Download Recurrent respiratory failure, complicated by bleeding of the left

One case of type Ⅱglycogen storage disease with recurrent respiratory
failure and left lateral ventricular hemorrhage
Type II glycogen storage disease which is called acid maltase deficiency
also known as Pompe disease is a kind of multi-organ involved autosomal
recessive genetic disease characterized by lysosomal glycogen storage
caused by acid maltase deficiency. The clinical manifestations of type II
glycogen storage disease are diverse due to different clinical types. We
now report one case of type II glycogen storage disease with recurrent
respiratory failure and left lateral ventricular hemorrhage then review the
relevant literatures in order to improve the understanding of clinicians for
this disease.
The Patient who was female and 36 years old then was admitted into the
department of cardiology, affiliated Zhongda hospital, Southeast
University on September 14, 2011 due to the chest tightness, palpitation
for more than 5 months and exacerbation for half a month. The patient had
the symptoms of chest tightness, palpitations after tiredness more than 5
months ago without chest pain, dizziness, amaurosis or sweating. The
symptoms were not cared due to they could be alleviated after break,
however, the symptoms recurred after tiredness several times to more than
ten times every week. Half a month ago, the patient often felt chest
tightness and palpitations aggravated then alleviated in several minutes
without any obvious incentive. Cyanosis in lips and nails could be seen in
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sleep without cough, sputum, fever, chest pain, nausea or vomiting so the
patient went into our hospital for the further treatment. The past medical
history: no history of bronchial asthma, hypertension, diabetes, hepatitis,
tuberculosis or typhoid fever; no history of trauma or blood transfusion;
no history of food or drug allergy; no hobbies of smoking or alcohol; no
family genetic history; one surgical treatment in department of gynecology
of our hospital for ovarian cyst eight years ago(no detail); cesarean section
in department of obstetrics of our hospital four years ago. The physical
examination at admission:T36.6℃, P120/min, R18/min, BP100/65mmHg,
conscious, apathetic, bilateral pupils were equal and round about 4mm in
diameter, conjunctival edema, cyanosis of lips, no neck resistance, trachea
in the center, no jugular vein distention, no thyroid enlargement; no
thoracic deformity, quiet lung breath sound, no moist and dry rales, apex
beat 0.5cm inside the left mid-clavicular line at 5th intercostal, no
significant expansion of the relative cardiac dullness, heart rate 120 / min,
regular rhythm, no pathological murmurs at any auscultatory valve
area; flat and soft abdomen, two scars about 5cm and 8cm at lower
abdomen, whole abdominal tenderness, rebound tenderness, no significant
palpation of enlarged liver and spleen under ribs, no percussion pain in
liver and kidney district, bowel sounds normal, no edema in both lower
limbs. The laboratory tests: blood RT: normal;D-dimer: 437μg / L;
troponin, renal function, electrolytes were all normal; blood gas
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analysis:pH:7.24,
PaCO2:
102mmHg,
PaO2:
50mmHg,
HCO3-:47.3mmol/L,lactic acid:1.0mmol/L; heart ultrasonography was
normal, ECG : sinus tachycardia. Chest CT : a little exudative lesions in
lower lobe of left lung,old lesions in upper lobes of bilateral lungs,
irregular slight high density shade at vascular gap, heart shadow slightly
larger, suspicious limited thickening in pericardium,left pleural thickening
( Figure 1); Arterial blood gas analysis: type II respiratory failure,
respiratory acidosis combined with metabolic alkalosis. The patient was
transferred to the department of respiratory medicine on September 14,
2011. The physical examination showed low limb myodynamia, upper
limbs level 4, lower limbs level 2, limb tendon reflex was not elicited. The
laboratory tests: urine, stool, thyroid function, ESR, CRP, IgE, creatine
kinase (CK), CK-MB, antinuclear antibodies, anti-Sm antibodies,
anti-single-stranded DNA antibody and anti-neutrophil antibodies were all
normal; 24-hour urine protein quantitative:0.32g/24h; blood triglycerides:
0.72mmol/L, total cholesterol: 2.47mmol/L, high density lipoprotein
cholesterol:0.49mmol/L, low-density lipoprotein cholesterol: 1.42mmol/L;
EMG: suspicious myogenic damage. Abdominal B ultrasound: the
superoinferior diameter of left lobe in liver was 9.3cm, the anteroposterior
diameter was 5.4cm, the oblique diameter of right lobe in liver was
17.2cm, shape regular, envelope smooth, the echo of parenchyma
distributed uniformly; the length of spleen was 18.9cm, the splenic
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thickness was 4.9cm, shape regular, the echo of parenchyma distributed
uniformly, no obvious abnormal echo; hepatic vessels were clear, the
diameter of portal vein was 1.6cm, no expansion of intrahepatic bile ducts;
abdominal B ultrasound showed hepatomegaly, splenomegaly and
widened portal vein; Lung function test: FEV1 was 25.8% of the predicted
value, FVC was 25% of the predicted value, PEF% was 35.7% of the
predicted value, FEV1/FVC ratio: 107.7%, diffusion capacity was normal;
polysomnography showed alveolar hypopnea syndrome. The consultation
with the neurologists considered the possibility of neuromuscular disease
so muscle biopsy and further treatment in neurology was recommended.
