430.3 🩺 內科專科考前版

430.3.0.1 📌 一頁重點

22E updates / 新藥：
- Pegunigalsidase alfa（Elfabrio，FDA 2023）：Fabry，PEG conjugated longer half-life
- Avalglucosidase alfa（Nexviazyme，FDA 2021）：Pompe，better muscle targeting M6P receptor
- Cipaglucosidase alfa + miglustat（Pombiliti + Opfolda，FDA 2023）：Pompe LOPD combo
- Olipudase alfa（Xenpozyme，FDA 2022）：ASMD (Niemann-Pick B)，第一個 ASMD ERT
- Cerliponase alfa（Brineura，FDA 2017）：CLN2 IT，第一個 intracerebroventricular ERT
- AAV gene therapy：multiple LSDs in phase II/III（Pompe AT845, Fabry AVR-RD-01, Gaucher PR001 for PD）
- Substrate depletion：cyclodextrin for NPC1（trials）
- Newborn screening expansion：Pompe, MPS I, Krabbe, Gaucher, Fabry, MPS II 已在多國列為 NBS panel
內分泌相關：
- Fabry 影響 endocrine 並不少：可能有 hypogonadism、subclinical hypothyroidism、osteoporosis
- Gaucher 骨骼變化常需與 PHPT 引起的 cortical thinning 區別
- GBA1 carrier 是 Parkinson disease 最大 single genetic risk factor（OR ~5-10）
- GSD II Pompe 跨 LSD + GSD 類別
Taiwan：
- Newborn screening 含 Pompe（since 2005）、Fabry（since 2008）、MPS I（recent expansion）（台灣 NBS programme 全球領先 LSD screening）
- 健保 ERT 給付 for Gaucher、Fabry、Pompe（IOPD + LOPD severe）、MPS I/II/IVA/VI、ASMD type B，多需 pre-approval
- 罕病基金會（Taiwan Foundation for Rare Disorders） 是台灣罕病 advocacy 主軸
- 內科專科 board 經常出 Gaucher、Fabry、Pompe；MPS 偶出

430.3.0.2 🌟 Pearls（15）

430.3.0.2.1 Gaucher

GBA1 N370S/L444P 是 Ashkenazi 最常見組合；N370S/N370S 多輕；L444P/L444P 多嚴重（含 type 2/3）
Eliglustat CYP2D6 phenotyping 必做 before 開立（poor metabolizer 風險、ultra-rapid metabolizer 效果不佳）
Splenectomy 在 ERT 時代基本不必做；做了反而增加肺動脈高壓 + 加速骨病；只有 emergent splenic rupture / massive 不可控 cytopenia 才考慮
GBA1 carriers 也有 Parkinson disease 風險升高（碰到 Gaucher 家族 carrier 也要 q1-2 yr neuro exam）
Bone disease 對 ERT response 慢於 visceral：需 12-24 個月才見明顯改善；嚴重 AVN 不可逆

430.3.0.2.2 Fabry

女性 heterozygote 50-70% 會 symptomatic（lyonization 隨機 X inactivation）— 不能因「女性」排除診斷
基因檢測優於酵素活性 in females（因 lyonization）
Migalastat amenable mutations：需用 GLP-HEK assay 確認；約 35-50% 突變 amenable；不能憑文獻 in silico 預測決定
Pegunigalsidase alfa（Elfabrio） 適用於 anti-agalsidase antibody-positive 病人或偏好 less frequent infusion 者
Fabry pain crisis 多伴 fever + 高度焦慮 — 排除 infection 後 high-dose 止痛 + 補水

430.3.0.2.3 Pompe

CRIM-negative IOPD 啟動 ERT 前必做 immune tolerance induction（rituximab + MTX + IVIG），否則 anti-rhGAA antibody 致 ERT 失效
LOPD 診斷常延誤 5-10 年（被當 LGMD / myositis）；任何 unexplained limb-girdle weakness + diaphragmatic involvement（supine FVC drop > 10%）+ scapular winging 都應 DBS GAA
Avalglucosidase alfa clinical trial 對 LOPD 比 alglucosidase alfa 更好的 6MWT + FVC 改善
Pompe pregnancy + ERT 多 safe，建議 continue throughout pregnancy

430.3.0.2.4 MPS / Other LSDs

MPS I H HSCT 啟動越早越好（< 18-24 mo idealy），延遲啟動 CNS 進展不可逆；MPS II HSCT 對 CNS 無效（不建議）；MPS III/IV/VI HSCT efficacy 待商榷

