Chinese Medical Sciences Journal ›› 2021, Vol. 36 ›› Issue (4): 265-278.doi: 10.24920/003883
• Original Articles • Previous Articles Next Articles
Yan Xu1, Shixuan Liu2, Wenbing Xu1, Jinmei Luo1, Jingwen Niu3, Zhi Liu3, Jinming Gao1, Jinglan Wang1, Yi Dai3, *(), Mengzhao Wang1, *(
)
Received:
2021-01-25
Published:
2021-12-31
Online:
2021-10-09
Contact:
Yi Dai,Mengzhao Wang
E-mail:pumchdy@pumch.cn;mengzhaowang@sina.com
In this report, the authors describe a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209Leu mutation in BAG3 who presented with skeletomuscular and peripheral nerve dysfunction in childhood and gradually appearing symptoms of hypercapnia that required assisted ventilation, suggesting that BAG3-associated MFM should be considered as a rare differential diagnosis of hypercapnia. |
Yan Xu, Shixuan Liu, Wenbing Xu, Jinmei Luo, Jingwen Niu, Zhi Liu, Jinming Gao, Jinglan Wang, Yi Dai, Mengzhao Wang. BAG3-Related Myofibrillar Myopathy Presenting as Hypercapnia: A Case Report and Literature Review[J].Chinese Medical Sciences Journal, 2021, 36(4): 265-278.
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Table 1
Results of nerve conduction study"
Nerve stimulated | Recording site | Distal or peak latency (ms) | Amplitude (mv) | Conduction velocity (m/s) |
---|---|---|---|---|
Medianus Motor Left | Wrist-APB | 3.91 (30%↑) | 10.5 | |
Elbow-Wrist | 9.34 | 9.9 | 44.2 (32%↓) | |
Medianus Motor Right | Wrist-APB | 3.96 (32%↑) | 7.1(68%↓) | |
Elbow-Wrist | 8.96 | 5.8(68%↓) | 44.0 (32%↓) | |
Ulnaris Motor Left | Wrist-ADM | 2.42 | 8.9 | |
Above Elbow-Wrist | 8.34 | 8.2 | 43.1 (34%↓) | |
Ulnaris Motor Right | Wrist-ADM | 2.6 | 8.3 | |
Above Elbow-Wrist | 8.56 | 8.5 | 41.1 (37%↓) | |
Tibialis Motor Left | Ankle-AH | NR | NR | |
Peroneus Motor Left | Ankle-EDB | NR | NR | |
Fibula Head-Ankle | NR | NR | ||
Peroneus Motor Right | Ankle-EDB | NR | NR | NR |
Fibula Head-Ankle | NR | NR | NR |
Figure 3.
Pathological evaluation of the left quadriceps femoris muscle. A. Hematoxylin/eosin staining showed transverse sections, with greater variability in muscle-fiber size and some scattered angular muscle fibers (×200). Several degenerated fibers are seen, and a few fibers contained cytoplasmic aggregates. There was no peri-fascicular atrophy, necrosis, or phagocytosis. B. Modified Gomori trichrome staining shows dark stained cytoplasmic aggregates in some fibers (×400). C. Nicotinamide adenine dinucleotide staining indicates irregular internal architecture in a few muscle fibers (×200). D. Acid phosphatase staining reveals deep stained positive particles in a few individual muscle fibers (×200)."
