高雄地區第492次小兒科聯合病例討論會

1. 高雄地區第492次
小兒科聯合病例討論會
A 18 y/o Girl Presenting with Recurrent Muscle
Weakness/Soreness and Hypoglycemia
王登豪1 許博堯2 王禎鞠3 郭佩雯3 王碩郁1 蕭惠彬1
1 高醫小兒遺傳內分泌科
2 高醫肝膽內科
3 高醫遺傳諮詢中心

2. Patient Profile
• Name: 蔡ＯＯ
• Age/Gender: 18-year-old, Female
• Height: 155 cm; Weight: 64 kg; BMI: 26.6 kg/m²
• Drug or food allergy: None
• Past history
• No known chronic disease
• 2 episodes of general muscle weakness before

3. Chief Complaint
Conscious change noted this morning.

4. Present Illness
Conscious change noted this morning
Associated symptoms for more than 1 week
- Dizziness, general malaise, nausea with vomiting
Denied
- Fever, headache, blurred vision, URI or GI symptoms
- Trauma, medicine use or pregnancy history
- TOCC history
2022.05.20

5. Physical Examination (at ER)
TPR : BT: 37.1 ℃; HR: 122 bpm; RR: 18 cpm; BP: 128/50 mmHg
Conjunctiva: Not pale
Sclera/Conjunctiva: Anicteric
Neck: Supple
Chest:
- Symmetric movement
- Breath sound: Clear
- Heart sound: Regular, no murmur
Abdomen:
- Inspection: Normal
- Bowel sound: Normoactive
- Palpation: Soft, no tenderness
- Percussion: Normal Flank
- Knocking pain: Absent

6. Laboratory Data (At ER)
CRP 0.7 mg/L Ammonia 278 ug/dL
BUN 15.1 mg/dL Lactate 5.8 mmol/L
Creatinine 0.8 mg/dL Keto 0.6 mmol/L
SGOT 386 IU/L CPK 1096 IU/L
SGPT 400 IU/L CK-MB 41 ng/mL
Na 135 mmol/L Tropo-I 0.045 ng/mL
K 4.0 mmol/L Sugar 26 mg/dL
Cl 99 mmol/L Sugar: 26 -> 99
(After glucose treatment)
PT(INR) 1.15
Uric acid 3.3 mg/dL Bil. (T) 0.83 mg/dL
TSH 0.90 uIU/mL Bil. (D) 0.19 mg/dL
Free T4 1.08 ng/dL BNP 65.6 pg/mL

7. Laboratory Data (At ER)
WBC 12.65 10^3/uL
Hgb 10.6 g/dL
PLT 450 10^3/uL
RDW 16.4 %
Neu 88.2 %
pH 7.366
CO2 34.2 mmHg
HCO3
- 19.1 mmol/L

8. Urine Routine (At ER)
Sugar - (<30) Color Light-Yellow
BIL - (<0.5) Appearance Clear
KET +/- RBC 0-2 /HPF
SG 1.015 sWBC 0-2 /HPF
OB - (<0.03) Epi. cell 0~2 /HPF
PH 5.5
PRO - (<10)
URO Normal (<1.5)
NIT -
WBC - (<25)

9. Neurological Examination (at ER)
General Diplopia(-), slurred speech(-), lethargy(+), drowsy(+), stiff neck(-)
GCS Consciousness: Drowsy, E3V4~5M6
Cranial Nerves Pupil:3.5/3.5, light reflex:+/+
Hemianopia(threatening test):+/+
EOM(Doll's eye):free, nystagmus(-)
Facial sensation(to pain):symmetric; Facial palsy(-)
Muscle Power
(R’t/L’t)
Upper Proximal 5 5
Upper Distal 5 5
Lower Proximal 5 5
Lower Distal 5 5
DTR
(R’t/L’t)
Biceps reflex ++ ++
Brachiaradialis ++ ++
Knee jerk ++ ++
Ankle jerk ++ ++
Babinski sign: plantar flexion/plantar flexion
Sensation Symmetric
Primitive Reflex Glabellar(-), Grasp(-), Palmomental reflex(-), Suck(-), Snout(-)

10. Brain CT(-) (At ER)
Impression:
- No definite evidence of intracranial lesion.

11. Tentative Diagnosis
• Altered mental status
• favor severe hypoglycemia induced
• Hypertransaminasemia
• favor acute or chronic hepatitis
• HyperCKemia
• suspect rhabdomyolysis
Admission to ordinary ward for further evaluation

12. Whipple’s Triad
• Symptoms consistent with hypoglycemia
• A low plasma glucose concentration measured
when symptoms are present
• Resolution of symptoms after the plasma glucose
level is raised
Only those patients who meet the criteria for
Whipple's triad require full evaluation for causes of
a hypoglycemic disorder.