430.3.0.3 📍 Taiwan + 健保

430.3.0.3.1 藥物可近性 / 健保

Imiglucerase（Cerezyme）：Gaucher 健保（個案申請）
Velaglucerase（VPRIV）：Gaucher 健保
Eliglustat（Cerdelga）：Gaucher 健保（CYP2D6 phenotyping 後）
Agalsidase β（Fabrazyme）：Fabry 健保
Agalsidase α（Replagal）：Fabry 健保（部分）
Migalastat（Galafold）：Fabry 健保（amenable mutation 才給付）
Alglucosidase alfa（Myozyme/Lumizyme）：Pompe IOPD + LOPD 健保
Avalglucosidase alfa（Nexviazyme）：Pompe，22E 新藥，部分健保
Laronidase（Aldurazyme）：MPS I 健保
Idursulfase（Elaprase）：MPS II 健保
Elosulfase alfa（Vimizim）：MPS IVA 健保
Galsulfase（Naglazyme）：MPS VI 健保
Pegunigalsidase（Elfabrio）：Fabry 22E 新藥，自費 / 申請中
Cipaglucosidase + miglustat：Pompe 22E 新藥，自費
Olipudase alfa（Xenpozyme）：ASMD type B，22E 新藥，自費 / 申請
Sebelipase alfa（Kanuma）：LAL-D，22E 已上市
Cerliponase alfa（Brineura）：CLN2 IT，22E 已上市自費

430.3.0.3.2 Newborn screening

台灣 NBS 含 Pompe（since 2005）+ Fabry（since 2008）+ MPS I（recent）
全球領先 LSD newborn screening 之一
確診後早期 ERT 啟動顯著改善預後

430.3.0.3.3 學會 / 指引

罕病基金會（taiwan rare disease foundation）：advocacy + 經費協助
台灣罕見遺傳疾病防治學會
TES、Taiwan Society of Pediatric Endocrinology
MPS Brazil group consensus、Fabry Registry、Gaucher Registry（國際 registries 重要 RWE 來源）
ICGG（International Collaborative Gaucher Group）+ FOS（Fabry Outcome Survey）+ Pompe Registry

430.3.0.4 🎓 內專必懂（15）

Gaucher type 1 完整評估 + ERT/SRT decision tree
Gaucher type 2/3 區分 + CNS involvement
Gaucher PD risk + family counseling
Fabry classical vs cardiac/renal variants
Fabry female heterozygote diagnosis（基因 over 酵素）
Migalastat amenable mutation assessment
Pompe IOPD vs LOPD distinction
CRIM-negative IOPD immune tolerance
LOPD respiratory + neuromuscular surveillance
MPS I H HSCT timing + indications
MPS II Hunter X-linked + idursulfase
ASMD type B + olipudase alfa
CLN2 + intracerebroventricular ERT
AAV gene therapy landscape
22E 新藥：pegunigalsidase、avalglucosidase、cipaglucosidase+miglustat、olipudase、cerliponase

430.3.0.5 ⚙️ Gaucher Disease Management Workflow

Step 1 — Diagnosis
- Acid β-glucosidase activity (leukocytes, DBS)
- GBA1 gene sequencing (confirm mutation, 區分 type)
- Biomarkers: chitotriosidase, lyso-GL1, ferritin, ACE
- Imaging: MRI spleen/liver volume, bone MRI

Step 2 — Type classification
- Type 1: no CNS involvement
- Type 2: severe infant CNS, < 2 yr
- Type 3: variable CNS, slower

Step 3 — Type 1 treatment decision
- Severity-based:
  - Mild (no severe cytopenia/bone) → close observation possible
  - Moderate-severe → ERT or SRT
- ERT (imiglucerase / velaglucerase / taliglucerase): IV q2 wk
- SRT eliglustat:
  - CYP2D6 phenotyping required
  - Avoid in poor metabolizers
  - Drug interactions (CYP2D6 + CYP3A4 inhibitors)
- SRT miglustat: 限制 GI side effects, neuropathy

Step 4 — Avoid splenectomy
- 加速 bone disease + pulmonary HTN

Step 5 — Long-term monitoring
- q3-6 mo first year, then q6-12 mo
- CBC, ferritin, chitotriosidase, ACE
- Spleen/liver volume MRI q12-24 mo
- Bone MRI q24 mo
- DXA q24 mo
- Pulmonary HTN echo q12-24 mo
- PD neuro exam q12 mo（GBA1 risk）

Step 6 — Family cascade
- Carriers also PD risk
- Genetic counseling
- Prenatal diagnosis available

430.3.0.6 ⚙️ Fabry Disease Management Workflow

Step 1 — Diagnosis
- Male: plasma α-Gal A activity + GLA gene sequencing
- Female: GLA gene sequencing primary (lyonization)
- Biomarkers: plasma + urine lyso-Gb3
- Slit lamp: cornea verticillata
- Renal biopsy if proteinuria (Gb3 deposits)

