Neuromuscular Amyloidosis

Amyloidosis is a rare group of disorders caused by misfolding and extracellular deposition of proteins as amyloid fibrils. These amyloid deposits are resistant to cleavage and clearance processes and lead to tissue damage and dysfunction. Symptoms depend on which organs have the amyloid deposits, with a wide variety of symptoms and heterogeneous presentations, making diagnosis often a challenge.¹ Immunoglobulin light chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are the most common systemic amyloidosis, and both are treatable.²

AL amyloidosis is a plasma cell disorder characterized by production of monoclonal light chain of kappa or lambda type that misfolds and deposits on any tissue other than the central nervous system. Although AL amyloidosis is rare, with an incidence of 12 cases per million people per year and a median age at onset at 64 to 76,^2,3 it is the most common cause of neuromuscular amyloidosis. Peripheral neuropathy occurs in 15% to 35% of people with AL amyloidosis, whereas myopathy is seen in only 1.5% of cases. Other organs, including the heart (75%), kidneys (57%), and gastrointestinal tract (17%) are affected.⁴

Transthyretin is a tetrameric transport protein that carries thyroxine and retinol and can become unstable, dissociate into monomers, misfold, and form amyloid deposits. ATTR amyloidosis can be hereditary (ATTRv) or acquired (ATTRwt). ATTRv is caused by more than 130 missense mutations in the TTR gene,² and is autosomal dominant with variable penetrance. ATTRv incidence varies globally, with an estimated incidence of 8.7 cases per million persons per year in Portugal⁵ and 0.3 cases per million persons per year in the US.² Phenotypes vary depending on the mutation and, although these were classically divided into neuropathic and cardiac types, the vast majority are mixed with either neuropathy or cardiomyopathy being more predominant.⁶ Val30Met (p.Val50Met) is the most common mutation worldwide and generally causes a polyneuropathy-predominant phenotype.⁷ The most common mutation in the US is Val122Ile (p. Val142Ile), which causes a cardiomyopathy-predominant phenotype (frequently pure cardiomyopathy), and is present in 3.5% of people who identify as Black in the US.⁸

ATTRwt amyloidosis is presumably caused by age-related instability of wild-type transthyretin. The clinical prevalence of ATTRwt amyloidosis is estimated at 155 to 191 cases per million persons per year.² Classically thought to cause only cardiomyopathy, ATTRwt is now known to also cause carpal tunnel syndrome (CTS), spinal stenosis, tendinopathies, and very rarely a myopathy.⁴

Other very rare systemic amyloidosis can affect the neuromuscular system, like gelsolin amyloidosis, β-2 microglobulin amyloidosis, and AA amyloidosis. Herein we provide an update on the diagnosis and management of amyloid neuropathy and myopathy.

Amyloid Neuropathy

Clinical Features

Amyloid neuropathy is a length-dependent polyneuropathy with a predilection for small myelinated and nonmyelinated sensory and autonomic fibers. Symptoms usually begin with neuropathic pain, numbness, and tingling in the feet and progress to decreased sensation and weakness in a length-dependent fashion.⁹ Unlike most peripheral neuropathies, amyloid neuropathy relentlessly progresses.¹⁰ Approximately 2 years after symptom onset, essentially all patients have weakness in the distal lower extremities on examination.⁴ Table 1 summarizes neurologic and systemic manifestations of amyloidosis.

Autonomic neuropathy is among the most debilitating aspects of these conditions, occurring in up to 75% of people with AL-amyloid peripheral neuropathy (AL-PN)^11,12 and 82% with ATTRv amyloid peripheral neuropathy (ATTRv-PN). Autonomic neuropathy symptoms depend on genotype and geographic location,⁷ with the most common symptoms being orthostatic hypotension (74%), gastrointestinal symptoms (eg, diarrhea, constipation, and early satiety; 72%), and erectile dysfunction (67% of men). Dry eyes and mouth also occur.¹¹

Amyloid neuropathy can also present with small and large sensory nerve fiber involvement (panmodality sensory loss) and mild or no autonomic symptoms, indistinguishable from common causes of distal symmetric polyneuropathy (eg, diabetes or idiopathic polyneuropathy). This presentation is more common with ATTRv-PN in those who have non-Val30Met (p.Val50Met) mutations or those who have late-onset (age >50) ATTRv-PN due to Val30Met (p.Val50Met) mutation.^9,13 Amyloid neuropathy can also present as polyradiculoneuropathy, multiple mononeuropathies, and focal neuropathies.⁴

Amyloid neuropathy is caused only by systemic amyloidosis; almost all with amyloid neuropathy has ATTRv or AL amyloidosis. Notably, no biopsy-proven ATTRwt polyneuropathy has been reported to date. Examinatin should include a thorough review of systems, asking about dyspnea on exertion, orthopnea, lower extremity edema, weight loss, easy bruising, jaw claudication, and foamy urine. Bilateral CTS occurs up to 21% of people with AL, 75% of those with ATTRv, and 48% of ATTRwt amyloidosis cases.⁴ CTS may precede the start of lower extremity neuropathic symptoms by several years.¹⁴ Progression or recurrence of CTS after release should also raise suspicion for amyloid neuropathy.

