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Severe adolescent-onset limb-girdle muscular dystrophy due to a novel homozygous nonsense BVES variant

2020; Elsevier BV; Volume: 420; Linguagem: Inglês

10.1016/j.jns.2020.117259

1878-5883

Grayson Beecher, Connie Tang, Teerin Liewluck,

Tissue Engineering and Regenerative Medicine

Autosomal recessive limb-girdle muscular dystrophy 25 (LGMDR25) is a recently defined adult-onset muscular dystrophy due to loss-of-function mutations in the blood vessel epicardial substance gene (BVES). It is clinically characterized by varying degrees of slowly progressive proximal lower limb weakness and cardiac conduction defects [[1]Schindler R.F. Scotton C. Zhang J. Passarelli C. Ortiz-Bonnin B. Simrick S. et al.POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.J. Clin. Invest. 2016; 126: 239-253Crossref PubMed Scopus (56) Google Scholar,[2]Brand T. The Popeye domain containing genes and their function as cAMP effector proteins in striated muscle.J Cardiovasc Dev Dis. 2018 Mar 13; 5: 18Crossref Scopus (13) Google Scholar]. BVES encodes Popeye domain–containing 1 (POPDC1), a transmembrane protein prominently expressed in the plasma membrane of skeletal and cardiac muscle, where it plays a role in skeletal muscle plasma membrane trafficking and cardiac pacemaking and cardiomyocyte survival after ischemia, respectively [[1]Schindler R.F. Scotton C. Zhang J. Passarelli C. Ortiz-Bonnin B. Simrick S. et al.POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.J. Clin. Invest. 2016; 126: 239-253Crossref PubMed Scopus (56) Google Scholar,[2]Brand T. The Popeye domain containing genes and their function as cAMP effector proteins in striated muscle.J Cardiovasc Dev Dis. 2018 Mar 13; 5: 18Crossref Scopus (13) Google Scholar]. POPDC1 binds cyclic 3′,5′-adenosine monophosphate (cAMP) and loss of popdc1 expression in zebrafish leads to development of atrioventricular (AV) block and abnormal skeletal muscle development [[1]Schindler R.F. Scotton C. Zhang J. Passarelli C. Ortiz-Bonnin B. Simrick S. et al.POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.J. Clin. Invest. 2016; 126: 239-253Crossref PubMed Scopus (56) Google Scholar]. POPDC1 is also expressed in caveolae and reduced numbers of caveolae have been reported in Popdc1 null mutant mice and an LGMDR25 patient [[3]Indrawati L.A. Iida A. Tanaka Y. Honma Y. Mizoguchi K. Yamaguchi T. Ikawa M. Hayashi S. Noguchi S. Nishino I. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.Neuromuscul. Disord. 2020 Aug; 30: 674-679https://doi.org/10.1016/j.nmd.2020.06.004Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. To date, only 9 LGMDR25 patients have been described (Table 1) [[1]Schindler R.F. Scotton C. Zhang J. Passarelli C. Ortiz-Bonnin B. Simrick S. et al.POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.J. Clin. Invest. 2016; 126: 239-253Crossref PubMed Scopus (56) Google Scholar,[3]Indrawati L.A. Iida A. Tanaka Y. Honma Y. Mizoguchi K. Yamaguchi T. Ikawa M. Hayashi S. Noguchi S. Nishino I. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.Neuromuscul. Disord. 2020 Aug; 30: 674-679https://doi.org/10.1016/j.nmd.2020.06.004Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,[4]De Ridder W. Nelson I. Asselbergh B. De Paepe B. Beuvin M. Yaou R.B. et al.Muscular dystrophy with arrhythmia caused by loss-of- function mutations in BVES.Neurol. Genet. 2019; 5: e321Crossref PubMed Scopus (16) Google Scholar]. Herein, we report a patient with adolescent-onset lower limb weakness due to a novel homozygous nonsense BVES variant. The current patient expands the clinical spectrum of LGMDR25.Table 1Characterization of reported LGMDR25 cases.Present caseIndrawati et al. (2020)De Ridder et al. (2019)Schindler et al. (2016)Patient 1Patient 1Patient 2Patient 1Patient 2Patient 3Patient 4Patient 1Patient 2Patient 3BVES variantc.427A>Tc.788C>Ac.788C>Ac.816 + 2 T>Cc.816 + 2 T>Cc.262C>Tc.1A>Gc.602C>Tc.602C>Tc.602C>TAge (y), sex38, M69, M45, M41, F37, M65, F44, M81, M25, M19, MRegion of originIndiaJapanJapanNorth AfricaNorth