Table 1

Leukodystrophies presenting in adulthood

DisorderAge of onsetPrevalence of adult diseaseEthnic predilectionInheritanceUseful investigation(s)Gene(s)
X linked adrenoleukodystrophy adrenomyeloneuropathy (ALD/AMN)4 5Childhood to adulthoodUp to 40/million, adult cerebral ALD accounts for 5% of cases; 15%–20% of heterozygote women are symptomaticX linked. Female carriers can develop AMN/spastic paraparesisVery long chain fatty acid levelsABCD1
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)6 7*Migraine: mean 30 years (range 6–48 years). Ischaemic events: mean 50 years (range 20–70 years)10–40/millionAD and sporadicElectron microscopy of skin biopsyNOTCH3
Globoid cell leukodystrophy (Krabbe disease)8 9Up to 60 years10/million, 10% adult onsetARGalactocerebrosidase (GALC) enzyme activity (leukocytes/fibroblasts)GALC; PSAP
Metachromatic leukodystrophy (MLD)10Up to 70 years2/million, 20% adult onsetARArylsulfatase A (ARSA) enzyme activity (leukocytes/fibroblasts)†ARSA; PSAP
Cerebrotendinous xanthomatosis (CTX)8 11Juvenile to adulthood2/millionARSterol profile. Urine bile alcoholsCYP27A1
Mitochondrial disorders12–14*Childhood and adulthood—any ageTotal prevalence 100–165/million, prevalence of leukoencephalopathy in adults is not known, paediatric literature suggests it is commonMaternal, AD, ARLactate (blood/CSF). Mitochondrial respiratory chain enzyme activityVarious
Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS)15Mean 40 years (range 15–78 years)52 cases described in literature, incidence increasing with recent discovery of CSF1R geneAD and sporadicCharacteristic brain biopsy findings (now superseded by molecular genetic testing)CSFR1
Adult polyglucosan body disease (APBD)1640–60 years47 casesAshkenazi JewishARSural nerve biopsy. Glycogen brancher enzyme (GBE) activity (fibroblasts)GBE1
Alexander disease1712–62 years36 casesAD and sporadicCharacteristic brain biopsy findings (now superseded by molecular genetic testing)GFAP
Adult onset autosomal dominant leukodystrophy (ADLD)18 1930–50 yearsUnknown: at least 27 cases reported in literatureADLMNB1
Vanishing white matter disease (VWM)20Mean 30 years (range 16–62 years)177 cases in total, 25 with onset >16 yearsAReIF2B 1–5
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)21*20–50 yearsUnknown, thought to be rare, 50 cases described thus farMost reported cases in Japan and ChinaAROn brain pathology, CARASIL is characterised by intense arteriolosclerosis without the deposition of granular osmiophilic materials in small arteries and arterioles that is seen in CADASILHTRA1
Hexosaminidase A (HEX A) deficiency (GM2 gangliosidosis, adult onset Tay–Sachs disease)2220–40 yearsSmall case series64% Jewish originARβ-HEX A enzymatic activity (leukocytes)HEXA
Megalencephalic leukoencephalopathy with subcortical cysts (MLC)236 months–50 years11 cases aged >20 yearsAsian-Indian, TurkishARMLC1; HEPACAM
MTHFR deficiency24Any ageLimited case reportsARPlasma amino acid profileMTHFR
α-Mannosidosis25Adolescence, but severe ataxia 30–40 yearsLimited case reportsARUrine oligosaccharides. Vacuolated lymphocytes. α-Mannosidase enzyme activity (leukocytes)MAN2B1
Mucolipidosis type IV8 26Usually infant childhood, 1 case onset 16 years14Late onset reported due to attenuated phenotypeAshkenazi JewishARMCOLN1
Adult sialidosis27Usually childhood, but can be 20–30 yearsLimited case reportsFinnishARUrine oligosaccharides. Vacuolated lymphocytes. α-Neuroaminidase enzyme activity (fibroblasts)SLC17A5
Organic acidurias28–31Adolescence to adulthoodLimited case reportsARUrine organic acid profile (UOA)
1) Canavan disease↑ N-acetylaspartic acid (UOA). Aspartoacylase enzyme activity (fibroblasts)ASPA
2) Glutaricacidemia type 1↑Glutaric acid, 3-OH-glutaric acid (UOA). Acylcarnitine profileGCDH
3) L-2-hydroxyglutaric aciduria↑2-Hydroxyglutaric acid (UOA). ↑Lysine (CSF)L2HGDH
4) 3-Methylglutaconic aciduria type 1↑3-Methylglutaconate, 3-hydroxyisovaleric acid (UOA)AUH
Pelizaeus–Merzbacher disease (PMD)32 33Usually infant–childhood onset, case reports of adult onset up to age 45 yearsLimited case reportsX linked. Heterozygote women can develop spastic paraparesisPLP1
Recessive hypomyelinating leukoencephalopathy (Pelizaeus– Merzbacher-like disease)34Case report of onset age 15 yearsCase reportARGJC2; HSPD1; AIMP1
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation35Usually childhoodCase reportARMRS: elevated lactateDARS2
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu–Hokola disease)36Mean 30 years (range 10–45 years)33 cases in JapanMost reported cases in Finland and Japan, but occur worldwideARImaging of the handTYROBP; TREM2
Cockayne Syndrome37Usually infant/childhood. reported adult cases age 40 and 44 yearsOverall 1.8–2.7 per million births. Four cases reported with adult onsetCanada (aboriginal residents of Manitoba, Newfoundland), Japan, Middle East and West Asian countries35ARERCC6; ERCC8
  • The most frequently described adult onset inherited leukodystrophies.

  • *Not traditionally classified as a classical leukodystrophy.

  • †ARSA enzyme activity in leukocytes that is 5%–20% of normal controls may be caused by pseudodeficiency. Pseudodeficiency may be difficult to distinguish from true ARSA enzyme deficiency by biochemical testing alone. Therefore, the diagnosis of MLD is usually confirmed by molecular genetic testing of ARSA. Pseudodeficiency alleles are common polymorphisms that result in lower than average ARSA enzyme activity; however, these alleles are reported to still produce sufficient functional enzyme to avoid sulfatide accumulation and thus do not cause MLD in either the homozygous state or the compound heterozygous state with an MLD allele.

  • AD, autosomal dominant; AR, autosomal recessive; PLP, proteolipid protein.