Neurophysiologic Features

In early stages of amyloid neuropathy, nerve conduction studies (NCS) and EMG can be normal, because only small sensory and autonomic nerve fibers may be affected. At this stage, only the quantitative sudomotor axon reflex test (QSART), electrochemical skin conductance (ESC), or quantitative sensory test (QST), might demonstrate small nerve fiber dysfunction. As neuropathy progresses, NCS/EMG shows decreased amplitude of sensory and then motor responses in the lower extremities with eventual reduced recruitment and increased duration of the motor unit potentials in distal muscles. Neurophysiologic findings follow a length-dependent pattern.¹⁵ Rarely, NCS shows demyelinating features that would fulfill the European Federation of Neurologic Societies/Peripheral Nerve Society (EFNS/PNS) criteria for chronic inflammatory demyelinating polyneuropathy (CIDP)(see Chronic Inflammatory Demyelinating Disorders in this issue).¹⁶ NCS/EMG is also helpful in diagnosing bilateral median neuropathies at the wrist (eg, CTS) and assessing disease progression.

Neurofilament Light Chain

Neurofilament light chain (NfL) is a major component of the neuronal cytoskeleton released in plasma and cerebrospinal fluid after axon damage. In AL-PN, serum NfL (sNfL) level is increased in both symptomatic and asymptomatic patients compared with healthy subjects and is higher in symptomatic vs asymptomatic polyneuropathy. In ATTRv-PN, sNfL levels are higher in people with symptoms compared with ATTRv carriers and noncarriers, and levels increase as neuropathy progresses.¹⁷ After treatment of ATTRv with patisiran, sNfL levels decreased, whereas after placebo sNfL levels increased, suggesting that a reduction in nerve damage correlates with levels of sNfL.¹⁸ sNfL might be useful in the diagnosis and management of amyloid neuropathy.

Histopathologic Features

Amyloidosis is a pathologic diagnosis proven by the presence of amyloid deposits in biopsied tissue (not necessarily nerve). Salivary gland, fat pad aspirate, and skin are considered minimally invasive sites for taking samples for biopsy. Sensitivity of tissue biopsy varies with the cause of systemic amyloidosis and organs affected (Table 2).

Nerve biopsy has high sensitivity but does not rule out amyloid neuropathy.¹⁹ The most common findings on nerve biopsy are axon degeneration affecting primarily small myelinated and unmyelinated fibers with amyloid deposits around endoneurial and epineurial blood vessels.⁴

Diagnosis

The progressive nature and autonomic dysfunction are 2 of the most important features of amyloid neuropathy (see Red Flag List). We recommend serum protein electrophoresis with immunofixation and plasma free light chain assay in every person presenting with polyneuropathy of unclear etiology.²⁰ It is also essential to order a basic peripheral neuropathy workup with complete blood chemistry (CBC), vitamin B₁₂ levels, serum A1c, thyroid stimulating hormone (TSH) and free thyroxine (T₄) tests, liver enzyme levels, and renal function tests.

If monoclonal gammopathy (MG) screening is positive, MG of uncertain significance (MGUS) or, less commonly, a malignant plasma cell disorder is likely. We refer these individuals to hematology. MGUS occurs in 3% of the population over age 50 and 5% of those over age 70,²¹ and is usually not associated with peripheral neuropathy. Importantly, when kappa/lambda light chain ratio is normal, AL amyloidosis is unlikely.² Notably, radionuclide bone scintigraphy with 99mTc-pyrophosphate (PYP) or 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) has very high sensitivity and specificity for ATTR cardiomyopathy in people with a negative MG screen. Individuals who have cardiac uptake on bone scintigraphy should undergo TTR gene sequencing.^2,4

In persons with features highly suggestive of amyloid neuropathy (ie, progressive polyneuropathy, autonomic dysfunction, hypertrophic cardiomyopathy, cardiac arrhythmia, proteinuria, concomitant myopathy, unexplained weight loss of >10 lbs, or family history of neuropathy), we recommend a minimally invasive tissue biopsy (eg, salivary gland biopsy, fat pad aspirate, or skin punch biopsy) with Congo red stain and TTR gene sequencing. Below we discuss 4 possible diagnostic scenarios using this approach (Figure).