13. Clinical Course
Hypoglycemia
- 72-hour fasting test (05/23 23:00-05/25 20:00)
- Hypoglycemia symptoms noted after fasting 45 hours
- No elevated insulin & C-peptide level under hypoglycemic status
2022.05.23
Sugar 52 mg/dL TG 69 mg/dL
Ketone 0.4 mmol/L Cholesterol 163 mg/dL
hGH 2.24 ng/mL HDL-C 42.6 mg/dL
C-Peptide 0.52 ng/mL LDL-C 85.1 mg/dL
Insulin <1.0 uIU/mL
Cortisol 14.76 ug/dL

14. Clinical Course
Acute hepatitis
- Viral: No HAV, HBV, HCV, CMV, HSV, EBV, HIV infection
- Autoimmune hepatitis: ASMA, IgG4, anti-AMA negative
- Wilson Disease
- Mildly decreased level of Ceruloplasmin (14.7 mg/dL)
- 24-hr urine Copper: 59.8 µg/day
- Serum Copper: 59.1 µg/dL
- No Kayser–Fleischer ring
2022.05.23

15. Clinical Course
2022.05.23 (05.23) EEG
- No definite evidence of cortical dysfunction
(05.27) Arrange Liver echo, Liver Biopsy
(05.31) Arrange Liver MR(+)
2022.06.01 Consult Pediatric genetic specialist for suspect GSD
- Pompe screen, MSMS screen
- Avoid fasting
- Uncooked cornstarch at bedtime if oral feeding

16. Liver Echo (2022.05.27)
Impression:
- Chronic liver disease and hepatomegaly
- Mild fatty liver

17. Liver MR (2022.05.31)
Impression:
- Marked hepatomegaly with poor uptake of hepatobiliary
contrast agent and poor opacification of the biliary tract due
to impaired liver function and intrahepatic cholestasis.
- Fatty liver (estimated about 41.2%)

18. Pathology Report (2022.06.01)
• Pathologic Diagnosis
• Liver, needle biopsy, macrovesicular fatty changes and
glycogen accumulation
• The hepatocytes
• Macrovesicular fatty changes
• Significant glycogen accumulation in the cytoplasm
• No hepatocytes necrosis or bile stasis.
• No definite evidence of portal tract fibrosis.
• Differential diagnosis
• Liver failure secondary to drugs or chemical intoxication
• Inherited metabolic disease.

19. Chest X-ray (At ER)
Impression:
- No cardiomegaly or cardiopulmonary active lesion.

20. EKG (At ER)
Impression:
- Sinus tachycardia

21. Cardiac Echo
Impression:
- Normal LV systolic function (LVEF: 79.85%); Mild TR

22. Clinical Course
2022.05.23 (05.23) EEG
- No definite evidence of cortical dysfunction
(05.27) Arrange Liver echo, Liver Biopsy
(05.31) Arrange Liver MR(+)
2022.06.01 Consult Pediatric genetic specialist for suspect GSD
- Examination suggestion
○ Pompe screen, MSMS screen
○ UOA screen, BAA screen if hypoglycemia noted
○ Consider arrange WES
- Avoid fasting
- Uncooked cornstarch at bedtime if oral feeding

23. Clinical Course
2022.06.10 Consult Neurologist for ​​limbs weakness/soreness
- Lower> upper, proximal>distal
- Muscle weakness of neck (頭往後仰抬不起來)
Muscle Power
(R’t/L’t)
Upper proximal 4- 4-
Upper Distal 5 5
Lower proximal 3 3
Lower Distal 5 5
2 episodes of general muscle weakness before