Due to the financial difficulties, the family members of patient refused and
left the hospital voluntarily on September 22, 2011.
On November 25, 2011, the patient was admitted into the department of
cardiology once again due to chest tightness, palpitations for 7 months and
exacerbation with edema in lower limbs for 10 days. The patient felt chest
tightness and palpitations which were similar to the last occurring
aggravated with paroxysmal nocturnal dyspnea and pitting edema in lower
limbs. The physical examination at admission: T36.9℃, P124/min,
R22/min, BP120/80mmHg, conscious, listlessness, cyanosis of lips, no
neck resistance, quiet lung breath sounds, a little moist rales at bilateral
bottom lungs, heart rate 124/min, regular rhythm, myodynamia of upper
limbs level 4, myodynamia of lower limbs level 2, muscle tension is
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normal, moderate pitting edema in bilateral lower limbs. The admission
diagnosis: alveolar hypopnea syndrome, type II respiratory failure?
chronic heart failure, heart function level Ⅳ. At 7:30 pm, November 25,
2011, the patient manifested confusion and coma with oxygen saturation
declining progressively after the meal. The physical examination:
BP130/90mmHg, P118/min, SaO2:80%, confusion, cyanosis on lips and
cheeks, quiet lung breath sounds, moist rales at bilateral bottom lungs,
heart rate 118/min, regular rhythm, moderate pitting edema in
bilateral lower
limbs. The
emergent
arterial
blood
gas
analysis:
PaCO2:145mmHg, PaO2:46mmHg. The consciousness of patient returned
gradually with the oxygen saturation being maintained at 100% through
endotracheal intubation and mechanical ventilation. The family of patient
refused to transfer the patient to the ICU because of the financial
difficulties.
At 5:30 am, November 26, 2011, the arterial oxygen saturation of patient
dropped to 85%. The physical examination: T:39℃, P120/min, SaO2:85%
BP60/30mmHg, blurred mind, quiet lung breath sounds, moist rales at
bilateral
bottom
lungs,
heart
rate
120/min,
regular
rhythm,
moderate pitting edema in lower limbs. The emergent arterial blood gas
analysis:PaCO2:106mmHg,PaO2:58mmHg;blood BNP:68pg/ml;Bedside
echocardiography: moderate amount of pericardial effusion. The blood
pressure was elevated to 120/90mmHg gradually then the oxygen
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saturation was maintained at 95% to 100% through the repeated sputum
suctioning,
dopamine
pumping
and
metaraminol
intravenous
injection. blood RT: 14.3 × 109/L, N: 89%, CRP: 124mg/L. On November
27, 2011, the body temperature of patient returned to normal after the
patient having received the amoxicillin sulbactam sodium and
levofloxacin therapy. Reexamination of blood gas analysis: pH7.42,
PaCO2:44mmHg, PaO2:75mmHg.
