Journal of Neuromuscular Diseases - Volume 10, issue 3

Authors: van der Heul, A.M.B. | Nievelstein, R.A.J. | van Eijk, R.P.A. | Asselman, F. | Erasmus, C.E. | Cuppen, I. | Bittermann, A.J.N. | Gerrits, E. | van der Pol, W.L. | van den Engel-Hoek, L.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a hereditary motor neuron disorder, characterized by the degeneration of motor neurons and progressive muscle weakness. There is a large variability of disease severity, reflected by the classification of SMA types 1–4. Objective: The aim of this cross-sectional study was to determine the nature of swallowing problems and underlying mechanisms in patients with SMA types 2 and 3, and the relationship between swallowing and mastication problems. Methods: We enrolled patients (aged 13–67 years) with self-reported swallowing and/or mastication problems. We used a questionnaire, the functional oral intake scale, clinical tests …(dysphagia limit, and timed test swallowing, the test of mastication and swallowing solids), a videofluoroscopic swallowing study (VFSS), and muscle ultrasound of the bulbar muscles (i.e. digastric, geniohyoid and tongue muscles). Results: Non-ambulant patients (n  = 24) had a reduced dysphagia limit (median 13 ml (3–45), and a swallowing rate at the limit of normal (median 10 ml/sec (range 4–25 ml). VFSS revealed piecemeal deglutition and pharyngeal residue. We found pharyngo-oral regurgitation in fourteen patients (58%), i.e. they transported the residue from the hypopharynx back into the oral cavity and re-swallowed it. Six patients (25%) demonstrated impaired swallowing safety (i.e. penetration aspiration scale > 3). Muscle ultrasound revealed an abnormal muscle structure of the submental and tongue muscles. Ambulant patients (n  = 3), had a normal dysphagia limit and swallowing rate, but VFSS showed pharyngeal residue, and muscle ultrasound demonstrated an abnormal echogenicity of the tongue. Swallowing problems were associated with mastication problems (p  = 0.001). Show more

Keywords: Spinal muscular atrophy, SMN, Survival motor neuron gene, oral motor function, dysphagia, videofluoroscopy, muscle ultrasound

DOI: 10.3233/JND-221640

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 427-438, 2023

Authors: Clemens, Paula R. | Rao, Vamshi K. | Connolly, Anne M. | Harper, Amy D. | Mah, Jean K. | McDonald, Craig M. | Smith, Edward C. | Zaidman, Craig M. | Nakagawa, Tomoyuki | Hoffman, Eric P.

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and …safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping. Show more

Keywords: Duchenne muscular dystrophy, dystrophin, viltolarsen, exon skipping, clinical efficacy

DOI: 10.3233/JND-221656

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 439-447, 2023

Authors: Cheli, Marta | Brugnoni, Raffaella | Gibertini, Sara | Mantegazza, Renato | Maggi, Lorenzo

Article Type: Short Communication

Abstract: Congenital myasthenic syndromes (CMS) are rare diseases caused by mutation in genes coding for proteins involved in neuromuscular junction structure and function. DPAGT1 gene mutations are a rare cause of CMS whose clinical evolution and pathophysiological mechanisms have not been clarified completely. We present the case of two twins displaying an infancy-onset predominant limb-girdle phenotype and carrying a novel DPAGT1 mutation associated with unusual histological and clinical findings. CMS can mimic paediatric and adult limb-girdle phenotype, hence neurophysiology plays a fundamental role in the differential diagnosis.

Keywords: Congenital, myasthenia, DPAGT1, single-fiber EMG, salbutamol

DOI: 10.3233/JND-221675

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 449-458, 2023

Authors: Takahashi, Yoshiaki | Morimoto, Nobutoshi | Nada, Tomoaki | Morimoto, Mizuki | Eura, Nobuyuki | Minami, Narihiro | Nishino, Ichizo

Article Type: Case Report

Abstract: Immediately after the initial methionine codon, the PABPN1 gene encodes a stretch of 10 alanines, 1 glycine, and 2 alanines. Oculopharyngeal muscular dystrophy (OPMD) is caused by the expansion of the first 10 alanine stretches. The only exception is the missense mutation of glycine at the 12th residue into alanine, which elongates the stretch to 13 alanines by connecting the first and second stretch with the addition of one alanine in between, indicating that the expansion or elongation of the alanine stretch results in OPMD. We report a 77-year-old man with the novel missense mutation c.34G > T (p.Gly12Trp) in …PABPN1 gene whose clinicopathological findings were compatible with OPMD. He presented with slowly progressive bilateral ptosis, dysphagia, and symmetrical proximal dominant muscle weakness. Magnetic resonance imaging revealed selective fat replacement of the tongue, bilateral adductor magnus, and soleus muscles. Immunohistochemistry studies of the muscle biopsy sample revealed PABPN1-posibive aggregates in the myonuclei which have been reported to be specific to OPMD. This is the first OPMD case caused by neither the expansion nor the elongation of alanine stretch. The present case suggests that OPMD may be caused not only by triplet repeats but also by point mutations. Show more

Keywords: Oculopharyngeal muscular dystrophy, point mutation, PABPN1 protein, polyalanine, tryptophan

DOI: 10.3233/JND-221669

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 459-463, 2023

Authors: Summ, Oliver | Mathys, Christian | Grimm, Teresa | Groß, Martin

Article Type: Case Report

Abstract: Background: The occurrence of obstructive and central sleep apnea syndromes, ventilator pump failure and reduced hypercapnic ventilatory drive in myotonic dystrophy type 1 (DM1) is well established, and there are indications for an impairment of the hypoxic ventilator drive, too. Yet, it is still unknown, to which extent the respiratory rhythm is affected by DM1, thus if a central bradypnea, cluster breathing or ataxic (“Biot's”) breathing can occur. Additionally, the causes of the impairment of the central respiratory drive in DM1 are not known. Case Presentation: We present the case of a tracheotomized female patient with DM1 with …central bradypnea and ataxic breathing. A 57-year-old woman with DM1 was admitted to our Neurointensive Care Unit (NICU) due to refractory tracheobronchial retention of secretions resulting from aspiration of saliva. Due to a combination of chronic hypercapnic respiratory failure, severe central bradypnea with a minimal breathing frequency of 3 per minute and ataxic breathing a pressure-controlled home ventilation was initiated. Conclusions: In our patient central bradypnea and ataxic breathing possibly were respiratory sequale of DM1, that may have been caused by pontine white matter lesions affecting the pontine respiratory nuclei. From a clinical viewpoint, polygraphy is a suitable tool to objectify disorders of the respiratory rhythm in DM1 even in tracheotomized patients. Clinical studies combining respiratory diagnostics as polygraphy, transcutaneous capnometry and blood gas analysis with brain magnetic resonance imaging (MRI) are required to better understand disorders of respiratory regulation in DM1, and to identify their anatomical correlates. Show more

Keywords: Myotonic Dystrophy Type 1, breathing disorder, breathing regulation, clinical case report

DOI: 10.3233/JND-221652

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 465-471, 2023