Core Disease in an Adult.

The congenital myopathies are believed to be confined to pediatric age group, so neurologists are divided on their diagnosis and management in adults.[1] However, not all congenital myopathies are of early onset and may indeed present only in adulthood.[1]

Core disease is a form of congenital nonprogressive myopathy originally reported by Shy and Magre in 1956.[2] It is defined by areas of reduced oxidative enzyme activity along the longitudinal axis of the muscle and clinical features of congenital myopathy.[3] These cores results from an abnormality of ryanodine receptors in sarcoplasmic reticulum (SR), which regulate the release of calcium. Abnormality in the receptors allow excess calcium into the fibers which damages the mitochondria.[4] The RYR1 mutations linked to Malignant Hyperthermia and Central Core Disease are clustered in three relatively restricted regions of the protein or “hot spots”: N-terminal, central, and C-terminal. They are also called domains 1–3, respectively.[56] Most of the Central Core Disease mutations are clustered in domain 3, which is located in the C-terminus.[5]

The incidence of all congenital myopathies is estimated 6/100000 live births.[3] Core disease is the most common congenital myopathy.[3] While the overall incidence of Central core disease (CCD) is rare, the absence of symptoms in a significant number of patients may suggest that the actual incidence of CCD may be considerably higher than that perceived currently.[5] The phenotypic presentation varies considerably from no visible disability to lack of independent ambulation. The clinical hallmarks are diffuse muscle weakness, multiple bone deformities, and contractures.[7]

We report a case of 42-year-old male, which was referred to our tertiary care center for proximal weakness in lower limbs as a child. His developmental milestones were delayed and had history of delayed first walk at nearly 2 years of age. Myopathy of unknown etiology had been suspected since childhood. Patient is a known case of diabetic mellitus and hypertension since 10 years. The weakness in the limbs was very slowly progressive over the years. He has difficulty in walking up the stairs and getting up from squatting position involving both lower limbs simultaneously. The patient has difficulty in walking in the form of buckling of knees while walking, tripping over toe, associated with difficulty in wearing shoes (L > R), but no history of falling of slippers from feet. His daily activities are not particularly affected but weight bearing activities and running long distances are almost impossible for him. Tone of all the limbs is normal. Power (MRC Grade) of hips are 3/5, knee are 4/5, left foot 1/5, and right foot 2/5. Knee jerk and ankle jerk are absent and rest of the reflexes is normal. Bilateral calf hypertrophy is present. There is no history of relapsing, remitting illness, and no history of any diurnal variation. Patient does not give any history of difficulty of holding things in hands and raising arm above shoulder. There is no history of numbness, tingling, diplopia, deviation of angle of mouth, difficulty of swallowing, or respiratory distress. He has right elbow flexion contracture but no spinal deformity. There is no fasciculations or atrophy.

Systemic examination reveals no abnormal findings. Electrocardiogram (ECG) and 2D Echo are normal with no evidence of dysrhythmia or cardiomyopathy. His creatinine phosphokinase (CPK) was raised (440 IU/ml). Electromyography (EMG) showed myogenic pattern.

A biopsy from left adductor muscle was taken on histopathological examination. Biopsy showed relatively preserved fascicular architecture with perimysial and endomysial fat infiltration. There was mild variation in fiber size with few hypertrophic fibers and some fibers with internal nuclei. The interfascicular area was moderately widened by the ingrowth of fat tissues. Mild focal mononuclear inflammatory infiltrate was seen in perimysium. No necrosis or regenerating fibers were seen. No increase in fibrosis was seen on MT stain. Cryosections were evaluated for enzyme histochemistry. Although routine H and E stain showed relatively preserved architecture [Figure 1a], cores can be appreciated on H and E stain [Figure 1b].

