Leukodystrophies can be defined as genetic abnormalities primarily affecting the white matter of the central nervous system. It is typically myelin and glial cells (oligodendrocytes and astrocytes) that are affected. In most cases, there is a gradual deterioration.
Leukodystrophies can be classified into 2 main groups: hypomyelination pathologies and other pathologies. Research into leukodystrophies began in Amsterdam in 1987, shortly after the introduction of Magnetic Resonance Imaging (MRI) in medicine. MRI has been found to be a very useful tool in distinguishing different forms of leukodystrophies with consistent and distinct types of abnormalities detectable on MRI. It soon became evident that in more than half of the patients ( ~60%) with leukodystrophy, as revealed on MRI, a specific diagnosis could not be made.
Since then, many newer leukodystrophies have been defined and the responsible mutated genes have been identified, first by genetic linkage analysis and, more recently, by full exome sequencing. The following list of “new” leukodystrophies, which are other conditions associated with an identified genetic abnormality, is incomplete:
Alexander disease (GFAP mutations)
Vanishing white matter / CACH (EIF2B1-5)
Megalencephalic leukoencephalopathy with subcortical cysts / MLC (MLC1 and GLIALCAM) Acardi-Goutières syndrome (TREX1, RNASEH2B, RNASEH2C and RNASEH2A, RNASET2, SAMHD1, ADAR1 and IFIH1)
Mitochondrial tRNA synthetase defects: LBSL (DARS2), LTBL (EARS2), AARS2 related leukoencephalopathy
Cytoplasmic tRNA synthetase defects: HBSL (DARS), RARS-related leukoencephalopathy ClC-2 chloride channel defect (CLCN2)
Mitochondrial leukoencephalopathies (complex I: NDUFV1, NDUFS1, NDUFS4, NDUFS7, NDUFS8, NUPBL; complex II: SDHAF1, SDHA, SDHB; complex III: LYRM7; complex IV: SURF1, APOPT1; other: NFU1, BOLRX3, LIAS, LIAS)
Peroxisomal leukoencephalopathies (PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26, PHYH, PAHX, PEX7, DHAPAT, AGPS, ABCD1)
Diffuse neuroaxonal spheroidal hereditary leukoencephalopathy (CSF1R) Autosomal dominant leukoencephalopathy in adults (LMNB1).
Similar developments have been observed in the field of hypomyelination-related diseases, in which many new pathologies have been defined and the responsible genetic abnormalities have been identified. It is striking that, despite these incredible advances and the accumulation of knowledge over the past 25 years, physicians and families continue to experience that no diagnosis is made in about 50% of patients with a leukodystrophy. It is therefore important to question what is real. When looking at older data sets for unclassified leukodystrophies (eg, van der Knaap et al., Radiology 1999), the majority of reported cases are now diagnosed. The “new” unclassified cases are different and, based on the MRI results, should not be considered to be leukodystrophy. Indeed, many of them are primary neuronal disorders and some correspond to acquired, non-genetic lesions. Incorrect classification for leukodystrophy confuses patients and their families as well as physicians and can result in unnecessary efforts to apply inappropriate tests.
