Rigid Spine Muscular Dystrophy 1
A number sign (#) is used with this entry because rigid spine muscular dystrophy-1, severe classic multiminicore myopathy, and desmin-related myopathy with Mallory bodies, which are believed to be part of the same disease spectrum, are caused by homozygous or compound heterozygous mutation in the SEPN1 gene (606210) on chromosome 1p36.
DescriptionDesmin-related myopathies (DRM) are a clinically and genetically heterogeneous group of muscular disorders defined morphologically by intrasarcoplasmic aggregates of desmin (DES; 125660), usually accompanied by other protein aggregates. Approximately one-third of DRM are caused by mutations in the desmin gene (Ferreiro et al., 2004).
For other forms of DRM, see primary desminopathy (601419).
Clinical FeaturesRigid spine syndrome, first reported by Dubowitz (1973), is characterized by marked 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. There may be limitation of other joints, especially a limited extension of the elbows and the ankles. Although the condition is not progressive, the development of scoliosis and associated deformities often lead to respiratory failure.
Goebel et al. (1980) described 5 cases of 'congenital muscular dystrophy' 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. All came from a Roman Catholic enclave in a Protestant area. Ages at examination ranged from 2 to 10 years. Neuromuscular signs and symptoms were present from birth or early infancy. 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 cardiomyopathy was unlikely. Skeletal muscle biopsy showed a myopathic fiber diameter spectrum, mild endomysial fibrosis, and type I fiber predominance. Goebel et al. (1980) suggested autosomal recessive inheritance. Langenbeck (1986) proposed that the disorder be called the 'Eichsfeld' type of congenital muscular dystrophy. Langenbeck (1986) 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).
The family reported by Patel et al. (1983) had clinical features consistent with RSS. 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.
Fidzianska et al. (1995) reported 5 children from 3 families with a congenital myopathy characterized by the presence of fine hyaline plaques devoid of oxidative and ATPase enzyme activities. Ultrastructurally, the plaques were composed of helical filaments that showed immunoreactivity to desmin, ubiquitin, and dystrophin. Other patients with the same disorder were reported (Goebel and Fardeau, 2002). 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.
Moghadaszadeh et al. (1998) reported a large consanguineous family with 3 sibs with merosin-positive congenital muscular dystrophy, and 2 other consanguineous families with at least 1 member affected with the disorder. 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.
Multiminicore disease (MmD) is a clinically heterogeneous disorder of the skeletal muscle. Classic MmD is an autosomal recessive congenital disorder characterized clinically by the predominance of axial muscle weakness that leads, in two-thirds of patients, to the development of severe, life-threatening respiratory insufficiency and scoliosis. Other features include neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable. Muscle biopsy shows multiple, poorly circumscribed, short areas of sarcomere disorganization and mitochondria depletion (areas termed 'minicores') in most muscle fibers (Engel et al., 1971). Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present in multiminicore disease (Ferreiro et al., 2002).
Koch et al. (1985) described the case of a child with minimulticore findings on biopsy who had been hypotonic from birth, developed cardiac failure at age 2.5 years, and died of malignant hyperthermia 26 hours after cardiac catheterization during which lidocaine and ketamine were given. Heffner et al. (1976) reported affected twins and Ricoy et al. (1980) reported affected sibs.
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 of classic minicore myopathy. Features were similar to those reported by others and inheritance was autosomal recessive.
Venance et al. (2005) reported a patient with rigid spine muscular dystrophy 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. Genetic analysis identified a homozygous mutation in the SEPN1 gene (606210.0008). Nocturnal bilevel positive airway pressure resulted in reversal of pulmonary hypertension and right heart failure. 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.
Classification
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).
Moghadaszadeh et al. (2001) noted that in contrast to congenital muscular dystrophy patients with merosin deficiency, those with mutations in the SEPN1 gene were ambulant and presented a milder muscular dystrophy with no basal membrane alteration and almost normal levels of serum creatine kinase.
InheritanceAn excess of males with rigid spine syndrome had been observed, suggesting that this syndrome may be an autosomal recessive disorder with variable penetrance and sex-linked expression (Mussini et al., 1982).
The high incidence of this disorder in consanguineous families and the demonstration of homozygous or compound heterozygous mutations in the SEPN1 gene support autosomal recessive inheritance (Ferreiro et al., 2002).
Autosomal dominant transmission has also been described. Paljarvi et al. (1987) suggested autosomal dominant inheritance in a mother and son with nonprogressive weakness of both proximal and distal muscles and biopsy findings typical of minicore myopathy (focal defects of oxidative enzyme activity and disturbances of cross-striation). Paljarvi et al. (1987) pointed to 3 other reported families with multiminicore myopathy with a pattern of inheritance suggesting autosomal dominance. These included a father and 2 sons, all 3 of whom also had cardiomyopathy (Bender, 1979); mother, son, and granddaughter (Bethlem et al., 1978); and mother and 2 daughters (Vanneste and Stam, 1982).
MappingMoghadaszadeh et al. (1998) undertook a genomewide search by homozygosity mapping with 380 microsatellite markers in the large consanguineous family with merosin-positive CMD 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 rigid spine syndrome, Flanigan et al. (2000) demonstrated linkage to the RSMD1 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 RSMD1 locus with a summated maximum lod score of 6.29, and analysis of recombination events in the family of Flanigan et al. (2000) narrowed the previously reported RSMD1 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 RSMD1 in 1 of the 9 families. The other families were excluded from RSMD1, and the patients presented highly variable phenotypes suggesting the involvement of more than one gene locus in rigid spine syndrome.
Ferreiro et al. (2002) excluded linkage to 1p36 in 9 families with classic MmD, suggesting genetic heterogeneity.
Molecular GeneticsMoghadaszadeh et al. (2001) refined the map location of the RSMD1 locus and found evidence of linkage disequilibrium associated with the SEPN1 gene. They identified several mutations in the SEPN1 gene resulting in RSMD1 (e.g., 606210.0001).
On the basis of clinical and morphologic data, Ferreiro et al. (2002) suspected a relationship between classic multiminicore disease and RSMD due to mutations in the SEPN1 gene. They identified homozygous or compound heterozygous mutations in the SEPN1 gene in 17 patients with classic multiminicore disease, including 3 mutations that had been described in patients with rigid spine syndrome. 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 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, Ferreiro et al. (2002) concluded that RSMD and the most severe form of classic multiminicore disease are the same entity.
In 4 affected patients from the original German family with Mallory-body myopathy reported by Goebel et al. (1980), Ferreiro et al. (2004) identified homozygosity for a 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.
PathogenesisMoghadaszadeh 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.
NomenclatureFerreiro 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.