Alternative titles; symbols
SNOMEDCT: 240063002; ORPHA: 324604, 598, 84132, 97244; DO: 0110633;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11 | Congenital myopathy 3 with rigid spine | 602771 | Autosomal recessive | 3 | SELENON | 606210 |
A number sign (#) is used with this entry because of evidence that congenital myopathy-3 with rigid spine (CMYP3) is caused by homozygous or compound heterozygous mutation in the SEPN1 gene (SELENON; 606210) on chromosome 1p36.
Congenital myopathy-3 with rigid spine (CMYP3) is an autosomal recessive disorder of the skeletal muscle characterized by hypotonia and proximal muscle weakness apparent from birth or early childhood. Affected individuals show delayed motor development and develop progressive severe and deforming scoliosis ('rigid spine') in the first or second decades. Respiratory involvement due to diaphragmatic weakness is common, and most patients require ventilatory support due to nocturnal hypoventilation; recurrent respiratory infections are also observed. Additional features may include facial muscle weakness, amyotrophy, joint contractures, distal hyperlaxity, pulmonary hypertension with secondary cardiac dysfunction, and insulin resistance in those with a low BMI. The muscle weakness is not progressive, and most patients remain ambulatory. Skeletal muscle biopsy typically shows multiminicores, although there are often other abnormal nonspecific myopathic findings. This phenotype has been referred to as 'rigid spine syndrome' (Scoto et al., 2011; Fan et al., 2022; Varone et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Dubowitz (1973) reported a 17-year-old boy, born of unrelated parents, with a congenital myopathy characterized by proximal muscle weakness affecting the lower and upper limbs and progressive scoliosis. He walked at 14 months with a waddling gait, had frequent falls, and was never able to run or jump. From an early age he had difficulty moving his neck and back, and he developed an inability to extend the elbows. On examination, there was limitation in flexion of the whole dorsolumbar and cervical spine, owing to contracture of the spinal extensors and leading to loss of movement of the spine and the thoracic cage. He had generalized muscle atrophy, muscle weakness of the shoulder abductors, and inability to extend the elbows; otherwise the muscle weakness was nonprogressive. Creatine kinase was elevated and muscle biopsy showed a myopathic pattern with variation in fiber size. Dubowitz (1973) coined the term 'rigid spine syndrome,' noting the severity of the scoliosis and skeletal deformity, which can lead to respiratory failure.
Goebel et al. (1980) described 5 cases of congenital myopathy in a genetic isolate (the Eichsfeld) in the northeastern region of the Federal Republic of Germany. Four of the children were related by remote family links and 2 children were sibs, consistent with autosomal recessive inheritance. All came from a Roman Catholic enclave in a Protestant area. The patients, who ranged from 2 to 10 years, showed neuromuscular signs and symptoms from birth or early infancy. They had proximal muscle weakness with progressive muscle atrophy and decreased or absent tendon reflexes. Several had recurrent respiratory infections. Three developed scoliosis during school age. Three patients developed right ventricular hypertrophy after the age of 9 years, 2 of whom died of heart failure at the age of 11 years; however, the authors stated that primary cardiomyopathy was unlikely and suggested that the primary cause was pulmonary hypertension. Skeletal muscle biopsy showed a myopathic fiber diameter spectrum, mild endomysial fibrosis, and type I fiber predominance. Langenbeck (1986) proposed that the disorder be called the 'Eichsfeld' type of congenital muscular dystrophy and suggested that a patient described by McKusick (1972) had the same disorder; that patient died at the age of 20 years of cardiorespiratory failure. Fidzianska et al. (1983) found Mallory body-like inclusions in muscle fibers of 3 of the genetically-linked Eichsfeld patients. The inclusions were composed of granular material and 2 types of filaments that were stained with anti-desmin antibodies (Langenbeck, 1991). In 4 affected patients from the original German family with CMYP3 diagnosed as 'Mallory-body myopathy' (Goebel et al., 1980), Ferreiro et al. (2004) identified a homozygous 92-bp deletion in the SEPN1 gene (606210.0009).
The family reported by Patel et al. (1983) had a congenital myopathy with clinical features consistent with rigid spine syndrome. Two native American children, born of consanguineous parents, had delayed walking, muscle weakness of the face, neck, proximal limbs, and respiratory muscles, scoliosis, and 'cytoplasmic bodies' on skeletal muscle biopsy. Electron microscopy showed dense central zones surrounded by a lighter halo and outer shell. Streaming of the Z line was observed. One of the sibs died at age 14 years of respiratory arrest.
Topaloglu et al. (1994) described a brother and sister, aged 20 and 19 years, respectively, with a 10-year history of spinal rigidity and scoliosis. Muscle biopsies were consistent with nemaline myopathy. The parents were first cousins, suggesting autosomal recessive inheritance.
