Leukodystrophies are inherited disorders of myelin (formation, maintenance, or degeneration). MRI pattern recognition narrows the differential dramatically before testing — adrenoleukodystrophy targets corticospinal tracts; metachromatic leukodystrophy spares the U-fibers; Alexander disease prefers frontal lobes; vanishing white matter shows cystic degeneration. Several leukodystrophies are now treatable (X-ALD, MLD, CTX), making rapid diagnosis essential.

X-Linked Adrenoleukodystrophy (X-ALD)

• First-line test: plasma very-long-chain fatty acids (VLCFA) — elevated C26:0, C26:0/C22:0 ratio, C24:0/C22:0 ratio.
• Confirmation: ABCD1 sequencing.
• Female carrier testing: VLCFA can be normal in heterozygous females (~20% false negative); ABCD1 sequencing is mandatory.
• Now part of newborn screening in many US states (added to the Recommended Uniform Screening Panel in 2016).
• Phenotypes:
  • Childhood cerebral X-ALD (CCALD): 4–8 years; rapidly progressive demyelination; primary adrenal insufficiency precedes neurological signs.
  • Adolescent/adult cerebral form.
  • Adrenomyeloneuropathy (AMN): adult-onset spastic paraparesis + peripheral neuropathy + adrenal insufficiency.
  • Addison-only: ~10%.
• Treatment:
  • Allogeneic HSCT (best if early CCALD, Loes score <9, mild symptoms).
  • Elivaldogene autotemcel (Skysona) — ex vivo autologous lentiviral gene therapy.
  • Adrenal replacement (hydrocortisone + fludrocortisone).
• Cascade family testing + maternal counseling critical (X-linked).

Metachromatic Leukodystrophy (MLD)

• First-line test: arylsulfatase A (ASA) enzyme activity in leukocytes + urine sulfatides (elevated).
• Confirmation: ARSA sequencing.
• Pseudodeficiency alleles: ~7–15% of population have low ASA without disease. Combined low ASA + elevated urine sulfatides + ARSA sequencing distinguishes true MLD.
• If ARSA negative: PSAP sequencing (saposin B deficiency mimics MLD).
• Phenotypes:
  • Late-infantile (~50%): 1–2 years; gait regression, spasticity, neuropathy.
  • Juvenile: 4–14 years; behavior, cognitive decline.
  • Adult: psychosis-like presentation, mimics schizophrenia or FTD.
• Treatment:
  • Allogeneic HSCT for pre-symptomatic or very early juvenile cases.
  • Atidarsagene autotemcel (Lenmeldy in the US; Libmeldy in Europe) — ex vivo autologous lentiviral gene therapy approved for pre-symptomatic late-infantile / early juvenile MLD.

Krabbe Disease (Globoid Cell Leukodystrophy)

• First-line test: galactocerebrosidase (GALC) enzyme activity in leukocytes.
• Confirmation: GALC sequencing.
• Now part of newborn screening in several US states.
• Phenotypes:
  • Infantile (most common): 3–6 months; irritability, hypertonicity, optic atrophy; death by 2–3 years.
  • Late-infantile / juvenile / adult: progressive spasticity + neuropathy.
• Treatment: HSCT effective ONLY if performed pre-symptomatically (hence the value of newborn screening). Once symptomatic infantile Krabbe begins, HSCT does not arrest progression.

Alexander Disease

• First-line test: GFAP sequencing.
• Inheritance: autosomal dominant; ~95% are de novo mutations.
• Phenotypes:
  • Infantile: macrocephaly, seizures, developmental regression.
  • Juvenile: bulbar/pseudobulbar signs, spasticity.
  • Adult: bulbar findings, palatal myoclonus, ataxia.
• Imaging: frontal-predominant white matter changes; periventricular rim of T2 hypointensity (Van der Knaap criteria); brainstem (medulla) atrophy in adult form.

