腦白質病變（Leukoencephalopathy）是指大腦白質區域——主要由傳導神經訊號的有髓鞘軸突（Myelinated axons）所組成——因缺血、發炎、代謝異常或基因突變而受損的病理表現。在腦部影像學（特別是 MRI T2/FLAIR）上，常表現為White Matter Hyperintensities, WMH。主要可以分成Cerebral Small Vessel Disease、Genetic Leukoencephalopathies、Demyelinating diseases。病變程度較輕時常無明顯症狀，但隨著病灶累積，可能逐步引發認知功能衰退（如處理速度變慢、執行功能缺損）、步態不穩與平衡障礙、排尿障礙（頻尿、尿失禁）、情緒與人格改變，以及顯著增加後續缺血性腦中風與血管性失智症的風險。這個篇章感覺很難讀，大家加油！🔴表示比較常出現的疾病。
| 疾病 | 模式 | 基因 | 重點 |
| 🔴 PMD | X-D | PLP1 | Pelizaeus-Merzbacher disease ➡ 男性：severe cognitive impairment, spasticity (SPG2), head tremor；女性 (heterozygote): less common, spastic paraparesis；Usually infant–childhood onset, case reports up to age 45) 🧠 Brain MRI: hypomyelination |
| PMLD | AR | GJC2 HSPD1 AIMP1 | Pelizaeus-Merzbacher-like disease ➡ Hypomyelinating leukodystrophy，大約15歲發病 |
| 🔴 CADASIL | AD | NOTCH3 | Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ➡ NOTCH3 cysteine-altering mutations (EGFr domain) Recurrent subcortical ischemic strokes, migraine with aura, vascular dementia |
| 🔴 CARASIL | AR | HTRA1 | Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy ➡ 症狀Triad：Alopecia, lumbago, Binswanger-likeencephalopathy。發病 20–50 y/o，亞洲高發生率，腦部病理出現Intense arteriolosclerosis without osmiophilic material deposition |
| CARASAL | AD | CTSA | Cathepsin A-related arteriopathy with strokes and leukoencephalopathy ➡ Mutation: p.R325C，嚴重的腦白質病變，會出現therapy-resistant hypertension (via ET-1), recurrent ischemic/hemorrhagic stroke, later cognitive decline |
| 🔴 LBSL | AR | DARS2 | Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation ➡ Distal weakness with UMN signs and ataxia；Pyramidal tract and dorsal column dysfunction 🧠 MRS 腦白質會顯示lactate peak，但是blood and CSF lactate 不增加 |
| 🔴 FXTAS | X-linked | FMR1 | Fragile X-associated tremor/ataxia syndrome ➡ Premutation non-coding CGG trinucleotide expansion (55–200 repeats) in FMR1，會出現Intention tremor, cerebellar ataxia, parkinsonism, cognitive decline (premutation) 🧠 MRI會有MCP sign: hyperintensity in middle cerebellar peduncles) |
| 🔴 HDLS | AD | CSF1R | Hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia ➡ Mean onset: ~40 years (range: 15–78)，Rapid progressive cognitive decline和parkinsonian deficit 🧠 Axonal spheroids on brain biopsy |
| ADLD | AD | LMNB1 | Adult-onset autosomal dominant leukodystrophy ➡ Onset: 30–50 years，Autonomic dysfunction (orthostatic hypotension, bladder/bowel dysfunction) followed by ataxia and spasticity 🧠 腦部MRI： extensive symmetrical white matter involvement sparing periventricular rim |
| VWM | AR | EIF2B1 EIF2B2 EIF2B3 EIF2B4 EIF2B5 | Vanishing white matter disease ➡ Mean onset: ~30 years (range: 16–62)，Chronic progressive cerebellar ataxia and spasticity 🧠 腦部MRI： white matter rarefaction and cystic degeneration |
| AxD | AD | GFAP | Alexander disease ➡ Onset：12–62 years，Bulbar signs, palatal myoclonus, ataxia, spastic paraparesis，Rosenthal fibers on histology 🧠 腦部MRI：Tadpole like (medulla and upper spinal cord atrophy) |
| AARS2-L | AR | AARS2 | AARS2-related leukodystrophy ➡ Ovarioleukodystrophy phenotype in females (premature ovarian failure), progressive spasticity, cognitive decline |