Fidzianska et al. (1995) reported 5 children from 3 families with a congenital myopathy. Clinical characteristics included neonatal hypotonia, axial and proximal muscle weakness, and scoliosis with a limitation in flexion of the neck. Most children died of respiratory insufficiency before adulthood. Muscle biopsies were consistent in showing hyaline plaques that were rich in desmin, alpha-beta crystallin, ubiquitin, and dystrophin, with absence of oxidative and ATPase enzymatic activity. Ultrastructurally, 12-nm helical filaments and amorphous material were present. Other patients with a similar disorder were reported (Goebel and Fardeau, 2002).
Moghadaszadeh et al. (1998) reported a large consanguineous Moroccan family (family 1809) in which 3 sibs, aged 4-15 years, had CMYP3. Two additional patients, a 7-year-old girl, born of consanguineous Turkish parents (family T2), and a 13-year-old boy, born of consanguineous Iranian parents (family E1), with a similar disorder were also reported. Clinical features of all children included onset in infancy, motor delay, diffuse muscle weakness, spinal rigidity, and reduced respiratory vital capacity. Three patients had dystrophic changes on muscle biopsy, and 2 patients developed scoliosis.
Flanigan et al. (2000) described 4 sibs (3 boys and 1 girl) of northern European-American heritage, the offspring of a nonconsanguineous marriage, who had hypotonia and prominent neck weakness in infancy, early spinal rigidity, and early scoliosis. After initial improvement, muscle strength stabilized or slowly declined, and skeletal deformities and respiratory insufficiency supervened. Muscle biopsy in an affected child at 9 months of age demonstrated minimal, nonspecific myopathic changes, leading to a diagnosis of 'minimal change myopathy.' Muscle biopsy in his sib, at 14 years of age, revealed chronic and severe myopathic (dystrophic) changes, with normal staining for laminin-2 and for proteins of the dystrophin-glycoprotein complex.
Ferreiro et al. (2000) identified 38 cases of minimulticore myopathy in 29 families, with 17 families represented by sporadic cases. The inheritance pattern was autosomal recessive. Thirty of these patients shared the classic phenotype, characterized by early onset, delayed motor development, generalized muscle weakness and amyotrophy, and severe scoliosis with restrictive respiratory involvement. Muscle biopsies showed type 1 fiber predominance and hypertrophy, centrally located nuclei, multiple minicores in both type 1 and type 2 fibers, and sarcomere disorganization. The multiple small focal lesions had reduced or absent oxidative activity and lack of mitochondria. There was no clear correlation between the intensity of morphologic abnormalities and clinical severity.
Jungbluth et al. (2000) reported the clinical and pathologic findings of 19 cases with congenital myopathy and classic minicore lesions on skeletal muscle biopsy. About half of patients developed scoliosis after age 10 years and had decreased functional vital capacity with nocturnal hypoventilation, sometimes associated with cardiac right ventricular impairment. Inheritance was consistent with autosomal recessive.
On the basis of clinical and morphologic data, Ferreiro et al. (2002) suspected a relationship between classic multiminicore disease and rigid spine syndrome due to mutations in the SEPN1 gene. The most striking findings in the patients with SEPN1 mutations were early and severe respiratory failure and scoliosis. Reevaluation of muscle biopsies from 3 patients diagnosed with rigid spine syndrome with mutations in the SEPN1 gene revealed typical minicore lesions in 2 of them and dystrophic changes in the third. Ferreiro et al. (2002) noted discrepancies in biopsy findings between rigid spine syndrome, which occasionally has been reported to have dystrophic features (characteristic of a muscular dystrophy) and multiminicore disease (MmD), which typically does not have dystrophic features and contains minicore lesions (characteristic of a myopathy). However, due to the homogeneous clinical features of the 2 disorders and the finding of SEPN1 mutations in both diseases, Ferreiro et al. (2002) concluded that RSMD and the most severe form of classic multiminicore disease are the same entity.
Venance et al. (2005) reported a patient with rigid spine syndrome who presented at age 26 years with cor pulmonale characterized by rapidly progressive respiratory and right heart failure with cough, orthopnea, and daytime sleepiness. He was cyanotic with bibasilar crackles, hepatomegaly, pitting edema, severe nocturnal hypoventilation, and prolonged apneic episodes. Other milder features included restricted neck flexion, thoracolumbar scoliosis, and mild truncal and proximal limb weakness. Nocturnal bilevel positive airway pressure resulted in reversal of pulmonary hypertension and right heart failure. Genetic analysis identified a homozygous mutation in the SEPN1 gene (606210.0008). Two sibs who were heterozygous carriers of the mutation had mild neck restriction. Venance et al. (2005) emphasized the importance of early nocturnal ventilatory assistance in these patients.
