Leukodystrophies
Leukodystrophies
What Do You Need to Know?
- 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)
🚩 Don’t Miss — Test-Day Priorities
- 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
🔍 Buzzwords & Pathognomonic FindingsImaging 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 |
Metachromatic Leukodystrophy (MLD)
Genetics and Biochemistry
- Inheritance: autosomal recessive
- Gene: ARSA (22q13.33) → encodes arylsulfatase A
- Defect: sulfatide (cerebroside sulfate) cannot be degraded → accumulation in CNS and PNS myelin
- Sulfatide is a component of the myelin sheath; accumulation destroys both central and peripheral myelin
- Less common variant: saposin B deficiency (activator protein) → same phenotype with normal ARSA levels
Pathology
- Metachromatic granules — sulfatide deposits show metachromasia — stain golden-brown with cresyl violet (vs normal violet/purple) and red/red-purple (magenta) with toluidine blue (vs blue) → pathognomonic
- Found in Schwann cells, oligodendrocytes, macrophages, and neurons
- Demyelination affecting both CNS white matter and peripheral nerves
- EM: lamellated/herringbone ("tuffstone") inclusions in lysosomes
Clinical Forms
| Form | Onset | Key Features |
|---|---|---|
| Late infantile (most common) | 1–2 years | Gait difficulty, hypotonia → spasticity, peripheral neuropathy, cognitive decline, optic atrophy; death by 5–6 years |
| Juvenile | 4–12 years | Behavioral changes, school difficulties, gait problems, peripheral neuropathy |
| Adult | >16 years | Psychiatric symptoms (often misdiagnosed), cognitive decline, peripheral neuropathy, spasticity |
Diagnostic Clues
- Combined central white matter disease + peripheral neuropathy in a child
- NCS: slow nerve conduction velocities (demyelinating neuropathy)
- MRI: symmetric periventricular white matter T2 hyperintensity, sparing subcortical U-fibers initially
- Diagnosis: decreased arylsulfatase A enzyme activity in leukocytes or fibroblasts; elevated urine sulfatides
- Nerve biopsy: metachromatic granules (if performed)
- Treatment: atidarsagene autotemcel (Lenmeldy in the US; Libmeldy in Europe) — ex vivo lentiviral ARSA gene therapy; FDA indication (2024) covers pre-symptomatic late infantile MLD, pre-symptomatic early juvenile MLD, or early symptomatic early juvenile MLD; HSCT for selected pre-symptomatic patients
Board Pearl
- MLD = arylsulfatase A deficiency + metachromatic granules + combined CNS and PNS involvement. The combination of central white matter disease + demyelinating peripheral neuropathy in a child is the classic board stem.
- Metachromasia = tissue stains a different color than the dye itself (golden-brown with cresyl violet instead of violet/purple; red-purple/magenta with toluidine blue instead of blue) — this is the naming origin of the disease
Krabbe Disease (Globoid Cell Leukodystrophy)
Genetics and Biochemistry
- Inheritance: autosomal recessive
- Gene: GALC (14q31.3) → encodes galactocerebrosidase (galactosylceramidase)
- Defect: galactocerebroside cannot be degraded → accumulation of psychosine (galactosylsphingosine), which is directly toxic to oligodendrocytes and Schwann cells
- Paradox: galactocerebroside levels are NOT elevated in the brain (because oligodendrocytes die before they can produce it) — psychosine toxicity is the primary mechanism
Pathology
- Globoid cells — large multinucleated macrophages (PAS-positive) of microglial/hematogenous origin containing undigested galactocerebroside → pathognomonic
- Severe loss of oligodendrocytes and myelin
- Affects both CNS and PNS
Clinical Features
- Infantile form (most common, ~90%): onset 3–6 months
- Extreme irritability (classic presenting feature — "hyperirritability")
- Progressive spasticity, hypertonia
- Peripheral neuropathy (hyporeflexia may initially mask spasticity)
- Optic atrophy, cortical blindness
- Rapid decline; death by age 2–3 years
- Late-onset forms: juvenile and adult — slower progression, variable presentation
Diagnostic Features
- CSF: elevated protein (albuminocytologic dissociation)
- NCS: slow conduction velocities (peripheral demyelination)
- MRI: periventricular and deep white matter T2 hyperintensity; may show posterior predominance
- Diagnosis: decreased GALC enzyme activity in leukocytes or fibroblasts
- Treatment: Early HSCT (pre-symptomatic, identified via newborn screening in select states: NY, KY, MO, OH, IL) slows but does not cure disease — peripheral neuropathy and some neurologic decline persist. No effective therapy once symptoms appear.
