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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Multiminicore Disease

Synonyms: Minicore Disease, Minicore Myopathy, Multicore Disease, Multicore Myopathy, Multiminicore Myopathy. Includes: RYR1-Related Multiminicore Disease, SEPN1-Related Multiminicore Disease

, PhD and , MD, MMSc.

Author Information
, PhD
Program in Genomics and Division of Genetics
Boston Children's Hospital
Harvard Medical School
Boston, Massachusetts
, MD, MMSc
Program in Genomics and Division of Genetics
Boston Children's Hospital
Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Update: January 24, 2013.

Summary

Disease characteristics. Multiminicore disease (MmD) is broadly classified into four groups:

  • Classic form (75% of individuals)
  • Moderate form, with hand involvement (<10%)
  • Antenatal form, with arthrogryposis multiplex congenita (<10%)
  • Ophthalmoplegic form (<10%)

Onset of the classic form is usually congenital or early in childhood with neonatal hypotonia, delayed motor development, axial muscle weakness, scoliosis, and significant respiratory involvement (often with secondary cardiac impairment). Spinal rigidity of varying severity is present.

Diagnosis/testing. The diagnosis of MmD is based on the presence of multiple "minicores" visible on muscle biopsy using oxidative stains, clinical findings of static or slowly progressive weakness, and absence of findings diagnostic of other neuromuscular disorders. Mutations in SEPN1 and RYR1 are known to cause 50% of MmD cases reported; further genetic heterogeneity is suggested, but no other candidate region or gene has been identified to date.

Management. Treatment of manifestations: Respiratory support as needed; aggressive treatment of lower respiratory infections; nasogastric feeding and high caloric density formulas as needed; physical and occupational therapy to improve/maintain gross and fine motor function and reduce joint contractures; speech therapy as needed; orthopedic treatment of scoliosis.

Prevention of secondary complications: Yearly influenza and other respiratory infection-related immunizations.

Surveillance: Routine evaluations of: neuromuscular status to assess disease progression; respiratory function re the risk of insidious nocturnal hypoxia and sudden respiratory failure; cardiac status re the risk of cardiac impairment secondary to respiratory involvement; the spine for scoliosis particularly during childhood and adolescence.

Agents/circumstances to avoid: Depolarizing muscle relaxants and inhalational agents during surgery or childbirth, as they can trigger malignant hyperthermia.

Genetic counseling. MmD is most often inherited in an autosomal recessive manner. The occurrence of MMD in two generations in a few families has been reported, suggestive of autosomal dominant inheritance. Assuming autosomal recessive inheritance, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.

Diagnosis

Clinical Diagnosis

Multiminicore disease (MmD) has a wide clinical spectrum with four distinct phenotypes (see Clinical Description). Clinical findings that may support the diagnosis of MmD include the following:

  • Weakness (predominantly axial and proximal) and hypotonia; scoliosis and respiratory difficulty occur in approximately two-thirds of affected individuals.
  • Onset typically at birth or during infancy; sometimes in childhood

Testing

Muscle Biopsy

The diagnosis of MmD is based on the presence of multiple "minicores," small zones of sarcomeric disorganization and/or diminished oxidative activity that correlate with lack of mitochondria in muscle fibers. Unlike the cores typical of central core disease, minicores affect both type I and type II fibers and are short in length, spanning only a few sarcomeres in the fiber longitudinal axis.

Note: Because minicores are not specific to MmD, the diagnosis of MmD is based on the presence of minicores in a large proportion of muscle fibers associated with static or slowly progressive weakness and absence of findings diagnostic of other disorders.

H&E staining reveals moderate to marked variability in fiber size; the number of internal nuclei may be increased. Fat and/or connective tissue is normal or mildly increased. Myofibrillar ATPase staining may be normal, but frequently shows type I fiber predominance. Relative hypotrophy of type I fibers is often observed, with mean diameter of type I fibers smaller than that of type II fibers in many cases.