Step 2 — Risk stratification + organ assessment
- Renal: eGFR, UPCR
- Cardiac: echo, cardiac MRI (LGE pattern)
- CNS: brain MRI (WML)
- Audiometry, ophthalmology
- Endocrine: T, gonad

Step 3 — Treatment decision
- ERT indication:
  - Male: 早期啟動（理想 < 20 yr）
  - Female: 已 symptomatic 或 evidence of organ involvement
- ERT options:
  - Agalsidase α 0.2 mg/kg q2 wk (Replagal)
  - Agalsidase β 1.0 mg/kg q2 wk (Fabrazyme)
  - Pegunigalsidase α 1.0 mg/kg q2 wk (Elfabrio, 22E new)
- Migalastat 123 mg PO QOD (only amenable mutations, GLP-HEK assay)

Step 4 — Adjunctive
- ACEi / ARB for proteinuria
- Beta blocker for arrhythmia
- Anticoagulation if AF
- Acroparesthesia: gabapentin / carbamazepine
- Avoid: NSAIDs (CKD), excessive heat

Step 5 — Long-term monitoring
- q6-12 mo: eGFR, UPCR, echo, cardiac MRI annually
- Anti-drug antibody monitoring
- Family cascade screening (all first-degree relatives)

Step 6 — Cascade screening
- Genetic counseling for X-linked inheritance
- Daughter of affected male: 100% carrier
- Son of affected male: 0% (Y from father)
- Son of carrier female: 50% affected
- Daughter of carrier female: 50% carrier

430.3.0.7 ⚙️ Pompe LOPD Management Workflow

Step 1 — Suspicion
- Unexplained limb-girdle weakness + respiratory involvement
- FVC drop in supine position
- Scapular winging
- + delayed motor milestones (childhood)

Step 2 — Diagnosis
- DBS GAA enzyme activity → low
- GAA gene sequencing → two pathogenic variants
- Urine Glc4
- CK (may be normal in LOPD!)
- EMG: myopathic features
- Muscle biopsy if dx unclear (vacuoles with glycogen)

Step 3 — Pre-ERT assessment
- CRIM status (IOPD; LOPD less critical)
- Antibody assessment

Step 4 — ERT
- Alglucosidase alfa 20 mg/kg q2 wk (standard)
- Avalglucosidase alfa 20 mg/kg q2 wk (preferred for LOPD, 22E)
- Cipaglucosidase alfa + miglustat (LOPD, 22E combo)

Step 5 — Supportive
- Respiratory: BiPAP nocturnal, daytime as needed
- Physical therapy: aerobic + strength training
- Diet: high protein
- Cardiac surveillance (echo q1-2 yr, although LOPD usually no significant CM)
- Bone: DXA, vit D

Step 6 — Monitoring
- q6 mo: FVC sitting + supine, 6MWT, manual muscle test, CK, urine Glc4
- q1 yr: echo, sleep study
- ADA monitoring

Step 7 — Pregnancy
- Continue ERT
- High-risk OB co-management

430.3.0.8 ⚙️ MPS I Management Workflow

Step 1 — Suspicion / Diagnosis
- Coarse facies + hepatosplenomegaly + dysostosis + corneal clouding
- Urine GAG (dermatan + heparan sulfate)
- α-L-iduronidase enzyme activity in leukocytes
- IDUA gene sequencing
- Newborn screening (台灣 added recently)

Step 2 — Phenotype classification
- MPS I H (Hurler): severe CNS, < 2 yr presentation
- MPS I S (Scheie): mild, adult-onset
- MPS I H/S: intermediate

Step 3 — Treatment
- Severe (Hurler):
  - **HSCT before 2 yr** if possible (preserve CNS)
  - + ERT laronidase pre/post-HSCT
- Attenuated (Scheie, H-S):
  - ERT laronidase 0.58 mg/kg/wk IV indefinitely
  - No HSCT typically

Step 4 — Multidisciplinary care
- Cardiology: valves, cardiomyopathy
- Pulmonology: OSA, restrictive lung disease, airway anatomy
- Orthopedic: dysostosis, cervical instability, hip dysplasia
- Anesthesia: difficult airway pre-op planning
- ENT: hearing, tympanostomy, adenotonsillectomy
- Ophthalmology: corneal clouding, glaucoma
- Neurology: hydrocephalus, spinal cord compression
- Developmental: educational support

Step 5 — Long-term
- Annual evaluations multidisciplinary
- ERT antibodies monitoring
- Post-HSCT: graft monitoring, complications

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