On December 2, 2011, tracheotomy was implemented. On December 6,
2011, the consultation with the expert from Nanjing Brain Hospital
considered myasthenia gravis and mitochondrial myopathy possible then
suggested to detect blood acetylcholine receptor antibodies, thymic tumor
antibodies and muscle biopsy (refused by the patient' s family) as well as
to give diagnostic treatment of neostigmine.
On December 14, 2011, the patient was transferred to the NICU of
neurology. The patient said she began to appear weak lower limbs
especially in the proximal since teenage after further questioning of her
medical history; the physical examination: weakness in the psoas major
muscle, flaccid paralysis in the proximal lower limbs, no limb tendon
reflexes; the diagnosis of myasthenia gravis was not supported due to the
acetylcholine receptor antibody test was negative and neostigmine therapy
was ineffective. On December 16, 2011, lumbar puncture: color of
cerebrospinal fluid was brown, pressure of cerebrospinal fluid was
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160mmH2O(normal range:80mmH2O~180mmH2O), cerebrospinal fluid
biochemistry:
chlorine:113.5mmol/L(normal
range:120mmol/L~
130mmol/L), glucose 5mmol/L (normal range:2.5mmol/L ~ 4.5mmol/L),
protein:1200mg/L(normal
range:200mg~400mg/L);
(normal range:10mg/L ~ 40mg/L);
IgG29.4mg/L,
routine test: red blood cell count 280
× 106/L ( no red blood cells in normal cerebrospinal fluid ), white blood
cell count 10 × 106/L (normal range: 0 ~8 × 106/L); the pathological report
of cerebrospinal fluid: increase of red blood cell count, large amounts of
phagocytic cells of red blood cells and hemosiderin phagocytic cells were
seen (Figure 2), chronic Guillain-Barre syndrome? central nervous system
hemorrhage.
On December 20, 2011, muscle biopsy: the left vastus lateralis muscle was
lean, dark red and not obvious of muscle bundle in the anterolateral
incision of left lateral middle femur. Two muscle bundles about 1 × 2 cm
size of vastus lateralis were removed out for pathological examination.
Head CT on December 21, 2011 showed a small amount of high density
shade at the bottom corner of left lateral ventricle with fluid-fluid level
(Figure 3) so central nervous system hemorrhage was diagnosed although
the patient had no headache, nausea, vomiting and pathological signs. The
family members of patient refused to have head MRI and cerebral
angiography because of the financial difficulties. Chest CT scan: right
pleural effusion, a little inflammation at bilateral lower lungs; enlarged
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heart shadow, pericardial effusion; limited thickening of bilateral pleura.
On December 26, 2011, the pathological report of muscle biopsy showed
(Figure 4): large amounts of fibrous fat metaplasia in the striated muscle
tissue, muscle fiber atrophy and muscle fiber hypertrophy in part of fibers,
extensive vacuolar degeneration of muscle fibers, large amounts of
basophilic material in the majority of vacuoles, positive PAS
staining deposition of basophilic material which disappeared after salivary
amylase digestion in type I and type II fibers were showed through special
staining and immunohistochemistry(Figure 5). The clinical pathological
diagnosis: type II glycogen storage disease. The patient had fever, elevated
hemogram and bilateral lung pneumonia in the chest CT during
hospitalization in the NICU. The body temperature of patient gradually
returned to normal after she had received the piperacillin tazobactam and
other anti-infective drugs. Turning over, patting back and coughing were
encouraged then airway management, intermittent ventilator-assisted
breathing and respiratory muscles exercise with balloon-assisted
ventilation were strengthened for the patient. The patient was relatively
stable in the condition and discharged with balloon-assisted ventilation
through the incision on trachea to maintain the ventilatory function of
respiratory muscles after the above treatment on February 28, 2012.
Discussion
Glycogen is a highly branched polymer of glucose connected by alpha-1, 4
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and α-1, 6 glycosidic bonds with the majority of glucose connected by
alpha-1, 4 glycosidic bond (93% ) and the branch points connected by α-1,
6 glycosidic bond(7%). Glycogen is mainly stored in cytoplasm and
lysosomes as insoluble particles in liver (liver glycogen) and muscle
(muscle glycogen) combining with enzymes involved in glycogen
metabolism. Glycogen storage disease which had 11 known clinical types
in which type II glycogen storage disease is due to acid maltase encoding
gene mutation (chromosomal localization at 17q25 .2-q25 .3) with more
than 40 kinds of gene mutation patterns up to now can be led to by
lysosomal or non-lysosomal glycogen metabolic enzymes deficiency[1].
