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

Molecular Genetic Testing

Genes. Mutations in two genes account for MmD in approximately 50% of affected individuals:

• SEPN1. 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. 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.

• RYR1. Some forms of MmD are associated with RYR1 mutations inherited in an autosomal recessive manner.

Other loci. Further genetic heterogeneity is suggested; no other candidate region or gene has been identified to date.

Clinical testing

• Sequence analysis to identify mutations in SEPN1 and RYR1 is available clinically.

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

View in own window

Gene Symbol	Proportion of MmD Attributed to Mutations in This Gene	Test Method	Mutation Detection Frequency by Test Method 1	Test Availability
SEPN1	30%-54%	Sequence analysis	>90%	Clinical
RYR1	Unknown	Sequence analysis	Unknown	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis. 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, this testing should be done first.

• If no SEPN1 mutations are identified, testing of RYR1 should be considered, particularly for those individuals with non-classic forms of MmD.

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 for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

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.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

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 of insidious nocturnal hypoxia and sudden respiratory failure. Monitoring of respiratory function should include: 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; and 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.

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

Congenital Muscular Dystrophy International Registry (CMDIR)
The CMD International Registry is a patient self-report registry with the goal to register the global CMD population.
Phone: 310-938-2008
Fax: 310-872-5374
Email: counselor@cmdir.org
Web: www.cmdir.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Multiminicore disease (MmD) is inherited in an autosomal recessive manner [Ferreiro et al 2000, Jungbluth et al 2002].

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 available on a clinical basis 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, for example in inbred populations and in cases of consanguinity.

