临床表现为高碳酸血症的BAG3相关肌原纤维性肌病：一例病例报告及文献回顾

doi:10.24920/003883

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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.

Abstract

Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide. The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should be considered as a rare differential diagnosis of hypercapnia.
Methods We report a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209Leu mutation in BAG3 and reviewed the literatures for reported cases related to this mutation.
Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation. The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a de novo p.Pro209Leu mutation in BAG3. Totally twenty-one patients from twenty families with a confirmed diagnosis of BAG3-related myopathy were reported to date, including this patient and literature review. The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life. Most patients presented toe/clumsy walking or running as the onset symptom, followed by muscle weakness or atrophy. Creatine kinase levels were elevated in fourteen patients and were normal in three. Eighteen patients developed respiratory insufficiency during the disease course and thirteen (one could not tolerate non-invasive assisted ventilation) required non-invasive assisted ventilation for treatment. Except for one not reported, heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation. Z-disk streaming and aggregation could be observed in most of the patients’ muscle histology. In the long-term follow-up, five patients died of cardiac or respiratory failure.
Conclusion BAG3-associated myopathy is a rare type of myofibrillar myopathy. It should be considered as a rare differential diagnosis of hypercapnia.

Key words: myofibrillar myopathy, BAG3, respiratory insufficiency, 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.

Figures/Tables 8

Figure 1.

Figure 2.

Table 1

Figure 3.

Figure 4.

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.^[13]	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.^[11]	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.^[11]	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.^[11]	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.^[11]	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.^[11]	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.^[10]	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.^[10]	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.^[10]	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.^[10]	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.^[9]	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.^[14]	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.^[12]	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.^[8]	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.^[8]	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.^[8]	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.^[15]	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.^[3]	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.^[16]	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.^[2]	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 2

Figure 5.

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.

Table 3

References 21.

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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

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