Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

The clinical presentation of progressive weakness and atrophy of proximal upper or lower extremity and axial muscles, accompanied by dyspnea and/or dysphagia, represented the predominant clinical phenotype of SLONM. MGUS was a major feature, present in half of the patients, which was not only associated with more rapid disease progression, but also with a favorable response to treatment, especially with melphalan/auto-PBSCT.

Neck extensor weakness, sometimes resulting in dropped head, occurred in more than half of the SLONM patients during their disease course. In six cases, dropped head was an initial symptom; accompanied by limb weakness in four, by dysphagia in one patient, and as an isolated finding in another case. Respiratory affection resulting in dyspnea was present in four patients at disease onset. Interestingly, 3 of these 4 patients with dyspnea as a presenting symptom did not suffer symptoms from insufficient breathing prior to presentation. This lack of respiratory symptoms is considered to be due to the slowness of respiratory decline in SLONM.

Most patients presented with myopathic or mixed EMG patterns. However, one published case [30] and one of our patients (P 3) showed a neurogenic EMG pattern. Neurogenic EMG patterns can appear in severe chronic myopathies (in so-called ‘end-stage’ muscle) [36, 37]. This could explain at least one of the two cases with a neurogenic EMG [30], as this patient died as the result of her disease one year after presentation. In contrast, the other patient (P 3) did not present a particularly severe chronic myopathy. However, this patient suffered from chronic lower back pains radiating in the legs, which may explain the neurogenic changes on EMG in this patient. An additional peripheral neuropathy was excluded by nerve conduction studies in both patients.

In fact, SLONM should be considered in the differential diagnosis of sporadic inclusion body myositis (sIBM), idiopathic inflammatory myopathies (IIM) and amyotrophic lateral sclerosis (ALS). ALS, similar to SLONM, can present similarly with dropped head, bulbar weakness, dyspnea and fasciculations. There is even more overlap between IIM and SLONM; however, the former usually presents with high serum CK levels, while the latter shows only slight elevations. Inflammatory infiltrates are usually a prominent histopathological feature of IIM, but can also appear in SLONM. However, among the IIMs, polymyositis and sporadic inclusion body myositis (sIBM) are characterized by direct infiltration of muscle fibers by cytotoxic T-lymphocytes immunoreactive for CD8, which was absent in our SLONM cases. Perifascicular muscle fiber atrophy and loss of endomysial capillaries, typically found in dermatomyositis, were also absent in our cases. Sporadic inclusion body myositis may share many clinical similarities with SLONM, including age at onset in late adulthood, weakness of the proximal lower limbs and dysphagia. However, predominantly distal involvement is uncommon in SLONM, in contrast to sIBM. Histopathologically, both sIBM and SLONM present a myopathic pattern, but we could not identify any inclusion bodies (tubulofilamentous inclusions), and only rarely rimmed vacuoles in the SLONM cohort [38, 39]. Furthermore, in patients with sIBM, nemaline rods do not appear within muscle fibers.

Rarely, SLONM has been reported in combination with thyroid dysfunction. In our study, TSH has been increased in one and decreased in another patient. Since both hyper- and hypothyroidism, as such, may cause myopathy [40], a direct impact of the change in thyroid hormones on muscle might contribute to the disease.