Oxidative stains (NADH-TR, succinate dehydrogenase, cytochrome oxidase) reveal multiple small focal lesions ("minicores") of sarcomeric disorganization and/or reduced or absent oxidative activity in 60%-90% of fibers. These focal lesions are generally round, small, variable in size, multiple, and randomly distributed with poorly defined boundaries. The cores are often oriented transversely to the fibers and may span up to 15 to 20 sarcomeres [Ferreiro et al 2000, Jungbluth et al 2000]. While cytochrome oxidase staining is specific for lack of mitochondria, NADH-TR staining reveals both the lack of mitochondria and the myofibrillar disruption characteristic of "unstructured cores."

Immunohistochemistry. Reliable (but nonspecific) markers for MmD [Fischer et al 2002, Bönnemann et al 2003] include the following:

  • Anti-titin antibodies reveal disorganization of the normal striated pattern in unstructured cores.
  • Anti-desmin antibodies show increased reactivity in the core lesions.
  • AlphaB-crystallin, heat shock protein 27, and filamin C have shown increased immunoreactivity in core lesions (minicore, central core, and target fibers).

Anti-alpha-actinin and anti-actin antibodies do not reveal any abnormalities [Ferreiro et al 2000].

Electron microscopy. Cores are typically unstructured and often circular. Their appearance ranges from focal areas of Z line streaming and reduced or absent mitochondria to severe focal disorganization of myofibrillar structure [Ferreiro et al 2000, Jungbluth et al 2000]. "Structured" minicores, exhibiting intact sarcomeres and only absence of mitochondria, may be more difficult to detect [Ferreiro & Fardeau 2002].

Biochemical and Electrophysiologic Studies

Studies may suggest a myopathic process but have a limited role in making the diagnosis.

Serum creatine kinase concentration is normal or slightly elevated.

EMG ranges from normal to nonspecifically abnormal, with findings such as low-amplitude polyphasic potentials of short duration. The absence of a neurogenic pattern eliminates the possibility of denervation, which may also lead to presence of core lesions.

Molecular Genetic Testing

Genes. Mutations in two genes are known to cause MmD in approximately 50% of affected individuals.

Evidence for locus heterogeneity. Further genetic heterogeneity is suggested: a family with dilated cardiomyopathy and multiple minicores and another family with overlapping features of Laing distal myopathy and MmD have been described, both with heterozygous MYH7 mutations [Cullup et al 2012].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Multiminicore Disease

Gene 1Proportion of MmD Attributed to Mutations in This GeneTest MethodMutations Detected 2
SEPN1 30%-54% 3Sequence analysisSequence variants 4
UnknownDeletion/duplication analysis 5Unknown; none reported 6
RYR1 UnknownSequence analysisSequence variants 4
UnknownSequence analysis of select exons 7Sequence variants in select exons 4
UnknownDeletion/duplication analysis 5Unknown; none reported 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Autosomal recessive SEPN1 mutations account for approximately 30% of all MmD and approximately 50% of classic MmD [Ferreiro et al 2002b]. An estimated 40% of individuals with SEPN1 mutations are compound heterozygotes.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions or duplications involving SEPN1 or RYR1 have been reported to cause multiminicore disease.

7. Exons sequenced may vary by laboratory.

Test characteristics. Information on test sensitivity and specificity and other test characteristics can be found at www.eurogentest.org [Lillis et al 2012 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband. MmD is a clinicopathologic entity that requires histopathologic examination of a muscle biopsy for the diagnosis to be made.

Clinical evaluation includes the following:

  • Personal medical history and physical examination, with particular attention to features of congenital myopathy or muscular dystrophy (e.g., weakness, hypotonia, failure to thrive, scoliosis)
  • Family history, with particular attention to features of congenital myopathy or muscular dystrophy

Genetic diagnosis requires molecular genetic testing of SEPN1 and RYR1.

  • Because the majority of individuals with MmD have a mutation in SEPN1, sequence analysis should be done first.
  • If no SEPN1 mutations are identified, sequence analysis of RYR1 should be considered, particularly for those individuals with non-classic forms of MmD.
  • Although no deletions or duplications of either SEPN1 or RYR1 have been reported to date to cause MmD, deletion/duplication analysis of each of these genes could be considered in an individual with features of MmD in whom causative mutations in SEPN1 and RYR1 have not been identified through sequence analysis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Multiminicore disease (MmD) is characterized by axial and proximal muscle weakness. It is usually slowly progressive; however, fatal cases have been described. High-arched palate and chest deformities are common.

