Clinical 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. Pathogenic variants in SELENON (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 pathogenic variants in the family have been identified.

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

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 SELENON and RYR1.

• Because the majority of individuals with MmD have a pathogenic variant in SELENON, sequence analysis should be done first.
• If no SELENON pathogenic variants 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 SELENON 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 variants in SELENON and RYR1 have not been identified through sequence analysis.

Clinical Description

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 SELENON pathogenic variants 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

SELENON (SEPN1). Individuals with SELENON pathogenic variants 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 mutation of SELENON. The forms of MmD associated with RYR1 pathogenic variants 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.

SELENON (SEPN1)

Congenital fiber-type disproportion (CFTD) is a type of congenital myopathy characterized by hypotonia and mild-to-severe generalized muscle weakness at birth or within the first year of life. The diagnosis is made on muscle biopsy showing type 1 fibers that are at least 12% smaller than the mean diameter of type 2A and/or type 2B fibers in the absence of other significant pathologic findings (e.g., nemaline bodies, cores, or central nuclei).

In a recent study [Clarke et al 2006]:

• Two sibs with CFTD homozygous for a c.943G>A pathogenic variant in SELENON had clinical findings similar to those of SELENON-related myopathy.
• Three women in one family who were homozygous for the c.943G>A pathogenic variant had similar clinical findings. Only one had a muscle biopsy; it revealed type 1 fibers to be 10.5% smaller than type 2 fibers (for the diagnosis of CFTD, the type 1 fibers should be >12% smaller), consistent with nonspecific myopathy. No histopathologic features of MmD, RSMD, or desmin-related myopathy were found.

It is important to remember that a few cases of CFTD and centronuclear myopathy may show features consistent with MmD on ultrastructural examination [Nadaj-Pakleza et al 2007].

Desminopathy. SELENON pathogenic variants have been identified in individuals with desmin-related myopathy with Mallory body-like inclusions [Ferreiro et al 2004]. The clinical presentation is similar to that of MmD/RSMD; on muscle biopsy, hyaline plaques that are devoid of any NADH/SDH activity are seen in up to 10% of fibers under light microscopy. Ultrastructurally, these represent intramyofibrillar inclusions arranged in bundles composed of helical filaments 10-12 nm in diameter and surrounded by electron-dense amorphous material.

RYR1

Central core disease (CCD) is most often caused by autosomal dominant pathogenic variants in RYR1. The majority of CCD-causing variants are located in the C-terminal region (last 15 exons), which contributes to the formation of the Ca²⁺ (calcium)-conducting pore [Monnier et al 2001, Wu et al 2006]. Significant clinical and pathologic overlap between CCD and MmD has been identified in individuals who have homozygous or compound heterozygous pathogenic variants in RYR1:

• One family in whom muscle fibers showed coexistence of minicores, central cores, and a few rod-like structures had a homozygous RYR1 pathogenic variant in exon 101 [Jungbluth et al 2002].
• Another family homozygous for an RYR1 pathogenic variant in exon 71 had three affected children with a moderate form of minicore disease with hand involvement. Initial biopsy results for this family were consistent with MmD but subsequent biopsy showed progression to lesions typical of CCD [Ferreiro et al 2002a].
• Ten individuals in whom muscle biopsy revealed significant overlap between central cores and minicores were identified to carry compound heterozygous RYR1 pathogenic variants distributed throughout the gene. Nine of these ten affected individuals had opthalmoplegia [Monnier et al 2008].

Malignant hyperthermia susceptibility (MHS) is caused by RYR1 pathogenic variants predominantly in the N-terminal region of the gene, affecting the cytoplasmic domain of the protein that possibly interacts with dihydropyridine receptor. Approximately 50% of all reported MHS is caused by RYR1 pathogenic variants. Malignant hyperthermia is also associated with pathogenic variants affecting the central domain and more recently the RYR1 C-terminal region [Galli et al 2002]. Multiple minicores have been described in a small proportion of individuals with MHS (2.6%; n=534) [Guis et al 2004]. This study also reported a large family of 17 people with MHS, 16 of whom had multiminicores in muscle fiber and two missense variants of RYR1 on the same allele in exons 50 and 53.

CFTD resulting from biallelic RYR1 pathogenic variants has been identified by a recent study [Clarke et al 2010]. RYR1 variants were responsible for 10%-20% of the individuals with CFTD, making this the second most common cause (after TPM3). Individuals with CFTD who have ophthalmoplegia are more likely to have RYR1 pathogenic variants. Reduced ryanodine channel activity as a result of low protein expression has been postulated in some patients with recessive RYR1 pathogenic variants [Monnier et al 2008]; however, the mechanism for type I fiber hypotrophy associated with CFTD is unknown.

Centronuclear myopathy (CNM). Pathogenic variants in RYR1 have been recently identified as a common cause of CNM, further expanding the disease spectrum resulting from mutation of RYR1 [Wilmshurst et al 2010]. While the majority of pathogenic variants were present as compound heterozygous changes, the detection of only a single RYR1 pathogenic variant inherited from an asymptomatic parent was found in a few families, which could represent either monoallelic RYR1 expression or missed promoter variants/copy number variations in the second allele. Disease severity in individuals with CNM who have either single or homozygous/compound heterozygous RYR1 pathogenic variants is extremely variable, and like CFTD and core myopathies, opthalmoplegia is a common finding.

A missense RYR1 variant was reported with dominant congenital myopathy in a family with both nemaline bodies and cores [Scacheri et al 2000].

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
• Consultation with a clinical geneticist and/or genetic counselor

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 pathogenic variants 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 in the US and EU Clinical Trials Register in Europe 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.

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 mutated allele in skeletal muscle has been seen in some persons heterozygous at the genomic DNA level for recessive RYR1 pathogenic variants [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 mutated 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 mutated 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 (Heterozygote) Detection

Carrier testing for at-risk family members is possible once the pathogenic variants 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 pathogenic variants 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 populations/families with high rates 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SELENON or RYR1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MmD are possible.

SELENON (SEPN1)

Gene structure. SELENON 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. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Known non-pathogenic polymorphisms are included in Table 2 (pdf).

Pathogenic variants. The pathogenic variants in SELENON 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 pathogenic variants cause premature termination of translation; the remaining pathogenic variants are missense changes. Variants 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. SELENON mRNAs associated with frameshift or nonsense variants may be resistant to nonsense-mediated decay [Okamoto et al 2006].

RYR1

Gene structure. RYR1 has 106 exons encompassing a total of 160 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 25 missense dominant variants in RYR1 have been associated with malignant hyperthermia susceptibility and/or central core disease [Galli et al 2002]. Pathogenic variants 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 pathogenic variants 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 pathogenic variants 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 pathogenic variants associated with MmD phenotype have shown variable dysregulation of calcium homeostasis. While the p.Pro3527Ser variant caused decreased calcium release after stimulation, there was no reduction in the case of the p.Ser71Tyr variant, and increased calcium release was noted with the p.Asn2283His variant. One hypothesis is that these pathogenic variants cause instability of the ryanodine receptor macromolecular complex leading to altered binding of regulatory proteins. In contrast, the pathogenic variants p.Arg109Trp and 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].

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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

• 18 April 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation
• 24 January 2013 (me) Comprehensive update posted live
• 10 April 2008 (me) Comprehensive update posted live
• 10 January 2006 (cd) Revision: RYR1 mutation testing clinically available; SEPN1 mutation testing available through custom laboratories
• 26 July 2005 (me) Comprehensive update posted live
• 25 March 2003 (me) Review posted live
• 6 December 2002 (ab) Original submission