Clarke et al. (2006) reported 8 patients from 5 unrelated families with CMYP3. The patients, who ranged in age from 12 to 47 years, presented mostly with axial hypotonia and poor head control in infancy, although 3 sisters in family B had a later onset between 8 and 16 years. Progressive scoliosis developed in mid-childhood to adolescence, and many patients required spinal fusion. About half of patients had documented osteopenia; P2 had bilateral hip fractures in her twenties and was wheelchair-bound at age 30. All had decreased respiratory forced vital capacity (19 to 53% of normal), requiring nocturnal ventilation. The severity was variable, even among those with the same mutation. P4 was the most mildly affected, with mild neck weakness, mild scoliosis, relatively preserved lung function, and no osteopenia. All patients but P3 remained ambulatory. Skeletal muscle biopsy showed variable findings, including congenital fiber-type disproportion (CFTD) in 2 sisters from family A, nonspecific myopathic findings in P3 from family B, and muliminicore disease in P6 and P7. All 5 women from families A and B had abnormal glucose tolerance tests and showed biochemical abnormalities suggesting insulin resistance, particularly associated with low BMI.
Scoto et al. (2011) performed a retrospective study of 41 patients, ranging in age from 1 to 60 years, with CMYP3 confirmed by genetic analysis. The mean age at symptom onset was 2.7 years, ranging from birth to the second decade. Fifteen patients (36.5%) had a congenital presentation with hypotonia; rare patients had torticollis, feeding difficulties, and recurrent chest infections. About half of patients came to attention due to delayed motor milestones, difficulty walking or running, and frequent falls. A few patients presented in childhood with scoliosis, back stiffness, and general muscle wasting and weakness. All but 2 remained ambulatory; 1 became wheelchair-dependent in his late fifties and the other had difficulty walking at age 5. Joint contractures, including Achilles tendon, elbow, and finger contractures, were observed in 63% of patients; some patients had distal joint laxity. Rigidity of the spine and scoliosis developed in 70% of patients at a mean age of 10.2 years. All patients examined had reduced functional vital capacity (FVC) and most required nocturnal ventilation. Mild right ventricular hypertrophy and pulmonary hypertension were found in 16% of patients. Almost 60% of patients were underweight, and 3 were above the 97th percentile for weight. The disorder was nonprogressive in most patients. Two patients died from respiratory failure at 10 and 22 years, respectively. Skeletal muscle biopsy showed cores/multiminicores in 55% of cases, nonspecific changes in 24%, and type 1 fiber predominance in 21%. One patient had Mallory bodies. There was no correlation between clinical features and findings on muscle biopsy.
Varone et al. (2019) found abnormal glucose metabolism in 4 of 8 adult patients with CMYP3 confirmed by genetic analysis. Insulin resistance was only observed in patients with extremely low BMI.
Villar-Quiles et al. (2020) reported the clinical features of 101 patients with myopathy caused by mutation in the SEPN1 gene. The first symptoms were seen before 15 years of age in all of the patients, and within the first 2 years of life in 84.7%. Delayed motor development was the most common presenting sign. Independent ambulation was achieved in all but 1 patient. A rigid spine was seen in 87.8% of patients, usually before the age of 10 years. Scoliosis, characteristically causing a dorsal hyperlordosis, presented at an average age of 8.9 years, and was seen in 86.1% of patients. Spinal fusion surgery was performed in 32 postpubertal patients, and scoliosis usually remained stable after surgery. Birthweight was often normal, but body weight typically decreased significantly around puberty, leading to a loss of subcutaneous fat and a cachectic appearance. Restrictive hypoxemic and hypercapnic respiratory failure was present in 93% of patients and 81.9% of patients required assisted ventilation. Respiratory involvement was disproportionate to limb weakness, and most patients required ventilatory support while remaining ambulatory. Seventy-nine muscle biopsies were available for review, and multiminicores were the most frequent abnormal finding, seen in 59.5% of biopsies. Other findings included fiber size variation, type I fiber predominance and relative hypotrophy, and mildly dystrophic features. A subgroup of severely affected patients had ophthalmoparesis, rapidly progressive muscular weakness and respiratory failure, loss of ambulation before adulthood, and tetraparesis in the third decade of life. These patients had subcutaneous adiposity starting in childhood, with a predominant abdominal distribution. Most patients with good motor abilities were extremely underweight. Villar-Quiles et al. (2020) identified a significant correlation between body weight and disease severity.
Fan et al. (2022) reported 8 unrelated Chinese patients, ranging in age from 7 to 18 years, with CMYP3 associated with biallelic mutations in the SEPN1 gene. The patients presented at birth or within the first year of life with hypotonia and feeding difficulties followed by delayed motor development manifest as poor head control, delayed walking with frequent falls, proximal muscle weakness, and difficulty running or jumping. Deep tendon reflexes were diminished or absent. Four patients had facial weakness, high-arched palate, and nasal or high-pitched voice. All patients except the youngest (age 7 years) developed rigid spine and scoliosis between 4 and 12 years of age. All had respiratory involvement with decreased forced vital capacity and nocturnal hypoventilation, as well as upper and lower respiratory tract infections. Nocturnal ventilation resulted in improved oxygen saturation. Three patients had right cardiac ventricular enlargement and mild pulmonary hypertension secondary to respiratory insufficiency. Serum creatine kinase was normal or mildly increased. MRI showed diffuse fatty infiltration of the gluteus maximus and thigh muscles. Muscle biopsy showed chronic myopathic changes with fiber size variation, internal nuclei, and minicores. One patient died of pneumonia at age 8 years.
