General Child Neurology
Aug. 01, 2022
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Hereditary amyloidosis is a disease caused by mutations in the transthyretin gene that leads to systemic deposition of amyloid protein. Although patients have multisystem involvement of amyloidosis, cardiomyopathy and peripheral neuropathy with autonomic neuropathy are typically the most prominent disease manifestations and the primary drivers of disability and mortality. New small interfering RNA, or antisense oligonucleotide therapies approved by the United States food and drug administration, reduce the production of transthyretin protein and slow the progression of hereditary amyloid polyneuropathy and, in some cases, improve measures of neuropathy severity and associated disability. Although hereditary transthyretin amyloidosis is a rare disease, it is an exciting model for developing new treatments for genetic disease in neurology and in medicine broadly.
• Hereditary amyloid polyneuropathy primarily refers to patients with mutations in the transthyretin gene although mutations in other genes may present with amyloidosis and neuropathy.
• The symptoms of transthyretin-associated familial amyloid polyneuropathy are those of a sensorimotor polyneuropathy, with progressive sensory loss and weakness, often with prominent autonomic neuropathy. Neuropathy is often accompanied by amyloid cardiomyopathy.
• hATTR polyneuropathy is diagnosed and confirmed with genetic testing for TTR gene mutations. Amyloidosis may be detected on tissue biopsy in workup of idiopathic neuropathy or cardiomyopathy, which may lead to suspicion of a genetic diagnosis.
• Amyloid stabilizing agents, including diflunisal and tafamidis, may slow the progression of TTR-FAP, and liver transplantation has traditionally been used to reduce production of mutant transthyretin protein.
• New small interfering RNA and antisense oligonucleotide therapies that reduce TTR gene expression are effective, new treatments to slow the progression of hATTR polyneuropathy.
Rudolf Virchow first described amyloid deposits in 1858, noting their starch-like appearance and reaction to iodine and sulfuric acid. Congo red staining of amyloid was first described in 1922, and the typical apple-green birefringence was noted in 1927 in patients with Alzheimer disease (46).
Transthyretin protein is named in reference to its 2 primary transport functions: binding thyroxine and retinol-binding protein (43). The TTR gene was sequenced in 1974 by Kanda and colleagues; at that time the transthyretin protein was referred to as plasma thyroxine-binding prealbumin (30). In 1991, Benson described 10 TTR gene mutations associated with familial amyloid polyneuropathy (13). The number of TTR gene mutations associated with disease has grown. At the time of the writing of this review, 52 mutations associated with familial amyloid polyneuropathy were reported on the Online Mendelian Inheritance in Man website.
TTR gene mutations result in multisystem amyloid protein deposition, but the cardiac system and the peripheral nerve system are most prominently affected. Some mutations in the TTR gene are more associated with cardiac involvement and others with more prominent peripheral neuropathy. The V122I mutation is noted to have primarily cardiac manifestations whereas the V30M is the most common form of familial amyloid polyneuropathy, particularly amongst Portuguese, Swedish, and Japanese populations (12; 10). Polyneuropathy may be more common with V122I mutations than previously reported (41).
Often the first neurologic symptom associated with transthyretin-associated familial amyloid polyneuropathy is carpal tunnel syndrome, related to amyloid deposition in the carpal tunnel causing a compressive median mononeuropathy. Carpal tunnel syndrome may precede other amyloid symptoms by years or even decades.
The generalized polyneuropathy of TTR-FAP typically begins with primarily small fiber involvement with paresthesias, loss of small fiber sensory modalities (temperature and pain), and neuropathic pain. Skin biopsy in presymptomatic TTR mutation carriers may show reduced epidermal nerve fiber density (26; 33; 19), and patients with early symptoms of peripheral neuropathy may have normal nerve conduction studies but low epidermal nerve fiber density on skin biopsy consistent with small fiber neuropathy (52). Skin biopsy may also be used to detect amyloid deposition and correlates with disease severity in TTR-FAP (26; 19). As the peripheral neuropathy of TTR-FAP progresses, there is increasing loss of large fiber nerve function, with more loss of sensation, weakness, and gait imbalance. Symptoms that initially begin in the feet and lower legs will eventually progress to affect the hands and arms.