MG Screen Positive and Tissue Biopsy Negative for Amyloid and TTR Sequencing Negative. We recommend referral to hematology to further evaluate for possible plasma cell disorder in anyone with a MG. If there are features highly suggestive of amyloid neuropathy, we recommend a sensory nerve biopsy with Congo red stain, usually of the sural nerve. If the nerve biopsy is positive, we recommend amyloid typing by mass spectrometry-based proteomics, which has a sensitivity over 90% and specificity of 100% for identifying the amyloid protein.⁴ If the nerve biopsy, bone marrow biopsy, and fat pad aspirate are all negative for amyloid, we discuss with hematology what other tissue biopsy we should pursue. Sometimes, we perform peripheral nerve MRI of the lumbosacral plexus and sciatic nerves, looking for a potential target for a proximal fascicular nerve biopsy.

MG Screen Positive With Tissue Biopsy Positive for Amyloid. In this scenario, we highly recommend amyloid typing. Although these findings are seen most often in AL amyloidosis, up to 50% of people with ATTR amyloidosis can have a MG,²² and amyloid typing may show another infrequent cause of amyloidosis (eg, gelsolin).

MG Screen Negative With Tissue Biopsy positive for Amyloid and TTR Sequencing Negative. Again, amyloid typing is crucial with an amyloid-positive biopsy. If the amyloid deposits cannot be typed because the test is unavailable or the deposits were scant, the patient should have genetic tests for rare hereditary causes of amyloid neuropathy (eg, gelsolin, β 2 microglobulin, and apolipoprotein A1).

MG Screen Negative With Tissue Biopsy Negative for Amyloid and TTR Sequencing Positive for Pathogenic Variant. This is not uncommon in clinical practice, and when the described phenotype of the pathogenic TTR variant fits the patient’s phenotype, we think this is sufficient to diagnose ATTRv-PN, stop the investigation, and initiate treatment. We still believe, however, that minimally invasive biopsy should be pursued in the initial investigation because of the variable penetrance of TTR mutations and the potentially severe adverse side effects of ATTRv disease-modifying therapy.

Amyloid Myopathy

Clinical Features

Systemic-amyloidosis–associated myopathy usually presents with proximal predominant symmetrical weakness. One-third of people with AL amyloid myopathy present with dysphagia, which can also be the first manifestation of the disease. Axial weakness and muscular pseudohypertrophy are rarely seen. Of extreme importance is that nearly two-thirds of people with systemic amyloidosis-associated myopathies have normal creatine phosphokinase (CPK) levels.⁴ Although people with amyloid myopathy ususally do not have neuropathic symptoms, polyneuropathy is encountered on exam or NCS/EMG in 40% of AL amyloid myopathies²³ and 90% of ATTR myopathies.²⁴

In isolated amyloid myopathy, interstitial amyloid deposits are found only in skeletal muscles. This is usually associated with defects in dysferlin (DYSF) or anoctamin-5 (ANO5) genes, which cause limb-girdle muscular dystrophy or a distal myopathy (Miyoshi phenotype). In a few persons, no genetic defect can be identified.²³

Neurophysiologic Features

In amyloid myopathy, needle EMG usually shows short-duration, low-amplitude motor unit action potentials (MUAPs) with rapid recruitment, without fibrillation potentials. Length-dependent polyneuropathy is frequently encountered.⁴

Histopathologic Features

Muscle biopsy usually shows rare necrotic and regenerating fibers, variation in fiber size, and interstitial amyloid deposition in intramuscular blood vessels or in the perimysium or endomysium, occasionally encasing muscle fibers. In approximately 80% of amyloid myopathies, denervation atrophy is observed, confirming the presence of associated amyloid neuropathy. The sensitivity of muscle biopsy for the diagnosis of amyloid myopathy is unknown. It is important to alert the muscle biopsy laboratory if amyloid myopathy is suspected to request Congo red staining, which is not routinely done in all labs, and also ensure that some specimen is saved for potential paraffin embedding because amyloid subtyping can only be performed in paraffin-embedded tissue.⁴ In isolated amyloid myopathy, necrotic and regenerating fibers are frequently observed, and amyloid typing identifies all typical proteins associated with amyloid deposits but can’t find the amyloid protein.²³

Diagnosis

We recommend MG screening and muscle biopsy in almost all cases of myopathy of unclear etiology. If MG screening is positive, we refer the patient to hematology. If the muscle biopsy demonstrates interstitial amyloid deposits, we perform amyloid typing. If amyloid typing fails to identify the amyloidogenic protein, or no other organ is affected, patients should undergo a next-generation sequencing panel for inherited myopathies that includes TTR, DYSF, and ANO5.