24. Pedigree
No similar symptoms
in her family members.

25. Clinical Course
2022.06.11 Progressive consciousness disturbance since night
Coma with bilateral pupils dilation
- Brain CT: no ICH
- ABG: pH 7.156, CO2 81.9 mmHg, HCO3
- 28.3 mmol/L
- Ammonia 298 ug/dL, Sugar 154 mg/dL
Endotracheal intubation, transfer to ICU
- Keep Lactulose for hyperammonemia
- D50W pump for hypoglycemia
- Self-paid gene examination on 06.17
- Tracheostomy on 06.23
Transferred to ordinary ward, discharge on 07.19
2022.06.28

26. Clinical Course
2022.06.01
-
2022.06.11
Consult GS for liver transplantation
GOT
GPT
Bil.

27. Pompe Screening Test (2022.06.08)

28. MS/MS Screening (2022.06.06)

29. Whole Exome Sequencing (2022.06.17)

30. Urine Organic Acid

31. Final Diagnosis
• Glutaric acidemia, type 2, late-onset type
• Diet titration to high sugar, low fat, low
protein
• CO-Q10, Carnitine, Vit B2 supplement
• Impending liver failure, improved
• Hypercapnic respiratory failure
• post tracheostomy creation on 2022.06.23
• post decannulation on 2022.08.19
• Muscle weakness
• Improved while OPD follow-up later
Transferred to ordinary ward on 06.28, discharge on 07.19

32. Discussion
Glutaric Acidemia Type II
(戊二酸血症第二型)

33. Cause of Muscle Weakness

34. Cause of Hypoglycemia
• Insulin-mediated
• Fatty acid oxidation disorders
• Ketotic hypoglycemia
• Disorders of gluconeogenesis
• Other causes
• Medication, liver failure, sepsis…

35. Glycogen-Storage Diseases
Our patient:
Normal Ketone, UA and Lipid profile.

36. 簡介
• 一種脂肪酸氧化過程異常疾病
• 多發性醯基輔酶A去氫酶缺乏(MADD)
• 脂肪酸及支鏈胺基酸代謝異常
• 體染色體隱性遺傳疾病
• 台灣發生率約為53萬分之一
• 可分為
• 新生兒型且合併先天異常
• 新生兒型無先天異常
• 晚發型

37. Pathogenesis
Type I & II
Type III

38. 新生兒型且合併先天異常
• 出生後24小時內出現
• 嚴重非酮症性低血糖
• 肌張力減退
• 肝腫大
• 嚴重代謝性酸中毒
• 先天結構異常
• 多囊腎、中臉發育不全及腦部或肢體異常等
• 大多數患者在出生後一周內死亡

39. 新生兒型無先天異常
• 出生後24-48小時出現
• 嚴重低血糖
• 呼吸窘迫、肌張力低
• 肝腫大、心肌病變、腎臟異常
• 代謝性酸中毒和低鉀血症
• 大多數患者在出生一周內死亡
• 部份患者存活幾個月後死於嚴重的心肌病變

40. 晚發型
• 通常是孩童晚期或至成人期才有臨床症狀
• 肌肉無力(通常為第一個臨床症狀)
• 間歇性發作噁心、嘔吐
• 虛弱無力
• 肝臟腫大
• 類雷氏症候群(急性肝衰竭、腦病變)
• 在特殊狀況下(如病毒感染、運動等)時
• 會有一段時間發生低血糖
• 低血糖嚴重時會虛弱、步行搖晃及頭暈目眩

41. 篩檢與確診
• 新生兒篩檢
• 血片檢體中C4、C5短鏈脂肪酸之含量
• 確認診斷
• 尿液有機酸檢查
• 串聯質譜儀測量血中C4-C16醯基肉鹼的含量
• 相關基因突變分析
• ETFA, ETFB -> 早發型
• ETFDH -> 晚發型

42. 治療
• 飲食
• 高碳水
• 低蛋白
• 低脂質
• 補充
• 核黃素 (Riboflavin, B2)
• Co-enzyme Q10
• 肉鹼 (Carnitine)
• 避免飢餓與壓力

43. Back to Our Case
• Recurrent muscle weakness/soreness
• Initial data
• Hypoglycemia without ketonemia
• Hyperammonemia
• Hypertransaminasemia and HyperCKemia
• Treatment
• High carbohydrate diet
• Riboflavin, Co-Q10 and Carnitine supplement
WES diagnosis: Glutaric Acidemia Type II

44. Liver Biopsy
Liver biopsy finding:
Massive micro-macro vacuolar steatohepatitis picture with minimal fibrosis.

45. Glycogenosis