The positive FH for malignant hyperthermia lead us to test for skeletal muscle ryanodine receptor (RYR1) gene mutation. A previously described, disease associated, heterozygous mutation in Exon 47 of the RYR1 gene was discovered.
Diagnosis: myopathy secondary to RYR1 mutation.
The severe atrophy and weakness of quadriceps with sparing of rectus femoris , as demonstrated with MRI and EMG study, are described in central core disease (CCD). A biopsy was also done from the vastus lateralis. HE stain (A) shows chronic remodeling in the form of mild endomysial fibrosis and fatty replacement. There is also increased variation of fiber size, admixture of atrophic myofibers, and occasional hypertrophic myofibers. Some myofibers have inclusions that are visualized as areas of disrupted normal sarcoplasmic staining. In the ATPase reaction (B) fiber types are not reliably distinguished and the inclusions are associated with decreased enzyme reactivity. EM (C) shows that the inclusions consist of unstructured aggregates of filamentous sarcomeric elements with prominent aggregates of Z- band like material. These inclusions are consistent with cores of CCD.
RYR1 gene encodes the principal sarcoplasmic reticulum Ca2+ release channel and has a crucial role in excitation–contraction (E–C) coupling. RYR1 mutations are one of the most common causes of inherited neuromuscular disorders, often presenting with different clinical phenotypes and histopathological features. RYR1 related myopathies are commonly autosomal dominant with incomplete penetrance, but autosomal recessive cases are also reported. Muscle biopsy findings range from normal in the malignant hyperthermia susceptibility (MHS) trait, or show features typical of Central Core Disease (CCD),Multi-minicore Disease(MmD), Centronuclear Myopathy (CNM) and congenital fibre type disproportion (CFTD).
MHS trait is a typically autosomal dominant disorder which manifests as acute rhabdomyolysis on exposure to volatile anesthetics or succinylcholine during general anesthesia. Triggering drugs are to be avoided in genetically susceptible individuals who are going to undergo general anesthesia. Prophylactic use of dantrolene is not recommended. Susceptibility to MH is diagnosed by in vitro contracture testing (IVCT). The IVCT requires a fresh skeletal muscle sample, which is exposed in vitro to incremental doses of different specific testing agents – caffeine, halothane, and ryanodine and the contracture response is measured.
CCD may present in infancy with hypotonia, in early childhood, or in adulthood (milder phenotypes). Weakness is generally proximal (limb girdle), and axial muscles could be affected as well. Myalgia, exertional weakness with or without rhabdomyolysis may also be present. CK is generally normal, but rarely elevated (up to x14 times normal). The muscle ultrasound or MRI may show relative sparing of rectus femoris compared to vastuc intermedius.
MmD has a spectrum of clinical manifestations. In addition to the RYR1-related form, MmD has been described with recessive mutations in selenoprotein N (SEPN1) gene on chromosome 1p. The latter often present in early life with spinal rigidity, scoliosis, and respiratory impairment, and feeding difficulties.
At the histopathological level, CCD is defined by presence of central cores, which are large areas of reduced oxidative activity along the longitudinal axis of myofibers. On the other hand, MmD is characterized by minicores, i.e. multiple areas of reduced oxidative activity affecting only a few sarcomeres. With adenosine triphosphatase (ATPase) staining, some cores may have enhanced oxidative enzyme activity at their periphery, similar to target fibers. There is a marked predominance or uniformity of type 1 fibers in RYR1 related myopathies, which may precede the appearance of the cores.
CNM represents a heterogeneous group of congenital myopathies with the common denominator of abundant central nuclei on muscle biopsy. In addition to RYR1 mutations, CNM has been associated with mutations in the myotubularin (X-linked recessive, XLMTM), the dynamin 2 (autosomal-dominant) and the amphiphysin 2 (autosomal-recessive) genes.
Our patient had mild ptosis, it is unclear whether it was due to the myopathy. Ophthalmoplegia is prominent in CFTD and other recessively inherited RYR1 mutations such as some cases of CNM as well as MmD, but not in CCD.
Suggested readings:
1. Jungbluth H, Sewry CA, Muntoni F. Core myopathies. Seminars in pediatric neurology. Dec 2011;18(4):239-249.
2. Jungbluth H, Dowling JJ, Ferreiro A, Muntoni F. 182nd ENMC International Workshop: RYR1-related myopathies, 15-17th April 2011, Naarden, The Netherlands. Neuromuscular disorders : NMD. May 2012;22(5):453-462.