Board Pearl
- Krabbe = galactocerebrosidase deficiency + globoid cells (multinucleated macrophages) + irritable infant with rapid decline. Remember: "Krabbe = Globoid"
- Elevated CSF protein in an infant with white matter disease and peripheral neuropathy → think Krabbe (also consider MLD)
Adrenoleukodystrophy (ALD) / Adrenomyeloneuropathy (AMN)
Genetics and Biochemistry
- Inheritance: X-linked recessive
- Gene: ABCD1 (Xq28) → encodes a peroxisomal membrane transporter (ATP-binding cassette protein)
- Defect: impaired import of very long-chain fatty acids (VLCFA) into peroxisomes for beta-oxidation → VLCFA accumulation in CNS white matter, adrenal cortex, and Leydig cells
- This is a peroxisomal disorder (not lysosomal)
Clinical Phenotypes
| Phenotype | Onset | Key Features |
|---|---|---|
| Childhood cerebral ALD | Boys 4–8 years | Behavioral/cognitive decline, visual loss, posterior-predominant white matter disease with contrast enhancement at the leading edge, rapid decline to vegetative state |
| Adrenomyeloneuropathy (AMN) | Adult males (20–30s) | Slowly progressive spastic paraparesis + peripheral neuropathy + sphincter dysfunction; may later develop cerebral involvement |
| Addison-only | Any age | Isolated adrenal insufficiency without neurologic symptoms (may precede ALD/AMN by years) |
| Female carriers | Adulthood (>40 yr) | Most female carriers (≥80% by age 60) develop AMN-like myelopathy with age; adrenal insufficiency is rare in carriers |
Key Diagnostic and Clinical Points
- Adrenal insufficiency (Addison disease) — may be the first manifestation, years before neurologic symptoms; always check adrenal function in boys/men with unexplained Addison disease
- MRI: posterior/parieto-occipital white matter T2 hyperintensity (childhood cerebral form); contrast enhancement at the advancing edge of demyelination (active inflammation)
- Diagnosis: elevated plasma VLCFA levels (C26:0, C26:0/C22:0 ratio)
- Newborn screening: Newborn screening for X-ALD (elevated C26:0-lysophosphatidylcholine on dried blood spot) added to federal RUSP 2016; now performed in most US states
- Treatment:
- HSCT (or elivaldogene autotemcel/Skysona ex vivo lentiviral gene therapy, FDA-approved 2022) only effective in early cerebral ALD with low Loes score (typically ≤9) and minimal neurologic deficit; does NOT benefit AMN
- Lorenzo’s oil (erucic acid + oleic acid) — normalizes plasma VLCFA; may reduce risk of cerebral progression in asymptomatic boys with normal MRI, but no benefit once symptomatic cerebral disease is established
- Adrenal hormone replacement as needed
Clinical Pearl
- A boy with behavioral changes + declining school performance + visual problems → MRI shows posterior white matter disease with contrast enhancement → check VLCFA levels and adrenal function
- Any male with unexplained Addison disease should be screened for ALD with plasma VLCFA levels — neurologic symptoms may not appear for years
Board Pearl
- ALD = X-linked + VLCFA + posterior white matter + contrast enhancement at leading edge + adrenal insufficiency. It is a peroxisomal disorder (not lysosomal).