Bouman et al. (2022) performed a systematic review of the literature and metaanalysis to determine cardiac involvement in CMYP3. Among 192 cases, 29 (15%) were noted to have a cardiac abnormality, most commonly pulmonary hypertension (PH) (in 16 patients). Some patients even presented with pulmonary hypertension manifest as dyspnea and reduced exercise tolerance. Eight of the 16 with PH had right ventricular dysfunction secondary to respiratory failure or insufficiency; 2 patients died of secondary cardiac failure. The authors noted that restrictive lung disease, respiratory muscle weakness, and hypoventilation can lead to PH. Valvular heart disease was observed in 8 patients. Cardiac abnormalities were seen at a relatively young age (second decade), and the authors suggested that patients with the disorder should undergo cardiorespiratory surveillance starting in childhood.
Based on data collected in a series of 132 patients with myopathy caused by mutation in the SEPN1 gene, Villar-Quiles et al. (2020) developed management and surveillance recommendations, including the following: regular sleep studies, including in young children, regardless of the presence of respiratory failure or abnormal forced vital capacity (FVC); initiation of noninvasive ventilation as soon as respiratory failure or nocturnal hypoventilation are identified; regular ventilation management and sustained/intensified after arthrodesis; annual respiratory, cardiac, and spine evaluations, with spine evaluations increased to every 6 months around the adolescent growth spurt; oral glucose tolerance testing, particularly in adolescents and adults; and tailoring BMI control to known features and natural history of the disorder.
The transmission pattern of CMYP3 in the large kindred reported by Goebel et al. (1980) and in the families reported by Fan et al. (2022) was consistent with autosomal recessive inheritance.
The observation of an excess of males with rigid spine syndrome suggested that this syndrome may be an autosomal recessive disorder with variable penetrance and sex-linked expression (Mussini et al., 1982).
Moghadaszadeh et al. (1998) undertook a genomewide search by homozygosity mapping with 380 microsatellite markers in a large consanguineous family with congenital myopathy and rigid spine. The affected children were homozygous for several markers on 1p36-p35. Two additional consanguineous families with affected children also showed linkage to this region. A maximum cumulative lod score of 4.48, at a recombination fraction of 0.00, was obtained with D1S2885. This was the first description of a locus for a merosin-positive form of CMD.
In a family with CMYP3 with rigid spine, Flanigan et al. (2000) demonstrated linkage to a locus on chromosome 1p36-p35. (maximum lod score = 1.81 at theta = 0.0). In combination with the report of Moghadaszadeh et al. (1998), this syndrome is linked to the same locus with a summated maximum lod score of 6.29. Analysis of recombination events in the family of Flanigan et al. (2000) narrowed the previously reported locus to 3 cM.
In 7 families with classic MmD and 1 family with MmD with some atypical findings, Ferreiro et al. (2002) found linkage to 1p36 (maximum cumulative lod score = 5.5 at D1S3769).
In a study of the original German family with Mallory-body myopathy reported by Goebel et al. (1980), Ferreiro et al. (2004) found that all affected individuals were homozygous by descent for marker D1S2885 within the SEPN1 gene.
Genetic Heterogeneity
Moghadaszadeh et al. (1998) identified several families with features of rigid spine syndrome that did not show linkage to 1p36. They also noted, however, that rigid spine occurs in several distinct myopathies, since limitation of the flexion of the spine may develop because of replacement of spinal extensor muscles by fibrous and adipose tissue, resulting in their shortening. It has been observed, for example, in Emery-Dreifuss muscular dystrophy (310300), neurogenic facioscapuloperoneal muscular atrophy (Palmucci et al., 1991), nemaline myopathy (Topaloglu et al., 1994), and other myopathies.
Moghadaszadeh et al. (1999) described the clinical, morphologic, and genetic analysis of previously unreported patients affected by a congenital muscular dystrophy with rigid spine syndrome from 9 consanguineous families. Homozygosity mapping showed that the disease was linked to the locus on 1p36 in 1 of the 9 families. The other families were excluded from linkage to 1p36, and the patients presented highly variable phenotypes suggesting the involvement of more than one gene locus in the clinical presentation of rigid spine syndrome.
Ferreiro et al. (2002) excluded linkage to 1p36 in 9 families with classic MmD, suggesting genetic heterogeneity.
In affected members of 10 unrelated families with CMYP3, Moghadaszadeh et al. (2001) identified homozygous or compound heterozygous mutations in the SEPN1 gene (see, e.g., 606210.0001; 606210.0002; 606210.0004; 606210.0010; 606210.0013). Three of the families (1809, T2, and E1) had previously been reported by Moghadaszadeh et al. (1998).
In 17 patients from 12 unrelated families with CMYP3, Ferreiro et al. (2002) identified homozygous or compound heterozygous mutations in the SEPN1 gene (see, e.g., 606210.0003-606210.0008; 606210.0013). Analysis of 3 deltoid biopsy specimens from patients revealed a wide myopathologic variability, ranging from a dystrophic to a congenital myopathy pattern. A variable proportion of minicores was found in all samples. The authors concluded that CMYP3 and the most severe form of classic multiminicore disease are the same entity.
