Inherited Leukoencephalopathies

Leukoencephalopathies are conditions that selectively involve the white matter of the brain. A great deal has been written about acquired causes of leukoencephalopathy, which include inflammatory conditions such as multiple sclerosis, infections, nutritional disorders, neoplasia, acquired toxic causes, and disturbances of blood flow. This special issue of Seminars in Neurology focuses on hereditary leukoencephalopathies. In the past, the primary focus has been on those hereditary leukoencephalopathies with progressive destruction or loss of previously acquired myelin (leukodystrophies). In recent years, several new hereditary leukoencephalopathies have been described that are associated with impaired formation or metabolism of myelin (including conditions with dysmyelination or hypomyelination). Despite recent advances in our knowledge about the molecular causes of leukoencephalopathy ([Table 1]), ~50% of patients with hereditary leukoencephalopathies remain undiagnosed.

Table 1 Hereditary Leukoencephalopathies

Disease	Inheritance	Gene(s)	Protein(s)
Alexander's disease	AD	GFAP	Glial fibrillary acidic protein
Childhood ataxia with central hypomyelination/ vanishing white matter disease (CACH/VWMD)	AR	EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5	Eukaryotic translation initiation factor 2B, subunits 1–5
Megalencephalic leukoencephalopathy with subcortical cysts (MLC)	AR	MLC1
Megalencephalic leukoencephalopathy with subcortical cysts (MLC)	AR	HEPACAM	GlialCAM
Lysosomal disorders
Metachromatic Leukodystrophy	AR	ARSA PSAP	Arylsulfatase-A Saposin B
Multiple sulfatase deficiency	AR	SUMF1	Sulfatase modifying factor-1
Krabbe's disease	AR	GALC PSAP	Galactosylceramidase Saposin A
GM1-gangliosidosis	AR	GLB1	Beta galactosidase
Tay-Sachs disease, GM2-gangliosidosis	AR	HEXA	Hexosaminidase A
Mucolipidosis IV	AR	MCOLN1	Mucolipin-1
Fucosidosis	AR	FUCA1	Alpha-1-fucosidase
Fabry's disease	X-Linked	GLA	Alpha-galactosidase A
Salla's disease (free sialic acid storage disease)	AR	SLC17A5	Solute carrier family 17 (sodium phosphate cotransporter)
Peroxisomal disorders
Adrenoleukodystrophy	X-linked	ABCD1 (ALDP)	ATP-binding cassette (ABC) transporter
Peroxisomal biogenesis defects (Zellweger's spectrum disorders)	AR	Multiple PEX genes	Various peroxins
D-bifunctional protein deficiency	AR	HSD17B4	D-bifunctional protein
Peroxisomal acyl-CoA oxidase 1 deficiency	AR	ACOX1	Peroxisomal acyl-CoA oxidase 1
Rhizomelic chondrodysplasia punctata type 1	AR	PEX7	Peroxisomal type 2 targeting signal (PTS2) receptor
Rhizomelic chondrodysplasia punctata type 2	AR	GNPAT	Dihydroxyacetone phosphate acyltransferase
Rhizomelic chondrodysplasia punctata type 3	AR	AGPS	Alkyl-DHAP synthase
Mitochondrial disorders
Respiratory chain defects	Any	Multiple nuclear and mtDNA genes	Multiple
MNGIE (mitochondrial neurogastrointestinal encephalopathy syndrome)	AR	TYMP	Thymidine phosphorylase
MNGIE with normal thymidine	AR	RRM2B	P53 inducible-ribonucleotide reductase
POLG-related disorders	AD, AR	POLG	DNA polymerase gamma
Navaho neurohepatopathy (NNH)	AR	MPV17
LBSL (leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation)	AR	DARS2	Mitochondrial aspartyl-tRNA synthetase
Remethylation cycle disorders
MTHFR (methylenetetrahydrofolate reductase deficiency)	AR	MTHFR	Methylenetetrahydrofolate reductase
Cobalamin C disease	AR	MMACHC
Cerebral folate deficiency	AR	FOLR1	Folate receptor alpha
Organic acidemias
Canavan's disease	AR	ASPA	aspartoacylase
Glutaric aciduria type 1	AR	GCDH	Glutaryl-CoA dehydrogenase
L-2-hydroxyglutaric aciduria	AR	L2HGDH	L2-hydroxyglutarate dehydrogenase
3-methylglutaconic aciduria type 1	AR	AUH	3-methylglutaconyl-CoA hydratase