- ALD has posterior-predominant white matter disease; Alexander has frontal-predominant — this distinction is a board favorite
Alexander Disease
Genetics
- Inheritance: autosomal dominant (most cases are de novo mutations)
- Gene: GFAP (17q21.31) → encodes glial fibrillary acidic protein (intermediate filament of astrocytes)
- The classic and most commonly tested autosomal dominant leukodystrophy (LMNB1-related ADLD is a rare adult-onset exception) — this fact is tested repeatedly
- Gain-of-function mutations → abnormal GFAP aggregation in astrocytes
Pathology
- Rosenthal fibers — eosinophilic, elongated inclusions within astrocyte processes, composed of aggregated GFAP + alpha-B-crystallin + HSP27 → characteristic of Alexander disease but NOT specific (also seen in pilocytic astrocytoma and chronic reactive gliosis)
- Found throughout the brain, especially in subpial, perivascular, and subependymal regions
- White matter degeneration is secondary to astrocyte dysfunction
Clinical Forms
| Form | Onset | Key Features |
|---|---|---|
| Infantile (most common) | <2 years | Megalencephaly (macrocephaly), seizures, spasticity, psychomotor regression, frontal-predominant white matter disease |
| Juvenile | 2–12 years | Bulbar/pseudobulbar signs, spasticity, ataxia, cognitive decline |
| Adult | >12 years | Bulbar symptoms, palatal myoclonus, ataxia, spasticity, dysautonomia; brainstem and spinal cord atrophy |
MRI Criteria (van der Knaap)
- Frontal predominance of white matter changes (opposite of ALD)
- Periventricular rim of T1 hyperintensity / T2 hypointensity
- Basal ganglia and thalamic abnormalities
- Brainstem abnormalities
- Contrast enhancement of specific structures (ventricular lining, frontal white matter)
Board Pearl
- Alexander disease = the classic and most commonly tested autosomal dominant leukodystrophy (LMNB1-related ADLD is a rare adult-onset exception) + Rosenthal fibers + frontal-predominant white matter disease + megalencephaly
- Mnemonic: "Alexander = Autosomal dominant = Anterior (frontal) predominance"
Canavan Disease
Genetics and Biochemistry
- Inheritance: autosomal recessive
- Gene: ASPA (17p13.2) → encodes aspartoacylase
- Defect: aspartoacylase cleaves N-acetylaspartate (NAA) into aspartate + acetate; deficiency → NAA accumulation
- NAA is normally the most abundant amino acid derivative in the brain; NAA accumulation disrupts myelin lipid synthesis (loss of acetate substrate for oligodendrocyte fatty acid synthesis) and causes osmotic/spongiform white matter degeneration
- Ashkenazi Jewish predilection (carrier frequency ~1/40)
Clinical Features
- Onset: 3–6 months
- Megalencephaly (macrocephaly) — similar to Alexander disease
- Initial hypotonia (floppy infant) → progressive spasticity
- Poor head control, feeding difficulties
- Optic atrophy
- Seizures
- Death usually in first decade
Diagnostic Features
- Urine organic acids: markedly elevated NAA (pathognomonic, primary diagnostic test); confirm with ASPA sequencing
- MRS (magnetic resonance spectroscopy): elevated NAA peak — supportive imaging finding and a board favorite
- Pathology: spongiform degeneration of white matter (vacuolization of myelin sheaths)
- MRI: diffuse white matter T2 hyperintensity with early involvement of subcortical U-fibers (unlike MLD/ALD where U-fibers are spared initially)
Board Pearl
- Canavan = aspartoacylase deficiency + elevated NAA on MRS + megalencephaly + subcortical U-fiber involvement. NAA is normally the tallest peak on MRS; in Canavan it is even more elevated.
