431.3 🩺 內科專科考前版

431.3.0.1 📌 一頁重點

22E updates / 新藥：
- Empagliflozin（SGLT2 inhibitor）for GSD Ib neutropenia + IBD（22E 新適應症，game-changer for GSD Ib）
- Modified extended-release cornstarch（Glycosade） for GSD I/III/VI/IX — 延長 fasting 至 8-10 hr
- CGM（continuous glucose monitoring） routine for GSD I/III/VI/IX
- AAV gene therapy GSD Ia（DTX401，phase III）：AAV8-G6PC
- mRNA therapy GSD Ia：phase I
- Avalglucosidase + cipaglucosidase for Pompe（見 Ch 429）
- Tafenoquine：新一代 antimalarial，single dose 但 G6PD def 嚴格禁忌（FDA black box）
- Pegvisomant、somatostatin analog 對 GSD I + acromegaly-like rare scenarios
內分泌相關：
- GSD I 成人併發症 endocrine：osteoporosis、PCOS、thyroid autoimmunity (GSD Ib)
- Galactosemia POI 標準 internal medicine endocrine consult
- HFI 與 metabolic syndrome / NAFLD 在輕症成人型可能重疊
- G6PD def + DKA / TLS / 感染 在內科住院常見，是 acute hemolysis 三大住院誘因
Taiwan：
- G6PD NBS since 1985（世界最早，盛行率 ~3%）
- Galactosemia, Pompe, MPS I + others 已含 NBS
- 罕病基金會 support 各 GSD families
- 健保 dietary product 對 GSD/MSUD/PKU 部分給付
- 罕病醫療給付（包括 ERT、empagliflozin off-label 部分審查）

431.3.0.2 🌟 Pearls（15）

431.3.0.2.1 GSD I

GSD I 必避免 fructose / galactose：因 fructose/galactose 終 G6P → 走 lactate / lipid → 加重 hyperlactatemia + hyperlipidemia
CGM revolution：現代 GSD I 多裝 CGM，可精準調整 cornstarch dose + 餵食 timing；hypoglycemic alarm 大幅降低 morbidity
Modified extended-release cornstarch（Glycosade）：β-glycemic profile 更平緩，可拉長 fasting 至 8-10 hr，改變青少年/成人 GSD I 生活品質
GSD I HCC surveillance：肝臟 MRI（與 US 比更 sensitive 對 HCA）q12 mo；HCA → HCC transformation rate ~ 10%
GSD Ia 與 Ib 的 G188R variant：罕但 GSD Ia + neutropenia + IBD-like phenotype 報告
Empagliflozin in GSD Ib：機轉是 SGLT2 阻斷 1,5-anhydroglucitol 在 kidney 再吸收 → 降低 1,5-AG6P 在 neutrophil 累積 → neutrophil 功能恢復；改善 ANC、降低 IBD/infection；副作用 UTI、euglycemic DKA

431.3.0.2.2 GSD III, IV, VI, IX

GSD IIIa cardiomyopathy 常被「too much hepatomegaly」掩蓋；q1-2 yr echo + ECG 必做；severe → heart transplant；移植後 muscle disease still progress
GSD IV APBD（adult polyglucosan body disease）：Ashkenazi（carrier rate 1/48），spastic paraplegia + neurogenic bladder + cognitive；類似 ALS / HSP rule out 必想；不可逆
GSD VI / IX 嚴重 phenotype：以前認為 mild，現在認 spectrum 含 cirrhosis + HCC；需 lifelong surveillance

431.3.0.2.3 GSD V McArdle

McArdle pregnancy：多 well tolerated；avoid epidural / muscle relaxants 過量
McArdle 老年期 fixed weakness 30%：proximal muscle atrophy + 慢性疼痛；無 specific therapy
Aerobic training in McArdle：漸進低強度（walking, cycling）+ FFA-fueled exercise capacity 可顯著改善；強度練 anaerobic 禁止

431.3.0.2.4 其他

Galactosemia 中神經學併發症與 brain galactitol有關；早期 strict diet 無法完全 prevent；新 biomarkers（Gal-1-P chronically elevated）改善 monitoring
HFI 成人型 可被 unmasked by dietary indiscretion（朋友請喝果汁 / 蜂蜜茶 → 急性 hypoglycemia + 腹痛）
G6PD def Mediterranean variant（c.563C>T）較 African variant 嚴重，可有 chronic hemolysis；Canton variant（台灣高 prevalence）多 trigger-induced acute hemolysis；新生兒 hyperbilirubinemia 在 G6PD + UGT1A1 polymorphism 雙 hit 下 risk 顯著 ↑

431.3.0.3 📍 Taiwan + 健保

431.3.0.3.1 新生兒篩檢（NBS）

G6PD（1985-）：全面 screen，世界最早
Galactosemia：含於 NBS
PKU、MSUD、Pompe（IOPD）、Fabry、MPS I：含於 expanded NBS
確診後家族通報 + 罕病登錄 + 終生衛教