| MNGIE | AR | TYMP | Mitochondrial neurogastrointestinal encephalopathy ➡ Severe GI dysmotility, cachexia, ptosis, ophthalmoparesis, sensorimotor neuropathy, leukoencephalopathy，檢查會出現 elevated plasma thymidine & deoxyuridine |
| H-ABC | AD | TUBB4A | Hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum ➡ Adult-onset，Dystonia, ataxia, parkinsonism, spasticity 🧠 Progressive atrophy of putamen and cerebellum |
| 4H syndrome | AR | POLR3A POLR3B | POLR3-related leukodystrophy ➡ Hypomyelination，Hypodontia，Hypogonadotropic Hypogonadism，Progressive ataxia and motor deterioration 🧠 Brain MRI: hypomyelination with relative preservation of dentate nucleus/anteroventral thalamus |
| RVCL-S | AD | TREX1 | Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations ➡ 視力影響（retinal telangiectasias）stroke-like episodes, cognitive decline, renal/hepatic dysfunction 🧠 Brain MRI：Contrast-enhanced WM lesions |
| PADMAL/ HANAC | AD | COL4A1 | Pontine autosomal dominant microangiopathy and leukoencephalopathy；a.k.a. hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) 🧠 Brain MRI: diffuse leukoencephalopathy, cerebral microbleeds, porencephaly; Ophthalmology exam |
| LCC | AR | SNORD118 | Labrune syndrome（Leukoencephalopathy with cerebral calcifications and cysts） ➡ Intracranial hypertension 🧠 Brain MRI triad： 白質病變、鈣化、parenchymal cysts |
| GHS | AR | RNF216 | Gordon Holmes syndrome ➡ Hypogonadotropic hypogonadism, progressive cerebellar ataxia, dementia |
| PLOSL，Nasu-Hakola | AR | TYROBP TREM2 | Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy ➡ Onset：～30 years (range: 10–45)，容易骨折（bone cysts），FTD的表現 |
| X-ALD / AMN | X-L | ABCD1 | X-linked adrenoleukodystrophy / Adrenomyeloneuropathy ➡ 發病年齡：Childhood to adulthood，女性（異型合子）以AMN或spastic paraparesis為主，會有Adrenal insufficiency, progressive spastic paraparesis, sensory ataxia，診斷以抽血檢驗Very Long Chain Fatty Acids (VLCFA)升高。 |
| Krabbe disease | AR | GALC PSAP | Globoid cell leukodystrophy ➡ ～60 years，症狀會出現 Spastic paraparesis, progressive ataxia, peripheral neuropathy, optic atrophy |
| MLD | AR | ARSA PSAP | Metachromatic leukodystrophy ➡ ～70 years，會出現 psychosis, dementia, polyneuropathy, spasticity，診斷以檢驗Arylsulfatase A (ARSA) activity或24-hour urine sulfatides |
| CTX | AR | CYP27A1 | Cerebrotendinous xanthomatosis ➡ 青少年～成年，Tendon xanthomas，雙側白內障，chronic diarrhea，progressive ataxia，cognitive impairment，檢驗會出現Elevated serum cholestanol, urine bile alcohols |
| MTHFR deficiency | AR | MTHFR | Methylenetetrahydrofolate reductase deficiency ➡ 反覆出現thrombosis/strokes, seizures, encephalopathy, spasticity |
Multiple sclerosis
- Genetic susceptibility: Related to HLA alleles:
- HLA Class II alleles (Increased risk)
DRB1*1501(OR 3.1)、DRB1*0301(OR 1.26)、DRB1*1303(OR 2.4) - HLA Class I allele (Reduced risk / Protective)：
HLA-A2(OR 0.73)
- HLA Class II alleles (Increased risk)
- Overlap with other autoimmune diseases:
- 22% 的位點常常跟其他疾病重疊
DRB1*1501(hypothesized to confer CNS-specific autoimmunity)