Biotinidase deficiency	AR	BTD	biotinidase
Amino acid disorders
Serine synthesis defects	AR	PSAT1	Phosphoserine aminotransferase
		PHGDH	Phosphoglycerate dehydrogenase
Phenylketonuria (PKU)	AR	PAH	Phenylalanine hydroxylase
Associated with calcifications
Aicardi-Goutieres' syndrome
AGS1	AD,AR	TREX1	3' → 5' DNA exonuclease
AGS2	AR	RNASEH2B	ribonuclease H2, subunit B
AGS3	AR	RNASEH2C	ribonuclease H2, subunit C
AGS4	AR	RNASEH2A	ribonuclease H2, subunit A
AGS5	AR	SAMHD1	SAM-domain and HD-domain-containing protein 1
Cystic leukoencephalopathy without megalencephaly	AR	RNASET2	Ribonuclease T2
Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts)	AR	Unknown	Unknown
Nasu-Hakola's disease	AR	TREM2 DAP12	Triggering receptor expressed on myeloid cells 2 DNAX-activation protein 12
Cockayne's syndrome	AR	ERCC6 ERCC8	Excision repair cross-complementing group 6 and 8
Associated with hypomyelination
Pelizaeus-Merzbacher disease	X-linked	PLP1	Proteolipid protein 1
Pelizaeus-Merzbacher-like disease	AR	GJC2	Connexin 46.6
Allan-Herndon-Dudley's disease	X-linked	MCT8 (SLC16A2)	MCT8-specific thyroid hormone cell transporter
Hypomyelination with congenital cataracts (HCC)	AR	FAM126A	Hyccin
Hypomyelination with hypogonadotrophic hypogonadism and hypodontia (4H)	AR	POLR3A POLR3B	RNA polymerase III subunit 3A RNA polymerase III subunit 3B
Tremor-ataxia with central hypomyelination (TACH)
Leukodystrophy with hypodontia (LO)
Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC)	AR	POLR3A POLR3B	RNA polymerase III subunit 3A RNA polymerase III subunit 3B
Hypomyelination with atrophy of basal ganglia and cerebellum (HABC)	Unknown	Unknown	Unknown
Waadenburg-Hirshsprung's syndrome with peripheral neuropathy and central hypomyelination	AR	SOX10	Sry bOX10 transcription factor
Tay's syndrome (trichothiodystrophy with hypersensitivity to sunlight)	AR	ERCC3 ERCC2 GTF2H5	General transcription factor IIH subunits
Oculodentodigital syndrome	AD (AR)	GJA1	Connexin-43
West's syndrome with severe cerebral hypomyelination, spastic quadriplegia and developmental delay	AD	SPTAN1	Alpha-II spectrin
Hypomyelinating leukodystrophy 3 (HLD3)	AR	AIMP1	Aminoacyl-tRNA Synthetase complex-interacting multifunctional protein 1
Associated with vasculopathy
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)	AD	NOTCH3	Notch receptor
CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy)	AR	HTRA1	Serine protease HTRA1
Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC)	AD	COL4A1	Collagen, type IV, alpha-1
Retinal vasculopathy with cerebral leukodystrophy	AD	TREX1	3' → 5' DNA exonuclease
Associated with abnormal lipid metabolism
Cerebrotendinous xanthomatosis	AR	CYP27A1	Sterol 27-hydroxylase
Sjögren-Larsson's syndrome	AR	ALDH3A2	Fatty aldehyde dehydrogenase
ELOVL4 deficiency	AR	ELOVL4	Elongation of very long chain fatty acids-4
Spastic paraplegia 35	AR	FA2H	Fatty acid 2-hydroxylase
Associated with muscular dystrophy
Merosin-deficient congenital muscular dystrophy (MDC1A)	AR	LAMA2	Laminin alpha-2
Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6 (MDDGB6)	AR	LARGE	Acetylglucosaminyltransferase-like protein
Muscular dystrophy-dystroglycanopathy (congenital with and without mental retardation), type B, 5 (MDDGB5)	AR	FKRP	Fukutin-related protein
Adult-onset leukodystrophies
Adult-onset autosomal dominant leukodystrophy (ADLD)	AD	LMNB1	Lamin B1 duplication
Adult polyglucosan body disease	AR	GBE1	Glycogen brancher enzyme
Neuroaxonal leukodystrophy with spheroids	AD	Unknown	Unknown
Chromosome abnormalities
18q-deletion syndrome	De novo
Fragile X-associated tremor/ ataxia syndrome (FXTAS)	X-linked	FMR1 Trinucleotide repeat expansion	Fragile X mental retardation 1
Klinefelter's syndrome	De novo
Microdeletion syndromes	De novo