Pelizaeus-Merzbacher Disease (PMD)

• First-line test: PLP1 duplication analysis (MLPA or array CGH).
• Yield: ~60–70% of PMD have PLP1 duplication.
• Step 2: PLP1 sequencing.
• X-linked recessive: classic PMD in boys.
• Clinical clues: nystagmus in early infancy, hypotonia, delayed development, progressive spasticity.
• Imaging: hypomyelination — diffuse T2 white matter hyperintensity without atrophy.
• Related disorder: PLP1-null syndrome (deletion) — milder phenotype; SPG2 (allelic).
• Differential: PMD-like disease — GJC2 sequencing (HLD2).

Vanishing White Matter Disease (VWM / CACH)

• First-line test: eIF2B panel — EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5 sequencing.
• Clinical clues: episodic neurological deterioration triggered by febrile illness or minor head trauma; cerebellar ataxia + spasticity.
• Imaging: diffuse white matter abnormality with cystic / CSF-like degeneration (vanishing white matter); FLAIR signal lower than expected.

Cerebrotendinous Xanthomatosis (CTX)

• First-line test: serum cholestanol (elevated) + plasma bile alcohols.
• Confirmation: CYP27A1 sequencing.
• Clinical clues: chronic diarrhea in infancy, juvenile cataracts, tendon xanthomas, progressive ataxia/spasticity/cognitive decline.
• Imaging: dentate nucleus T2 hyperintensity, white matter changes.
• Treatment — TREATABLE: chenodeoxycholic acid (CDCA) replaces bile acid deficiency. Statins reduce cholestanol. Early treatment prevents neurological progression.

Aicardi-Goutières Syndrome (AGS)

• First-line test: AGS NGS panel — TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH1.
• Biomarker: elevated CSF interferon-α and interferon signature in blood.
• Clinical clues: encephalopathy in infancy mimicking congenital infection; chilblain skin lesions; calcification of basal ganglia (CT) and white matter abnormality.
• Treatment: JAK inhibitors (baricitinib) — disease-modifying.

Other Leukodystrophies Worth Knowing

• Megalencephalic leukoencephalopathy with subcortical cysts (MLC): MLC1 or HEPACAM.
• Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC): TUBB4A.
• POL3 hypomyelination (4H syndrome): POLR3A / POLR3B.
• Adult-onset leukoencephalopathy with axonal spheroids (ALSP): CSF1R — covered on Cognitive/Dementia page.
• Sjögren-Larsson syndrome: ALDH3A2; ichthyosis + spastic diplegia + intellectual disability.
• Canavan disease: ASPA; elevated urinary N-acetylaspartate; macrocephaly.
• Adult polyglucosan body disease (APBD): GBE1; spastic paraparesis + neurogenic bladder + neuropathy + cognitive decline.

MRI Pattern → Likely Diagnosis

Pitfalls and Pearls

• MRI pattern recognition is the cornerstone — drives targeted testing rather than blind WES.
• X-ALD female carriers: VLCFA can be normal (~20% false negative); always do ABCD1 sequencing in suspected female carriers.
• MLD pseudodeficiency: low ASA without disease in ~7–15% of population; combine with urine sulfatides + ARSA sequencing.
• Krabbe HSCT works only pre-symptomatically; symptomatic infantile cases are not rescuable.
• Alexander disease is usually de novo: family history is typically negative.
• PMD step 1 = PLP1 duplication (MLPA), step 2 = sequencing.
• VWM diagnostic clue: episodic deterioration after febrile illness or minor head trauma.
• CTX is treatable with CDCA — diagnose early, before cerebellar/cognitive damage is irreversible.
• AGS mimics congenital TORCH infection: think AGS when “congenital infection” workup is negative.
• Newborn screening for X-ALD and Krabbe has changed early detection — confirm panel composition in your state.
• If targeted testing negative + high suspicion: leukodystrophy NGS panel → trio WES.

References

1. Vanderver A, Prust M, Tonduti D, et al. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab. 2015;114(4):494-500.
2. 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.
3. Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy. Lancet. 2016;388(10043):476-487.
4. Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Engl J Med. 2005;352(20):2069-2081.
5. 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.
6. Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med. 1984;311(26):1649-1652.
7. Vanderver A, Adang L, Gavazzi F, et al. Janus kinase inhibition in the Aicardi-Goutières syndrome. N Engl J Med. 2020;383(10):986-989.