Table 2
Summary of the characteristics of the current patient and of the patients in the literature review"
Patient number | References | Sex (age at onset) | Symptoms at onset | Skeletal myopathy | Other features | CK levels | Electromyography | Neuropathy | Electroneuro- graphy | Respiratory function | Cardiomyopathy [QTc (ms)] | Treatment | Parents | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | Kostera-Pruszczyk et al.[ | Female (8 years old) | Toe-walking and foot deformity | Subclinical | Rigidity of cervical and thoracic spine, contractures at hips, knees, and ankles; bilateral pes cavus deformity, and absence of deep tendon reflexes in the lower extremities | 1.5-fold above normal | NR | Axonal-demyelinating sensory-motor polyneuropathy | Conduction velocity in the median/ulnar motor nerves, 38 m/s | Normal (FVC 87%) | Restrictive cardiomyopathy (mean 478 ms, max 574 ms) | NR | Unaffected | NR |
2 | Jaffer et al. [ | Female (1.5 years old) | Toe-walking | Proximodistal weakness, proximal muscle atrophy, and weakness of neck flexion | Rigid spine, Achilles tendon tightness, elbow/finger flexion contractures | NR | Chronic neurogenic changes, absent responses on stimulation of the phrenic nerves, and chronic denervation of the diaphragm | Giant axonal neuropathy (neuropathological axonal loss and giant thinly myelinated axons) | Some intermediate slowing of conduction velocity | NR | Restrictive cardiomyopathy (NR) | Heart transplantation at 13 years of age | Unaffected | NR |
3 | Jaffer et al. [ | Male (early childhood) | Toe-walking and high steppage gait | Proximal and distal muscle weakness and atrophy | Rigid spine, pectus carinatum, distal contractures and scoliosis | NR | Chronic neurogenic changes | Giant axonal neuropathy (giant thinly myelinated axons) | Some intermediate slowing of conduction velocity | FVC 63%→53%; nocturnal hypoventilation | Restrictive cardiomyopathy (NR) | Non-invasive ventilatory support | Unaffected | NR |
4 | Jaffer et al. [ | Male (11 months) | Toe-walking, clumsy, and frequent falls | Severe proximal and distal weakness | Rigid spine, scoliosis, Achilles tendon tightness, and lower limb deformities | 1054-2500 IU/L | NR | NR | NR | FVC 50% when standing, 39% when lying | Restrictive cardiomyopathy (NR) | Nocturnal non-invasive ventilatory support after the 9th month | Unaffected | Died of cardiorespiratory failure at age 12 years and 9 months |
5 | Jaffer et al. [ | Female (first decade) | Toe-walking and progressive mobility impairment | Minimal distal upper limb weakness and proximal weakness of the hip extensors and adductors | Pectus carinatum, tight Achilles tendons, and scoliosis (Cobb angle 104 °) | 154 IU/L | Chronic neurogenic changes | Axonal neuropathy | Some intermediate slowing of conduction velocity | FVC 46% | Restrictive cardiomyopathy (NR) | Nocturnal non-invasive ventilatory support | Her older sister and father similarly affected | NR |
6(older sister of patient No. 5) | Jaffer et al. [ | Female (8 years old, | Bilateral pes cavus and progressively impaired mobility | NR | NR | NR | NR | NR | NR | Respiratory weakness | NR | Nocturnal non-invasive ventilatory support in her 20s | As above | NR |
7 | Odgerel et al. [ | Male (12 years old) | Neck, proximal muscles of upper and lower extremities involved, and cardiomyopathy | Generalized muscle weakness and atrophy | Skeletal deformity | Normal | Neurogenic/myopathic changes | Giant axonal neuropathy | Axonal neuropathy | Respiratory weakness at 15 years of age | Restrictive/ hypertrophic cardiomyopathy (NR) | Heart transplantation at 14 years of age; ventilator dependency at age 29 years | Unaffected | Alive |
8 | Odgerel et al. [ | Male (9 years old) | Proximal muscles of upper and lower extremities involved, and cardiomyopathy | Generalized muscle weakness and atrophy | NR | NR | NR | NR | NR | Respiratory weakness at 19 years of age | Restrictive/ hypertrophic cardiomyopathy (NR) | NR | Unaffected | Sudden death at 9 years |
9 | Odgerel et al. [ | Female (12 years old) | Neck and distal lower extremity muscle weakness, bilateral pes cavus, and slight dorsal scoliosis | Neck and distal muscle weakness | Bilateral pes cavus and slight dorsal scoliosis | 2-3 times above normal | Myopathic changes | Giant axonal neuropathy | Axonal neuropathy | Respiratory weakness at 20 years of age | Restrictive/ hypertrophic cardiomyopathy (NR) | NR | Unaffected | Died at the age of 20 years of cardiac and respiratory failure |
