Table 1 Characteristics of leukodystrophies
From: The neurovascular unit in leukodystrophies: towards solving the puzzle
Leukodystrophy category | Disease | Abbreviation | Gene involved | Main cell type involved | Clinical phenotype | MRI characteristics | Contrast enhancement | Macroscopic pathology | Microscopic pathology | NVU involvement | References | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Hypomyelinating | Pelizaeus-Merzbacher disease | PMD | PLP1 | Oligodendrocytes | Onset in first months of life of pendular nystagmus, developmental delay and hypotonia | Inconstant signal on T1 and mild signal increase in T2 weighted images of WM compared to GM; WM atrophy | No | Small brains; large lateral ventricles; cerebellar, brainstem, and spinal cord WM appears greyish and are shrunken | Lack of myelin; no mature oligodendrocytes; increased astrogliosis and microgliosis | Redistribution of AQP4 in frontal WM; neuroinflammation with activated microglia | ||
Demyelinating | Metachromatic leukodystrophy | MLD | ARSA | Oligodendrocytes | Age-related. Impaired motor skills, behavioural and concentration problems in late-infantile and juvenile forms; psychiatric disorders, including schizophrenia, and cognitive decline in the adult form | Hyperintensities on T2-weighted images initially limited to the corpus callosum and then progressing to the periventricular and subcortical WM. Characteristic pattern of radiating stripes ("tigroid" pattern) with normal signal intensity within the abnormal WM | Yes, only in cranial nerves | The demyelinated WM appears greyish. Cerebellum, brainstem and optic nerves are atrophic | Demyelination with accumulation of sulfatides in glial cells, neurons and macrophages. Negative correlation between increased demyelination and reactive gliosis in the CNS | Redistribution of AQP4 in frontal WM. Lipid-laden macrophages in perivascular space of WM can release inflammatory mediators | ||
Myelin vacuolization | LARS2-related leukodystrophy | N/A | LARS2 | Astrocytes | Deafness early in life and developmental delay | Diffusely abnormal cerebral WM and elevated brain lactate levels on magnetic resonance spectroscopy | Yes | Enlarged lateral ventricles and rarefaction to cystic degeneration of the periventricular WM. U-fibres are spared | Loss of myelin and reactive astrocytes at the vasculature | Redistribution of ZO-1 and AQP4. Expression of laminin in perivascular astrocytes | ||
Astrocytopathies | Alexander disease | AxD | GFAP | Astrocytes | Infantile form, with macrocephaly, seizures, early cognitive and motor dysfunctions. Later onset form with bulbar signs, cognitive dysfunction and dysautonomia | T2-signal changes predominant in the anterior brain regions and medulla oblongata | Yes, at the midbrain ventricular lining and the cerebral hemispheric periventricular rim | Severe WM degeneration in the cerebrum, cerebellum and brainstem | RFs in cell bodies and processes of astrocytes, enriched at the endfeet. Enlarged astrocytes, lymphocytic infiltrates. Activated microglia | RFs, low expression of α-dystroglycan and redistribution of AQP4. RFs can also mechanically disrupt vascular function | ||
Astrocytopathies | Aicardi-Goutières syndrome | AGS | TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 or IFIH1/MDA | Astrocytes | Early-onset progressive loss of motor functions and severe intellectual impairment. Non-neurological symptoms. Elevated lymphocyte and IFN-α levels in CNS | Calcification of the basal ganglia, WM abnormalities in the frontotemporal brain regions | No | Small brains, atrophic WM, calcifications | Co-localization of IFN-α and CXCL10 with GFAP. Infiltrating T-cells and calcification in brain vasculature. Thickened tunica media and adventitia in the arterioles and precapillary vessels. Microangiopathy in the cerebral WM, cerebellum and striatum | Thickened tunica media and adventitia. Redistribution of ZO-1 and AQP4 | ||
Astrocytopathies | Megalencephalic leukoencephalopathy with subcortical cysts | MLC | MLC1 or GLIALCAM | Astrocytes | Early-onset, progressive cerebellar ataxia, mild cognitive decline and epilepsy. Variable disease severity | Abnormal T2 diffuse signal of the cerebral WM, swelling of the abnormal WM and subcortical cysts. Increased water content in the WM | No | Large, swollen brain with small lateral ventricles, subcortical cysts in the fronto-temporal regions | Astrocytosis in molecular layer. Vacuolized and thin myelin. Vacuoles in astrocytic endfeet. Fibrillary astrogliosis and scarce microglia activation | MLC1 and GlialCAM regulate ion-water homeostasis at the endfeet and the anchoring of other ion and water channels. Possible MLC1 role in inflammatory signalling at the NVU | ||
Microgliopathies | Adult-onset leukodystrophy with spheroids and pigmented glia | ALSP | CSF1R | Microglia | Adult-onset, progressive personality changes, dementia and spasticity. Heterogeneous phenotype | T2-hyperintense signal changes in the periventricular, deep and subcortical cerebral WM. Cerebral white matter atrophy | No | WM atrophic and greyish | WM vacuolization and myelin loss. Swollen axons and axonal spheroids. Reactive gliosis, scarce microglia activation, lipid-laden macrophages and pigmented glia | Reactive gliosis and redistribution of AQP4 in frontal WM. IL-34-related mechanisms. Oxidative stress | ||
Leuko-vasculopathies | Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy | CADASIL | NOTCH3 | VSMCs and pericytes | Adult-onset. Migraine aura, acute stroke syndromes, cognitive impairment, gait dysfunction, mood and behavioural changes | WM lesions and lacunar infarction. T2 hyperintensity deep WM, internal and external capsules, and temporal pole. Enlarged perivascular spaces. Cerebral microbleeds and brain atrophy | Yes | WM atrophy, U-fibres spared | Thickened vascular walls. Degeneration of VSMCs. Accumulation of fibrous ECM, narrowed blood vessels. Loss of myelin. Reactive astrogliosis | Granular osmiophilic material at the capillaries, microfilament bundles in BECs. AQP4 redistribution | ||
Leuko-vasculopathies | Cathepsin A-related arteriopathy with strokes and leukoencephalopathy | CARASAL | CTSA | Blood vessels | Adult-onset headaches or migraine, mild intellectual impairment and mild gait problems. Most patients develop hypertension, short ischemic attacks and strokes. Symptoms of brainstem dysfunction | Diffuse WM signal changes with infarcts and microbleeds in the basal nuclei, brainstem and cerebellum | No | Mild atrophy of the cerebral WM and small infarcts in subcortical and deep cerebral WM, basal nuclei, thalami, brainstem and cerebellum | Preserved axons, loss of myelin, astrogliosis and preserved oligodendrocytes. Loss of SMCs in the cerebral WM and basal nuclei. Upregulation of ET-1 in WM astrocytes | Reactive gliosis and redistribution of AQP4 in frontal WM. Prominent loss of SMA, thickening of basal lamina and occlusion of cerebral blood vessels | ||