MmD is broadly classified into four forms [Ferreiro et al 2000, Jungbluth et al 2000, Ferreiro & Fardeau 2002, Nadaj-Pakleza et al 2007]:

  • Classic form
  • Moderate form, with hand involvement
  • Antenatal form, with arthrogryposis multiplex congenita
  • Ophthalmoplegic form

In all forms, males and females are equally affected.

Classic MmD (75%)

  • Characteristic features
    • Onset is usually congenital or occurs in early childhood with neonatal hypotonia and delayed motor development including head lag, a common and early sign.
    • Axial muscle weakness leads to development of scoliosis and major respiratory involvement in approximately two thirds of individuals. Scoliosis develops at a mean age of 8.5 years and is generally cervicodorsal and progressive [Ferreiro et al 2000]. Varying severity of spinal rigidity is present.
    • Rigid spine muscular dystrophy (RSMD), characterized by limited flexion of dorsolumbar and cervical spine (caused by contractures of spinal extensor muscles) is now considered a form of classic MmD. The majority of individuals with these findings have SEPN1 mutations and minicores on muscle biopsy [Moghadaszadeh et al 2001, Ferreiro et al 2002b].
    • Strength of trunk and neck flexors is usually scored 1 to 2 out of 5, pelvic and shoulder girdle muscles 3 to 4, and distal muscles normal or only moderately weak (3+ to 5). Individuals are usually ambulatory, as limb muscle strength is relatively preserved.
    • Facial muscle strength ranges from normal to severe weakness; extraocular muscles are spared.
  • Cardiac. Cardiac involvement (right ventricular failure, cardiomyopathy) secondary to respiratory impairment is common. Mitral valve prolapse is occasionally seen.
  • Other features. Most individuals have short stature and failure to thrive. Some individuals are slender and have a marfanoid habitus but no other features of Marfan syndrome.
  • Course. Scoliosis is progressive and associated with loss of respiratory function in mid-later childhood, after which the course is often static.

    Individuals may walk well into adulthood despite severe scoliosis and need for ventilatory support. In a few severe cases the disease may progress slowly through adolescence and adulthood, eventually leading to loss of ambulation.

    Death often occurs as a result of respiratory infection in a setting of severe respiratory insufficiency.

    Late onset of the disease is usually associated with better prognosis.

Moderate form with hand involvement (<10%). The characteristic feature is distal weakness of the upper limbs with joint hyperlaxity. Distal lower limbs are relatively normal. Scoliosis and respiratory involvement are mild or absent.

Antenatal form with arthrogryposis multiplex congenita (AMC) (<10%). The characteristic feature is generalized joint contractures at birth as a result of poor fetal movement. Associated distinctive features are dolicocephaly, prominent nasal root, oblique palpebral fissues, high-arched palate, low-set ears, short neck, and clinodactyly.

Ophthalmoplegic form (<10%) usually presents in the neonatal period or early infancy with marked generalized hypotonia and weakness. Failure to thrive and pronounced weakness of the axial and proximal muscles are common. External ophthalmoplegia predominantly affects upward and lateral gaze. Ligaments are universally lax. Respiratory function is moderately impaired but nocturnal hypoventilation is usually not a finding [Jungbluth et al 2000, Jungbluth et al 2005].

Genotype-Phenotype Correlations

SEPN1. Individuals with SEPN1 mutations have classic MmD. May develop early and severe scoliosis resulting in respiratory insufficiency requiring respiratory assistance [Ferreiro et al 2002b].

RYR1. The disease is usually milder than that caused by mutations in SEPN1. The forms of MmD associated with RYR1 mutations include the moderate form with hand involvement [Ferreiro et al 2002a] and the ophthalmoplegic form [Monnier et al 2003, Jungbluth et al 2005].

Nomenclature

Rigid spine muscular dystrophy or rigid spine syndrome are now considered the same entity as severe classic MmD.