Several clinical clues, including age at onset, distinguish SLONM from congenital nemaline myopathies. Mean age at onset in the SLONM cohort was 52 years, whereas patients with hereditary nemaline myopathy usually develop symptoms during infancy or early childhood. Furthermore, perinatal hypotonia, delayed motor milestones, scoliosis and a high-arched palate are features of congenital nemaline myopathies and were therefore exclusion criteria for our study. Histopathologically, fiber type 1 predominance, which is typically seen in the congenital forms, was not present in the SLONM cohort. Both congenital and late-onset nemaline myopathies are characterized by the presence of rods in the muscle fibers [1, 41]. Our genetic analysis did not disclose any mutations in genes known to cause congenital nemaline myopathy. We did not include the very recently reported myopalladin gene (MYPN) in our gene panel, which in case of mutations was shown to cause nemaline myopathy as well [42]. Thus, mutations in MYPN were not searched for in our SLONM cohort. Furthermore, we did not perform an analysis of copy number variations. In intranuclear rod myopathy, which is a congenital nemaline myopathy with more severe disease course, nemaline rods are frequently found inside myonuclei [43]. Until recently, the only known causative gene was ACTA1 [44]. However, very recently, mutations in the myopalladin gene (MYPN) were also found to cause intranuclear rods [44], in a relatively mild, childhood- to adult-onset nemaline myopathy with slowly progressive muscle weakness. The publication did not include any patients with SLONM that met our inclusion criteria, as three patients experienced first symptoms in their first decade and the fourth patient showed a positive family history for myopathy with consanguinity and neonatal muscular weakness. Interestingly, the muscle biopsy of two SLONM patients with MGUS and of two SLONM patients lacking immunoelectropheresis revealed intranuclear rods, whereas this feature was not seen in any of our SLONM patients without paraproteinemia. In all four cases with SLONM and intranuclear rods, nemaline bodies were also present in the sarcoplasm [4, 12, 21]. Genetic analysis of ACTA1 was not performed in any of the four cases. The clinical phenotype of patients with SLONM with intranuclear rods was not significantly different compared to other patients with SLONM. In SLONM, nemaline rods are the most striking feature, but other unspecific changes such as fiber atrophy, internalization of nuclei, myofibrillar disintegration were also frequent. Mitochondrial changes, including ragged-red fibers, COX-negative fibers and/or paracrystalline intramitochondrial inclusions detectable by EM, occurred frequently (64%). These findings might be considered unspecific and age-related in part; however, a more direct effect of Z-disc remodeling on skeletal muscle fiber mitochondria cannot be excluded.

HIV-associated nemaline myopathy showed the same constellation of features seen in SLONM, including proximal limb weakness, myopathic EMG and slightly elevated serum CK levels. However, HIV-NM appears to be more confined to certain muscle groups, since neither facial nor respiratory involvement has been reported to date. Apart from one patient with dysphagia, bulbar weakness has not been described either. Interestingly, the majority of patients (73%) showed clinical signs of myopathy before the HIV infection was detected. Therefore, it is important to screen (especially younger) patients with SLONM for HIV infection. Of note, one case has even been described with negative serology at presentation with HIV seropositivity developing only a year after myopathy onset [45]. Histopathologically, there were marginal differences: rods were smaller with <1 μm radius [15, 46] and they did not appear inside the nucleus in HIV-NM. Moreover, we observed significantly more frequent myonecrosis and inflammatory infiltrates in HIV-NM. The most compelling difference, however, is the good clinical response of treated HIV-NM cases to immunosuppressive therapy. Combined with muscle involvement during the early stage of HIV infection, this finding might suggest either a direct impact of the viral particles on the formation of rods or an immunological trigger, rather than a degenerative mechanism due to T-cell suppression/immunodeficiency. An HIV-caused genome disturbance has also been discussed as a basis for rod formation [46].

In SLONM with MGUS, not merely the aggregation of paraproteins but rather their effects on autogenous antigens, especially sarcomeric proteins, are thought to cause the formation of rods [47, 48]. In fact, one case of SLONM with MGUS was described with sarcolemmal deposits of the paraprotein [10], and another suggested immunoreactivity of the sarcolemma to IgG with the paraprotein light chain [11], lending support to this theory. However, a similar immunohistochemical pattern was reported in another publication of a patient without MGUS [28], suggesting a similar pathogenic pathway in SLONM without MGUS. SLONM patients with accompanying autoimmune diseases such as systemic lupus erythematosus (SLE) [49] or Sjögren’s syndrome [50] often improved during immunosuppressive medication, whereas the majority of SLONM cases showed a disappointing response rate. This observation might hint at a different nonimmunogenic cause. Another hypothesis suggested that rod formation is part of a regenerative process without the traditional features of muscle repair [29]; however, our findings fail to support this assertion. The chronology of the appearance of rods in relation to disease course varied: Nine cases did not show any rods at symptom onset on light microscopy, but only in a subsequent biopsy (P 4) [8, 25, 26, 29, 49, 51‐53]. Six cases revealed rods only after severe clinical deterioration (P4) [8, 25, 29, 51, 52]. Interestingly, this clinical correlation has also been observed the other way around: clinical improvement after auto-PBSCT was accompanied by the disappearance of rods [54, 55] as well as paraprotein reduction in SLONM patients with MGUS [56]. Therefore, multiple biopsies during the disease course may be necessary to confirm the diagnosis of SLONM.

Overall, the pathomechanisms of SLONM remain unsolved.