Lysosomal Leukodystrophies Lysosomal Storage Diseases Associated With White Matter Abnormalities

Abstract

The leukodystrophies are a group of genetic metabolic diseases characterized by an abnormal development or progressive degeneration of the myelin sheath. The myelin is a complex sheath composed of several macromolecules covering axons as an insulator. Each of the leukodystrophies is caused by mutations in genes encoding enzymes that are involved in myelin production and maintenance. The lysosomal storage diseases are inborn disorders of compartmentalized cellular organelles with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes and related organelles. The more than 60 different lysosomal storage diseases are rare diseases; however, collectively, the incidence of lysosomal storage diseases ranges just over 1 in 2500 live births. The majority of lysosomal storage diseases are associated with neurologic manifestations including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. These inborn organelle disorders show wide clinical variability affecting individuals from all age groups. In addition, several of neurologic, also known as neuronopathic, lysosomal storage diseases are associated with some level of white matter disease, which often triggers the diagnostic investigation. Most lysosomal storage diseases are autosomal recessively inherited and few are X-linked, with females being at risk of presenting with mild, but clinically relevant neurologic manifestations. Biochemical assays are the basis of the diagnosis and are usually confirmed by molecular genetic testing. Novel therapies have emerged. However, most affected patients with lysosomal storage diseases have only supportive management to rely on. A better understanding of the mechanisms resulting in the leukodystrophy will certainly result in innovative and efficacious disease-modifying therapies.

The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia

“…Krabbe disease, also known as globoid cell leukodystrophy, occurs in patients with deficiency of the lysosomal enzyme galactocerebrosidase (encoded by GALC ). 68 , 69 Patients with Krabbe disease accumulate both galactosylceramide and galactosylsphingosine (also known as psychosine), leading to widespread demyelination with reactive gliosis remarkable for both multinucleated microglia (globoid cells) and astrocytosis. 70 , 71 Interestingly, in vitro work has shown that psychosine alone is sufficient to produce a globoid cell-like phenotype, 72 suggesting that globoid-cell formation may occur independently of oligodendroglial death rather than as a reaction to it.…”

Quantification of 3D Brain Microangioarchitectures in an Animal Model of Krabbe Disease

“…Krabbe disease [1,2], also known as globoid cell leukodystrophy (GLD), belongs to the class of lysosomal storage diseases caused by the lysosomal accumulation of specific macromolecules [3] as a consequence of inherited genetic mutations [4]. In Krabbe disease, the deficit of the β-galactocerebrosidase enzyme (GALC, E.C.…”

“…In Krabbe disease, the deficit of the β-galactocerebrosidase enzyme (GALC, E.C. 3.2.1.46) causes the accumulation of the lysosphingolipid β-galactosylsphyngosine, which is also known as “psychosine”, and is a major degradative product of myelin sheet turnover [4,5]. The effects of this accumulation are extremely severe and life expectancy for newborns, in the absence of treatments, is reduced to approximately two years because of extensive central nervous system (CNS) atrophy and demyelination [6].…”

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

“…Lysosomal storage diseases (LSDs) are inborn organelle disorders characterized by multisystemic and progressive manifestations, being most of them neurological in nature ( Table 1 ) (Patil and Maegawa, 2013 ; Maegawa, 2019 ). Intravenous enzyme replacement therapy (ERT), the mainstay treatment for several LSDs, does not address the neurological problems, as these recombinant proteins, large molecular-weight molecules, are unable to permeate through the blood-brain barrier (BBB) effectively.…”