Leukodystrophies and leukoencephalopathies in childhood – classification, diagnosis and treatment
Keywords:
leukodystrophy, leukoencephalopathy, MRI, biochemic tests, genetic tests, next generation sequencing, whole exome sequencingAbstract
Leukodystrophies and leukoencephalopaties are rare genetic conditions with childhood onset and progressive course, due to defects of the synthesis of myelin in the central nervous system and in some cases in the peripheral nervous system as well. Their current classification, based on genetic background, pathogenesis and structural lesions is encompassing:
1. Myelin disorders with hypomyelination: Pelizeaus-Merzbacher disease, Cx47-related Pelizaeus- Merzbacher-like disease, Peripheral neuropathy, central hypomyelination, WaardenburgHirschsprung;
2. Demyelination: metachromatic leukodystrophy, multiple sulfatase deficiency, globoid cell leukodystro phy (Krabbe disease), X-linked adrenoleukodystrophy);
3. Astro cytopathies (Alexander disease, Megalencephalic leukoen - cephalopathy with subcortical cysts, vanishing white matter disease, ClC-2-related disease, Aicardi-Goutières syndrome and variants, oculodentodigital dysplasia (Cx43), giant axonal neuropathy.
4. Myelin vacuolization: Canavan disease, Mitochondrial diseases with leukoencephalopathy, phenylketonuria);
5. Microgliopathies: CSF1R-related disorders, Hereditary diffuse leukoencephalopathy with spheroids, Pigmentary ortochromatic leukodystrophy, Nasu-Hakola disease;
6. Leuko-axonopathies: hypomyelination with atrophy of the basal ganglia and cerebellum, hypomyelination with congenital cataract, early-onset neuronal degenerative disorders, infantile neuronal ceroid lipofuscinosis, gangliosidosis GM1 and GM2, AGC1-, AIMP1- and HSPD1-related disorders; Pol III – related leukodystrophies, leukoencephalopathy with brainstem and spinal cord involvement and high lactate, hypomyelination with brainstem and spinal cord involvement and leg spasticity, giant axonal neuropathy;
7. Leuko-vasculopathies: cerebral AD and AR arteriopathy with
subcortical infarcts and leukoencephalopathy, Cathepsin A-related arteriopathy with strokes and leukoencephalopathy, cerebral amyloid angiopathy, leukoencephalopathy with calcifications and cysts). The diagnosis is based on neuroimaging, mainly brain MRI, biochemical evaluations for diverse enzyme deficiencies, genetic testing (whole exome sequencing) and pathological studies. The main differential diagnoses are made with progressive disorders (encephalitis, metabolic diseases) and cerebral palsy.
Enzyme replacement therapy with cereponase alfa is indicated for CLN2 with tripeptidyl peptidase I (TPP1) defficiency; Haemopoetic stem cells are tested for Krabbe disease, metachromatic leukodystrophy, adrenoleukodystrophy, with promising results in the beginning of the therapy but the long term effect is still under debate.
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