Genetic neuromuscular disease co-existing with another genetic or acquired neuromuscular disorder in the same individual, termed “double trouble,” is uncommon and often presents a diagnostic conundrum. Reference Granger, Beecher and Liewluck1 Thorough phenotyping across the neuromuscular clinical and laboratory evaluation is required in atypical neuromuscular disease presentations to ensure co-existing disorders are not overlooked.
Spinal-bulbar muscular atrophy (SBMA), or Kennedy disease, is an X-linked recessive, rare neuromuscular disorder caused by a CAG trinucleotide repeat expansion in the androgen receptor gene. Reference Leckie, Joel and Martens2–Reference Hashizume, Fischbeck, Pennuto, Fratta and Katsuno5 The prevalence of SBMA is estimated at 1–2 per 100,000, however, the true prevalence may be underestimated due to under-recognition and the founder effect that the condition exhibits. Reference Leckie, Joel and Martens2,Reference Hashizume, Fischbeck, Pennuto, Fratta and Katsuno5 SBMA primarily affects motor neurons, although co-existing sensory neuronopathy is well-recognized. Reference Hashizume, Fischbeck, Pennuto, Fratta and Katsuno5 Typical clinical manifestations include bulbar and proximal-predominant limb weakness, prominent perioral fasciculations, areflexia, sensory neuronopathy, creatine kinase (CK) elevation, and androgen insensitivity. Reference Leckie, Joel and Martens2–Reference Hashizume, Fischbeck, Pennuto, Fratta and Katsuno5
Immune-mediated necrotizing myopathy (IMNM) is an acquired inflammatory myopathy sub-categorized by the European Neuromuscular Centre based on the presence of autoantibodies targeting hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or signal recognition particle, or, if seronegative, occurs in the presence of typical myopathological features of muscle fiber necrosis and regeneration with minimal to no inflammatory infiltrate. Reference Allenbach, Benveniste, Stenzel and Boyer6,Reference Merlonghi, Antonini and Garibaldi7 IMNM accounts for approximately 35% of idiopathic inflammatory myopathies with an estimated global prevalence of 2.4–33.8 per 100,000. Reference Allenbach, Benveniste, Stenzel and Boyer6 The typical clinical presentation is subacute onset of progressive, proximal-predominant weakness with or without bulbar weakness, and significantly elevated CK. Reference Allenbach, Benveniste, Stenzel and Boyer6,Reference Merlonghi, Antonini and Garibaldi7
Herein, we report a patient presenting with two simultaneous neuromuscular diagnoses, anti-HMGCR IMNM superimposed on undiagnosed SBMA. We highlight the importance of careful characterization of clinical history and examination findings, consideration of local epidemiology relevant to Canadian neuromuscular practice, and correlation of clinical-electrophysiological findings with myopathological and genetic testing results for accurate diagnosis, with treatment implications.
A 72-year-old Indigenous Cree male with dyslipidemia on atorvastatin presented with 8 months of subacute onset, progressive, severe limb weakness, and oropharyngeal dysphagia. He had background history of years of slowly progressive proximal-predominant limb weakness, atrophy, fasciculations, and dysphagia for which he did not seek medical attention. There was no known familial neuromuscular disease.
Neurological examination demonstrated tongue atrophy and fasciculations, perioral fasciculations, bifacial weakness, and flaccid dysarthria. There was atrophy and fasciculations of deltoids and quadriceps, neck flexor weakness (Medical Research Council [MRC] grade 4/5), and proximal, symmetric upper and lower limb weakness (MRC grade 2/5). He had areflexia, flexor plantar responses, and length-dependent large and small fiber sensory loss.
CK was persistently elevated over the preceding 3 months, peaking at 2624 U/L (normal < 250 U/L). Nerve conduction studies demonstrated a length-dependent sensory axonal polyneuropathy. EMG was consistent with a chronic diffuse disorder of lower motor neurons, with a superimposed proximal and axial myopathy with fibrillation potentials and myotonic discharges (Table 1).
L = left; MUPs = motor unit potentials; PSW = positive sharp waves.
With the patient’s history of a chronic, progressive lower motor neuron syndrome with examination features suspicious for SBMA, and known high prevalence of SBMA in Indigenous Cree populations, Reference Leckie, Joel and Martens2 genetic testing was performed, revealing a pathogenic expansion of 40 CAG repeats in the androgen receptor gene, diagnostic of SBMA. The atypical subacute progression of severe weakness, with superimposed myopathic changes and myotonia on EMG, markedly elevated CK, and statin exposure, suggested comorbid anti-HMGCR IMNM. Muscle biopsy findings were consistent with IMNM (Fig. 1). Anti-HMGCR antibodies were positive (Mitogen Labs, Calgary; titer 108.4 CU, normal < 20 CU). CT chest, abdomen, and pelvis were negative for associated malignancy.