Autonomic neuropathy is often prominent in patients with TTR-FAP. Symptoms and signs may include orthostatic hypotension, resting tachycardia, urinary retention, gastroparesis, erectile dysfunction, and abnormal sweating. In contrast to other types of autonomic neuropathy in which constipation predominates, patients with hereditary amyloidosis typically have prominent diarrhea, likely related to direct amyloid deposition in the bowel wall.
Depending on the genetic subtype of TTR-FAP, some patients will have an associated amyloid cardiomyopathy. Although the cardiac manifestations of amyloidosis are outside the scope of this article, the typical findings of are of a hypertrophic or infiltrative cardiomyopathy. When evaluating a patient with an otherwise “idiopathic” peripheral neuropathy, autonomic neuropathy, and hypertrophic cardiomyopathy, a diagnosis of TTR amyloidosis should be considered.
Other organ systems that often can be affected by amyloidosis in TTR-FAP include ocular deposition, gastrointestinal dysfunction with diarrhea, and renal involvement.
Untreated, transthyretin-associated familial amyloid polyneuropathy leads to progressive worsening of peripheral neuropathy, with increasing sensory loss, weakness, and gait imbalance as well as more severe autonomic dysfunction with orthostatic hypotension. Combined with the associated cardiac amyloidosis, patients are at increased risk for cardiac arrhythmia. Historically, this has been a fatal disease in many patients, primarily driven by the cardiac and autonomic morbidity, although significant phenotypic variability occurs within and between families (18; 03). One series of patients with V30M mutations described life expectancy average of 7.3 years from time of disease diagnosis (32).
Disease-modifying treatment, including gene silencing therapies and amyloid stabilizers, can now significantly slow down the course of the disease and in some cases may lead to clinical improvement. The expected prognosis for this disease is now significantly improved since the approval of these medications.
A 48-year-old man presented with years of sensory loss in the lower legs and feet that had slowly worsened; at the time of presentation he reported weakness and trouble walking as well as increased sensory loss and weakness in the hands with prominent neuropathic pain over the past year. He had orthostatic dizziness with multiple syncopal events, difficulty with urinary retention, chronic diarrhea, and nausea and abdominal pain after eating. He had no other significant medical history. He underwent carpal tunnel release surgery bilaterally 10 years earlier.
Family history was notable for peripheral neuropathy in his father, who died in middle age from cardiac complications, and a younger brother had milder sensory symptoms in his feet. Physical examination was notable for orthostatic hypotension on vital sign testing; there was distal sensory loss to light touch, pinprick, and vibration in the lower legs and hands; there was mild weakness of ankle dorsiflexion and interosseous muscles bilaterally; deep tendon reflexes were reduced in the arms and absent at the patellae and ankles. Electrodiagnostic testing demonstrated a severe axonal sensorimotor polyneuropathy. In evaluation for his chronic diarrhea, he underwent colonoscopy, and colonic biopsy showed amyloid deposits with congo red staining. Echocardiography showed a hypertrophic cardiomyopathy. Testing for multiple myeloma and light-chain amyloid was negative. Genetic testing demonstrated the V30M mutation in the TTR gene, confirming the diagnosis of familial amyloid polyneuropathy.
He was initiated on diflusinal for amyloid stabilization and then antisense oligonucleotide therapy for hereditary transthyretin amyloidosis with stabilization of his symptoms. He required treatment with gabapentin for pain, midodrine and pyridostigmine for orthostatic hypotension, and close cardiology management for his cardiomyopathy. He was counseled regarding risk to family members and offered the option for genetic testing for others in the family.
