Sporadic Late-Onset Nemaline Myopathy: Clinical Clues, Diagnostic Approach, and Treatment Considerations

Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired, adult-onset myopathy, characterized histopathologically by the presence of nemaline rods in muscle fibers and clinically by progressive proximal and axial muscle weakness.¹ Although its prevalence remains unknown, emerging data suggest that SLONM is likely underdiagnosed, particularly among adults with acquired myopathies.² SLONM is a potentially treatable cause of adult-onset myopathy, making early recognition clinically meaningful. In this article, we summarize the clinical features, diagnostic workup, and treatment landscape of SLONM, with an emphasis on practical considerations relevant to clinicians evaluating adults with progressive proximal or axial weakness.

SLONM Presentation and Features

SLONM typically presents between the fourth and sixth decades of life with a relatively equal sex distribution.¹ The pathogenesis is not completely understood, but there is accumulating evidence that immune-mediated processes play a key role, based on the frequent presence of inflammatory features on muscle biopsy and observed clinical responsiveness to immunomodulatory and plasma cell–directed therapies.^3-5

SLONM can be broadly classified into 2 subtypes: associated with monoclonal gammopathy or not associated with monoclonal gammopathy. SLONM associated with monoclonal gammopathy is the most common subtype, representing approximately half of all SLONM cases in published cohorts.^1,6,7 The monoclonal gammopathies most commonly associated with SLONM are immunoglobulin G (IgG) kappa and IgG lambda occurring in isolation without evidence of systemic plasma cell–related disease.⁸ Less commonly, SLONM has been associated with isolated light chain monoclonal gammopathy and rarely with multiple myeloma or amyloid light chain amyloidosis.^4,8 Among cases not associated with monoclonal gammopathies, human immunodeficiency virus (HIV) infection and autoimmune conditions are the most frequently described associations.³

Clinical Features

Although there is clinical heterogeneity, SLONM is classically characterized by progressive symmetric or asymmetric weakness, primarily affecting proximal and axial muscles, typically evolving subacutely over months.^1,3 Prominent axial involvement is a key clinical feature. Dropped head—present in ~38% of individuals at disease onset in the largest systematic review of SLONM to date—and camptocormia, when seen in the appropriate clinical context, should raise suspicion for SLONM.^1,5 Additional features may include distal weakness, facial weakness, dysphagia, and dysarthria.¹ Although SLONM most often presents as a subacute adult-onset myopathy, important exceptions exist, including HIV-associated cases, which tend to present at a younger age, as well as more slowly progressive forms, which may be misclassified as acquired or inherited myopathies, contributing to delayed diagnosis.^2,9

Respiratory involvement is common, occurring in ~50% of reported cases, typically showing a restrictive pattern on pulmonary function tests.⁵ In some cases, respiratory involvement may be disproportionate to limb weakness.¹ Neck pain and myalgias are frequently reported and may be prominent early symptoms.¹

More recent series have reported cardiac manifestations—most commonly cardiomyopathy or conduction abnormalities—in a subset of individuals with SLONM, occurring in ~21% of cases in a recent review.¹

Individuals with monoclonal gammopathy–associated SLONM tend to exhibit a more severe disease course, including earlier and more pronounced respiratory involvement, underscoring the importance of identifying an underlying plasma cell disorder.¹

Clinical pearls and diagnostic clues for SLONM are summarized in Table 1.

Differential Diagnosis

SLONM should be considered in adults presenting with subacute progressive proximal or axial weakness, particularly when accompanied by dropped head, camptocormia, dysphagia, or unexplained respiratory compromise. Several neuromuscular disorders have overlapping features and should be considered in the differential diagnosis.

Immune-mediated necrotizing myopathy can present similarly but is characterized by markedly elevated creatine kinase in contrast to SLONM and is frequently associated with anti-HMGCR or anti-SRP antibodies.¹⁰

Sporadic inclusion body myositis is another important mimic with a similar age at onset as SLONM, but it typically evolves slowly over years and involves distal as well as proximal muscles.¹¹

Myasthenia gravis can present with dysphagia and head drop but features fluctuating, fatigable weakness and abnormal neuromuscular junction test results, neither of which is seen in SLONM.¹²

Amyotrophic lateral sclerosis (ALS) may also present with bulbar symptoms and respiratory compromise, and rare phenotypes—including respiratory-onset ALS with early diaphragm weakness and axial variants presenting with stooped posture from paraspinal involvement—may share features with SLONM. However, upper motor neuron signs, fasciculations, and widespread denervation on EMG support ALS.¹³

Key distinguishing features of SLONM vs immune-mediated necrotizing myopathy, sporadic inclusion body myositis, myasthenia gravis, and ALS are summarized in Table 2.

