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Congenital myopathy with a novel SELN missense mutation and the challenge to differentiate it from congenital muscular dystrophy
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Case Reports / Journal of Clinical Neuroscience 62 (2019) 238–239
Congenital myopathy with a novel SELN missense mutation and the challenge to differentiate it from congenital muscular dystrophy Mohamed Kazamel ⇑, Margherita Milone Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
a r t i c l e
i n f o
Article history: Received 27 November 2018 Accepted 23 December 2018
Keywords: Multiminicore Respiratory insufficiency Rigid spine Scoliosis Selenoprotein SELN
a b s t r a c t Multiminicore disease is a myopathy that is pathologically characterized by the presence of multiple areas of small, short, and poorly delineated zones of sarcomeric disorganization lacking mitochondria (minicores) that can be observed in both type 1 and type 2 fibers. Most cases of multiminicore disease typically present with early-onset axial weakness, respiratory insufficiency, scoliosis, and rigid spine. There is no correlation between the frequency of minicores and clinical severity. Multiminicore disease is genetically heterogeneous and can result from recessive or dominant mutations. Genetic testing is needed to establish the precise diagnosis and provide overall prognosis. Here we report a 23-year-old woman with respiratory failure, distal joint hyper-laxity, scoliosis and rigid spine due to multiminicore disease caused by a novel compound heterozygous mutation in the selenoprotein N1-encoding gene (SELN). The preserved ambulation into adulthood and normal creatinine kinase (CK) favor the diagnosis of congenital myopathy over congenital muscular dystrophy (CMD). However, the nonspecific myopathic histopathological changes and extremely rare minicore-like structures can make it challenging to differentiate between SELN-myopathy and congenital muscular dystrophies, such as Ullrich or lamin A/C-CMD. Ó 2018 Elsevier Ltd. All rights reserved.
1. Introduction Multi-minicore disease (MmD) is a congenital myopathy that can present with four major clinical phenotypes: (1) Classical, characterized by early-onset axial weakness, respiratory insufficiency, scoliosis, and rigid spine (this phenotype accounts for >75% of cases); (2) Moderate, manifesting with pelvic-girdle, hand atrophy and joint hyper-laxity; (3) Ophthalmoplegic (otherwise similar to the classical form); and (4) Severe prenatal, with arthrogryposis [1]. MmD is pathologically homogeneous but genetically heterogeneous. It can be the result of recessively inherited mutations in a variety of genes, including selenon (SELN), ryanodine receptor 1 (RYR1), titin (TTN), multiple epidermal factor like domain 10 (MEGF10), and selenocysteine insertion sequencebinding protein 2 (SECISBP2) genes. SELN and RYR1 mutations cause approximatively 50% of MmD cases. Autosomal dominant mutations in the skeletal muscle a-actin (ACTA1), coiled-coil domain–containing protein 78 (CCDC78), and b heavy chain of cardiac myosin (MYH7) genes also cause MmD [2]. Multiple minicores can be observed in short-chain acyl-COA dehydrogenase deficiency and congenital myopathy caused by calcium channel (CACNA1S) mutations [3]. We describe a patient with a novel SELN mutation, occurring in compound heterozygosity with a known pathogenic variant, and nonspecific myopathic changes. We also highlight the clinical challenge in differentiating SELN-myopathy from some congenital muscular dystrophies (CMD), especially when the former lacks minicores as a dominant pathologic finding. 2. Case report A 23-year-old woman who was referred to the neuromuscular clinic for evaluation of myopathy of unknown type. She had been diagnosed with nemaline myopathy, although an earlier muscle biopsy was reportedly inconclusive. She was born at 29-weeks,
weighed 1 pound and 10 ounces and required mechanical ventilation for 3 months. Her motor development was delayed. She never gained good neck control and started ambulating at age 3. A year later, she developed scoliosis, which required two spine fusions and started experiencing frequent respiratory infections. She needed non-invasive ventilation and full-time mechanical ventilation for the last 9 years. She reported generalized axial and limb weakness but was still able to ambulate independently indoors. She denied visual symptoms and dysphagia. Her twin brother, a younger sister, and her parents were asymptomatic. There was no parental consanguinity. On general exam, she had elongated face, temporomandibular joint contracture limiting mouth opening, high-arched palate, diffuse muscle atrophy, mildly limited neck flexion, metacarpophalangeal and interphalangeal joints hyper-laxity, mild contractures at the knees and ankles, and severe scoliosis (Fig. 1A and B). Neurologic exam showed mild facial and tongue weaknesses, spared extraocular motility; severe weakness of neck flexors and extensors, mild-to-moderate proximal upper limb weakness, mild weakness of finger extensors, and lower limb weakness, which was moderate proximally and mild distally. Tendon reflexes were absent in the upper limbs and normal in the lower limbs. Her gait was waddling and compromised by the severe scoliosis and hyperlordosis. She had no cognitive or sensory abnormal findings. 2.1. Investigations Her CK value was normal. Electromyography showed evidence of a chronic diffuse myopathy with occasional fibrillation potentials. Repetitive nerve stimulation (2 Hz) and nerve conduction studies were normal. The histochemical findings of the biceps brachii are shown in Fig. 2. Minicores were not the main pathological finding. Muscle collagen VI and merosin immunoreactivities were similar to control muscle. ECG and echocardiogram were normal. 2.2. Genetic testing
⇑ Corresponding author at: Department of Neurology, University of Alabama at Birmingham, 1720 7th Ave S, SC271, Birmingham, AL 35294, USA. E-mail address: [email protected] (M. Kazamel).
