What causes multiminicore disease?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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Answer

Multiminicore disease is most commonly autosomal recessive. There are two main genes involved, RYR1 and the selenoprotein N gene (SEPN1), but there are others that have been associated. Mutations in RYR1, while they can cause a central core disease as noted above, can also result in multiminicore, but the exact mechanism to differentiate why they have different causes is unknown. Potential defects may be related to instability of the RYR1 macromolecular complex or to a reduction in the number of RYR1 receptors on the sarcoplasmic reticulum. [30]

In mutations in the SEPN1, the gene can present as a congenital myopathy but can also have a phenotype more consistent with a congenital muscular dystrophy. The role of selenoprotein N in causing multiminicore disease is unknown, but its expression is developmentally regulated in muscle. More than 20 mutations have been described, with more than half resulting in a truncated protein that is likely degraded. Selenoprotein N may play a role in redox reactions of membrane proteins, including the ryanodine receptor, and lack of this protein may result in oxidative stress leading to abnormal receptor function. [30]  In multiminicore disease due to a mutation in the Selenocysteine insertion sequence-binding protein 2 (SECISBP2) gene, the reduced synthesis of all selenoproteins including selenoprotein N likely accounts for the similar pathology. [31]

How mutations in the rare causes of multiminicore disease result in similar muscle pathology is unknown.

The classic and most common phenotype presents with spinal rigidity, axial weakness, scoliosis, and early respiratory impairment. In this type, the onset occurs in infancy or early childhood and is characterized by proximal and axial weakness and hypotonia that is either nonprogressive or only minimally progressive. There is often associated facial and bulbar weakness. The progressive respiratory weakness is often out of proportion to the muscle weakness. This results in ambulant patients requiring ventilatory support in some cases. There is typically normal intelligence and no clear association with malignant hypertheramia but there are some cases of older patients associated. [32]

As with other congenital myopathies, arthrogryposis can be associated with early-onset symptoms. In patients with RYR1 myopathy, central core type phenotypes exist with the multiminicore pathologic features.

The pathologic hallmark of the disease is the presence of multiple areas of sarcomeric disorganization associated with diminished mitochondrial oxidative activity.

The disease is best identified with muscle reacted for oxidative enzymes NADH, SDH, and COX. Reduced staining for myosin ATPase, glycogen, and phosphorylase may also be noted.

Multiminicores differ from central cores in the following ways: occur in type 1 and type 2 fibers; poorly defined limits; vary in orientation to muscle fiber axis; multiple lesions within one muscle fiber; and smaller in size, never extending the length of the muscle fiber.

Other features may include increased endomysial connective tissue, increased internal nuclei, and type-1 muscle fiber predominance.

Multiminicores may be present as a nonspecific feature in many other diseases, including mitochondrial diseases, CNS disorders, and denervation.

Rare causes of muscle pathology showing multicores or minicores include the following:

Mutations in SECISBP2 lead to multisystem selenoprotein deficiency including in SEPN1. [31]  Patients have a multisystem disorder including early onset of axial and proximal muscle weakness, stiff spine, respiratory difficulty, and fatigue. Other features include developmental delay, azoospermia, cutaneous photosensitivity, Raynaud’s, hearing loss, impaired T-lymphocyte proliferation abnormal mononuclear dell cytokine secretion, and telomere shortening.

SCAD (Short-chain acyl-CoA dehydrogenase) deficiency; [33]  neonatal onset patients had hypotonia, developmental delay, speech delay, myopathy, lethargy, and feeding difficulties. Later onset patients had ophthalmoplegia, ptosis, weakness and scoliosis.

EMARDD (early-onset myopathy with areflexia, respiratory distress and dysphagia) due to a mutation in multiple epidermal growth factor-like domains 10 (MEGF10); [34] presentation before 1 year with severe proximal and distal weakness, hypotonia, respiratory impairment, scoliosis and joint contractures with stabilization in teenage years.

Titin (LGMD2J) gene mutation was reported to cause a minicore-like disease with early-onset myopathy and fatal cardiomyopathy in 2 consanguineous families. [35] Presentation was before 1 year of age with symmetric proximal, distal and facial weakness, ptosis, joint and neck contractures, spinal rigidity, and progressive dilated cardiomyopathy with concomitant ventricular rhythm disturbances and sudden cardiac death.

Myosin – Cardiac b heavy chain (MYH7) mutations most often cause myosin storage myopathy/hyaline body myopathy (see below), but a variant syndrome causes multi-minicore disease with variable cardiac involvement. [36]  Presentation is in childhood with slowly progressive weakness, proximal or distal, facial weakness, scapular winging, contractures, spinal rigidity and variable degrees of cardiorespiratory impairment later in life. Sudden cardiac death may occur.


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