Amyloidosis generally refers to a group of diseases that share the common pathological feature of amyloid deposition on tissue pathology. Amyloid may be formed from a number of different proteins that assemble into a beta-sheet conformation causing the common pathological findings noted on tissue biopsy (45). The type of amyloidosis is categorized by associated disease or cause, including immunoglobulin light-chain amyloidosis, reactive systemic amyloidosis in chronic disease, wild type transthyretin (“senile”) amyloidosis (ATTR), and hereditary transthyretin amyloidosis (hATTR). Although this article focuses on hereditary amyloidosis and its neurologic manifestations, it should be noted that when patients present with systemic amyloidosis with neurologic involvement, it is often not known initially which subtype of amyloid is present, and evaluation requires workup with a multidisciplinary team of specialists.
Familial amyloidosis is most often caused by mutations in the TTR gene, encoding transthyretin protein, but other genetic mutations may also cause hereditary amyloidosis, including mutations in fibrinogen alpha-chain, lect2, apolipoproteinA1, lysozyme, and gelsolin. Transthyretin-associated familial amyloid polyneuropathy is the type most strongly associated with peripheral neuropathy, but neuropathy can occur in some of these other subtypes of hereditary amyloidosis. Mutations in the TTR gene result in expression of abnormal transthyretin protein that then forms the beta-sheet conformation of amyloid, depositing in tissues and causing multisystem manifestations of disease. The majority of transthyretin protein is produced in the liver, but other tissues also produce transthyretin protein, including choroid plexus and retinal pigment epithelium.
Familial amyloid polyneuropathy related to TTR mutations occurs at a frequency of less than 1:100,000 in Europe but with higher frequency in certain populations. The Val30Met mutation has a prevalence of 1:538 in Portugal (47). The Val122Ile mutation is carried by 3% to 4% of the African American population (29). Other mutations are seen at increased rates in other populations worldwide. Variable and incomplete penetrance of disease in mutation carriers additionally complicates assessing the prevalence of disease.
New genetic therapies targeting TTR gene expression can slow or prevent the progression of hereditary amyloid polyneuropathy in patients who have developed symptoms of disease. There are no current data to support treating asymptomatic TTR mutation carriers to prevent onset of disease. Increasingly, asymptomatic family members of patients affected by transthyretin-associated familial amyloid polyneuropathy are electing to have genetic testing. Presymptomatic carriers of TTR gene mutations must be followed closely for early clinical symptoms and signs of disease (37). Genetic counseling and preimplantation reproductive testing may be considered.
The differential diagnosis of hATTR polyneuropathy includes acquired causes of amyloidosis with peripheral neuropathy, most notably light-chain amyloidosis. A patient found to have amyloid deposits on pathology with peripheral neuropathy must undergo hematologic evaluation for plasma cell malignancy. Other conditions that may present similarly to hATTR polyneuropathy include other genetic or hereditary peripheral neuropathies or Charcot Marie Tooth disease (CMT); for this reason TTR gene testing is included in many commercially available genetic testing panels for hereditary neuropathy.
There are many more common causes of peripheral neuropathy that will present with similar clinical features as amyloidosis. Clinicians must consider diabetes, toxic exposures (including alcohol), immune-mediated causes, celiac disease, and vitamin toxicity and deficiency states when approaching a patient with progressive sensory or sensorimotor polyneuropathy.
hATTR polyneuropathy is commonly misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP), an immune mediate cause of progressive sensory loss and weakness (34; 24; 39). Clinicians should always consider this diagnosis amyloidosis in a patient being treated for chronic inflammatory demyelinating polyneuropathy without clinical response to immunotherapy.
Hereditary amyloid polyneuropathy, particularly in the early stages, may mimic other, more common causes of peripheral neuropathy and may not be considered a cause for neuropathy until there is more advanced multiorgan involvement or the finding of amyloid deposits is discovered on tissue biopsy.
