Abstract
Introduction/Aims
Nutritional management of adults with Duchenne muscular dystrophy (DMD) is an important clinical issue. However, it is not clear which dysphagia‐related factors should ...prompt introduction of alternative nutrition (AN). We aimed to determine which patients with DMD were introduced to AN.
Methods
This retrospective study included 56 patients with DMD (median age, 23.5 years). They were divided into patients able to continue oral feeding (OF) and those introduced to AN. Body weight, frequency of ventilator use, daily meals, history of steroid treatment, results of videofluoroscopic examination of swallowing (VF), and awareness of dysphagia were evaluated.
Results
Of 56 patients, 19 were in the AN group. After AN introduction, 93% of the patients continued oral intake. The proportion of patients who consumed chopped and liquid diets was higher, and body weight was lower, in the AN than in the OF group. There were no significant differences in age, upper limb function of feeding, frequency of ventilator use, or history of steroid therapy between the two groups. The frequencies of aspiration and residue in the pyriform sinus in VF were higher in the AN group than in the OF group. Decision‐tree analysis showed that food form and subjective difficulty swallowing solid foods were the most important factors affecting the decision‐making for AN.
Discussion
Patients with DMD who had difficulty eating solid foods were started on AN because they were unable to maintain their weight. These findings provide information for future longitudinal studies to assess the value of AN.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction
We previously identified UDP‐N‐acetylglucosamine 2‐epimerase (GNE) myopathy patients with sleep apnea and a past history of thrombocytopenia, but without disease‐specific cardiac ...involvement. This study aimed to clarify the occurrence, severity, and serial changes of these complications.
Methods
Thirty‐three genetically confirmed GNE myopathy patients who participated in a 5‐y longitudinal observational history study underwent platelet count and platelet‐associated immunoglobulin G (PA‐IgG) measurements, a sleep study, and electrocardiography (ECG), Holter ECG, and echocardiogram examinations.
Results
Among the 33 patients, three had low platelet counts and 17 out of 26 were PA‐IgG positive. No patient exhibited bleeding tendencies, and 3 out of 28 had low platelet counts. Muscle weakness was more pronounced, and summed MMT and grip power significantly lower, in PA‐IgG‐positive patients than in PA‐IgG‐negative patients. Of 19 patients, 7, 4, and 3 who underwent a sleep study had mild, moderate, and severe sleep apnea, respectively, and three started continuous positive airway pressure (CPAP). The respiratory disturbance index was not significantly correlated with physical evaluation items or forced vital capacity. All patients underwent ECG, 32 underwent cardiac ultrasound, and 25 underwent Holter ECG. No disease‐specific cardiac involvement was noted, no serial changes during the follow‐up period were observed for ECG and echocardiography, and none of the patients required therapy for cardiac abnormalities.
Discussion
PA‐IgG is a potential disease biomarker in GNE myopathy patients, although its significance needs to be clarified. While none of the patients in this study experienced cardiomyopathy or arrythmia due to myopathy, sleep apnea was identified as a frequent complication.
See editorial on pages 263–265 in this issue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims
Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease ...(NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy.
Methods
We analysed the frequency of p62‐positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC n = 2, OPDM_GIPC1 n = 6 and OPDM_LRP12 n = 3), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2).
Results
The p62‐postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy.
Conclusion
Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.
We investigated the presence of intranuclear inclusions in skin biopsies from patients with oculopharyngodistal myopathy (OPDM) and muscle diseases with similar pathology to evaluate if skin biopsy can provide similar diagnostic findings in OPDM. We found p62‐positive intranuclear inclusions in skin specimen from patients with OPDM with the CGG expansion in LRP12, GIPC1, NOTCH2NLC. Intranuclear inclusion in skin biopsy samples is not specific to neuronal intranuclear inclusion disease, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Lewy body‐related α‐synucleinopathy (Lewy pathology) has been reported in patients with myotonic dystrophy (DM) type 1 (DM1), but no detailed report has described the prevalence and extent of its ...occurrence. We studied consecutive full autopsy cases of DM1 at the National Center of Neurology and Psychiatry (NCNP) Brain Bank for intractable psychiatric and neurological disorders. Thirty‐two cases, genetically determined to be DM1 (59.0 ± 8.7 years), obtained from the NCNP Brain Bank, were compared with control cases obtained from the Brain Bank for Aging Research (BBAR) in Japan. The investigated anatomical sites followed the Dementia with Lewy Bodies Consensus Guideline, expanding to the peripheral autonomic nervous system, temporal pole, and occipital cortex, in addition to the olfactory epithelium and spinal cord. Of the 32 patients, 11 (34.4%) had Lewy pathology, with a significantly higher prevalence than that in the control cases from the BBAR (20.1%). Lewy pathology detected in DM1 was widespread, but no macroscopic depigmentation of the substantia nigra was observed in any DM1 case; this was commensurate with the microscopic paucity of Lewy pathology in the substantia nigra and amygdala. Lewy pathology in DM1 does not appear to follow either Braak's ascending paradigm or the olfactory–amygdala extension. Lewy neurites and dots in DM1 were very sparse in the cerebral cortex and distinct from those observed in BBAR control cases. This study was the first demonstration of unique Lewy pathology in DM1 and may contribute to the understanding of the protein propagation hypothesis of Lewy pathology.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
GNE myopathy is an autosomal recessive adult‐onset distal myopathy caused by biallelic variants in the GNE gene, which encodes a protein with two key enzymatic activities in the biosynthesis of ...sialic acid. In 1981, there was a report of a Japanese family in which muscle biopsies showed rimmed vacuoles in tibialis anterior with relative sparing of the quadriceps muscles. Twenty years later, the causative gene was identified to be GNE. Our group has constructed a mouse model that recapitulates the symptoms of GNE myopathy in patients and demonstrates the therapeutic effects of oral sialic acid supplementation on muscle phenotypes. The first clinical trial of N‐acetylneuraminic acid (NeuAc) was conducted in 2010 at Tohoku University, and several clinical trials are now underway at multiple sites. Patient registries have also been started, including the Japanese Registry of Muscular Dystrophy (Remudy, established in 2012) and the online international GNE Myopathy Disease Monitoring Program (launched in 2014). These registries have allowed collection of comprehensive patient data, including new clinical features suggesting that GNE myopathy is not only a disease of skeletal muscle. In this review, we summarize the history of research on GNE myopathy and discuss the mechanism of the disease and its more recently identified features.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Objective
Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for ...prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.
Methods
We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.
Results
The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline.
Interpretation
The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short‐term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967–978
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction/Aims
Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients, which can progress at different rates over time. Changing muscle strength due to disease progression ...or from an investigational product is associated with changing functional ability. The purpose of this study was to compare three methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time.
Methods
Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed‐frame system (Fixed) was used at a subset of seven sites. Screening and baseline visits were evaluated for reliability. Data over a 1‐year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups.
Results
HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P < .01). Strength summed scores were significantly correlated with functional scales (rho = 0.68‐0.92, P < .001). Individual muscle groups, however, showed high levels of variability between visits.
Discussion
Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction/Aims
There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively ...whether dysfunction in either system is part of the dysferlinopathy phenotype.
Methods
As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3‐y interval between tests, in 188 genetically confirmed patients aged 11–86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo).
Results
Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P‐wave abnormalities indicative of delayed trans‐atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.
Discussion
These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow‐up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK