Leukodystrophies
Leukodystrophies
What You'll Learn
- Leukodystrophies = inherited disorders primarily affecting CNS white matter/myelin; they can be hypomyelinating, dysmyelinating, demyelinating, or degenerative — distinguish from acquired demyelination (MS, ADEM, PML)
- Most leukodystrophies are autosomal recessive; Alexander disease is the classic and most commonly tested autosomal dominant leukodystrophy (GFAP mutations) — LMNB1-related ADLD is a rare adult-onset exception
- Krabbe disease: galactocerebrosidase (GALC) deficiency → globoid cells (pathognomonic); infantile onset, rapid decline
- Metachromatic leukodystrophy (MLD): arylsulfatase A deficiency → sulfatide accumulation → metachromatic granules on nerve biopsy
- Adrenoleukodystrophy (ALD): X-linked, ABCD1 gene → VLCFA accumulation; posterior-predominant white matter disease + adrenal insufficiency
- Canavan disease: aspartoacylase deficiency → elevated NAA on MRS (diagnostic); megalencephaly; Ashkenazi Jewish predilection
- MRI pattern recognition is high-yield: frontal = Alexander, posterior = ALD/Krabbe, diffuse hypomyelination = PMD
- Know treatable leukodystrophies: early HSCT (Krabbe, ALD), chenodeoxycholic acid (CTX), dietary phytanic acid restriction (Refsum)
HighYield Pearls
- MLD = arylsulfatase A (ARSA) deficiency: AR; sulfatide accumulation; tigroid/striated white matter on MRI; metachromatic granules on nerve biopsy; combined CNS demyelination + peripheral demyelinating neuropathy in a child
- Krabbe = galactocerebrosidase (GALC) deficiency: AR; globoid (multinucleated) macrophages are pathognomonic; infantile irritability + spasticity + optic atrophy; HSCT only works if given pre-symptomatic (via newborn screening) — no effective therapy once symptoms appear
- X-ALD = ABCD1 (Xq28), peroxisomal: elevated plasma VLCFA; childhood cerebral form shows posterior/parieto-occipital white matter with contrast-enhancing leading edge; Loes score guides HSCT/gene-therapy eligibility (typically ≤9 with minimal deficit)
- Always screen any male with unexplained primary adrenal insufficiency for VLCFA — Addison disease may precede neurologic ALD by years
- AMN = adult-onset spastic paraparesis variant of X-ALD (same ABCD1 gene); HSCT/gene therapy does not benefit AMN, only early cerebral ALD
- Canavan = aspartoacylase (ASPA) deficiency: AR; elevated NAA peak on MRS + megalencephaly + early subcortical U-fiber involvement; Ashkenazi Jewish predilection; AAV gene therapy under investigation
- Alexander = GFAP mutations (AD, often de novo): the classic AD leukodystrophy; frontal-predominant white matter + macrocephaly + Rosenthal fibers; infantile/juvenile/adult forms (adult = bulbar + palatal myoclonus)
- PMD = PLP1 duplications/mutations (XLR): diffuse hypomyelination that never matures on serial MRI; nystagmus from birth + stridor in infancy; failure of myelination, not demyelination
- VWM/CACH = EIF2B 1–5 mutations (AR): white matter progressively replaced by CSF-isointense signal on FLAIR; episodic deterioration triggered by febrile illness or minor head trauma; ovarian failure in females
- Treatment landscape: atidarsagene autotemcel (Lenmeldy in the US, Libmeldy in Europe) gene therapy — FDA indication: pre-symptomatic late infantile MLD, pre-symptomatic early juvenile MLD, or early symptomatic early juvenile MLD; elivaldogene autotemcel (Skysona) gene therapy for early active cerebral X-ALD (boys 4–17 yr); HSCT remains key for early cerebral X-ALD and pre-symptomatic Krabbe; Lorenzo’s oil lowers VLCFA but does NOT reverse established cerebral disease in symptomatic X-ALD
🔍 Quick ReferenceImaging signs (MRI pattern) · Clinical · Enzyme / gene / pathology
Imaging signs (MRI pattern)
- Tigroid / leopard-skin pattern of white matter → MLD (also seen in PMD — not exclusive)
- Posterior / parieto-occipital symmetric white matter with contrast-enhancing leading edge + Loes scoring → X-ALD (childhood cerebral)
- “Milky pyramids” + cerebellar atrophy + posterior periventricular white matter → Krabbe
- Frontal-predominant white matter + macrocephaly + periventricular T1-hyperintense rim → Alexander disease
- Diffuse white matter T2 hyperintensity with early subcortical U-fiber involvement + macrocephaly → Canavan