- Both Canavan and Alexander present with megalencephaly, but Canavan = AR, NAA elevated, U-fibers involved vs. Alexander = AD, Rosenthal fibers, frontal predominance
Pelizaeus-Merzbacher Disease (PMD)
Genetics and Pathology
- Inheritance: X-linked recessive
- Gene: PLP1 (Xq22.2) → encodes proteolipid protein 1, the most abundant protein in CNS myelin
- Most commonly caused by PLP1 duplications; point mutations and deletions also occur
- Pathology: "tigroid" or "leopard-skin" pattern — patchy/tigroid hypomyelination with islands of relatively preserved (perivascular) myelin against a background of absent/deficient myelin — reflects failure of myelination (hypomyelination), not demyelination
- Note: the tigroid/leopard-skin pattern occurs on MRI in both MLD (radial/striated demyelination) AND PMD — not specific to PMD
Clinical Features
- Nystagmus from infancy — often the earliest and most recognizable sign (roving or pendular nystagmus appearing in the first weeks of life)
- Progressive spasticity, ataxia, titubation
- Cognitive impairment
- Stridor (laryngeal involvement in severe forms)
- Slow progression; survival into adolescence or adulthood (variable)
MRI
- Diffuse hypomyelination — white matter remains T2 hyperintense and T1 hypointense throughout life (appears as if myelination never occurred)
- Distinguished from other leukodystrophies by the absence of myelin maturation on serial imaging
Clinical Pearl
- An infant with nystagmus from birth + progressive spasticity + MRI showing diffuse hypomyelination → think Pelizaeus-Merzbacher disease
- PMD is an X-linked hypomyelinating disorder — myelin is never properly formed, unlike other leukodystrophies where myelin forms and then degenerates
Other Leukodystrophies
| Disease | Gene / Inheritance | Key Clinical Features | Diagnostic Clue | Treatment |
|---|---|---|---|---|
| Vanishing white matter disease (VWM/CACH) | EIF2B1–5 / AR | Episodic deterioration with febrile illness or minor head trauma; progressive ataxia and spasticity; ovarian failure in females (ovarioleukodystrophy) | MRI: progressive cystic degeneration of white matter (CSF-like signal); stress-triggered decline | Supportive; avoid physiologic stress |
| Cerebrotendinous xanthomatosis (CTX) | CYP27A1 / AR | Tendon xanthomas (especially Achilles), bilateral cataracts (juvenile), chronic diarrhea, progressive ataxia + spasticity, cognitive decline | Elevated cholestanol; low/normal cholesterol; elevated urine bile alcohols | Chenodeoxycholic acid (treatable!) |
| Refsum disease | PHYH (or PEX7) / AR | Retinitis pigmentosa, peripheral neuropathy (demyelinating), cerebellar ataxia, elevated CSF protein, ichthyosis, sensorineural hearing loss, cardiomyopathy | Elevated phytanic acid | Dietary phytanic acid restriction (treatable!); plasmapheresis for acute crises |
| LBSL | DARS2 / AR | Slowly progressive ataxia, spasticity, dorsal column dysfunction; leukoencephalopathy with brainstem and spinal cord involvement | MRI: brainstem + spinal cord + cerebral white matter; elevated lactate on MRS | Supportive |
| MLC (megalencephalic leukoencephalopathy with subcortical cysts) | MLC1 / AR | Macrocephaly + subcortical cysts (anterior temporal); slowly progressive | MRI: diffuse leukoencephalopathy with anterior temporal subcortical cysts | Supportive |
| APBD (adult polyglucosan body disease) | GBE1 / AR | Adult-onset gait + bladder dysfunction + neuropathy; glycogen branching enzyme deficiency | Polyglucosan bodies (in nerve/tissue biopsy) | Supportive |
| CARASIL | HTRA1 / AR | Subcortical strokes + alopecia + spondylosis | MRI: subcortical infarcts + leukoencephalopathy; HTRA1 mutations | Supportive |
Board Pearl