When encountering a patient with “idiopathic” peripheral neuropathy with prominent autonomic neuropathy and hypertrophic cardiomyopathy, hATTR must be strongly considered. Testing for hereditary TTR amyloidosis should also be considered in any patient with peripheral neuropathy with prominent autonomic neuropathy, peripheral neuropathy with a family history of similar, or sensorimotor neuropathy that is more severe than typically seen in other “idiopathic” cases. Expert consensus recommendations to improve diagnosis of transthyretin amyloidosis with polyneuropathy suggest that the diagnosis be considered in any patient with neuropathy plus at least one “red flag” symptom suggestive of multisystem involvement. This would include any patient with an idiopathic progressive sensorimotor polyneuropathy together with a suggestive family history, bilateral carpal tunnel syndrome, autonomic dysfunction, gait change, unexplained weight loss, cardiac hypertrophy or heart rhythm disorder, vitreous opacities, or renal abnormalities (01). Some guidelines suggest that TTR gene testing may be indicated in any patient with an idiopathic peripheral neuropathy, even without red flag symptoms (06).
When encountering a patient in whom a diagnosis of hATTR polyneuropathy is considered, initial testing typically includes routine studies obtained in the general evaluation of peripheral neuropathy, including electrodiagnostic testing (nerve conduction studies and electromyography), in some cases skin biopsy for epidermal nerve fiber density, and lab testing for common reversible and treatable causes of neuropathy. When the clinical picture is suggestive of hATTR polyneuropathy, the next step is typically genetic testing to assess for mutations in the TTR gene.
In some cases of severe idiopathic polyneuropathy, nerve biopsy is obtained in an effort to find treatable causes of the disease, and pathology can demonstrate congo red staining of deposits leading to the amyloidosis diagnosis and, thus, suspicion for hereditary cause. Nerve biopsy for amyloid has been reported to have a sensitivity of 80% in patients with hATTR polyneuropathy (18; 03; 32).
Other tissues may also be biopsied in evaluating a patient with a systemic syndrome in whom there is a concern of amyloidosis, including but not limited to endomyocardium, bowel, kidney, fat pad (48; 10), or labial salivary gland (25). The finding of amyloid deposits then leads to evaluation to determine the type of amyloidosis--whether hereditary or acquired. Mass spectrometry can be performed on amyloid detected on tissue biopsy to determine the type, TTR, or light-chain amyloidosis and, thus, guide further testing and management (31).
Nuclear medicine imaging can also be used to identify cardiac transthyretin deposition. Bone-seeking radionucleotide tracers ⁹⁹m-technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (⁹⁹mTc-DPD) and ⁹⁹mTc-pyrophosphate (⁹⁹mTc-PYP) can be used when cardiac transthyretin amyloidosis (including hereditary and wild type transthyretin) is suspected and may be used by cardiologists or amyloid specialists when evaluating patients with a cardiomyopathy suspected to be related to amyloidosis (42; 28; 17). Additional cardiac testing in patients suspected or confirmed to have TTR amyloidosis include echocardiogram, 12-lead electrocardiogram, serum B-type natriuretic peptide (BNP), and in some cases, cardiac magnetic resonance imaging (MRI). Collaboration with cardiologists familiar with the management of amyloidosis is key to the interdisciplinary management of these patients.
Treatment of transthyretin-associated familial amyloid polyneuropathy includes amyloid-stabilizing medications that prevent misfolding and, thus, deposition of transthyretin protein in tissues, traditionally liver transplantation to reduce production of transthyretin protein, and now genetic therapies that reduce expression of the TTR gene.
There are now 2 approved gene-silencing treatments for patients with hATTR polyneuropathy: patisiran and inotersen. Patisiran is an RNA-interfering drug that targets the 3’ untranslated region of transthyretin mRNA in the liver and inhibits the synthesis of both mutant and wild-type transthyretin protein. The APOLLO study, published in 2018, was a phase 3 randomized placebo controlled trial in which intravenous patisiran or placebo was given every 3 weeks over 18 months. The patisiran treatment group had improved outcome when compared to placebo in a number of measurements of neuropathy severity and quality of life. Over half of the patients treated with patisiran in this trial had improvement in their neuropathy impairment score over the course of the study. The most common side effects were related to infusion reactions (02). Open label extension studies of the phase II and APOLLO trials of patisiran demonstrated continued improvement in neuropathy impairment scores with extended use. Exploratory analyses showed improved nerve fiber density and reduced amyloid burden in skin biopsies (20; 04).