- Diffuse hypomyelination that fails to mature on serial MRI → PMD (PLP1)
- CSF-isointense “vanishing” white matter on FLAIR → VWM / CACH
- Anterior temporal subcortical cysts + macrocephaly → Megalencephalic leukoencephalopathy with subcortical cysts (MLC1)
- Elevated NAA peak on MRS → Canavan
- Elevated lactate on MRS + brainstem + spinal cord white matter → LBSL (DARS2)
Clinical signs
- Young male with adrenal insufficiency + posterior cerebral white matter disease → X-ALD
- Adult male with progressive spastic paraparesis + sphincter dysfunction + peripheral neuropathy → AMN (X-ALD variant)
- Macrocephaly + developmental regression in an infant → Canavan or Alexander
- Extreme irritability + stiffness + optic atrophy in a 3–6 month-old infant → Krabbe
- Demyelinating peripheral neuropathy + spasticity + cognitive decline in a child → MLD
- Episodic neurologic regression triggered by minor head trauma or febrile illness → VWM / CACH
- Rapid head growth in infancy → Alexander or MLC1
- Congenital nystagmus + stridor in infancy → later spastic paraparesis → Pelizaeus-Merzbacher (PMD)
- Adult-onset psychiatric symptoms + cognitive decline + peripheral neuropathy → Adult MLD
Enzyme / gene / pathology
- ARSA deficiency + sulfatide accumulation + metachromatic granules → MLD
- GALC deficiency + psychosine toxicity + globoid (multinucleated PAS+) macrophages → Krabbe
- ABCD1 mutation + elevated VLCFA + peroxisomal lamellar inclusions → X-ALD / AMN
- ASPA deficiency + elevated NAA on urine organic acids and MRS + spongiform white matter → Canavan
- GFAP mutation + Rosenthal fibers (GFAP + αB-crystallin + HSP27 aggregates) → Alexander disease
- PLP1 duplication / mutation → Pelizaeus-Merzbacher (PMD)
- EIF2B 1–5 mutation → Vanishing white matter (VWM / CACH)
- MLC1 / HEPACAM mutation → Megalencephalic leukoencephalopathy with subcortical cysts
- CYP27A1 + elevated cholestanol + tendon xanthomas → CTX (treatable with chenodeoxycholic acid)
Overview: Demyelination vs. Dysmyelination
Key Distinction
| Feature | Demyelination (Acquired) | Dysmyelination (Leukodystrophy) |
|---|---|---|
| Mechanism | Loss of normally formed myelin | Genetically defective myelin formation or maintenance |
| Myelin | Initially normal, then destroyed | Never properly formed or maintained |
| Course | May be relapsing or monophasic | Progressive, often relentless |
| Examples | MS, ADEM, PML, NMOSD | Krabbe, MLD, ALD, Alexander, Canavan, PMD |
| Inheritance | Not Mendelian (complex genetic risk) | Mendelian: most AR; Alexander = AD; ALD/PMD = X-linked |
| Age of onset | Typically adolescence/adulthood | Often infancy or early childhood (adult forms exist) |
Board Pearl
- If a question describes progressive white matter disease in an infant or child with a positive family history or consanguinity → think leukodystrophy (dysmyelination), not MS
- Leukodystrophies typically show symmetric, bilateral white matter changes on MRI without the perivenular dissemination pattern of MS
Master Leukodystrophy Table
| Disease | Inheritance | Gene / Protein | Chromosome | Enzyme / Defect | Pathology Hallmark | MRI Pattern | Onset |
|---|---|---|---|---|---|---|---|
| MLD | AR | ARSA | 22q13.33 | Arylsulfatase A | Metachromatic granules | Periventricular, symmetric | Late infantile (1–2 yr) |
| Krabbe | AR | GALC | 14q31.3 | Galactocerebrosidase | Globoid cells | Periventricular, posterior | Infantile (3–6 mo) |
| ALD | X-linked | ABCD1 | Xq28 | Peroxisomal VLCFA transporter | Perivascular lymphocytes | Posterior/parieto-occipital | Boys 4–8 yr |
| Alexander | AD | GFAP | 17q21.31 | Glial fibrillary acidic protein | Rosenthal fibers | Frontal predominance | Infantile (<2 yr) |
| Canavan | AR | ASPA | 17p13.2 | Aspartoacylase | Spongiform degeneration | Diffuse, subcortical U-fibers early | Infantile (3–6 mo) |
| PMD | X-linked | PLP1 | Xq22.2 | Proteolipid protein 1 | Tigroid pattern | Diffuse hypomyelination | Infancy |
| VWM/CACH | AR | EIF2B (1–5) | Various | Eukaryotic initiation factor 2B | Cystic white matter | Vanishing white matter | Childhood (2–6 yr) |
| CTX | AR | CYP27A1 | 2q35 | Sterol 27-hydroxylase | Xanthomas, cholestanol deposits | Cerebellar white matter | Childhood–adult |
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