*Due to acid maltase deficiency, the inhibited glycogenolysis induces
glycogen deposition in the lysosomes of muscle fibers to cause lysosomal
hyperplasia, destruction and release of abnormal lysosomal enzymes
which lead to a series of subcellular structural damage.
Type II glycogen storage disease includes three clinical types: infantile,
juvenile and adult, among them the latter two are collectively known as
late onset type with the incidence rate of about 1/40，000[2]. The main
clinical manifestations of infantile onset: low muscle tension, general
weakness, feeding difficulties, prominent respiratory muscle weakness,
macroglossia, hepatomegaly and cardiac hypertrophy within 1.6 to 2.0
months after birth. The majority of this type usually die within 2 years
with the average life expectancy for about 6.0 to 8.7 months due to the
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rapid progression of disease. This type involves spinal cord, brain stem
and cerebral cortex with the clinical manifestation of malignant
hyperthermia. The main clinical manifestations of juvenile onset: motor
developmental
delay,
progressive
limb-girdle
muscle
weakness,
respiratory related muscle weakness, respiratory failure and gastrocnemius
hypertrophy before 10 years old. This type usually die at 20 to 30 years
old due to respiratory failure with slow progression. The main clinical
manifestations of adult onset: slowly progressive proximal muscular
weakness mainly involving pelvic girdle muscles, limb girdle muscular
dystrophy or polymyositis, lowered or no tendon reflexes, scapular and
peroneal muscular weakness, face tongue muscular weakness, asymmetric
muscular weakness, macroglossia (8% ~ 10%), involvement of respiratory
muscles at age of 30 to 40 years old. The involved skeletal muscles of late
onset type are mainly in limb-girdle muscles, para-spinal muscles and
proximal limbs usually more in lower limbs than in upper limbs and rare
in brain dominating muscles[3]. Late onset type often have some slight
muscle involvement symptoms at the early age[4] consistent with the
manifestation of this patient. The serum CK of three clinical types all can
be elevated especially in the infantile type (up to 10 times of
normal). EMG mainly shows myogenic damage as well as neurogenic
changes such as myotonic discharge and fibrillation potentials[5].The
severity degree of the disease depends on the residual acid α-glucosidase
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enzyme activity determined by the gene mutation. Enzyme activity of the
infantile is completely absent or remnant of 1% less than normal while the
residual enzyme activity of late onset type is usually not more than 30% of
normal. The one whose enzyme activity is more than 40% of normal will
not have onset[2].
The diagnosis of this disease is mainly based on histochemical staining,
electron microscopy examination and gene mutation analysis of muscle
biopsy. Muscle histopathology: typical basophilic vacuole in which
periodic acid Schiff staining and acid phosphatase staining are positive in
a large amount of muscle fibers especially the type II fiber can be seen
through light microscope. Glycogen lake among myofibril and a lot of
autophagy
vacuoles
can
be
seen
through
electron
microscope. Disease-causing mutation in genetic testing is not essential
for the diagnosis of Pompe disease but mainly for family screening and
genetic counseling. The main differential diagnosis: muscular dystrophy,
polymyositis, spinal muscular atrophy, acute Guillain-Barre syndrome and
other metabolic myopathies such as lipid metabolism disorders myopathy
and mitochondrial myopathy.
The support of cardiopulmonary function, rehabilitation training, low
sugar high protein or branched chain amino acid diet in clinic at present
can not prevent the progression of this disease due to the disease lacks of
specific treatment. In recent years, enzyme replacement therapy (ERT)
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such as recombinant human acid α-glucosidase enzyme (rhGAA) can
obviously improve cardiac and skeletal muscle function of patients with
infantile type so as to significantly extend their life in clinical trials
bringing new hope for Pompe patients[6], however, the treatment of this
enzyme is ineffective for glycogen deposition in central nervous system
due to it can not pass blood-brain barrier[7]. GAA transgenic therapy shows
its potential application prospect[8-10].
