Leukodystrophies and other hereditary leukoencephalopathies [233 genes]

Leukodystrophies are a heterogeneous group of inherited disorders that affect the white matter of the central nervous system (CNS), regardless of the structural component involved, the molecular process affected, the course of the disease, and whether the peripheral nervous system is also affected. Numerous hereditary conditions affect the white matter secondarily and are known as genetic or hereditary leukoencephalopathies. Thus, while primary leukodystrophies mainly affect glial cells, hereditary leukoencephalopathies are disorders with primary neuronal, vascular, or systemic involvement in which changes in the white matter are considered secondary. Thus, although all leukodystrophies can be considered hereditary leukoencephalopathies, not all hereditary leukoencephalopathies are leukodystrophies.

These 2 groups of diseases include pathologies with onset from the neonatal period to adulthood and, although the characteristics of each disease may be different, they all present white matter abnormalities on magnetic resonance imaging (MRI) or CNS pathology, and the motor disorders usually dominate the clinical picture, especially in younger individuals.

Due to difficulties in diagnosis, the true prevalence and incidence of all leukodystrophies are difficult to establish and combined incidence estimates range between 1/50,000 and 1/7,663 newborns.

It covers the entire spectrum of causal genes for leukodystrophies and other leukoencephalopathies. Genetic diagnosis in this group of diseases allows advice on prognosis, supportive treatment, and in some cases disease-modifying treatment.

In general terms, early recognition of leukodystrophy can be complicated since they usually appear insidiously, are clinically very heterogeneous, and are often not considered until abnormalities are identified on MRI. Even then, due to limited knowledge about their etiology, they may remain undiagnosed or misdiagnosed. Although advances in neuroimaging pattern recognition have improved diagnostic performance, current treatments are very limited, and definitive diagnosis is crucial for appropriate symptom management, prognosis, and genetic counseling.

Clinical suspicion of leukodystrophy