AfricaBelgiumBelgiumAlbaniaAlbaniaAlbaniaWeakness onset (y)164544NANA35NA40NANAOnset locationRight proximal LEProximal lower LELeft distal legNANAProximal LENAProximal LENANAPattern of weaknessPeriscapular, humeral, pectoral, proximal LELimb-girdle, periscapularDistal LENARight gastrocnemius⁎In association with right S1 radiculopathy.Limb-girdle, anterior tibial, periscapularNALimb-girdleNANAAsymmetrical muscle involvementYesYesYesNANAYesNANoNANAAssociated features [age (y) at onset]NAExercise-induced myalgia (7), lordosisSyncope (21)Exercise-induced myalgia (27)Palpitations, presyncope (19)NACalf myalgia (39)⁎⁎6 months after initiation of fibrate, with alleviation of myalgias with discontinuation.Recurrent syncope (59)Exertional syncope (17)Recurrent syncope (12)CK (IU/L)4054218–700014191300–36611074–550019183500–4000750–130012163182–7643ElectromyographyMyopathicNPMyopathicNormalMyopathicMyopathicMyopathicNPNPNPMuscle biopsyDystrophic, ring fibersAge 40: myopathicAge 67: dystrophic, with lobulated fibers, absent POPDC1 and reduced POPDC2 sarcolemmal expressionMyopathic, absent POPDC1 and reduced POPDC2 sarcolemmal expressionNPMyopathic, reduced POPDC1 and POPDC2 sarcolemmal expressionMyopathic, reduced POPDC1 and POPDC2 sarcolemmal expressionMyopathic, reduced POPDC1 and POPDC2 sarcolemmal expressionMyopathic, reduced POPDC1 and POPDC2 sarcolemmal expressionNPReduced POPDC1 and POPDC2 sarcolemmal expressionMuscle imaging - LEAtrophy: thighs, glutei, lateral gastrocnemius, soleusSpared: Right iliopsoas and rectus femoris, medial gastrocnemiusAtrophy: Posterior distal leg, adductor magnus, vasti, biceps femorisSpared: Rectus femoris, sartorius, gracilis, semimembranosus, semitendinosusAtrophy: Posterior distal leg, adductor magnus, biceps femorisSpared: Rectus femoris, sartorius, gracilis, semimembranosus, semitendinosusNormalAtrophy: Right gastrocnemius, soleus, biceps femoris⁎In association with right S1 radiculopathy.Atrophy: Posterior thigh, left vastus lateralisSpared: Distal legsNPNPNormalNormalCardiac findings1st degree AV block1st degree AV block, dilated cardiomyopathy1st degree AV block, LV hypokinesis1st degree AV block2nd degree AV block, iRBBB1st degree AV block1st degree AV block, nocturnal 2nd degree AV block2nd degree AV block2nd degree AV block2nd degree AV block, sinus bradycardiaAbbreviations: AV, atrioventricular; CK, creatine kinase; iRBBB, incomplete right bundle branch block; LE, lower extremity; LV, left ventricle; NA, not applicable; NP, not performed; POPDC1, Popeye domain–containing 1; POPDC2, Popeye domain–containing 2; y, years. In association with right S1 radiculopathy. 6 months after initiation of fibrate, with alleviation of myalgias with discontinuation. Open table in a new tab Abbreviations: AV, atrioventricular; CK, creatine kinase; iRBBB, incomplete right bundle branch block; LE, lower extremity; LV, left ventricle; NA, not applicable; NP, not performed; POPDC1, Popeye domain–containing 1; POPDC2, Popeye domain–containing 2; y, years. A 38-year-old male presented with slowly progressive asymmetrical limb weakness. Perinatal and developmental history was unremarkable. At age 16, he gradually developed right proximal lower limb weakness, with difficulty ascending stairs and performing squats. By age 25, he had left proximal lower limb and prominent right greater than left proximal upper limb weakness, with associated bilateral scapular winging. He began falling by age 35 but remained ambulatory without walking aids. He denied oculobulbar, respiratory or cardiac symptoms. He reported no myalgias or pigmenturia. His asymptomatic parents were born in different regions in India and were unrelated. There were no other affected family members. Neurological examination revealed bilateral scapular winging, pectoral atrophy with inverted axillary folds and atrophy of proximal limb muscles (Fig. 1A-D ). Cranial and neck weakness was absent. There was Medical Research Council (MRC) grade 1 strength of bilateral biceps, triceps, quadriceps and right hamstrings. MRC grade 2 strength was