- CTX is a treatable leukodystrophy — tendon xanthomas + cataracts + diarrhea + ataxia + elevated cholestanol → treat with chenodeoxycholic acid
- Refsum = elevated phytanic acid + retinitis pigmentosa + peripheral neuropathy + cerebellar ataxia → treat with dietary phytanic acid restriction (avoid dairy fat, ruminant meat, certain fish)
- VWM/CACH = episodic decline triggered by fever or trauma + ovarian failure in females — MRI shows white matter progressively replaced by CSF-like signal
MRI Pattern Recognition
White Matter Distribution by Disease
| MRI Pattern | Disease | Key Distinguishing Feature |
|---|---|---|
| Frontal predominance | Alexander disease | Megalencephaly, Rosenthal fibers, AD inheritance |
| Posterior / parieto-occipital predominance | ALD (childhood cerebral) | Contrast enhancement at leading edge; VLCFA elevated; X-linked |
| Posterior / parieto-occipital predominance | Krabbe (later stages) | Globoid cells; infantile irritability; AR |
| Periventricular, symmetric | MLD | Metachromatic granules; U-fibers spared initially; peripheral neuropathy |
| Diffuse hypomyelination | PMD | Nystagmus from infancy; X-linked; tigroid pattern on pathology |
| Vanishing (cystic) white matter | VWM/CACH | Episodic deterioration with stress/fever; ovarian failure |
| Subcortical U-fibers involved early | Canavan disease | NAA elevated on MRS; megalencephaly; Ashkenazi Jewish |
| Cerebellar white matter | CTX | Tendon xanthomas; cataracts; elevated cholestanol |
Clinical Pearl
- On boards, the MRI distribution is often the most important clue: frontal = Alexander, posterior = ALD, diffuse hypomyelination = PMD, vanishing white matter = VWM
- When the MRI shows bilateral symmetric white matter disease in a child, always consider leukodystrophy before MS — MS is rare in young children and typically shows asymmetric, perivenular lesions
Quick Reference Table
High-Yield Associations
| Buzzword / Finding | Diagnosis |
|---|---|
| Metachromatic granules on nerve biopsy | MLD |
| Globoid cells (multinucleated macrophages) | Krabbe |
| Elevated VLCFA + adrenal insufficiency | ALD |
| Rosenthal fibers + frontal predominance | Alexander |
| Elevated NAA on MRS + megalencephaly | Canavan |
| Nystagmus from birth + hypomyelination | PMD |
| Episodic decline with fever + ovarian failure | VWM/CACH |
| Tendon xanthomas + cataracts + ataxia + elevated cholestanol | CTX |
| Elevated phytanic acid + retinitis pigmentosa + neuropathy | Refsum |
| Classic AD leukodystrophy (rare exception: LMNB1-related ADLD) | Alexander |
| X-linked leukodystrophy + peroxisomal defect | ALD |
| X-linked leukodystrophy + hypomyelination | PMD |
| Posterior white matter + contrast enhancement at leading edge | ALD |
| Combined CNS + PNS demyelination in a child | MLD or Krabbe |
| Treatable leukodystrophy with bile acid therapy | CTX |
References
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw Hill; 2023.
- van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134(3):351–382.
- Parikh S, Bernard G, Leventer RJ, et al. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephalopathies. Mol Genet Metab. 2015;114(4):501–515.
- Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. 2005;294(24):3131–3134.
- Wenger DA, Rafi MA, Luzi P. Krabbe disease: one hundred years from the bedside to the bench to the bedside. J Neurosci Res. 2016;94(11):982–989.
- Brenner M, Johnson AB, Boespflug-Tanguy O, et al. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001;27(1):117–120.
- Matalon R, Michals-Matalon K. Canavan disease. In: GeneReviews. University of Washington, Seattle; updated 2023.
- Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2017;377(17):1630–1638.
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