In 4 affected patients from the original German family with CMYP3 diagnosed as 'Mallory-body myopathy' (Goebel et al., 1980), Ferreiro et al. (2004) identified a homozygous 92-bp deletion in the SEPN1 gene (606210.0009). The parents were heterozygous for the mutation. Ferreiro et al. (2004) stated that the clinical features of Mallory-body desmin-related myopathy and SEPN-related myopathies (SEPN-RM) are indistinguishable, and suggested that the disorders are part of an SEPN-RM disease spectrum.
In 5 affected women from 2 unrelated families with CMYP3, Clarke et al. (2006) identified a homozygous missense mutation in the SEPN1 gene (G315S; 606210.0008). All 5 patients had abnormal glucose tolerance tests and showed biochemical abnormalities suggesting insulin resistance. Three additional patients with CMYP3 were also found to carry biallelic mutations (see, e.g., 606210.0003 and 606210.0009).
Villar-Quiles et al. (2020) reported 65 mutations in the SEPN1 gene, 32 of which were novel, in a series of 132 pediatric and adult patients with myopathy caused by mutation in the SEPN1 gene. Seventy-two patients had homozygous mutations, and 59 had compound heterozygous mutations. The mutations included 23 missense, 14 indels, 13 deletions, 8 nonsense, 6 intronic splice sites, and 1 mutation in the 3-prime untranslated region. There was also an SEPN1 copy number variant identified that was predicted to result in a deletion affecting exons 7 to 12. There was a cluster of mutations in exons 1, 6, 7, and 11 and no mutations in exon 3. The most common mutation, identified in 15 unrelated families, was a mutation of the start codon (c.1A-G; 606210.0003) that changed the initiator methionine to valine. Three founder mutations were identified: c.817G-A (G273E; 606210.0001) in Iran and Turkey; c.943G-A (G315S; 606210.0008) in northern Europe; and c.713dupA (606210.0006) in western Europe.
In 8 Chinese patients with CMYP3, Fan et al. (2022) identified compound heterozygous mutations in the SELENON gene (see, e.g., 606210.0011 and 606210.0012). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. Most of the mutations were frameshift mutations, predicted to be subject to nonsense-mediated mRNA decay. Missense mutations were located around or in the catalytic site. Seven of the 16 identified variants occurred in exon 1. There were no genotype/phenotype correlations. Functional studies of the variants and studies of patient cells were not performed. Fan et al. (2022) stated that excessive oxidation damage resulting from SELENON deficiency induces dysfunction and degradation of muscle fibers.
Villar-Quiles et al. (2020) reported genotype-phenotype correlations in a series of 101 patients with myopathy and mutations in SEPN1. Overall, patients who were homozygous or compound heterozygous for 2 mutations predicted to cause an absence of SEPN1 protein (either due to loss of the start codon or nonsense-mediated decay) had more severe phenotypes. Three mutations in exon 1 (c.1A-G (606210.0003), c.-19_73del (606210.0009), and c.13_22dup) and a mutation in exon 6 (c.818G-A) were most commonly found in patients with a severe phenotype. Other mutations, e.g., c.943G-A (606210.0008) in exon 7, c.1315C-T in exon 10, and c.1446delC in exon 11, were often found in milder cases. Only missense mutations were identified in the selenoprotein N putative catalytic site; these were observed in 23 patients, 7 of whom were homozygous, and most of these patients had disease of moderate severity. There was no correlation between genotype and histopathologic findings.
Moghadaszadeh et al. (2001) suggested that SEPN1 may play a key role in the physiology of skeletal muscles such as the diaphragm by maintaining the redox environment of the cell and preventing it from oxidant damage.
Arbogast et al. (2009) found that ex vivo cultures of myoblasts derived from myopathy patients with SEPN1 mutations showed oxidative and nitrosative stress with increased intracellular reactive oxygen species (ROS) and nitric oxide. These cells also contained proteins with increased oxidation, including the contractile proteins actin and myosin. Absence of SEPN1 was associated with altered calcium homeostasis and abnormal susceptibility to hydrogen peroxide-induced stress. This phenotype could be ameliorated by treatment with the antioxidant N-acetylcysteine. The findings indicated that SEPN1 plays a role in redox homeostasis and protection against oxidative stress.
Varone et al. (2019) found abnormal glucose metabolism in 4 of 8 adult patients with CMYP3 confirmed by genetic analysis. Insulin resistance was only observed in patients with extremely low BMI. In vitro studies of murine C2C12 muscle cells showed that loss of selenon resulted in abnormal ER and mitochondrial function and morphology. Lack of selenon increased palmitate-inducted lipotoxicity as a result of fatty acid accumulation, which elicited ER stress and blunted insulin-dependent glucose uptake in muscle. Loss of selenon in adult mice caused similar metabolic alterations, including glucose intolerance in response to a high-fat diet.