10 | Odgerel et al. [ | Male (5 years old) | Problem running | Proximal muscle weakness | NR | Normal | Neurogenic/myopathic changes | Giant axonal neuropathy | Axonal neuropathy | Respiratory weakness at 10 years of age | Restrictive/ hypertrophic cardiomyopathy (NR) | Heart transplantation at 13 years of age; ventilator dependent at 13 years of age | Unaffected | Died at 15 years of age |
11 | Lee et al. [ | Female (6 years old) | Progressive clumsy walking and easy falling during exercise | Mild proximal muscle weakness of both legs and later both arms | Rigid spine and scoliosis, contractures, and foot deformity | 991 IU/L (normal range < 154) | Increase in duration of the action potential with normal amplitude | Axonal neuropathy | Decreased motor (tibial and peroneal) amplitudes and latencies | Restrictive lung disease | Restrictive/ hypertrophic cardiomyopathy (450-570 ms) | NR | Her father was a carrier of c.772C>T (p. Arg258 Trp) | NR |
12 | Konersman et al. [ | Male (8 years old) | Restrictive cardiomyopathy | Severe diffuse muscle atrophy and weakness (distal> proximal), and mild bilateral lower facial weakness | Toe walking, imbalance, foot deformity, spinal rigidity | 669 to 1099 IU/L (normal range: 55-170) | Fibrillation potentials in the proximal and distal muscles, giant motor unit potentials (> 10 mV) in the distal muscles, and reduced recruitment in all muscles | Sensorimotor polyneuropathy with mixed axonal and demyelinating features and indolent primarily axonal neuropathy with secondary demyelination/remyelination | Upper extremity motor conduction velocities were in the “intermediate” range | Difficulty breathing with hypercapnic respiratory insufficiency of neuromuscular etiology; intermittent ventilation during the day and continuous at night | Restrictive cardiomyopathy | Orthotopic heart transplant at 8 years of age, intermittent ventilation throughout the day and continuous ventilation at night via tracheostomy | Unaffected | NR |
13 | Noury et al.[ | Female (10 years old) | Inability to run and maintain prolonged standing | Proximal and distal lower limb weakness; neck flexion was impossible | Rigid spine, varus foot deformity, bilateral scapular winging, and hypophonia | Normal | Mild myogenic changes in the upper limb proximal muscles | Severe sensory-motor axonal neuropathy predominant in the lower limbs with mild myogenic changes in the upper limb proximal muscles | NR | FVC 42% | Normal (NR) | No | NR | NR |
14 | Selcen et al.[ | Male (early childhood) | Toe-walking | Severe diffuse muscle weakness and atrophy | Contractures at the knees and ankles and bilateral diaphragm paralysis | 3-fold above normal | NR | NR | NR | Respiratory insufficiency | Restrictive cardiomyopathy (NR) | Heart transplantation at 13 years of age | NR | NR |
15 | Selcen et al.[ | Female (13 years old) | Scoliosis, rigid spine, and easy fatigability | Axial, moderately severe proximal and distal muscle weakness | Spinal stiffness, and hypernasal speech | 6-fold above normal | Myopathic motor unit potentials | Axonal and demyelinating peripheral neuropathy | Axonal and demyelinating peripheral neuropathy | Restrictive respiratory insufficiency | Hypertrophic cardiomyopathy (NR) | Nocturnal non-invasive ventilatory support | NR | NR |
16 | Selcen et al.[ | Male (7 years old) | Toe-walking | Weakness of the axial and proximal limb muscles | Valgus ankle deformity, thoracic scoliosis, scapular winging, and rigid spine | 15-fold above normal | NR | NR | NR | Reduced FVC and respiratory insufficiency | Restrictive cardiomyopathy (NR) | Did not tolerate nocturnal ventilatory support | NR | Died following a chest infection |
17 | Schänzer et al.[ | Male (4 years old) | Restrictive cardiomyopathy | Proximal muscle weakness | Mild scoliosis | Slightly increased (227 IU/L; normal range < 180) | Myopathic pattern | Combined demyelinating and axonal polyneuropathy | Combined demyelinating and axonal polyneuropathy | VC 53% and nocturnal hypoxemia and hypercapnia | Restrictive cardiomyopathy | Heart transplantation, non-invasive ventilatory support | Unaffected | NR |