Prevalence

MmD is thought to be rare. Actual prevalence figures are unknown. The disease occurs in diverse ethnic and racial groups.

Differential Diagnosis

All forms of congenital myopathy have a number of common clinical features: generalized proximal weakness, hypotonia, hyporeflexia, poor muscle bulk, and features secondary to myopathy (e.g., elongated facies, high arched palate, pectus carinatum, scoliosis, foot deformities). Presence of severe rapidly progressive scoliosis favors a diagnosis of classic multiminicore disease (MmD); however, marked clinical overlap exists among MmD and congenital myopathies as well as other neuromuscular disorders including congenital muscular dystrophy. Therefore, the diagnosis of MmD rests on the presence of typical structural changes on muscle biopsy.

Minicore lesions can coexist with central cores, rods or centrally located nuclei, and variable fibrosis. The differential diagnosis in those cases can include central core disease, nemaline myopathy, centronuclear myopathy, or one of the muscular dystrophies. Of these conditions, central core disease is most difficult to differentiate because minicores may be the predominant histopathologic finding in central core disease. In this situation, presence of pronounced hip girdle weakness, only mild facial involvement, lack of significant respiratory impairment, and myalgias or muscle cramps may support a diagnosis of central core disease. Central cores in central core disease have sharply defined boundaries, involve exclusively type I fibers, and extend throughout the entire fiber length, often centrally. However, it is important to remember that the differentiation between minicores and central cores is not always straightforward, and a continuum of histopathologic changes may be present in individuals.

Dominant mutations in ACTA1 have been described in individuals with congenital myopathy with atypical cores (not typical of central cores or multiple minicores) and those with coexisting cores and nemaline rods [Jungbluth et al 2001, Kaindl et al 2004]. Nemaline bodies with cores have been described in a family with recessive CFL2 mutation [Agrawal et al 2007]. Similarly, a locus on chromosome 15q21-q23 has been linked to a dominantly inherited nemaline myopathy with core-like lesions [Gommans et al 2003].

Secondary MmD. Multiple minicore lesions can also be secondary to other conditions including SCAD (short-chain acyl-COA dehydrogenase) deficiency, multiple pterygium syndrome with hypertrophic cardiomyopathy, other cardiomyopathies, hypohidrotic ectodermal dysplasia, Marfan syndrome, anesthetic reaction, and neurogenic conditions including denervation.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multiminicore disease (MmD), the following evaluations are recommended:

  • Comprehensive respiratory evaluation including assessment of breathing rate, signs of respiratory distress, ability to maintain oxygen saturations, pulmonary function studies, and sleep studies to rule out nocturnal hypoxia
  • Assessment of feeding abilities including suck, swallow, gastroesophageal reflux, and maintenance of airway while feeding; evaluation of growth parameters to identify failure to thrive and determine need for interventions including gavage feeds and gastrostomy tube insertion
  • Spinal x-rays to evaluate for presence of scoliosis; physical examination for joint contractures
  • Cardiac evaluation for cardiomyopathy/cardiac involvement secondary to respiratory complications
  • Physical and occupational therapy evaluation to develop interventions based on the distribution and extent of weakness
  • Speech evaluation, especially if dysarthria or hypernasal speech is present
  • Orthodontic evaluation for palatal anomalies
  • Medical genetics consultation

Treatment of Manifestations

Treatment is aimed at prevention of disease manifestations, early diagnosis by regular screening, and aggressive management of complications that may develop. Effective treatment requires a multidisciplinary approach that can improve both quality of life and survival for the affected individual.

Ongoing careful assessment of the potential need for part-time or permanent respiratory support is absolutely critical, as affected individuals may rapidly enter respiratory crisis or may unknowingly suffer from potentially fatal nocturnal hypoventilation.

Feeding support with tube/gavage feeds is needed if oral intake is poor. Failure to thrive may need to be overcome with high-caloric density formulas/feeds. Gastroesophageal reflux (if present) is treated in the usual manner.

Physical and occupational therapy may help to improve/maintain gross motor and fine motor functions.

Speech therapy should be provided for individuals with dysarthria/hypernasal speech.

Prevention of Secondary Complications

Annual influenza and other respiratory infection-related immunizations are advised.