Ferreiro et al. (2004) proposed the term 'SEPN-related myopathy (SEPN-RM)' as a single nosologic entity encompassing the muscular dystrophies caused by mutation in the SEPN gene.
Heffner et al. (1976) reported affected twins with congenital myopathy with multicore disease, and Ricoy et al. (1980) reported affected sibs with a congenital myopathy associated with multiple minicores.
Vestergaard et al. (1995) reported a family in which of 2 of 3 sons had congenital myopathy and insulin-resistant diabetes mellitus. The brothers, aged 15 and 8 at the time of the study, were born of nonconsanguineous healthy parents. Both had delayed milestones and muscle weakness. Skeletal muscle biopsy in both probands at the age of 6 years. Muscle biopsy showed 74% small type 1 fibers of 16 micro m diameter and 26% type 2 fibers of 22 micro m diameter, consistent with a pathologic diagnosis of congenital fiber-type disproportion (CFTD). No nemaline bodies were seen. Physical examination showed universal muscle hypotrophy and hirsutism. Glucosuria and postprandial hyperglycemia were discovered by chance at the age of 13 years in proband 1 and 6 years in proband 2; neither had been symptomatic. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity.
Dubowitz (1997) described the attempts to classify merosin-positive congenital muscular dystrophy (CMD) patients at an international workshop. Subgroups included CMD clinically close to merosin deficiency but without white matter alterations, rigid spine syndrome, Ullrich syndrome (254090) with marked hyperextensibility of distal joints, and other cases without features described above, some of which may represent mild forms of the dystroglycanopathies (see, e.g., MDDGA1; 236670).
Arbogast, S., Beuvin, M., Fraysse, B., Zhou, H., Muntoni, F., Ferreiro, A. Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment. Ann. Neurol. 65: 677-686, 2009. [PubMed: 19557870] [Full Text: https://doi.org/10.1002/ana.21644]
Bender, A. N. Congenital myopathies. In: Vinken, P. J.; Bruyn, G. W. (eds.): Handbook of Clinical Neurology. Diseases of Muscle. Part II. Vol. 41. Amsterdam: North Holland (pub.) 1979. Pp. 1-26.
Bethlem, J., Arts, W. F., Dingemans, K. P. Common origin of rods, cores, and focal loss of cross-striations. Arch. Neurol. 35: 555-556, 1978. [PubMed: 687182] [Full Text: https://doi.org/10.1001/archneur.1978.00500330003002]
Bouman, K., Gubbels, M., van den Heuvel, F. M. A., Groothuis, J. T., Erasmus, C. E., Nijveldt, R., Udink Ten Cate, F. E. A., Voermans, N. C. Cardiac involvement in two rare neuromuscular diseases: LAMA2-related muscular dystrophy and SELENON-related myopathy. Neuromusc. Disord. 32: 635-642, 2022. [PubMed: 35868898] [Full Text: https://doi.org/10.1016/j.nmd.2022.06.004]
Clarke, N. F., Kidson, W., Quijano-Roy, S., Estournet, B., Ferreiro, A., Guicheney, P., Manson, J. I., Kornberg, A. J., Shield, L. K., North, K. N. SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann. Neurol. 59: 546-552, 2006. [PubMed: 16365872] [Full Text: https://doi.org/10.1002/ana.20761]
Dubowitz, V. Rigid spine syndrome: a muscle syndrome in search of a name. Proc. Roy. Soc. Med. 66: 219-220, 1973. [PubMed: 4697975]
Dubowitz, V. 50th ENMC International Workshop: congenital muscular dystrophy, 28 February 1997 to 2 March 1997, Naarden, The Netherlands. Neuromusc. Disord. 7: 539-547, 1997. [PubMed: 10712016]
Engel, A. G., Gomez, M. R., Groover, R. V. Multicore disease--a recognised congenital myopathy associated with multifocal degeneration of muscle fibres. Mayo Clin. Proc. 46: 666-681, 1971. [PubMed: 5115748]
Fan, Y., Xu, Z., Li, X., Gao, F., Guo, E., Chang, X., Wei, C., Zhang, C., Yu, Q., Que, C., Xiao, J., Yan, C., Wang, Z., Yuan, Y., Xiong, H. Novel SEPN1 Mutations in exon 1 are common in rigid spine with muscular dystrophy type 1 in Chinese patients. Front. Genet. 13: 825793, 2022. [PubMed: 35368679] [Full Text: https://doi.org/10.3389/fgene.2022.825793]