He underwent treatment for IMNM with methylprednisolone 1g IV daily for 5 days and intravenous immunoglobulin (IVIG) 2g/kg over 5 days, followed by maintenance IVIG 1g/kg monthly and prednisone 60 mg daily with a taper. CK normalized within 3 weeks. At 6-month follow-up, he was ambulating independently with residual mild weakness secondary to SBMA.
This patient, diagnosed concurrently with SBMA and anti-HMGCR IMNM, highlights important considerations when evaluating suspected neuromuscular double trouble.
First, consideration of local epidemiological factors and disease prevalence rates in specific patient populations can expedite appropriate genetic testing. This is relevant here, given the patient is of Cree First Nations ancestry, which is associated with highly increased prevalence of SBMA (14.7 per 100,000) due to a founder effect, Reference Leckie, Joel and Martens2 compared to the generally estimated prevalence of 1–2 per 100,000. Reference Chahin, Klein, Mandrekar and Sorenson3 The increased prevalence seen in Western Canadian Indigenous communities is likely still underestimated, however, owing to the relative preservation of functional independence in SBMA Reference Leckie, Joel and Martens2,Reference Chahin, Klein, Mandrekar and Sorenson3 and thus, patient under-recognition of symptoms, unless there is a concomitant, more severe disease process, as in this case. Additionally, longstanding social barriers to accessing the healthcare system within this population suggest that many patients may not have access to or present to specialty neuromuscular clinics. Reference Leckie, Joel and Martens2
Second, awareness of the natural history and expected progression of the underlying genetic neuromuscular disorder helps prevent premature diagnostic closure and here, facilitated recognition of a disease course atypical for SBMA. While bulbar and proximal-predominant weakness occurs in SBMA, Reference Leckie, Joel and Martens2–Reference Hashizume, Fischbeck, Pennuto, Fratta and Katsuno5 this is slowly progressive and patients often remain functionally independent for most activities of daily living. Reference Chahin, Klein, Mandrekar and Sorenson3 Therefore, the subacute, progressive, and severe weakness prompted evaluation for comorbid diagnoses including IMNM.
Identification of atypical laboratory and electrodiagnostic features for SBMA further assisted recognition of superimposed IMNM. The degree of CK elevation (peak 2624 U/L), while rarely observed in SBMA, was greater than the mean CK (939 ± 590 U/L) reported amongst patients with a mean disease duration of 8 years. Reference Chahin and Sorenson4 Decline in CK and improvement in strength after immunotherapy supported CK elevation being predominantly referable to IMNM than SBMA alone. EMG was key to identifying a myopathic process superimposed upon chronic neurogenic changes and reiterated the importance, in this clinical context, of recognizing associated myotonic discharges, which are validated as a diagnostic feature and biomarker of treatment response in IMNM. Reference Triplett, Shelly and Livne8
Lastly, the patient’s myopathological findings further supported dual pathology, owing to the presence of an active immune-mediated myopathy with sarcolemmal positivity of MHC-I and C5b-9 on both necrotic and non-necrotic fibers, consistent with IMNM, and denervation atrophy likely referable to SBMA.
Most importantly, identification of double trouble can positively impact patient outcomes. Anti-HMGCR IMNM is treatable with immunotherapy Reference Allenbach, Benveniste, Stenzel and Boyer6,Reference Merlonghi, Antonini and Garibaldi7 as demonstrated by our patient’s significant improvement, while no disease-modifying therapy exists for SBMA. Reference Leckie, Joel and Martens2–Reference Hashizume, Fischbeck, Pennuto, Fratta and Katsuno5
Acknowledgments
The authors would like to acknowledge and thank the patient and their family for their consent and participation in the creation of this case report.
Competing interests
None.
Statement of authorship
The author confirms contribution to the manuscript as follows: BMR contributed to preparation of the manuscript, creation of figures and tables, data analysis, and revisions. LS contributed to preparation of the manuscript and data collection and analysis with regard to pathological sections provided. WJ contributed to revisions of the manuscript. GB contributed to preparation of the manuscript, creation of figures and tables, data analysis, and revisions. All authors reviewed and approved the final manuscript.