Inotersen is an antisense oligonucleotide that targets the transthyretin RNA transcript, reducing production of transthyretin protein. The NEURO-TTR study, also published in 2018, was a phase 3 randomized placebo-controlled trial in which patients were treated with either inotersen or placebo subcutaneously 3 times in the first week followed by once weekly over 64 weeks. Results from this study showed that patients receiving inotersen when compared to placebo had better outcome in neuropathy severity scores and quality of life. Thirty-six percent of patients receiving inotersen had improvements in neuropathy impairment score over the course of the study. Glomerulonephritis and thrombocytopenia were noted as adverse events in the inotersen treatment group, and strict platelet and renal monitoring are now implemented in patients receiving this medication (11). An open label extension study of inotersen showed continued benefit in those continuing on the medication, and those patients who switched from placebo to inotersen had improvement in scores of neuropathy severity and quality of life (16).
Both inotersen and patisiran are now FDA-approved therapies for hATTR polyneuropathy in the United States. Selection of which RNA interfering therapy to prescribe for any given patient may be driven by accessibility of infusion facilities, medical comorbidity, and laboratory monitoring requirements.
New longer acting and less frequently administered subcutaneous formulations of antisense and interfering RNA therapies are currently in clinical trials. More information about these clinical trials can be accessed at the following sites clinicaltrials.gov/NCT03759379 and clinicaltrials.gov/NCT04136184.
Other TTR gene silencing therapies in development include those using a CRISPR-Cas9 system for gene editing. A 2021 study reported safety and pharmacodynamic effects of a single dose of CRISPR-Cas9 based gene editing therapy, with 87% reduction in TTR protein concentration at the highest tested dose (27). Longer-term follow up studies of safety and efficacy of this therapy are planned.
Prior to the approval of patisiran and inotersen, the primary treatment strategies for the management of hereditary TTR amyloidosis were amyloid stabilization and liver transplantation.
Transthyretin stabilizers are medications that aim to stabilize the transthyretin protein and prevent misfolding and tissue deposition. Tafamidis is a benzoxazole derivative lacking nonsteroidal antiinflammatory drug activity that binds to transthyretin and prevents the dissociation of tetramers into monomers, thus, stabilizing the protein and preventing transthyretin-amyloid deposition. A large double-blind, placebo-controlled, phase 3 trial of tafamidis in transthyretin amyloid cardiomyopathy (both hereditary and wild-type) showed reductions in mortality and cardiovascular hospitalization as well as reduced decline in functional capacity and quality of life (35). Tafamidis has been studied in hATTR polyneuropathy in a number of trials. In a phase II/III placebo-controlled study, a greater percentage of patients with hATTR polyneuropathy receiving tafamidis were responders when compared to placebo with regards to preventing worsening on neuropathy severity measures (22; 23). Another randomized study demonstrated delay in neuropathy progression in patients treated with tafamidis (49). Long-term safety and efficacy of tafamidis in TTR-FAP has also been reported (09; 21). Tafamidis has been available for a number of years in Europe and was recently approved by the Food and Drug Administration for use in the United States for the indication of TTR amyloid cardiomyopathy.
Diflunisal, a prostaglandin inhibitor, also has been demonstrated to be a transthyretin stabilizer. Studies have shown diflunisal to be effective and generally well tolerated in treating hATTR polyneuropathy (15; 44) but is not FDA approved for this indication. Other transthyretin stabilizers sometimes used in clinical practice include doxycycline and tauroursodeoxycholic acid (36).