Ferreiro, A., Ceuterick-de Groote, C., Marks, J. J., Goemans, N., Schreiber, G., Hanefeld, F., Fardeau, M., Martin, J.-J., Goebel, H. H., Richard, P., Guicheney, P., Bonnemann, C. G. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann. Neurol. 55: 676-686, 2004. [PubMed: 15122708] [Full Text: https://doi.org/10.1002/ana.20077]
Ferreiro, A., Estournet, B., Chateau, D., Romero, N. B., Laroche, C., Odent, S., Toutain, A., Cabello, A., Fontan, D., dos Santos, H. G., Haenggeli, C.-A., Bertini, E., Urtizberea, J.-A., Guicheney, P., Fardeau, M. Multi-minicore disease-searching for boundaries: phenotype analysis of 38 cases. Ann. Neurol. 48: 745-757, 2000. [PubMed: 11079538]
Ferreiro, A., Quijano-Roy, S., Pichereau, C., Moghadaszadeh, B., Goemans, N., Bonnemann, C., Jungbluth, H., Straub, V., Villanova, M., Leroy, J.-P., Romero, N. B., Martin, J.-J., Muntoni, F., Voit, T., Estournet, B., Richard, P., Fardeau, M., Guicheney, P. 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. Genet. 71: 739-749, 2002. [PubMed: 12192640] [Full Text: https://doi.org/10.1086/342719]
Fidzianska, A., Goebel, H. H., Osborn, M., Lenard, H. G., Osse, G., Langenbeck, U. Mallory body-like inclusions in a hereditary congenital neuromuscular disease. Muscle Nerve 6: 195-200, 1983. [PubMed: 6343859] [Full Text: https://doi.org/10.1002/mus.880060305]
Fidzianska, A., Ryniewicz, B., Barcikowska, M., Goebel, H. H. A new familial congenital myopathy in children with desmin and dystrophin reacting plaques. J. Neurol. Sci. 131: 88-95, 1995. [PubMed: 7561954] [Full Text: https://doi.org/10.1016/0022-510x(95)00090-o]
Flanigan, K. M., Kerr, L., Bromberg, M. B., Leonard, C., Tsuruda, J., Zhang, P., Gonzalez-Gomez, I., Cohn, R., Campbell, K. P., Leppert, M. Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. Ann. Neurol. 47: 152-161, 2000. [PubMed: 10665485]
Goebel, H. H., Fardeau, M. Desmin-protein surplus myopathies, 96th European Neuromuscular Centre (ENMC)-sponsored International Workshop held 14-16 September 2001, Naarden, The Netherlands. Neuromusc. Disord. 12: 687-692, 2002. [PubMed: 12207939] [Full Text: https://doi.org/10.1016/s0960-8966(02)00024-x]
Goebel, H. H., Lenard, H.-G., Langenbeck, U., Mehl, B. A form of congenital muscular dystrophy. Brain Dev. 2: 387-400, 1980. [PubMed: 7224095] [Full Text: https://doi.org/10.1016/s0387-7604(80)80052-0]
Goto, I., Nagasaka, S., Nagara, H., Kuroiwa, Y. Rigid spine syndrome. J. Neurol. Neurosurg. Psychiat. 42: 276-279, 1979. [PubMed: 438838] [Full Text: https://doi.org/10.1136/jnnp.42.3.276]
Heffner, R., Cohen, M., Duffner, P., Daigler, G. Multicore disease in twins. J. Neurol. Neurosurg. Psychiat. 39: 602-606, 1976. [PubMed: 985853] [Full Text: https://doi.org/10.1136/jnnp.39.6.602]
Jungbluth, H., Sewry, C., Brown, S. C., Manzur, A. Y., Mercuri, E., Bushby, K., Rowe, P., Johnson, M. A., Hughes, I., Kelsey, A., Dubowitz, V., Muntoni, F. Minicore myopathy in children: a clinical and histopathological study of 19 cases. Neuromusc. Disord. 10: 264-273, 2000. [PubMed: 10838253] [Full Text: https://doi.org/10.1016/s0960-8966(99)00125-x]
Koch, B. M., Bertorini, T. E., Eng, G. D., Boehm, R. Severe multicore disease associated with reaction to anesthesia. Arch. Neurol. 42: 1204-1206, 1985. [PubMed: 4062619] [Full Text: https://doi.org/10.1001/archneur.1985.04060110086024]
Langenbeck, U. Personal Communication. Frankfurt, Germany 11/20/1986.
Langenbeck, U. Personal Communication. Frankfurt, Germany 8/23/1991.
McKusick, V. A. Heritable Disorders of Connective Tissue. (4th ed.) St. Louis: C. V. Mosby (pub.) 1972. P. 143 only. Note: Fig. 3-50.