18 | D’Avila et al.[ | Female (11 years old to 14 years old) | Spinal contractures causing spinal rigidity, scapular winging, and later postural muscle atrophy | Postural muscle atrophy and proximal weakness in a limb girdle distribution pattern with loss of deambulation | Spinal contractures causing spinal rigidity, scapular winging | Normal to 1.500 U/L | Axonal neuropathy | Axonal neuropathy | NR | Respiratory insufficiency | Impaired conduction, arrhythmia, and cardiac hypertrophy | Ventilatory support on a continuous basis or overnight. | Unaffected | NR |
19 | Latham et al.[ | Male (2 years old) | Toe walking and progressive decreased range of motion of the neck and lower extremities | Loss of gross and fine motor control | Severe contractures of the lower extremities, scoliosis, rigid spine, and neck extension contracture | 110 to 510 IU/L (normal range: 35-230) | NR | NR | NR | Obstructive sleep apnea, and severe restrictive lung disease | Restrictive cardiomyopathy | Cardiac transplantation, nighttime noninvasive ventilation | NR | NR |
20 | Semmler et al.[ | Male (34 years old) | Distal lower limb weakness and symmetrical calve atrophy | Skeletal muscle weakness | Scapular winging | 1050 IU/L | Mixed pattern | Axonal sensorimotor polyneuropathy | NR | Normal | Normal | NR | NR | NR |
21 | Current patient | Female (14 years old) | Scoliosis | Axial, both upper and lower extremity muscle weakness and atrophy | Clumsy walking, difficulty in squatting, unstable gait | 2-fold above normal | Neurogenic damage pattern combined with evidence of myogenic damage | Demyelinating and axonal neuropathy | Both motor and sensory nerves were impaired; the condition of the nerves in the lower extremities was more severe than that of nerves of the upper extremities and there was no wave on the peroneus nerve test | Severe restrictive ventilation dysfunction | Normal (461 ms) | Non-invasive ventilatory support | Unaffected | Alive |
Table 3
Summary of the histology of the muscle biopsy of the current patient and of the patients in the literature review"
Patient number | Histology of the muscle biopsy |
---|---|
1 | Large deposits in fibers, Z-disc streaming, disorganization of myofibrils, and sarcomeric disorganization with accumulation of polymorphic dense structures; focal changes containing granulomatous material. |
2 | NR |
3-4 | Accumulation of myotilin and desmin, small atrophic fibers consistent with denervation, granulomatous material, myofibrillar loss, Z-line streaming. |
5 | NR |
6 | NR |
7-8 | Myofibrillar breakdown, presence of desmin-reactive inclusions, Z-line streaming. |
9 | Accumulation of dark dense material, increment of intermyofibrillar spaces, and multiple core areas, desmin positive inclusions, electron dense filamentous and granular material disrupting the Z-lines |
10 | Atrophic fibers, focal myofibrillar disorganization, and dark inclusions with prominence of desmin |
11 | Atrophic fibers, focal myofibrillar disorganization, accumulation of electron-dense granulofilamentous materials, myofibrillar degeneration with minicores |
12 | Fiber size variation with atrophic and hypertrophic fibers, myofibrillar disruption, scattered fibers with inclusions and vacuoles |
13 | Accumulation of granulofilamentous material originating from the Z-disk disrupting the sarcomeres, accumulation of dense granulomatous material |
14-16 | Fiber size variation, protein accumulation, Z disk streaming and accumulation of electron dense structures, disarray of myofibrils, mitochondrial cluster, and apoptotic nuclei |
17 | Myofibrillar disintegration, intracytoplasmic inclusions containing different proteins, myofibrillar disintegration, and Z-disk streaming |
18 | Z disk aggregates and atrophic type I fibers, whereas typeⅡfibers were hypertrophic |
19 | Myofibril dissolution and accumulation of degradation products at the Z-disk |
20 | Z-disk streaming and accumulation of granulofilamentous material |
21 | Variability in muscle-fiber size, some scattered angular muscle fibers and several degenerated fibres. Dark stained cytoplasmic, irregular internal architecture, deep stained positive particles could be seen in fibers. |
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