The head CT scan of the patient on December 21, 2011 showing the left
lateral ventricular hemorrhage is considered to result from the disease
involving the cerebral vessels. The literatures show: there were several
case reports of late onset Pompe disease with cerebrovascular lesions
[11]
such as basilar artery aneurysm and expansionary artery disease with the
common clinical manifestations of cerebral hemorrhage, subarachnoid
hemorrhage or cerebral infarction, transient ischemic attack, cerebral
edema and hydrocephalus. Pathological study of the stroke patients died of
this disease found there was significant vacuolar degeneration caused by
glycogen storage in the smooth muscle cells of cerebral vascular
walls[12]. The lumbar puncture report of the patient on December 16, 2011
showing the cerebrospinal fluid protein concentration was significantly
increased and the majority of the cells was red blood cells while white
blood cells were slightly increased is considered to result from the
intraventricular hemorrhage rather than Guillain-Barre syndrome. Why the
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patient did not have headache or other positive pathological signs may be
associated with the less bleeding volume.
In conclusion, type II glycogen storage disease has certain characteristics
but lacks of specificity and notably involves respiratory muscles and
trunk muscles similar to polymyositis and muscular dystrophy in the
clinical. The disease is often suspected when serum muscle enzymes are
elevated or even normal and definitely diagnosed with muscle
pathological examination. Head CT, MRI, cerebral angiography and
cerebrospinal fluid examination are helpful for the diagnosis of type II
glycogen storage disease with cerebrovascular lesions.
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Reference
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for human acid alpha-glucosidase, detection of an intron in the 5' untranslated
leader sequence, definition of 18-bp polymorphisms, and differences with
previous cDNA and amino acid sequences. DNA Cell Biol,1990,9(2):85-94.
[2]
van
der
Ploeg
AT,Reuser
AJ.
Pompe's
disease.
Lancet,2008,11;372(9646):1342-1353.
[3] Barnes D,Hughes RA,Spencer GT,et al. Adult-onset acid maltase deficiency with
prominent bulbar involvement and ptosis.J R Soc Med,1993,86(1):50.
[4] Laforêt P,Nicolino M,Eymard PB,et al. Juvenile and adult-onset acid maltase
deficiency
in
France:
genotype-phenotype
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Neurology,2000,55(8):1122-1128.
[5] Katzin LW,Amato AA.Pompe disease: a review of the current diagnosis and
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[6] Schoser B,Hill V,Raben N,et al. Therapeutic approaches in glycogen storage
disease type II/Pompe Disease. Neurotherapeutics,2008,5(4):569-578.
[7] Lacaná E,Yao LP,Pariser AR,et al. The role of immune tolerance induction in
restoration of the efficacy of ERT in Pompe disease. Am J Med Genet C Semin
Med Genet,2012,160(1):30-39.
[8] Bali DS,Goldstein JL,Banugaria S,et al.Predicting cross-reactive immunological
material (CRIM) status in Pompe disease using GAAmutations: lessons learned
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Med Genet,2012,160(1):40-49.
[9] Messinger YH,Mendelsohn NJ,Rhead W,et al.Successful immune tolerance
induction to enzyme replacement therapy in CRIM-negative infantile Pompe
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[10] Muraoka T,Murao K,Imachi H,et al.Novel mutations in the gene encoding acid
α-1,4-glucosidase in a patient with late-onset glycogen storage disease type II
(Pompe disease) with impaired intelligence. Intern Med,2011;50(24):2987-2991.
[11] Laforêt P,Petiot P,Nicolino M,et al. Dilative arteriopathy and basilar artery
dolichoectasia
complicating
late-onset
Pompe
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Neurology,2008,70(22):2063-2066.
[12] Scriver CR, Beaudet AL, Sly WS, et a1.The metabolic and molecular basic of
inherited disease．New York：McGraw-Hill,2001:1521-1551.
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Fig 1
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Fig 3
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Fig 5
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