observed in bilateral pectoralis major, brachioradialis, hip adductors, and left hamstrings. Left iliopsoas and right gluteus medius and maximus were MRC grade 4-, while bilateral deltoids, infraspinatus, right iliopsoas and left gluteus medius and maximus were MRC grade 4. Distal upper and lower limb muscles were spared on isometric testing; however, he had mild difficulty walking on his heels and toes. Laboratory investigation revealed elevated creatine kinase (CK) at 4054 U/L (normal, < 308 U/L). Nerve conduction studies were normal, including repetitive nerve stimulation (2 Hz) of spinal accessory and ulnar nerves. Needle electromyography demonstrated short duration polyphasic motor unit potentials with rapid recruitment in proximal upper and lower limb muscles, with fibrillation potentials in few muscles. MRI of bilateral lower limbs identified diffuse fatty atrophy in the thigh, lateral gastrocnemius and soleus, with relative sparing of right greater than left iliopsoas, right rectus femoris, proximal left rectus femoris, and medial gastrocnemius (Fig. 1E-G). Right quadriceps muscle biopsy performed at age 27 at an outside institution (slides no longer available) reported marked variation in fiber size, fiber splitting, rare necrotic fibers, rare ring fibers and marked endomysial and perimysial fibrosis without inflammation. Pulmonary function testing was normal. Electrocardiogram and 24-h Holter monitoring demonstrated sinus bradycardia with 1st degree AV block. Echocardiogram was normal. Genetic evaluation for facioscapulohumeral muscular dystrophy (FSHD) types 1 and 2 was normal. Next generation sequencing of 77 myopathy-related genes (supplementary material) identified a novel homozygous c.427A>T (p.Arg143Ter) variant in exon 4 of BVES (NM_007073.4), a heterozygous c.2086G>A (p.Val696Met) variant in GNE, and a heterozygous c.72757C>T (p. Pro24253Ser) variant in TTN. The novel BVES variant is predicted to result in protein truncation or nonsense mediated mRNA decay and is absent in general population databases (dbSNP, ExAC Browser, gnomAD, and Exome Sequencing Project-Exome Variant Server). The identified GNE variant is a known pathogenic variant causing recessive distal myopathy when occurs in homozygous or compound heterozygous state and is identified in 1.3% of the South Asian population. The variant in TTN is considered of uncertain significance as it is identified in 0.003% of the South Asian population and in silico analysis suggests the amino acid change is unlikely to impact protein function. The present patient had early onset of asymmetrical proximal lower limb weakness which subsequently gave way to severe humeral-pectoral region weakness and bilateral scapular winging within the first decade of his disease course. Among 9 reported LGMDR25 patients, 4 had weakness with onset in their fourth to fifth decade, while 1 patient developed right gastrocnemius weakness in the third decade, attributed to S1 radiculopathy. Four had myalgia or syncope without weakness, 2 of whom were in their fifth decade. [[1]Schindler R.F. Scotton C. Zhang J. Passarelli C. Ortiz-Bonnin B. Simrick S. et al.POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.J. Clin. Invest. 2016; 126: 239-253Crossref PubMed Scopus (56) Google Scholar,[3]Indrawati L.A. Iida A. Tanaka Y. Honma Y. Mizoguchi K. Yamaguchi T. Ikawa M. Hayashi S. Noguchi S. Nishino I. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.Neuromuscul. Disord. 2020 Aug; 30: 674-679https://doi.org/10.1016/j.nmd.2020.06.004Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,[4]De Ridder W. Nelson I. Asselbergh B. De Paepe B. Beuvin M. Yaou R.B. et al.Muscular dystrophy with arrhythmia caused by loss-of- function mutations in BVES.Neurol. Genet. 2019; 5: e321Crossref PubMed Scopus (16) Google Scholar]. Distribution of weakness appears highly variable, however, the majority demonstrate proximal lower limb involvement and periscapular weakness was present in 3. Unilateral distal leg onset was uniquely described in one case [[3]Indrawati L.A. Iida A. Tanaka Y. Honma Y. Mizoguchi K. Yamaguchi T. Ikawa M. Hayashi S. Noguchi S. Nishino I. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.Neuromuscul. Disord. 2020 Aug; 30: 674-679https://doi.org/10.1016/j.nmd.2020.06.004Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Prominent humeral-pectoral weakness and inverted axillary folds in our patient, resembling facial-sparing FSHD [[5]Statland J.M. Tawil R. Facioscapulohumeral Muscular Dystrophy.Continuum (Minneap Minn). 2016 Dec; 22 (6, Muscle and Neuromuscular Junction Disorders): 1916-1931PubMed Google Scholar], has not been described. Asymmetry at onset or in distribution of involvement by imaging studies is common. Early involvement of posterior thigh muscles occurred in 3 reported patients. Anterior thigh muscles may be involved at a later stage of the disease [[3]Indrawati L.A. Iida A. Tanaka Y. Honma Y. Mizoguchi K. Yamaguchi T. Ikawa M. Hayashi S. Noguchi S. Nishino I. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.Neuromuscul. Disord. 2020 Aug; 30: 674-679https://doi.org/10.1016/j.nmd.2020.06.004Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. The severe fatty replacement of quadriceps in the current patient correlates with the severity and chronicity of weakness. Rectus femoris sparing has been reported in a couple patients [[3]Indrawati L.A. Iida A. Tanaka Y. Honma Y. Mizoguchi K. Yamaguchi T. Ikawa M. Hayashi S. Noguchi S. Nishino I. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.Neuromuscul. Disord. 2020 Aug; 30: 674-679https://doi.org/10.1016/j.nmd.2020.06.004Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Our patient shows that rectus femoris can be spared even at the advanced stage of LGMDR25. Myopathic biopsies were seen in 6 patients, including 2 without weakness, while reduced POPDC1/POPDC2 sarcolemmal expression was present in all 7 patients where performed, including in 1 without histopathologic features of myopathy, highlighting the potential utility of POPDC1/POPDC2 immunohistochemistry in suspected LGMD cases. In contrast to heterogeneity of skeletal muscle phenotypes is the striking commonality of AV block to all patients, either first or second degree, adding to the growing list of inherited bradyarrhythmias [[6]Rezazadeh S. Duff H.J. Genetic determinants of hereditary Bradyarrhythmias: a contemporary review of a diverse group of disorders.Can. J. Cardiol. 2017 Jun; 33: 758-767Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] and LGMDs associated with cardiac involvement [[7]Silvestri N.J. Ismail H. Zimetbaum P. Raynor E.M. Cardiac involvement in the muscular dystrophies.Muscle Nerve. 2018 May; 57: 707-715https://doi.org/10.1002/mus.26014Crossref PubMed Scopus (14) Google Scholar]. This highlights the importance of cardiac screening in patients with either genetically-identified LGMD subtypes known to be associated with cardiac involvement or genetically-uncharacterized LGMD [[8]Narayanaswami P. Weiss M. Selcen D. et al.Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine.Neurology. 2014; 83: 1453-1463Crossref PubMed Scopus (121) Google Scholar]. Hyperpolarization of cells in the AV node may underlie the pathomechanism by which AV block occurs [[1]Schindler R.F. Scotton C. Zhang J. Passarelli C. Ortiz-Bonnin B. Simrick S. et al.POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.J. Clin. Invest. 2016; 126: 239-253Crossref PubMed Scopus (56) Google Scholar]. In 2 of 4 BVES patients with AV block without weakness, electromyography was myopathic, suggesting this modality may have utility in detecting subclinical myopathy in patients with unexplained combined AV nodal block and persistently elevated CK. In summary, this case expands the highly variable skeletal myopathy phenotype in LGMDR25 with a relatively severe phenotype of scapular winging and prominent humeral-pectoral weakness, and the earliest age of onset of weakness described to date. Grayson Beecher: Dr. Beecher reports no disclosures. Connie Tang: Dr. Tang reports no disclosures. Teerin Liewluck: Dr. Liewluck reports no disclosures. None.