Moghadaszadeh, B., Desguerre, I., Topaloglu, H., Muntoni, F., Pavek, S., Sewry, C., Mayer, M., Fardeau, M., Tome, F. M. S., Guicheney, P. Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36. Am. J. Hum. Genet. 62: 1439-1445, 1998. [PubMed: 9585610] [Full Text: https://doi.org/10.1086/301882]
Moghadaszadeh, B., Petit, N., Jaillard, C., Brockington, M., Roy, S. Q., Merlini, L., Romero, N., Estournet, B., Desguerre, I., Chaigne, D., Muntoni, F., Topaloglu, H., Guicheney, P. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nature Genet. 29: 17-18, 2001. [PubMed: 11528383] [Full Text: https://doi.org/10.1038/ng713]
Moghadaszadeh, B., Topaloglu, H., Merlini, L., Muntoni, F., Estournet, B., Sewry, C., Naom, I., Barois, A., Fardeau, M., Tome, F. M. S., Guicheney, P. Genetic heterogeneity of congenital muscular dystrophy with rigid spine syndrome. Neuromusc. Disord. 9: 376-382, 1999. [PubMed: 10545040] [Full Text: https://doi.org/10.1016/s0960-8966(99)00051-6]
Mussini, J. M., Mathe, J. F., Prost, A., Gray, F., Labat, J. J., Feve, J. R. Le syndrome de la colonne raide: un cas feminin. Rev. Neurol. 138: 25-37, 1982. [PubMed: 7100735]
Paljarvi, L., Kalimo, H., Lang, H., Savontaus, M.-L., Sonninen, V. Minicore myopathy with dominant inheritance. J. Neurol. Sci. 77: 11-22, 1987. [PubMed: 3806134] [Full Text: https://doi.org/10.1016/0022-510x(87)90202-4]
Palmucci, L., Mongini, T., Doriguzzi, C., Maniscalco, M., Schiffer, D. Familial autosomal recessive rigid spine syndrome with neurogenic facio-scapulo-peroneal muscle atrophy. J. Neurol. Neurosurg. Psychiat. 54: 42-45, 1991. [PubMed: 2010758] [Full Text: https://doi.org/10.1136/jnnp.54.1.42]
Patel, H., Berry, K., MacLeod, P., Dunn, H. G. Cytoplasmic body myopathy: report on a family and review of the literature. J. Neurol. Sci. 60: 281-292, 1983. [PubMed: 6886734] [Full Text: https://doi.org/10.1016/0022-510x(83)90069-2]
Ricoy, J. R., Cabello, A., Goizueta, G. Myopathy with multiple minicores: report of two siblings. J. Neurol. Sci. 48: 81-92, 1980. [PubMed: 6448277] [Full Text: https://doi.org/10.1016/0022-510x(80)90152-5]
Scoto, M., Cirak, S., Mein, R., Feng, L., Manzur, A. Y., Robb, S., Childs, A. M., Quinlivan, R. M., Roper, H., Jones, D. H., Longman, C., Chow, G., Pane, M., Main, M., Hanna, M. G., Bushby, K., Sewry, C., Abbs, S., Mercuri, E., Muntoni, F. SEPN1-related myopathies: clinical course in a large cohort of patients. Neurology 76: 2073-2078, 2011. [PubMed: 21670436] [Full Text: https://doi.org/10.1212/WNL.0b013e31821f467c]
Topaloglu, H., Gogus, S., Yalaz, K., Kucukali, T., Serdaroglu, A. Two siblings with nemaline myopathy presenting with rigid spine syndrome. Neuromusc. Disord. 4: 263-267, 1994. [PubMed: 7919974] [Full Text: https://doi.org/10.1016/0960-8966(94)90028-0]
Vanneste, J. A. L., Stam, F. C. Autosomal dominant multicore disease. J. Neurol. Neurosurg. Psychiat. 45: 360-365, 1982. [PubMed: 7077346] [Full Text: https://doi.org/10.1136/jnnp.45.4.360]
Varone, E., Pozzer, D., Di Modica, S., Chernorudskiy, A., Nogara, L., Baraldo, M., Cinquanta, M., Fumagalli, S., Villar-Quiles, R. N., De Simoni, M. G., Blaauw, B., Ferreiro, A., Zito, E. SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biol. 24: 101176, 2019. [PubMed: 30921636] [Full Text: https://doi.org/10.1016/j.redox.2019.101176]
Venance, S. L., Koopman, W. J., Miskie, B. A., Hegele, R. A., Hahn, A. F. Rigid spine muscular dystrophy due to SEPN1 mutation presenting as cor pulmonale. Neurology 64: 395-396, 2005. [PubMed: 15668457] [Full Text: https://doi.org/10.1212/01.WNL.0000149755.85666.DB]
Vestergaard, H., Klein, H. H., Hansen, T., Muller, J., Skovby, F., Bjorbaek, C., Roder, M. E., Pedersen, O. Severe insulin-resistant diabetes mellitus in patients with congenital muscle fiber type disproportion myopathy. J. Clin. Invest. 95: 1925-1932, 1995. [PubMed: 7706500] [Full Text: https://doi.org/10.1172/JCI117874]
Villar-Quiles, R. N., von der Hagen, M., Metay, C., Gonzalez, V., Donkervoort, S., Bertini, E., Castiglioni, C., Chaigne, D., Colomer, J., Cuadrado, M. L., de Visser, M., Desguerre, I., and 26 others. The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: a case series. Neurology 95: e1512-e1527, 2020. [PubMed: 32796131] [Full Text: https://doi.org/10.1212/WNL.0000000000010327]
Vogel, P., Goebel, H. H., Seitz, D. Rigid spine syndrome in a girl. J. Neurol. 228: 259-265, 1982. [PubMed: 6188813] [Full Text: https://doi.org/10.1007/BF00313416]