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|Year : 2019 | Volume
| Issue : 5 | Page : 1344-1346
X-Linked Myopathy with Excessive Autophagy; A Case Report
Shilpa Rao1, SR Chandra2, Gayathri Narayanappa1
1 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
|Date of Web Publication||19-Nov-2019|
Dr. Gayathri Narayanappa
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
X-linked myopathy with excessive autophagy (XMEA) is a rare, slowly progressive muscle disease characterized by membrane-bound sarcoplasmic vacuoles distinct from other forms of myopathies with vacuoles. We report this rare condition in a 5-year-old boy with proximal muscle weakness and morphological evidence of autophagic vacuoles.
Keywords: Autophagy, vacuoles, X-linked myopathy with excessive autophagy
Key Message: X linked slowly progressive disorder.
|How to cite this article:|
Rao S, Chandra S R, Narayanappa G. X-Linked Myopathy with Excessive Autophagy; A Case Report. Neurol India 2019;67:1344-6
X-linked myopathy with excessive autophagy (XMEA), also referred to as X-linked vacuolated myopathy (XVM), is a rare childhood onset, slowly progressive disorder affecting males. It is morphologically characterized by membrane-bound sarcoplasmic vacuoles. The disease causing gene is mapped to the long arm of the X chromosome (Xq28). Patients present with proximal lower limb weakness and abundant high frequency myotonic discharges without clinical myotonia. There is no cardiomyopathy, respiratory involvement, or cognitive decline. Patients remain ambulant until a later age unlike its morphologic mimics (Pompe disease, Danon disease). Hence, recognition of XMEA has clinical implications and needs to be differentiated from Pompe disease and Danon disease. To our knowledge, we report this rare condition for the first time in India.
| » Case Report|| |
A 5-year-old boy born of nonconsanguineous parentage presented with a history of delayed motor and language milestones. On examination, there was proximal muscle weakness (4/5) involving both the upper and lower limbs. He had pointed chin, cupid bow lips with bilateral facial weakness, and difficulty in whistling. His creatine kinase (CK) was normal (130 U/L). There was no cardiac or respiratory muscle involvement. Electromyography showed myopathic potentials. With a clinical diagnosis of congenital muscular dystrophy, a biopsy of the left biceps was performed.
Fresh frozen muscle sections subjected to a battery of enzyme stains [Succinic dehydrogenase (SDH), nicotinamide adenine dinucleotide tetrazolium reductase (NADH-Tr), adenosine tri phosphatase (ATPase) pH 9.4 and 4.6, acid phosphatase, modified gomori trichrome (MGT), periodic acid Schiff (PAS) with and without diastase] revealed myofibers with peripheral and/or sarcoplasmic vacuolations. The vacuoles contained basophilic granular material, which on MGT appeared red granular, intensely stained on NADH-TR, positive to acid phosphatase [Figure 1], and failed to demonstrate PAS positivity. Electron microscopy revealed membrane-bound vacuoles containing degenerated organelles, small vesicles, granular debris, and membrane whorls [Figure 2]. With these pathological features in a male child, a final diagnosis of XMEA was made.
|Figure 1: Transversely cut skeletal muscle tissue showing (a) peripheral vacuole with granular material (arrow, HE 200×), (b) vacuole-containing red granular material (arrow, MGT 200×), (c) intensely stained for oxidative stain (arrow, NADH-TR 200×), and (d) acid phosphatase positive material within the vacuole (arrow, 100×)|
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|Figure 2: Electron micrograph showing low (a, 9300×) and high (b, 23000×) magnification of membrane-bound autophagic vacuoles containing granular debris, small vesicles, degenerating mitochondria, and membrane whorls (arrow)|
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| » Discussion|| |
XMEA is characterized by slowly progressive muscle weakness and autophagic vacuoles on muscle biopsy. Kalimo et al. first described a Finnish family with 3 brothers, maternal grandfather, and a great uncle with childhood onset, slowly progressive muscle weakness and evidence of excessive autophagic activity on muscle biopsy and named the entity X-linked myopathy with excessive autophagy. Subsequently, Villanova et al. (1995) reported a family with five affected males, all in their teens, who presented with slowly progressive, proximal lower limb weakness and significant thigh atrophy but remained ambulant till death. Till date, 16 families with similar features have been described.,,
Clinically, a slowly progressive weakness, atrophy of proximal muscles, and sparing of cardiac and respiratory muscles have been reported in all families. Shoulder and hip girdle muscles are mainly affected with atrophy of thigh muscles in some patients. Female carriers are asymptomatic or only mildly affected. Yan et al. described a patient with progressive muscle weakness involving the facial and neck muscles. In addition, he had cardiac conduction block, which was not reported in other cases. The disease classically has childhood onset except for rare cases with infantile and late onset. Our patient presented with proximal and facial muscle weakness. There was no cardiac or respiratory involvement and creatine kinase was normal.
Histopathologically, the muscle biopsy shows presence of vacuoles positive to acid phosphatase suggesting lysosomal nature, as seen in the present case. In addition, sarcolemmal deposition of the complement membrane attack complex (MAC) and calcium has been observed. Electron microscopy reveals characteristic multilayered basal lamina with numerous exocytosed materials in between. Vacuoles are seen in the subsarcolemmal and intermyofibrillar spaces and often adjacent to or in communication with exocytosed material. Ultrastructurally, characteristic membrane-bound vacuoles with degraded material and membrane whorls is noted, as in our case. The vacuoles are immunopositive for sarcolemmal proteins dystrophin, caveolin, dysferlin, and spectrin, and helps in differentiating from LAMP2 positive vacuoles in Danon disease. It has been reported that mutation in Xq28 results in the deficiency of VMA21, an essential assembly chaperone of proton pump complex V-ATPase (vacuolar-ATPase). According to the authors, deficiency of VMA21 results in increase in lysosomal pH, thereby causing defective hydrolase activity and blocking autophagy. The result of failed autophagy is accumulation of autophagosomes containing incompletely digested material seen as debris between the basal lamina layers on electron microscopy.
While the pathogenic mechanism remains unclear, studies have proposed that these disorders may be caused by abnormal autophagy. Kalimo et al. described vacuoles to be autophagosomes that function in clearing the sarcoplasmic debris following injury to the muscle fibres, further resulting in extrusion of material between the basal lamina layers. The presence of acid phosphatase positive material seen within the vacuoles in our case corroborates with the earlier reports. Secondary invagination of the membrane and/or endocytosis due to deposition of MAC was proposed by Villonova et al. An unknown change in the membrane of the affected fiber leading to calcium and MAC deposits resulting in autophagic vacuole has also been suggested.
There is no effective treatment for XMEA. The differential diagnoses include other hereditary myopathies with autophagic vacuoles such as rimmed vacuolar myopathies, acid maltase deficiency disorder, Danon disease, and autophagic vacuolar myopathies (AVM). Morphologically, the vacuoles noted in Pompe disease do not express complement, and electron microscopy reveals membrane-bound vacuoles with aggregates of glycogen granules, whereas in Danon disease there is no duplication of the basal lamina, a feature distinct from XMEA. Skeletal muscle, cardiac and liver involvement are noted clinically in Pompe disease; is noted in Pompe disease; skeletal and cardiac muscle are involved with mental retardation in infantile AVM and Danon disease, whereas skeletal muscle, liver, and kidney are affected in adult-onset AVM. In XMEA patients, there is no cardiac or respiratory muscle involvement; they have a slowly progressive course and remain ambulant till late in life.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
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[Figure 1], [Figure 2]