Next generation sequencing of 20 genes causative of congenital myopathies showed two heterozygous variants in SELN: 1) A
Case Reports / Journal of Clinical Neuroscience 62 (2019) 238–239
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3. Discussion Our patient has a SELN-myopathy stemming from a novel missense variant in compound heterozygosity with a known pathogenic variant and nonspecific myopathological changes. Not all SELN-myopathies manifest with multiminicores. Two additional pathological phenotypes were indeed reported: congenital fiber type disproportion [4] and desmin-positive Mallory body-like inclusions [5]. Other congenital myopathies, such as RYR1, nebulin, tropomyosin-3 or ACTA1-myopathy can also manifest with rigid spine and respiratory failure, but specific structural abnormalities often help distinguishing these various myopathies [6] and targeting genetic testing. SELN-myopathy was initially described as a form of CMD with rigid spine and normal merosin expression. In contrast to merosin-CMD, SELN-myopathy patients often remain ambulant into adulthood and have almost normal CK levels [7], as observed in our patient. Other CMD, such as Ullrich-CMD and lamin A/C-CMD can mimic SELN-myopathy. These remain difficult to differentiate from SELN-myopathy, especially when the latter lacks classic minicores as the main pathological feature, like in our patient, and require genetic testing for diagnosis.
Fig. 1. Patient. (A) Photograph showing marked scoliosis, hyper-lordosis and a surgical incision from extensive spine surgeries. (B) Distal joint hyper-laxity, as suggested by patient’s ability to bring the thumb distal phalanx over the dorsum of the hand.
Conflicts of interest The authors report no conflict of interests. Dr. Kazamel has no relevant disclosure. Dr. Milone receives research support from a Mayo Clinic benefactor and an honorarium as associate editor of Neurology Genetics. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References
Fig. 2. Left biceps brachii muscle biopsy. (A) Hematoxylin and Eosin (H&E) section shows muscle fiber size variability and increased endomysial and perimysial fibrous connective tissue. (B) High power H&E section reveals increased number of internalized nuclei and fiber splitting (arrows). (C) In nicotinamide adenine dinucleotide-tetrazolium reductase and (D) cytochrome c oxidase-stained sections only extremely rare fibers showed small irregular attenuations of oxidative enzymes reactivity (arrows) reminiscent of minicores.
known mutation, c.713dupA; 2) A novel variant, c.1028 T > G, p. Met343Arg, affecting an evolutionary highly conserved amino acid and predicted to be deleterious by three in silico prediction programs. Parental targeted Sanger sequencing demonstrated that patient’s SELN variants are in trans. https://doi.org/10.1016/j.jocn.2018.12.024
[1] Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bonnemann C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Gen 2002;71:739–49. [2] Liewluck T, Milone M, Tian X, Engel AG, Staff NP, Wong LJ. Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel MEGF10 mutations. Muscle Nerve 2016;53:984–8. [3] Schartner V, Romero NB, Donkervoort S, Treves S, Munot P, Pierson TM, et al. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathol 2017;133:517–33. [4] Clarke NF, Kidson W, Quijano-Roy S, Estournet B, Ferreiro A, Guicheney P, et al. SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol 2006;59:546–52. [5] Ferreiro A, Ceuterick-de Groote C, Marks JJ, Goemans N, Schreiber G, Hanefeld F, et al. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 2004;55:676–86. [6] North KN, Wang CH, Clarke N, Jungbluth H, Vainzof M, Dowling JJ, et al. Approach to the diagnosis of congenital myopathies. Neuromuscul Dis 2014;24:97–116. [7] Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Quijano Roy S, Merlini L, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nature Gen 2001;29:17–8.