Aggressive treatment of lower respiratory infections is critical.

Surveillance

Monitoring for potential complications that can influence the prognosis of MmD includes the following:

  • Frequent and regular monitoring of the spine particularly during childhood and adolescence when scoliosis can rapidly progress during the adolescent growth spurt
  • Careful monitoring of respiratory function from an early stage because of the risk for insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include the following:
    • Close attention to nocturnal hypoventilation symptoms including early morning headaches, daytime drowsiness, loss of appetite, and deteriorating school performance
    • Lung function tests (FEV1 and FVC)
    • Sleep studies
    • Assessment of the need for intermittent or permanent ventilation. Nocturnal ventilation, when indicated, may significantly improve the prognosis.
  • Assessment of cardiac status because of the risk of cardiac impairment secondary to respiratory involvement

Growth should be assessed regularly.

Regular neuromuscular evaluation to assess disease progress is indicated.

Agents/Circumstances to Avoid

Risk for malignant hyperthermia. Depolarizing muscle relaxants (e.g., succinylcholine) and inhalational agents (e.g., halothane, isoflurane, desflurane) can cause malignant hyperthermia and therefore need to be avoided during surgical procedures/childbirth, as RYR1 mutations are associated with both malignant hyperthermia susceptibility and MmD.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In women with MmD, there is risk for malignant hyperthermia during delivery if inhalational anesthetic agents are used. A woman who has a fetus affected by MmD may develop polyhydramnios during pregnancy and may report a history of poor fetal movements. Abnormal presentation of an affected fetus may complicate delivery.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Multiminicore disease (MmD) is most often inherited in an autosomal recessive manner [Ferreiro et al 2000, Jungbluth et al 2002]. The occurrence of MmD in two generations in a few families has been reported, suggestive of autosomal dominant inheritance.

Note: Monoallelic expression of just the mutant allele in skeletal muscle has been seen in some persons heterozygous at the genomic DNA level for recessive RYR1 mutations [Zhou et al 2006].

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Carriers (heterozygotes) are asymptomatic.

Offspring of a proband. The offspring of a proband with MmD are obligate carriers (heterozygotes) for the mutant allele causing MmD.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Occurrence in more than one generation. In a few families, occurrence in two generations has been reported. Whether this situation represents autosomal dominant inheritance or "pseudodominant inheritance" of an autosomal recessive disorder is unclear. To establish that a disorder is inherited in an autosomal dominant manner, transmission through a minimum of three generations and/or the presence of heterozygous disease-causing mutations is required; it is not clear that MmD has met these criteria.

Note: Pseudodominant inheritance is more likely to occur in autosomal recessive disorders with a high carrier frequency (e.g., in inbred populations and in cases of consanguinity).

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • Congenital Muscle Disease International Registry (CMDIR)
    The CMD International Registry is a patient self-report registry with the goal to register the global congenital muscle disease population which includes congenital myopathy and congenital muscular dystrophy.
    1712 Pelican Avenue
    San Pedro CA 90732
    Phone: 800-363-2630
    Fax: 310-872-5374
    Email: counselor@cmdir.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Multiminicore Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Multiminicore Disease (View All in OMIM)

117000CENTRAL CORE DISEASE OF MUSCLE
180901RYANODINE RECEPTOR 1; RYR1
255320MINICORE MYOPATHY WITH EXTERNAL OPHTHALMOPLEGIA
602771RIGID SPINE MUSCULAR DYSTROPHY 1; RSMD1
606210SELENOPROTEIN N, 1; SEPN1
607552MINICORE MYOPATHY, ANTENATAL ONSET, WITH ARTHROGRYPOSIS

SEPN1

Normal allelic variants. SEPN1 has 13 exons spanning 18.5 kb. The transcription product is 4.5 kb and the open reading frame has 1770 nucleotides. The functional transcript has one in-frame TGA codon in exon 10, which is read as selenocysteine because of the presence of a selenocysteine insertion sequence (SECIS) element in the 3' UTR region. Known non-pathogenic polymorphisms are included in Table 2 (pdf).

