INTRODUCTION
Spinal muscular atrophy (SMA) is a progressive motor neuron disease, and type 4 SMA is a subtype presenting in adulthood with a better prognosis in terms of motor function and ambulation.[1,2] Nephrotic syndrome is rarely reported in medical literature in association with SMA.[3] Here, we report a case of a middle-aged gentleman presenting with SMA and primary membranous nephropathy (PMN) and highlight the treatment dilemmas associated with the management of nephrotic syndrome in the background of significant muscle dysfunction.
CASE PRESENTATION
A 48-year-old gentleman presented with progressive weakness involving the left upper limb proximal muscles with difficulty in lifting objects above the shoulder. It gradually involved the right upper limb, followed by the lower limbs in a span of 3 months in July 2012. He was unable to squat and get up from the sitting position, and there was no sensory dysfunction, higher central nervous system function abnormality, or bladder involvement. On evaluation, he was found to have wasting of the shoulder and arm muscles [Figure 1a] with a decrease in power in the proximal muscles of the shoulder and thigh. Magnetic resonance imaging of the cervical spine was normal, and an electromyogram (EMG) was suggestive of a myogenic pattern with poor reinnervation. Nerve conduction studies (NCS) revealed a reduction in ‘M’ wave amplitude, suggestive of motor axonal loss of chronic nature with preserved sensory nerve action potentials. Muscle biopsy of the right deltoid [Figure 1b] and left biceps revealed groups of small rounded atrophic fibers admixed with hypertrophic fibers, Pan fascicular atrophy, and fatty infiltration suggestive of SMA. Due to logistic constraints, genetic analysis was not conducted, and he was managed conservatively with physiotherapy and muscle-strengthening exercises.
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Figure 1: (a) Wasting of upper limb proximal (black arrow) and trunk muscles (Magnification: 2174 × 11748 cm; 600 dpi) (b) Haemotoxylin and Eosin (H and E) stain of right deltoid muscle revealing groups of atrophic fibers admixed with hypertrophic fibers suggestive of spinal muscular atrophy (Magnification: 400×; 600 dpi) (c) Haematoxylin and Eosin (H and E) stain showing single glomerulus with thickened capillary loops suggestive of membranous nephropathy (Magnification: 400×; 600 dpi) (d) Immunofluorescence shows 2+ IgG staining along capillary walls of a single glomerulus (Magnification: 400×; 600 dpi) (e) Immunofluorescence shows 2+ PLA2R staining along capillary walls of the two glomeruli (Magnification: 400×; 600 dpi)
In August 2022, he presented with bilateral pedal edema of 3 months duration. He had normal renal function, and 24-h urine protein was 5460 mg/day. Secondary causes of adult-onset nephrotic syndrome were ruled out. Renal biopsy revealed 16 glomeruli with spike and pinhole lesions in the glomerular basement membrane with capillary wall thickening [Figure 1c] and coarse granular immunoglobulin G (IgG) [Figure 1d] and C3 positivity along the capillary wall along with phospholipase A2 receptor (PLA2R) positivity [Figure 1e]. Serum PLA2R antibody levels were 14.96 RU/ml, suggestive of PMN.
He was started on Telmisartan in maximum tolerated doses, and at 3 months, his PLA2R level decreased to 5.64 RU/ml with proteinuria of 3960 mg/day. In mid-January 2023, his proteinuria increased to 8200 mg/day, and he was given Injection Rituximab as per protocol. His CD 19 cell count was <3 cells/high power field indicative of adequate B cell suppression. His proteinuria worsened to 11.2 g/day in April 2023 despite maximum telmisartan dosage and suppressed CD19 cell count. The patient was not keen for a repeat renal biopsy, and tacrolimus or steroids could not be introduced initially because of the risks of muscle dysfunction associated with tacrolimus and steroids. He was planned for a mycophenolate mofetil-based regimen devoid of steroids for the treatment of PMN. However, as per the patient’s request, due to financial constraints, he was started on low-dose tacrolimus 3 mg/day with prednisolone 10 mg/day after explaining the risks of muscle dysfunction associated with the tacrolimus-based regimen. On follow-up after 3 months, his urine protein creatinine ratio decreased to 2.86, and whole blood tacrolimus trough levels were maintained at 5 ng/ml without any further deterioration of muscle strength.
DISCUSSION
Adult-onset type 4 SMA is a progressive motor neuron disorder characterized by symmetrical muscle weakness and atrophy with mean age of onset of around 30 years.[1] Type 4 SMA is characterized by better motor function, ambulation, and median survival compared to other subtypes.[1] Diagnosis of adult-onset SMA includes molecular genetic analysis of single motor neuron (SMN) gene, EMG, NCS, and rarely muscle biopsy.[2] The differentials of type 4 SMA include X-linked spinobulbar muscular atrophy and amyotrophic lateral sclerosis.[1] Management of SMA involves multidisciplinary care involving orthopedics, physical rehabilitation, nutrition, pulmonary, and palliative care.[2]
Membranous nephropathy has been associated with neurological disorders like myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.[3,4] This case report is unique since Adult-onset SMA with concurrent PLA2R membranous nephropathy is rarely reported in the medical literature. We postulate that SMA gene defects cause genotoxic stress-inducing alteration in kidney structures, gene, and protein expression,[5] thereby contributing to podocytopathy and nephrotic syndrome. The management challenge, in this case, involves a lack of treatment options in a failed Rituximab regimen because of the risk of tacrolimus and steroid-induced toxic myopathies.[6] Calcineurin is an important player in muscle hypertrophy and remodeling through upregulation of myogenin and downregulation of myostatin, and hence tacrolimus usage can be detrimental in patients of spinal muscular atrophy.[7] Corticosteroids activate the ubiquitin-proteasome and cathepsin pathway leading to proteolysis of myofibrillar proteins, thereby inflicting insult to already weakened muscles.[8] This case reflects a clinical conundrum with restricted treatment options like mycophenolate mofetil,[9] low-dose tacrolimus with steroids, and cyclophosphamide with low-dose steroids for inducing clinical resolution in PMN with adult-onset SMA. This case illustrates the utility of low-dose tacrolimus with minimal steroids as a viable treatment option for PMN in the background of muscle dysfunction.
Ethical approval
Informed written consent of the patient was taken before the manuscript submission as per the EQUATOR guidelines (CARE Checklist).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Erasmus Plus program of the European Union for support in setting up SinnoLab.
Conflicts of interest
There are no conflicts of interest.
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