Case Reports / Journal of Clinical Neuroscience 62 (2019) 238–239
Congenital myopathy with a novel SELN missense mutation and the challenge to differentiate it from congenital muscular dystrophy Mohamed Kazamel ⇑, Margherita Milone Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
a r t i c l e
i n f o
Article history: Received 27 November 2018 Accepted 23 December 2018
Keywords: Multiminicore Respiratory insufficiency Rigid spine Scoliosis Selenoprotein SELN
a b s t r a c t Multiminicore disease is a myopathy that is pathologically characterized by the presence of multiple areas of small, short, and poorly delineated zones of sarcomeric disorganization lacking mitochondria (minicores) that can be observed in both type 1 and type 2 fibers. Most cases of multiminicore disease typically present with early-onset axial weakness, respiratory insufficiency, scoliosis, and rigid spine. There is no correlation between the frequency of minicores and clinical severity. Multiminicore disease is genetically heterogeneous and can result from recessive or dominant mutations. Genetic testing is needed to establish the precise diagnosis and provide overall prognosis. Here we report a 23-year-old woman with respiratory failure, distal joint hyper-laxity, scoliosis and rigid spine due to multiminicore disease caused by a novel compound heterozygous mutation in the selenoprotein N1-encoding gene (SELN). The preserved ambulation into adulthood and normal creatinine kinase (CK) favor the diagnosis of congenital myopathy over congenital muscular dystrophy (CMD). However, the nonspecific myopathic histopathological changes and extremely rare minicore-like structures can make it challenging to differentiate between SELN-myopathy and congenital muscular dystrophies, such as Ullrich or lamin A/C-CMD. Ó 2018 Elsevier Ltd. All rights reserved.
1. Introduction Multi-minicore disease (MmD) is a congenital myopathy that can present with four major clinical phenotypes: (1) Classical, characterized by early-onset axial weakness, respiratory insufficiency, scoliosis, and rigid spine (this phenotype accounts for >75% of cases); (2) Moderate, manifesting with pelvic-girdle, hand atrophy and joint hyper-laxity; (3) Ophthalmoplegic (otherwise similar to the classical form); and (4) Severe prenatal, with arthrogryposis [1]. MmD is pathologically homogeneous but genetically heterogeneous. It can be the result of recessively inherited mutations in a variety of genes, including selenon (SELN), ryanodine receptor 1 (RYR1), titin (TTN), multiple epidermal factor like domain 10 (MEGF10), and selenocysteine insertion sequencebinding protein 2 (SECISBP2) genes. SELN and RYR1 mutations cause approximatively 50% of MmD cases. Autosomal dominant mutations in the skeletal muscle a-actin (ACTA1), coiled-coil domain–containing protein 78 (CCDC78), and b heavy chain of cardiac myosin (MYH7) genes also cause MmD [2]. Multiple minicores can be observed in short-chain acyl-COA dehydrogenase deficiency and congenital myopathy caused by calcium channel (CACNA1S) mutations [3]. We describe a patient with a novel SELN mutation, occurring in compound heterozygosity with a known pathogenic variant, and nonspecific myopathic changes. We also highlight the clinical challenge in differentiating SELN-myopathy from some congenital muscular dystrophies (CMD), especially when the former lacks minicores as a dominant pathologic finding. 2. Case report A 23-year-old woman who was referred to the neuromuscular clinic for evaluation of myopathy of unknown type. She had been diagnosed with nemaline myopathy, although an earlier muscle biopsy was reportedly inconclusive. She was born at 29-weeks,
weighed 1 pound and 10 ounces and required mechanical ventilation for 3 months. Her motor development was delayed. She never gained good neck control and started ambulating at age 3. A year later, she developed scoliosis, which required two spine fusions and started experiencing frequent respiratory infections. She needed non-invasive ventilation and full-time mechanical ventilation for the last 9 years. She reported generalized axial and limb weakness but was still able to ambulate independently indoors. She denied visual symptoms and dysphagia. Her twin brother, a younger sister, and her parents were asymptomatic. There was no parental consanguinity. On general exam, she had elongated face, temporomandibular joint contracture limiting mouth opening, high-arched palate, diffuse muscle atrophy, mildly limited neck flexion, metacarpophalangeal and interphalangeal joints hyper-laxity, mild contractures at the knees and ankles, and severe scoliosis (Fig. 1A and B). Neurologic exam showed mild facial and tongue weaknesses, spared extraocular motility; severe weakness of neck flexors and extensors, mild-to-moderate proximal upper limb weakness, mild weakness of finger extensors, and lower limb weakness, which was moderate proximally and mild distally. Tendon reflexes were absent in the upper limbs and normal in the lower limbs. Her gait was waddling and compromised by the severe scoliosis and hyperlordosis. She had no cognitive or sensory abnormal findings. 2.1. Investigations Her CK value was normal. Electromyography showed evidence of a chronic diffuse myopathy with occasional fibrillation potentials. Repetitive nerve stimulation (2 Hz) and nerve conduction studies were normal. The histochemical findings of the biceps brachii are shown in Fig. 2. Minicores were not the main pathological finding. Muscle collagen VI and merosin immunoreactivities were similar to control muscle. ECG and echocardiogram were normal. 2.2. Genetic testing
⇑ Corresponding author at: Department of Neurology, University of Alabama at Birmingham, 1720 7th Ave S, SC271, Birmingham, AL 35294, USA. E-mail address: [email protected] (M. Kazamel).