Pathogenic allelic variants. The pathogenic mutations in SEPN1 associated with MmD are summarized in Table 3 (pdf) [Ferreiro et al 2002a, Ferreiro et al 2002b, Tajsharghi et al 2005, Zorzato et al 2007].

Up to two thirds of mutations cause premature termination of translation; the remaining mutations are missense changes. Mutations appear to be distributed throughout the gene.

Normal gene product. The gene encodes a 590-amino acid protein called selenoprotein N. The function of selenoprotein N is not known, but it is found in virtually all tissues examined by western blot. The protein is expressed in very low levels and most studies require overexpression. An enzymatic function has been hypothesized for selenoprotein N based on protein structure and analogies with other selenoproteins with known function. Most of the selenoproteins identified to date are catalysts either in redox processes or in thyroid hormone processing.

Selenoprotein N has an EF hand Ca2+ binding motif similar to that found in proteins like calmodulin, suggesting that Ca2+ may play a role in Ca homeostasis and/or in modulation of selenoprotein N function.

Abnormal gene product. The abnormal gene product either is a truncated protein or may contain a missense amino acid substitution. The functional significance of these abnormal products is unknown. SEPN1 mRNAs associated with frameshift or nonsense mutations may be resistant to nonsense-mediated decay [Okamoto et al 2006].

RYR1

Normal allelic variants. RYR1 has 106 exons encompassing a total of 160 kb.

Pathogenic allelic variants. More than 25 missense dominant mutations in RYR1 have been associated with malignant hyperthermia susceptibility and/or central core disease [Galli et al 2002]. Mutations in RYR1 associated with MmD described to date have been homozygous (see Table 4 [pdf]) [Ferreiro et al 2002a, Jungbluth et al 2002, Jungbluth et al 2005, Zhou et al 2007, Zorzato et al 2007].

Zhou et al [2006] found that RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing, and this unveils recessive mutations in individuals with core myopathies.

Normal gene product. RYR1 encodes ryanodine receptor 1, the calcium release channel of skeletal muscle sarcoplasmic reticulum. Ryanodine receptor 1 is one of the largest known proteins, with 5038 amino acids. The functional channel is composed of four identical subunits of 565 kd each and has been shown to interact with a number of regulatory proteins. The first 4000 amino acids comprise the hydrophilic cytoplasmic domain that bridges the gap between the transverse tubules and sarcoplasmic reticulum; the last 1000 amino acids form the hydrophobic membrane-spanning plate containing the pore [Tilgen et al 2001].

Abnormal gene product. Most RYR1 mutations associated with malignant hyperthermia (MH) and central core disease (CCD) affect calcium homeostasis by either making the calcium channels hypersensitive to activation (associated with MH) or decreasing the amount of calcium released after activation (CCD phenotype) [Dulhunty et al 2006]. Studies on RYR1 mutations associated with MmD phenotype have shown variable dysregulation of calcium homeostasis. While the p.Pro3527Ser mutation caused decreased calcium release after stimulation, there was no reduction in the case of the p.Ser71Tyr mutation, and increased calcium release was noted with the p.Asn2283His mutation. One hypothesis is that these mutations cause instability of the ryanodine receptor macromolecular complex leading to altered binding of regulatory proteins. In contrast, the mutations p.Arg109Trp, p.Met485Val, and the 14646+2.99 kb intronic splicing variant are associated with very low endogenous ryanodine receptor protein levels [Ducreux et al 2006, Zorzato et al 2007].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

Author Notes

Web page: www.childrenshospital.org

Acknowledgments

The authors gratefully acknowledge generous support by the Lee and Penny Anderson Family Foundation and the Muscular Dystrophy Association (USA) for ongoing research on multiminicore disease.

Revision History

  • 24 January 2013 (me) Comprehensive update posted live
  • 10 April 2008 (me) Comprehensive update posted to live Web site
  • 10 January 2006 (cd) Revision: RYR1 mutation testing clinically available; SEPN1 mutation testing available through custom laboratories
  • 26 July 2005 (me) Comprehensive update posted to live Web site
  • 25 March 2003 (me) Review posted to live Web site
  • 6 December 2002 (ab) Original submission
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