431.3.0.3.2 健保

Diet products：GSD I cornstarch、PKU low-Phe formula、galactosemia lactose-free formula 部分健保 / 罕病基金會補助
Allopurinol、ACEi、statin、fibrate、citrate：健保
G-CSF：健保（GSD Ib 等 indications）
Empagliflozin：健保（DM 適應症）；GSD Ib 適應症外使用：罕病基金會協助個案申請
AAV gene therapy / mRNA therapy：clinical trials，台灣部分中心參與

431.3.0.3.3 學會

罕病基金會（Taiwan Foundation for Rare Disorders）
台灣罕見遺傳疾病防治學會
台灣兒科內分泌與遺傳代謝學會
TES（adult endocrinology 相關）
罕病醫療團隊（台大、林口長庚、台北榮總、高雄長庚、中國附醫）

431.3.0.4 🎓 內專必懂（15）

GSD I 完整 management（diet, UCCS, CGM, complications）
GSD Ib empagliflozin 機轉 + indication
GSD III diet + cardiac surveillance
GSD V McArdle exercise prescription
GSD VI / IX 不再「mild」概念
Pompe IOPD / LOPD（cross-reference Ch 429）
Danon, PRKAG2 cardiomyopathy + arrhythmia
APBD（GSD IV adult）rule out for adult-onset spasticity
Classic galactosemia POI workup + HRT
HFI lifelong dietary management
G6PD def medications to avoid（必背清單）
G6PD def acute hemolysis management
G6PD def 新生兒 hyperbilirubinemia + UGT1A1 互作
NBS panel 台灣 specific
22E updates：empagliflozin GSD Ib、gene therapy GSD Ia、tafenoquine G6PD 警示

431.3.0.5 ⚙️ GSD I Management Workflow（內專）

Step 1 — Diagnosis
- NGS panel for GSDs（G6PC, SLC37A4, AGL, GBE1, PYGL, PHKA2, etc.）
- 確診 GSD Ia or Ib subtype
- 不再需 liver biopsy

Step 2 — Baseline assessment
- LFT, lipid, uric acid, lactate, glucose, ketone
- Renal: UPCR, eGFR
- Bone: DXA
- Cardiac: echo (PHTN screen)
- Liver imaging: MRI baseline (HCA / HCC)
- GSD Ib: CBC, ANC, neutrophil function, GI eval

Step 3 — Diet
- Infant: q2-3 hr feeding + nocturnal G-tube continuous feed
- > 1 yr: UCCS 1.6-2.5 g/kg q4-6 hr + nocturnal UCCS
- > 5 yr / adult: modified extended-release cornstarch (Glycosade) 可拉長 fasting
- High complex CHO (~ 60-65%)
- AVOID fructose, galactose, lactose, sucrose
- Vitamin / mineral supplementation

Step 4 — CGM
- Routine in 所有 GSD I 病人
- Alarm hypoglycemia
- Adjust UCCS dosing/timing

Step 5 — Pharmacologic
- Allopurinol（hyperuricemia → gout prevention）
- HMG-CoA reductase inhibitor + fibrate（lipid）
- ACEi（microalbuminuria → renal protection）
- Citrate（nephrocalcinosis prevention）
- For GSD Ib：
  - Empagliflozin 10 mg/d（22E new! neutropenia + IBD）
  - G-CSF as needed
  - 注意 UTI, euglycemic DKA risk

Step 6 — Complications surveillance
- q6-12 mo: lab + UCCS adjustment + CGM review
- q12 mo: liver MRI (HCA / HCC)
- q12-24 mo: DXA (osteoporosis)
- q12 mo: renal function + UPCR + renal US
- q12 mo: echo (PHTN)
- Thyroid antibody q12 mo (GSD Ib)
- HCA → resection / RFA / liver transplant
- ESRD → kidney transplant

Step 7 — Emerging therapy
- AAV gene therapy DTX401（GSD Ia phase III）
- mRNA therapy（phase I）
- Patient registry + clinical trial enrollment

431.3.0.6 ⚙️ GSD III Management Workflow

Step 1 — Diagnosis
- AGL gene sequencing → 確診 + IIIa vs IIIb
- IIIa: exons 2-? mutations + variable; IIIb: exon 2 specific

Step 2 — Baseline
- Liver: LFT, urine Glc4, hepatic imaging
- Muscle (IIIa): CK, EMG, manual strength, 6MWT
- Cardiac (IIIa): echo, ECG, Holter
- Bone: DXA
- Lipid, glucose

Step 3 — Diet
- Frequent feedings + UCCS + AVOID prolonged fasting
- **HIGH PROTEIN（與 GSD I 相反！）**：因 gluconeogenesis intact, AA → glucose
- IIIa: 部分病人 high-fat + MCT supplementation 改善 myopathy
- CGM useful

Step 4 — Surveillance（特別 IIIa）
- q6-12 mo: LFT, CK, urine Glc4
- q1 yr: echo, ECG, Holter（arrhythmia screening）
- q2 yr: liver MRI (HCA / HCC)
- q2 yr: DXA
- Annual neuromuscular assessment

Step 5 — Advanced complications
- Liver failure → liver transplant
- Cardiac failure → heart transplant
- 注意：移植後 muscle disease 仍 progress（unmet need）

