Table 1

Leukodystrophies presenting in adulthood

Disorder	Age of onset	Prevalence of adult disease	Ethnic predilection	Inheritance	Useful investigation(s)	Gene(s)
X linked adrenoleukodystrophy adrenomyeloneuropathy (ALD/AMN)4 5	Childhood to adulthood	Up to 40/million, adult cerebral ALD accounts for 5% of cases; 15%–20% of heterozygote women are symptomatic		X linked. Female carriers can develop AMN/spastic paraparesis	Very long chain fatty acid levels	ABCD1
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/million		AD and sporadic	Electron microscopy of skin biopsy	NOTCH3
Globoid cell leukodystrophy (Krabbe disease)8 9	Up to 60 years	10/million, 10% adult onset		AR	Galactocerebrosidase (GALC) enzyme activity (leukocytes/fibroblasts)	GALC; PSAP
Metachromatic leukodystrophy (MLD)10	Up to 70 years	2/million, 20% adult onset		AR	Arylsulfatase A (ARSA) enzyme activity (leukocytes/fibroblasts)†	ARSA; PSAP
Cerebrotendinous xanthomatosis (CTX)8 11	Juvenile to adulthood	2/million		AR	Sterol profile. Urine bile alcohols	CYP27A1
Mitochondrial disorders12–14*	Childhood and adulthood—any age	Total prevalence 100–165/million, prevalence of leukoencephalopathy in adults is not known, paediatric literature suggests it is common		Maternal, AD, AR	Lactate (blood/CSF). Mitochondrial respiratory chain enzyme activity	Various
Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS)15	Mean 40 years (range 15–78 years)	52 cases described in literature, incidence increasing with recent discovery of CSF1R gene		AD and sporadic	Characteristic brain biopsy findings (now superseded by molecular genetic testing)	CSFR1
Adult polyglucosan body disease (APBD)16	40–60 years	47 cases	Ashkenazi Jewish	AR	Sural nerve biopsy. Glycogen brancher enzyme (GBE) activity (fibroblasts)	GBE1
Alexander disease17	12–62 years	36 cases		AD and sporadic	Characteristic brain biopsy findings (now superseded by molecular genetic testing)	GFAP
Adult onset autosomal dominant leukodystrophy (ADLD)18 19	30–50 years	Unknown: at least 27 cases reported in literature		AD		LMNB1
Vanishing white matter disease (VWM)20	Mean 30 years (range 16–62 years)	177 cases in total, 25 with onset >16 years		AR		eIF2B 1–5
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)21*	20–50 years	Unknown, thought to be rare, 50 cases described thus far	Most reported cases in Japan and China	AR	On brain pathology, CARASIL is characterised by intense arteriolosclerosis without the deposition of granular osmiophilic materials in small arteries and arterioles that is seen in CADASIL	HTRA1
Hexosaminidase A (HEX A) deficiency (GM2 gangliosidosis, adult onset Tay–Sachs disease)22	20–40 years	Small case series	64% Jewish origin	AR	β-HEX A enzymatic activity (leukocytes)	HEXA
Megalencephalic leukoencephalopathy with subcortical cysts (MLC)23	6 months–50 years	11 cases aged >20 years	Asian-Indian, Turkish	AR		MLC1; HEPACAM
MTHFR deficiency24	Any age	Limited case reports		AR	Plasma amino acid profile	MTHFR
α-Mannosidosis25	Adolescence, but severe ataxia 30–40 years	Limited case reports		AR	Urine oligosaccharides. Vacuolated lymphocytes. α-Mannosidase enzyme activity (leukocytes)	MAN2B1
Mucolipidosis type IV8 26	Usually infant childhood, 1 case onset 16 years14	Late onset reported due to attenuated phenotype	Ashkenazi Jewish	AR		MCOLN1
Adult sialidosis27	Usually childhood, but can be 20–30 years	Limited case reports	Finnish	AR	Urine oligosaccharides. Vacuolated lymphocytes. α-Neuroaminidase enzyme activity (fibroblasts)	SLC17A5
Organic acidurias28–31	Adolescence to adulthood	Limited case reports		AR	Urine 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 profile	GCDH
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 33	Usually infant–childhood onset, case reports of adult onset up to age 45 years	Limited case reports		X linked. Heterozygote women can develop spastic paraparesis		PLP1
Recessive hypomyelinating leukoencephalopathy (Pelizaeus– Merzbacher-like disease)34	Case report of onset age 15 years	Case report		AR		GJC2; HSPD1; AIMP1
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation35	Usually childhood	Case report		AR	MRS: elevated lactate	DARS2
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu–Hokola disease)36	Mean 30 years (range 10–45 years)	33 cases in Japan	Most reported cases in Finland and Japan, but occur worldwide	AR	Imaging of the hand	TYROBP; TREM2
Cockayne Syndrome37	Usually infant/childhood. reported adult cases age 40 and 44 years	Overall 1.8–2.7 per million births. Four cases reported with adult onset	Canada (aboriginal residents of Manitoba, Newfoundland), Japan, Middle East and West Asian countries35	AR		ERCC6; 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.