Next generation sequencing of 20 genes causative of congenital myopathies showed two heterozygous variants in SELN: 1) A
Case Reports / Journal of Clinical Neuroscience 62 (2019) 238–239
239
3. Discussion Our patient has a SELN-myopathy stemming from a novel missense variant in compound heterozygosity with a known pathogenic variant and nonspecific myopathological changes. Not all SELN-myopathies manifest with multiminicores. Two additional pathological phenotypes were indeed reported: congenital fiber type disproportion [4] and desmin-positive Mallory body-like inclusions [5]. Other congenital myopathies, such as RYR1, nebulin, tropomyosin-3 or ACTA1-myopathy can also manifest with rigid spine and respiratory failure, but specific structural abnormalities often help distinguishing these various myopathies [6] and targeting genetic testing. SELN-myopathy was initially described as a form of CMD with rigid spine and normal merosin expression. In contrast to merosin-CMD, SELN-myopathy patients often remain ambulant into adulthood and have almost normal CK levels [7], as observed in our patient. Other CMD, such as Ullrich-CMD and lamin A/C-CMD can mimic SELN-myopathy. These remain difficult to differentiate from SELN-myopathy, especially when the latter lacks classic minicores as the main pathological feature, like in our patient, and require genetic testing for diagnosis.
Fig. 1. Patient. (A) Photograph showing marked scoliosis, hyper-lordosis and a surgical incision from extensive spine surgeries. (B) Distal joint hyper-laxity, as suggested by patient’s ability to bring the thumb distal phalanx over the dorsum of the hand.
Conflicts of interest The authors report no conflict of interests. Dr. Kazamel has no relevant disclosure. Dr. Milone receives research support from a Mayo Clinic benefactor and an honorarium as associate editor of Neurology Genetics. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References
Fig. 2. Left biceps brachii muscle biopsy. (A) Hematoxylin and Eosin (H&E) section shows muscle fiber size variability and increased endomysial and perimysial fibrous connective tissue. (B) High power H&E section reveals increased number of internalized nuclei and fiber splitting (arrows). (C) In nicotinamide adenine dinucleotide-tetrazolium reductase and (D) cytochrome c oxidase-stained sections only extremely rare fibers showed small irregular attenuations of oxidative enzymes reactivity (arrows) reminiscent of minicores.
known mutation, c.713dupA; 2) A novel variant, c.1028 T > G, p. Met343Arg, affecting an evolutionary highly conserved amino acid and predicted to be deleterious by three in silico prediction programs. Parental targeted Sanger sequencing demonstrated that patient’s SELN variants are in trans. https://doi.org/10.1016/j.jocn.2018.12.024
[1] Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bonnemann C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Gen 2002;71:739–49. [2] Liewluck T, Milone M, Tian X, Engel AG, Staff NP, Wong LJ. Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel MEGF10 mutations. Muscle Nerve 2016;53:984–8. [3] Schartner V, Romero NB, Donkervoort S, Treves S, Munot P, Pierson TM, et al. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathol 2017;133:517–33. [4] Clarke NF, Kidson W, Quijano-Roy S, Estournet B, Ferreiro A, Guicheney P, et al. SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol 2006;59:546–52. [5] Ferreiro A, Ceuterick-de Groote C, Marks JJ, Goemans N, Schreiber G, Hanefeld F, et al. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 2004;55:676–86. [6] North KN, Wang CH, Clarke N, Jungbluth H, Vainzof M, Dowling JJ, et al. Approach to the diagnosis of congenital myopathies. Neuromuscul Dis 2014;24:97–116. [7] Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Quijano Roy S, Merlini L, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nature Gen 2001;29:17–8.