It is not currently known whether the combination of an amyloid stabilizing medication together with a TTR suppressing therapy (patisiran or inotersen) is superior to use of the gene suppressing therapies alone.
As the majority of transthyretin protein is produced in the liver, liver transplantation has been used to reduced mutant transthyretin protein production in the treatment of hATTR polyneuropathy. Two large studies have demonstrated that patients treated with liver transplant had significantly improved survival compared to an untreated group (50; 51). Liver transplantation may also be combined with heart transplant in patients with severe cardiomyopathy associated with their amyloidosis (08; 50). A cohort study of patients who have received liver transplantation for familial transthyretin amyloidosis has been reported and used to create an online calculator to predict 5-year survival after transplant (07). There are obvious barriers to using liver transplantation on a large scale. With the development of genetic therapies, it will likely become a less utilized therapeutic intervention.
In addition to amyloid stabilization and reduction of transthyretin production through either RNA interference therapy or liver transplantation, patients with hATTR polyneuropathy require symptomatic management of peripheral neuropathy and autonomic dysfunction. Pain is common and can be treated with medications typically used for management of neuropathic pain, including gabapentin, pregabalin, duloxetine, tricyclic antidepressants, and others. For patients with significant weakness, ankle foot orthotics and other bracing measures can help with mobility. Assistive devices and physical therapy are critical for fall prevention.
Autonomic dysfunction in patients with amyloidosis can be challenging to manage, but a number of medications can be used to treat autonomic symptoms. Treatments for orthostatic hypotension include elimination of medications that reduce intravascular volume or lower blood pressure, liberal salt and fluid intake, use of compression stockings, and pharmacologic treatment. Medications that can be prescribed for orthostatic hypotension include midodrine, fludrocortisone, and droxidopa (40). Caution must be taken with these agents in patients with significant cardiomyopathy. Pyridostigmine can also be used to treat orthostatic hypotension and has less risk of causing supine hypertension. Treatment of urinary dysfunction can include pelvic floor exercises, duloxetine, intermittent catheterization, antimuscarinic agents, pyridostigmine, and botulinum injections (14). Treatment of gastrointestinal dysmotility due to amyloidosis can include dietary changes and nutritional supplementation, erythromycin, metoclopramide, and other promotility agents. For diarrhea related to amyloidosis, cholestyramine, loperamide, and octreotide can be used (38).
Patients with hereditary TTR amyloidosis have an increased risk for entrapment neuropathies, particularly carpal tunnel syndrome at the wrist. In some cases, referral for carpal tunnel release surgery is indicated to alleviate progressive sensory loss and weakness in the hands. Patients are also at increased risk for spinal stenosis. In cases of severe spinal stenosis, surgical management in collaboration with neurosurgery or orthopedic surgery may be necessary.
Multidisciplinary care is critical for the management of patients with hATTR polyneuropathy and has been recommended by a European consensus statement on the diagnosis and management of the disease (05). The physician team typically includes at least a neurologist, cardiologist, and ophthalmologist. In evaluation of patients with amyloidosis of uncertain cause, oncologists and nephrologists are often involved. Geneticists and genetic counselors are key to guiding testing in patients and asymptomatic family members (37). Many allied health providers are critical for multidisciplinary care, including physical and occupational therapists, nutritionists, social workers, and many others.
Other supportive measures are discussed in the article titled “Peripheral neuropathies: supportive measures and rehabilitation.”
As discussed above, treatment of hATTR polyneuropathy with TTR gene silencing therapies, patisiran and inotersen, results in slowed progression, and in some cases improvement in scores of neuropathy severity. Treatment earlier in the course of the neuropathy before severe axonal loss and weakness has developed results in better outcomes.
Rebecca E Traub MD
Dr. Traub of the University of North Carolina received research support from Alnylam Pharmaceuticals, Ionis Pharmaceuticals, Pharnext, and Argenx as principal investigator.See Profile
Louis H Weimer MD
Dr. Weimer of Columbia University has received consulting fees from Roche.See Profile
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