Diagnosis and Workup

Muscle biopsy is required for definitive diagnosis of SLONM; electrodiagnostic studies, imaging, and laboratory testing play essential roles in supporting the diagnosis. Careful selection of an appropriate biopsy target is key and should be guided by the clinical pattern of weakness, EMG evidence of myopathy, and imaging abnormalities, when available.

SLONM is confirmed histopathologically by the presence of nemaline rods in muscle biopsies. Nemaline rods are rod-like inclusions found within the sarcoplasm of myofibers that stain red or blue on modified Gomori trichrome stain (Figure).¹⁴ They are derived from abnormal sarcomeric Z-band material.¹⁴ Nemaline rods are not specific to sporadic late-onset nemaline myopathy; they are also a defining feature of congenital nemaline myopathies. However, these entities differ in important clinical and pathologic respects. Congenital nemaline myopathies typically present in infancy or childhood and are genetically determined, whereas SLONM is an acquired disorder with adult onset.¹⁵ In addition, in contrast to congenital nemaline myopathies, nemaline rods tend to be present in a smaller proportion of muscle fibers and are generally smaller in SLONM.^3,16 Rod-containing fibers can also appear smaller and atrophic compared with adjacent non–rod-containing fibers in SLONM.³

Figure. Nemaline rods in sporadic late-onset nemaline myopathy. Modified Gomori trichrome–stained muscle biopsy at 40x magnification (A) and 60x magnification (B) demonstrates sarcoplasmic nemaline rods (asterisks), visible as dark, rod-shaped inclusions within muscle fibers (scale bar, 50 µm).
Reproduced from Lauletta A, Forcina F, Merlonghi G, et al. Sporadic late-onset nemaline myopathy (SLONM): data from a case series and literature review of 144 patients. Autoimmun Rev. 2026;25(2):103960¹ under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0).

Nemaline rod distribution in SLONM can be patchy and can vary by muscle; thus, multiple muscle biopsies may be required for definitive diagnosis.^1,5 Furthermore, routine Gomori trichrome staining may fail to identify nemaline rods.¹⁷ Immunohistochemical techniques can further aid biopsy assessment; in particular, staining for α-actinin has been proposed as a sensitive method for identifying nemaline rods in SLONM.^3,17 Nemaline rods can also be identified on electron microscopy.³

EMG of affected muscles typically shows a myopathic pattern with spontaneous activity, most commonly in the form of fibrillation potentials, although mixed myopathic and neurogenic features have been reported.^1,9,18 These findings are supportive but nonspecific, underscoring the importance of muscle biopsy. In the absence of an unrelated comorbid condition, nerve conduction studies are generally normal, and peripheral neuropathy is not a typical feature of SLONM.¹

Muscle MRI findings are not well-characterized in SLONM, but imaging may demonstrate selective muscle involvement and may be useful in guiding biopsy site selection.^6,9

Laboratory evaluation should include testing for the presence of a monoclonal gammopathy and for HIV, given the strong association of both with SLONM and the therapeutic implications of identifying these subtypes. Creatine kinase levels are usually normal or mildly elevated.¹

Once the diagnosis is established, baseline pulmonary function testing is essential to assess respiratory involvement and guide longitudinal monitoring.

Treatment

There is no universally accepted treatment strategy for SLONM. Available evidence is derived primarily from retrospective observational studies and case reports. Treatment decisions are guided by disease severity and the presence or absence of an associated monoclonal gammopathy.

In monoclonal gammopathy–associated SLONM, plasma cell–directed therapies—including chemotherapy and autologous stem cell transplantation—were historically emphasized based on early reports describing severe disease and poor outcomes in untreated individuals.⁸ More recent retrospective cohorts and case series suggest that intravenous immunoglobulin (IVIg) may lead to clinical improvement or stabilization in some individuals with monoclonal gammopathy–associated SLONM, and several authors have proposed IVIg as an initial therapeutic approach.^6,9 Contemporary data indicate that monoclonal gammopathy–associated SLONM is characterized by greater disease severity and worse outcomes compared with non–monoclonal gammopathy-associated disease.¹ The optimal selection and sequencing of IVIg and plasma cell–directed therapies remains uncertain.

In individuals without an associated monoclonal gammopathy, immunomodulatory therapies remain the cornerstone of treatment. IVIg has emerged as the most consistently effective option; corticosteroids and other immunosuppressive agents have demonstrated variable benefit.³

Conclusion

SLONM is a rare but increasingly recognized adult-onset acquired myopathy that is frequently underdiagnosed. The diagnosis should be considered in adults with acquired axial or proximal myopathy—particularly when accompanied by dropped head, camptocormia, respiratory involvement, or an associated monoclonal gammopathy. Diagnostic challenges arise from its heterogeneous clinical presentation and the patchy distribution of nemaline rods on muscle biopsy, which can lead to false-negative results. SLONM is a potentially treatable condition, particularly when recognized early and appropriately subtyped. Increased awareness, careful diagnostic evaluation, and individualized treatment strategies are essential for improving outcomes in this challenging disorder.