AD, autosomal dominant; AR, autosomal recessive.

The contributions in this issue first outline the formation and metabolism of normal myelin and the developmental evolution of normal myelin as seen on magnetic resonance imaging (MRI). A general approach to leukoencephalopathies is provided that forms a foundation for a clinical / etiology-based approach to hereditary leukoencephalopathies. The articles in this issue of Seminars in Neurology focus not on individual disorders, but present a more expansive evaluation of hereditary leukoencephalopathies based on common clinical features or underlying etiology.

M. Mateo Paz Soldán, M.D., Ph.D., and Istvan Pirko, M.D., multiple sclerosis specialists at the Mayo Clinic, share their extensive knowledge of normal myelin formation and metabolism in a concise and very understandable introductory article that forms the basis for the understanding of the pathology associated with hereditary leukoencephalopathies. To evaluate the pattern of abnormal myelination demonstrated by MRI, it is important to understand the evolution of normal myelin development. Kirk M. Welker, M.D., and Alice Patton, M.D., pediatric neuroradiologists at the Mayo Clinic, present the normal neuroimaging appearance of myelin at different ages.

Leukoencephalopathies associated with macrocephaly comprise a distinct group including Alexander's disease and Canavan's disease as well as less known leukoencephalopathies that should be considered in the differential diagnosis of these conditions. Bwee Tien Poll-The, M.D., Ph.D., an internationally recognized expert in peroxisomal disorders from Emma Children's Hospital AMC and the University of Amsterdam, presents a thorough review of peroxisomal biogenesis defects and single enzyme disorders that present with leukoencephalopathy. Metachromatic leukodystrophy and Krabbe disease are among the most recognized hereditary disorders of white matter. In recent years, white matter abnormalities have been found in other lysosomal storage disorders, which are also described. Mitochondrial disorders are increasingly recognized in patients with hereditary leukoencephalopathy. Lee-Jun C. Wong, Ph.D., Professor of Molecular and Human Genetics at Baylor College of Medicine, has recently described a detailed molecular algorithm for mitochondrial disorders and shares her approach to the classification and diagnosis of these complicated disorders with us.

Pelizaeus-Merzbacher disease is by the far the most recognized leukoencephalopathy associated with hypomyelination. Grace M. Hobson, Ph.D., Head of the Neurogenetics Research Laboratory and Director of Diagnostics for Pelizaeus-Merzbacher Disease at the Nemours Alfred I. duPont Hospital for Children, has contributed significantly to our understanding of the molecular mechanisms in Pelizaeus-Merzbacher disease. James Y. Garbern, M.D., Ph.D., was an internationally recognized expert in Pelizaeus-Merzbacher disease who traveled the world to share his clinical expertise. The leukodystrophy community was saddened by Dr. Garbern's death on November 10, 2011 after a battle with cancer.

Disorders of vitamin B12 and folate metabolism are underrecognized but potentially treatable causes of leukoencephalopathy. It is a privilege to have Dr. Bridget Wilcken, an internationally recognized expert in homocysteine and vitamin B12 metabolism from The Children's Hospital at Westmead, Australia, describe these important pathways and their contribution to white matter disorders. Neuroicthyoses are also underrecognized causes of leukoencephalopathies. William B. Rizzo, M.D., is at the forefront of this field and provides a unique perspective and approach to the patient with neuroicthyosis.

In recent years, an increasing number of hereditary leukoencephalopathies have been described with onset in adulthood. Jan-Mendelt Tillema, M.D., a Multiple Sclerosis Fellow at the Mayo Clinic, reviews our current knowledge of adult-onset leukoencephalopathies.