but can lead to blindness in some cases if left untreated. Clinical vigilance is required. By carefully monitoring disease progression holistically, physicians are best positioned to support their patients by administering timely care when necessary. 

References

Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overviewNeurol Sci. 2022;43(Suppl 2):595-604. doi:10.1007/s10072-020-04889-2

Minnella AM, Rissotto R, Antoniazzi E, et al. Ocular involvement in hereditary amyloidosisGenes (Basel). 2021;12(7):955. doi:10.3390/genes12070955