A further complication is the uncertainty of the diagnosis of MmD in the cases reported by Paljarvi et al [1987]. The affected individuals may have either autosomal dominant central core disease, with coexisting minicores, or secondary minicores possibly caused by denervation.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for RYR1-related and SEPN1-related MmD is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Agrawal PB, Greenleaf RS, Tomczak KK, Lehtokari VL, Wallgren-Pettersson C, Wallefeld W, Laing NG, Darras BT, Maciver SK, Dormitzer PR, Beggs AH. Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2. Am J Hum Genet. 2007;80:162–7. [PMC free article: PMC1785312] [PubMed: 17160903]
2. Bonnemann CG, Thompson TG, van der Ven PF, Goebel HH, Warlo I, Vollmers B, Reimann J, Herms J, Gautel M, Takada F, Beggs AH, Furst DO, Kunkel LM, Hanefeld F, Schroder R. Filamin C accumulation is a strong but nonspecific immunohistochemical marker of core formation in muscle. J Neurol Sci. 2003;206:71–8. [PubMed: 12480088]
3. Clarke NF, Kidson W, Quijano-Roy S, Estournet B, Ferreiro A, Guicheney P, Manson JI, Kornberg AJ, Shield LK, North KN. SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol. 2006;59:546–52. [PubMed: 16365872]
4. Ducreux S, Zorzato F, Ferreiro A, Jungbluth H, Muntoni F, Monnier N, Muller CR, Treves S. Functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central core disease, expressed in immortalized lymphocytes. Biochem J. 2006;395:259–66. [PMC free article: PMC1422771] [PubMed: 16372898]
5. Dulhunty AF, Beard NA, Pouliquin P, Kimura T. Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies. J Muscle Res Cell Motil. 2006;27:351–65. [PubMed: 16909197]
6. Ferreiro A, Ceuterick-de Groote C, Marks JJ, Goemans N, Schreiber G, Hanefeld F, Fardeau M, Martin JJ, Goebel HH, Richard P, Guicheney P, Bonnemann CG. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol. 2004;55:676–86. [PubMed: 15122708]
7. Ferreiro A, Estournet B, Chateau D, Romero NB, Laroche C, Odent S, Toutain A, Cabello A, Fontan D, dos Santos HG, Haenggeli CA, Bertini E, Urtizberea JA, Guicheney P, Fardeau M. Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases. Ann Neurol. 2000;48:745–57. [PubMed: 11079538]
8. Ferreiro A, Fardeau M (2002) 80th ENMC International Workshop on Multi-Minicore Disease: 1st International MmD Workshop. 12-13th May, 2000, Soestduinen, The Netherlands. Neuromuscul Disord 12:60-8 .
9. Ferreiro A, Monnier N, Romero NB, Leroy JP, Bonnemann C, Haenggeli CA, Straub V, Voss WD, Nivoche Y, Jungbluth H, Lemainque A, Voit T, Lunardi J, Fardeau M, Guicheney P. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol. 2002a;51:750–9. [PubMed: 12112081]
10. Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bonnemann C, Jungbluth H, Straub V, Villanova M, Leroy JP, Romero NB, Martin JJ, 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. 2002b;71:739–49. [PMC free article: PMC378532] [PubMed: 12192640]
11. Fischer D, Matten J, Reimann J, Bonnemann C, Schroder R. Expression, localization and functional divergence of alphaB-crystallin and heat shock protein 27 in core myopathies and neurogenic atrophy. Acta Neuropathol (Berl). 2002;104:297–304. [PubMed: 12172916]
12. Galli L, Orrico A, Cozzolino S, Pietrini V, Tegazzin V, Sorrentino V. Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C- terminal region. Cell Calcium. 2002;32:143–51. [PubMed: 12208234]
13. Gommans IM, Davis M, Saar K, Lammens M, Mastaglia F, Lamont P, van Duijnhoven G, ter Laak HJ, Reis A, Vogels OJ, Laing N, van Engelen BG, Kremer H. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain. 2003;126:1545–51. [PubMed: 12805120]
14. Guis S, Figarella-Branger D, Monnier N, Bendahan D, Kozak-Ribbens G, Mattei JP, Lunardi J, Cozzone PJ, Pellissier JF. Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol. 2004;61:106–13. [PubMed: 14732627]
15. Jungbluth H, Muller CR, Halliger-Keller B, Brockington M, Brown SC, Feng L, Chattopadhyay A, Mercuri E, Manzur AY, Ferreiro A, Laing NG, Davis MR, Roper HP, Dubowitz V, Bydder G, Sewry CA, Muntoni F. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology. 2002;59:284–7. [PubMed: 12136074]
16. Jungbluth H, Sewry C, Brown SC, Manzur AY, Mercuri E, Bushby K, Rowe P, Johnson MA, Hughes I, Kelsey A, Dubowitz V, Muntoni F. Minicore myopathy in children: a clinical and histopathological study of 19 cases. Neuromuscul Disord. 2000;10:264–73. [PubMed: 10838253]
17. Jungbluth H, Sewry CA, Brown SC, Nowak KJ, Laing NG, Wallgren-Pettersson C, Pelin K, Manzur AY, Mercuri E, Dubowitz V, Muntoni F. Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle alpha-actin (ACTA1) gene. Neuromuscul Disord. 2001;11:35–40. [PubMed: 11166164]
18. Jungbluth H, Zhou H, Hartley L, Halliger-Keller B, Messina S, Longman C, Brockington M, Robb SA, Straub V, Voit T, Swash M, Ferreiro A, Bydder G, Sewry CA, Muller C, Muntoni F. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology. 2005;65:1930–5. [PubMed: 16380615]
19. Kaindl AM, Ruschendorf F, Krause S, Goebel HH, Koehler K, Becker C, Pongratz D, Muller-Hocker J, Nurnberg P, Stoltenburg-Didinger G, Lochmuller H, Huebner A. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet. 2004;41:842–8. [PMC free article: PMC1735626] [PubMed: 15520409]
20. Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Roy SQ, 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. Nat Genet. 2001;29:17–8. [PubMed: 11528383]
21. Monnier N, Ferreiro A, Marty I, Labarre-Vila A, Mezin P, Lunardi J. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet. 2003;12:1171–8. [PubMed: 12719381]
22. Monnier N, Romero NB, Lerale J, Landrieu P, Nivoche Y, Fardeau M, Lunardi J. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum Mol Genet. 2001;10:2581–92. [PubMed: 11709545]
23. Nadaj-Pakleza A, Fidzianska A, Ryniewicz B, Kostera-Pruszczyk A, Ferreiro A, Kwiecinski H, Kaminska A. Multi-minicore myopathy: a clinical and histopathological study of 17 cases. Folia Neuropathol. 2007;45:56–65. [PubMed: 17594595]
24. Okamoto Y, Takashima H, Higuchi I, Matsuyama W, Suehara M, Nishihira Y, Hashiguchi A, Hirano R, Ng AR, Nakagawa M, Izumo S, Osame M, Arimura K. Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene. Neurogenetics. 2006;7:175–83. [PubMed: 16779558]
25. Paljarvi L, Kalimo H, Lang H, Savontaus ML, Sonninen V. Minicore myopathy with dominant inheritance. J Neurol Sci. 1987;77:11–22. [PubMed: 3806134]
26. Scacheri PC, Hoffman EP, Fratkin JD, Semino-Mora C, Senchak A, Davis MR, Laing NG, Vedanarayanan V, Subramony SH. A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology. 2000;55:1689–96. [PubMed: 11113224]
27. Tajsharghi H, Darin N, Tulinius M, Oldfors A. Early onset myopathy with a novel mutation in the Selenoprotein N gene (SEPN1). Neuromuscul Disord. 2005;15:299–302. [PubMed: 15792869]
28. Tilgen N, Zorzato F, Halliger-Keller B, Muntoni F, Sewry C, Palmucci LM, Schneider C, Hauser E, Lehmann-Horn F, Muller CR, Treves S. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. Hum Mol Genet. 2001;10:2879–87. [PubMed: 11741831]
29. Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, Nonaka I, Noguchi S, Hayashi YK, Nishino I. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006;129:1470–80. [PubMed: 16621918]
30. Zhou H, Brockington M, Jungbluth H, Monk D, Stanier P, Sewry CA, Moore GE, Muntoni F. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Am J Hum Genet. 2006;79:859–68. [PMC free article: PMC1698560] [PubMed: 17033962]
31. Zhou H, Jungbluth H, Sewry CA, Feng L, Bertini E, Bushby K, Straub V, Roper H, Rose MR, Brockington M, Kinali M, Manzur A, Robb S, Appleton R, Messina S, D'Amico A, Quinlivan R, Swash M, Muller CR, Brown S, Treves S, Muntoni F. Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. Brain. 2007;130:2024–36. [PubMed: 17483490]
32. Zorzato F, Jungbluth H, Zhou H, Muntoni F, Treves S. Functional effects of mutations identified in patients with multiminicore disease. IUBMB Life. 2007;59:14–20. [PubMed: 17365175]

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

• 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