Figure 1

(a) Preserved architecture with moderate variation in fiber size and fiber showing internal nuclei (HE 40×). (b) Occasional core in muscle fiber (HE 80×). (c) Well demarcated cores in PAS stain (PAS 80×). (d) Type 1 fiber predominance (ATP 9.4)

Histochemical staining for Nicotinamide dehydrogense -tetrazolium reductase (NADHTR), Cyclo-oxygenase (COX) [Figure 2c and 2d], and succinate dehydrogenase (SDH) [Figure 2a and 2b] in this case showed staining defect in cores which indicate mitochondrial absence. Periodic acid Schiff (PAS) stain also delineated these cores clearly [Figure 1c].

Figure 2

(a) SDH stain shows cores of varying sizes in transverse section (40×). (b) SDH stain shows cores along the entire length in longitudinal section (80×). (c) COX stain shows cores in transverse section (80×). (d) SDH stain shows cores along the entire length in longitudinal section (80×)

ATPase stain (pH 9.4) showed type 1 fiber predominance [Figure 1d] in this case. In a normal muscle, 35% to 40% Type 1 fibers, and 60% to 65% Type 2 fibers are variable according to function and anatomic location. CCD almost always represents predominance of Type 1 fibers. This results from the fusion of myotubes during the 24th to 28th week of gestation, caused by arrested development of Type 1 fibers or by the abnormal conversion of Type 2 to Type 1 fibers.[4] There are speculations that fiber differentiation may be related to change in the pattern of motor neurons or muscle activity involvement.[48] Cases with adult onset are reported to have more severe Type 1 predominance reinnervated by Type 1 exons than cases of early onset, whose clinical manifestation depend on the age of onset and rate of progression of this process.[2]

Although, there is no correlation between the number of fibers containing cores and severity of disease or progression.[29] Upto 20% to 100% of muscle fibers in a muscle biopsy specimen show pathognomic features of central core disease. The key morphological abnormalities in this disorder include the presence of central or eccentric cores within muscle fibers that do not stain for glycogen, phosphorylase, or oxidative enzymes but sometimes do stain for ATPase.[10] The clinical manifestations of our patient are generally consistent with those of most reported cases, which have been described as a benign and non-progressive/very slowly progressive course of muscle weakness since birth. The developmental milestones were delayed. The results of muscle biopsy showed Type 1 fiber predominance over 80% of fibers with central cores, thus reflecting disease progression.

A significantly increased portion of both, absolute calf hypertrophies and pseudohypertrophies as compared with the control group were found in core disease by Reimers et al.[11] Additional extraocular muscle involvement, contracture, kyphoscoliosis, and distal muscle involvement may also be seen[35] as is seen here.

In terms of core structure, most patients had single core, but multiple cores were also seen especially in patients with heterozygous non-C-terminal mutations, and may be associated with Malignant Hyperthermia susceptibility. In patients with C-terminal mutations, cores were noted to be characteristic: these were ovoid and with clearly demarcated borders, mostly single, and were central.[5] In mutations outside domain 3, most cores were peripheral or subsarcolemmal.

Genetic analysis for mutation in the gene for RYR1 receptor and follow-up for malignant hyperthermia was advised. The susceptible individuals develop generalized muscle contracture followed by a hypermetabolic state due to massive calcium release from the SR, when they are exposed to inhaled general anesthetics or to the depolarizing muscle relaxant succinylcholine (Malignant Hyperthermia).[5] Dominant RYR1 mutations associated with Malignant Hyperthermia susceptibility trait have been recently identified as a common cause of (exertional) rhabdomyolysis presenting throughout life.

Improvements in supportive care and development of novel therapies are likely to reduce morbidity and mortality, resulting in an increasing number of patients with early-onset myopathies transitioning to adult neuromuscular services.[3] Finally, induced and episodic phenotypes such as (exertional) rhabdomyolysis or periodicparalysis are implicated.[3]

CONCLUSION

Central core disease is thought to be rare due to variability in clinical features and slowly progressive nature of the disease. Clinician should be aware of the disease presentation in adults, because of its association with malignant hyperthermia. The diagnosis is confirmed by muscle biopsy, which is the most cheap and cost effective method.

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Conflicts of interest

There are no conflicts of interest.