431.3.0.7 ⚙️ GSD V McArdle Exercise Prescription

Pre-exercise:
- 30 g sucrose 30 min before exercise
- Warm-up gentle 5-10 min (slow walking, easy cycling)
  → 啟動 "second-wind"

During exercise:
- Submaximal aerobic（heart rate 60-70% max）
- Avoid:
  - Sudden intense exertion
  - Isometric / heavy weight lifting
  - Prolonged high-intensity anaerobic

Training program:
- 漸進 aerobic（walking, swimming, light cycling）
- 改善 oxidative capacity over months
- 物理治療師 + 運動醫學 supervised

Medications:
- AVOID statin (rhabdomyolysis additive)
- Cautious: succinylcholine (anesthesia)
- Hydration always

Acute attack:
- Rest, hydrate, monitor urine color
- Rhabdomyolysis → ER + IV fluid + monitor renal function
- Medical alert bracelet at all times

Long-term:
- 30% develop fixed proximal weakness after age 40
- 物理治療 + adaptive equipment as needed

431.3.0.8 ⚙️ Galactosemia POI Surveillance + Treatment

Childhood:
- Lifelong galactose / lactose restricted diet
- Compliance monitoring：red cell Gal-1-P quarterly

Adolescence onset:
- q12 mo from age 10:
  - FSH, LH, E2
  - Tanner staging
  - Menarche timing
- AMH baseline at age 12-14
- If FSH ↑ early or amenorrhea: refer reproductive endocrinology

Once POI confirmed:
- HRT (estrogen + progestin, oral or transdermal)
- Continue until age 50-52 (natural menopause age)
- Calcium + vitamin D supplementation
- Bone density q1-2 yr
- Bisphosphonate if T < -2.5 + young

Reproductive counseling:
- Spontaneous pregnancy rare but possible
- Egg cryopreservation if some reserve (rare ovarian function)
- Donor egg IVF main option
- Genetic counseling pre-conception
- Partner GALT carrier screening

Long-term (other complications):
- Cognitive: neuropsychology assessment
- Speech: speech-language pathology
- Motor: physical therapy
- Cataract: ophthalmology
- Bone: lifelong vigilance

431.3.0.9 ⚙️ G6PD Deficiency Management (Internal Medicine)

Diagnosis:
- Suspicion: hemolysis post-trigger
- G6PD quantitative spectrophotometric assay
  → 注意急性溶血期 false-normal (new reticulocytes have higher G6PD)
  → Retest 2-3 mo after acute episode
- G6PD gene sequencing if carrier / female heterozygote / unclear

Acute hemolysis management:
- Identify + REMOVE trigger
- IV hydration（prevent AKI from hemoglobinuria）
- Monitor:
  - Hb, retic count, LDH, bilirubin, haptoglobin
  - Renal function, urine output
  - DIC labs if severe
- Transfusion if Hb < 7 or symptomatic
- Folate supplementation if chronic hemolysis

Lifelong prevention:
- Medical alert bracelet
- Patient education on trigger drugs:
  - Antimalarials: primaquine, tafenoquine, dapsone, chloroquine high-dose
  - Sulfa: sulfamethoxazole, sulfadiazine
  - Antibiotics: nitrofurantoin
  - Other: methylene blue, rasburicase, high-dose aspirin/IV vit C, phenazopyridine
- Foods: fava beans (whole or processed)
- Environmental: naphthalene mothballs
- Triggers: infection, DKA, metabolic acidosis

Hospital scenarios to be vigilant:
- TLS prevention：**AVOID rasburicase** in G6PD def, use allopurinol + IV fluid
- 感染 admission：select non-trigger antibiotics
- DKA：correct cautiously, hemolysis can complicate
- Anesthesia：avoid methylene blue (e.g., for methemoglobinemia treatment is paradoxical)
- Malaria prophylaxis：use atovaquone-proguanil OR doxycycline (G6PD safe)

Newborn screening (台灣 1985-):
- All babies tested
- Confirmed → family education pamphlet
- Phototherapy threshold lower in G6PD def neonates
- Watch for kernicterus risk

431.3.0.10 ⚙️ Emerging Therapies in GSDs

Gene replacement therapy:
- **AAV-G6PC (DTX401) for GSD Ia**：phase III ongoing
  - One-time IV infusion
  - Restores hepatic G6Pase
  - Preliminary: reduces UCCS need, normalizes lab

mRNA therapy:
- **GSD Ia mRNA**：phase I/II
  - Lipid nanoparticle delivery
  - Repeated dosing required

CRISPR / gene editing:
- Pre-clinical for various GSDs

Substrate reduction:
- GYS1 (glycogen synthase 1) inhibition for Pompe
- 減少 glycogen synthesis upstream

ERT next-gen:
- Avalglucosidase / cipaglucosidase for Pompe (22E approved)

Repurposed drugs:
- **Empagliflozin for GSD Ib** (22E paradigm shift)
- Imatinib for some cardiomyopathies

Patient registries:
- Gaucher Registry (ICGG)
- Fabry Registry (FOS)
- Pompe Registry
- GSD Registry (AGSDA)
- 台灣 罕病基金會 registry

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