Disease-Modifying Therapy

AL Amyloidosis

The first step in treating AL amyloidosis is determining patient eligibility for autologous stem cell transplantation (ASCT). ASCT has achieved up to 91% survival over 4 years of follow-up—much higher than the 38% survival rate for chemotherapy alone. ASCT can also halt neuropathy progression whereas isolated chemotherapy does not. Unfortunately, only 20% to 25% of patients are considered eligible for ASCT. For those who are ineligible for ASCT, bortezomib-based chemotherapy should be initiated. There are several possible regimens with many different drugs that can be used (Table 3); treatment choice must be individualized considering specific characteristics of the individual, genetics, and stage of the disease.^2,3

Daratumumab, a novel monoclonal antibody against CD38, was recently approved for treatment of relapsed multiple myeloma as monotherapy or in combination with lenalidomide or bortezomib, and clearly shows activity in the treatment of patients with AL amyloidosis. Daratumumab is a promising novel therapy for AL amyloidosis,² and received accelerated approval as adjunctive therapy with bortezomib, cyclophosphamide, and dexamethasone for people newly diagnosed with AL amyloidosis. This approval may be contingent on confirmatory clinical trials of clinical benefit.

ATTRv Amyloidosis

Until recently, orthotopic liver transplantation was the only option for treating ATTRv, which is not a good option during later stages of life, malnourishment, advanced disease, or a nonVal30Met mutation. Orthotopic liver transplant carries high risk involved and posttransplant follow-up is very complex. Fortunately, pharmacologic options are available now, and liver transplant is rarely recommended (Table 3).²⁵

Tafamidis is a TTR stabilizer that binds to TTR selectively with high affinity to reduce dissociation and was the first drug approved (in Europe, South America, and Asia) to treat ATTRv polyneuropathy. Tafamidis slows but does not halt disease progression and is safe with no major side effects.^25,26 In the US, tafamidis is approved only for ATTRv cardiomyopathy. Diflunisal is a nonsteroidal anti-inflammatory medication repurposed for ATTRv-PN. Diflunisal also stabilizes TTR, reduces dissociation of TTR, and slows but does not halt disease progression. There is a concern about the long-term safety of diflunisal, especially in cardiac and renal function.²⁵

The small RNA inhibitor patisiran and the antisense oligonucleotide (ASO) inotersen are gene silencing drugs that suppress TTR protein synthesis. Patisiran and inotersen both dramatically decrease circulating TTR levels and can halt the progression of the neuropathy or even improve the clinical manifestations of ATTRv.^27,28 Patisiran is given intravenously every 3 weeks, and the most common side effects are peripheral edema and infusion-related reactions. Inotersen is given as a weekly subcutaneous injection and requires frequent monitoring of platelet and renal function because of the risk of severe thrombocytopenia and glomerulonephritis. Open-label extension studies have shown that both patisiran and inotersen are efficacious in the long term.^29,30TTR gene silencing therapy may be used in cases of disease progression after liver transplant.³¹

ATTRwt Amyloidosis

Although ATTRwt is the most prevalent subtype of amyloidosis, the only drug available for its treatment is tafamidis, which has been shown to improve survival and reduce hospitalizations in persons with ATTR cardiomyopathy.²⁶

Summary

Amyloidosis is a multisystem disorder in which prognosis relies mainly on early diagnosis and treatment. Amyloidosis must be actively considered in any person with a progressive neuropathy or myopathy of uncertain etiology. A thorough review of neurologic and nonneurologic systems and well characterization of the neuromuscular syndrome is fundamental. We recommend serum MG screening for all these patients, followed by a referral to hematology if results are positive. Neurologists should be aware that any neuropathy or myopathy associated with autonomic dysfunction, hypertrophic cardiomyopathy, cardiac arrhythmia, proteinuria, unexplained weight loss of more than 10 lbs, or family history of neuropathy is highly suggestive of amyloidosis. Promising biomarkers and novel drugs currently under investigation will potentially shorten the time to diagnosis and improve treatment efficacy in patients with neuromuscular amyloidosis.