To our knowledge, we describe the first comprehensive survey of complications among GNE myopathy patients. This survey will contribute to better manage GNE myopathy patients and help physicians provide early diagnosis and treatment.
Previous studies have reported thrombocytopenia in three Japanese GNE myopathy patients [6], two Chinese siblings with GNE myopathy [7], and a Caucasian woman with GNE myopathy [8], but no study had assessed its frequency in a larger cohort of GNE myopathy patients. In the present study, 4.1% (5/123) of participants had a diagnosis of ITP. However, given the lack of data on the frequency of ITP collected in the same manner for the general Japanese population, the risk is difficult to evaluate. Nonetheless, based on the reported frequency of ITP for the general Japanese population of 2.16/100,000/yr1)[9], about 0.2% of Japanese people are estimated to have ITP, suggesting that the frequency of ITP among GNE myopathy patients is much higher than that of the general Japanese population.
Pathogenic GNE variants lead to decreased enzymatic activities of UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) / N-acetylmannosamine kinase (ManNAc kinase), the rate-limiting enzyme of sialic acid biosynthesis encoded by the GNE gene [10]. UDP-GlcNAc 2-epimerase was reported to regulate cell surface sialylation in human hematopoietic cell lines and the function of specific cell surface adhesion molecules [11]. Moreover, a correlation between the shortening of mean platelet life span after removal of sialic acid and an increase in platelet-associated IgG has been reported [12]. These results suggest that pathogenic GNE variants may lead to cell surface hyposialylation and impair cell surface adhesion molecules in platelets, inducing antigens that bind to IgG on the platelet membrane, ultimately leading to thrombocytopenia. The high incidence of ITP observed in GNE myopathy patients in our survey suggests a potential relationship between pathogenic GNE variants and ITP, highlighting the importance of conducting routine blood tests in these patients. Further studies on this topic, such as a matched cohort study comparing GNE myopathy patients with the general population, are warranted.
The frequency of SAS in the general Japanese population is estimated to be about 3.3% in males and 0.5% in females [13]. In the present survey, 16.3% of males and 6.6% of females had a diagnosis of SAS. Although those who indicated having SAS in our survey might include those whose SAS had been cured, overall the results point to Japanese GNE myopathy patients having a higher frequency of SAS than the general Japanese population. SAS is reportedly associated with many muscle diseases, such as acid maltase deficiency [14, 15], Duchenne muscular dystrophy [16], myotonic dystrophy [17], oculopharyngeal muscular dystrophy [18], facioscapulohumeral muscular dystrophy [19], and inflammatory myopathy [20]. Specific features of neuromuscular diseases, such as pharyngeal weakness, macroglossia, bulbar manifestations, and low lung volume, might increase the susceptibility of patients to sleep-disordered breathing. To our knowledge, no study has reported on the association between SAS and GNE myopathy. The main risk factor for obstructive SAS is obesity and BMI [21]. Therefore, we compared BMI between participants with and without SAS, but found no significant difference between the two groups (data not shown). In addition, no correlation was observed between the frequency of SAS and %FVC, indicating that diaphragm weakness is unlikely to be a major cause of SAS among GNE myopathy patients. Muscle weakness of the upper airway muscles could contribute to SAS, however, they are not evaluated in majority of GNE myopathy patients. Upper airway muscle function had better be examined among GNE myopathy patients. Since SAS is considered to pose a greater risk for death than diabetes mellitus and stroke [22], screening for SAS in GNE myopathy patients will be important for early diagnosis and therapeutic intervention.
Frequencies of valvular heart disease, hypertrophic cardiomyopathy, and coronary artery disease in the general Japanese population have been reported to be 20%, 0.02%, and 0.8%, respectively [23–25]. Frequencies of valvular heart disease and coronary artery disease did not significantly differ between our study population and the general Japanese population. Hypertrophic cardiomyopathy was observed in 1.7% (2/125) of participants, although the number of the affected individuals are so small and difficult to glean useful comparison. Two GNE myopathy siblings with cardiomyopathy have been reported previously [26]. In contrast, disease-specific cardiac involvement was not observed in the present survey and the previous GNEM-DMP survey [2]. While it is possible some patients may not be regularly monitoring cardiac function, prospective data collection will be necessary to draw conclusions.
Frequencies of developmental disorders, psychiatric diseases, and problematic behaviors were not significantly higher in the present study population compared to the general Japanese population [5, 27–30], suggesting that GNE myopathy may not impact central nervous system development and may not be associated with psychiatric diseases. Interestingly, our previous Remudy-questionnaire survey conducted among Becker muscular dystrophy patients revealed that 7.2% and 12.0% of participants had developmental disorders and problematic behavior, respectively [31]. These frequencies are higher than that observed in our present study population. Psychiatric diseases observed among physically disabled patients tend to be lumped together, but it is important to be aware that the risk of developing a psychiatric disease differs by underlying disease.
This study has some limitations. First, the range of 95% CIs was wide and thus may have hindered the detection of significant differences due to the small sample size. Nonetheless, it is difficult to secure a large sample size with this very rare disease, and the present study represents one of the largest surveys of complications in GNE myopathy patients conducted to date. Second, self-reported data are not objective and it was difficult to obtain details of the disease for some of the questions as the patients did not remember the name of the disease. Third, there may have been selection bias, as those with severe phenotypes may have been more willing to participate in the national registry. Fourth, we did not adopt a matched case-control design, therefore, other factors such as age or frequency of medical examination might have affected the frequency. Notwithstanding these potential limitations, we believe that this first and largest survey of complications in GNE myopathy patients will raise awareness among physicians which could potentially lead to early diagnosis and early therapeutic invention.
In conclusion, GNE myopathy was found to be associated with ITP and SAS. For better management of GNE myopathy patients, physicians should be mindful of these complications and test for blood cell counts and sleep-disordered breathing in routine clinical assessments. A natural history study of a large GNE myopathy patient cohort, including an assessment of these complications, would be highly informative.