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DTI of Developmental and Pediatric Disorders
Published in Andrei I. Holodny, Functional Neuroimaging, 2019
Michael J. J. Kim, James M. Provenzale
Globoid cell leukodystrophy, also known as Krabbe disease, is an autosomal recessive white matter disorder caused by the deficiency of β-galactocerebrosidase (26). In the normal brain, galactolipids that are toxic to brain tissue are formed during white matter myelination but are quickly hydrolyzed by the enzyme β-galactocerebrosidase. However, in Krabbe disease, diminished levels of this enzyme allow galactolipids to accumulate and myelin-forming oligodendroglia are destroyed. In early-onset Krabbe disease, this leads to the failure of normal myelin production in infants and subsequent development of severe neurological deficits (27). These children typically deteriorate neurologically until they reach a vegetative state and ultimately die within two to four years. Hematopoietic stem cell transplantation has been suggested as a treatment for asymptomatic infantile Krabbe disease (28). There are currently no proven therapeutic options for symptomatic patients with the infantile form of Krabbe disease. Therefore, early diagnosis of the disease is critical for any treatment to be effective.
Genetic diseases mimicking multiple sclerosis
Published in Postgraduate Medicine, 2021
Chueh Lin Hsu, Piotr Iwanowski, Chueh Hsuan Hsu, Wojciech Kozubski
Krabbe disease, also known as globoid cell leukodystrophy, is a rare autosomal recessive leukodystrophy caused by deficient galactosylceramidase (GALCase) activity as a result of mutations in the GALC gene. The resulting unmetabolized galactolipids build up and are directly toxic to oligodendrocytes and Schwann cells, which manifests as progressive neurodegenerative symptoms including loss of vision, hearing, seizures, and premature death [73]. The newborn initial screening test of GALC enzyme activity is usually conducted to detect Krabbe disease. However, low levels of GALC enzyme activity cannot indicate the clinical type and the course of the disease. The genetic testing of Krabbe disease should be taken to confirm the diagnosis [73]. The four clinical types are classified by the age of onset [74], of which adult- onset Krabbe disease (AOKD) is of particular interest in this discussion due to its similar clinical pictures to MS [75].
Enzyme replacement combinational therapy: effective treatments for mucopolysaccharidoses
Published in Expert Opinion on Biological Therapy, 2021
Azam Safary, Hakimeh Moghaddas-Sani, Mostafa Akbarzadeh-Khiavi, Alireza Khabbazzi, Mohammad A. Rafi, Yadollah Omidi
The usefulness of this approach has been shown in the treatment of other LSDs, including the ERT/SRT in the Gaucher disease [152], the GT/BMT in the neuronal ceroid lipofuscinosis [153], and the globoid cell leukodystrophy [154]. Besides, PCs have been proposed for the treatment of diseases due to the misfolded proteins, specifically LSDs, to rescue endogenous mutant enzymes [22,155]. Further, chaperones were also shown to improve the stability and cellular trafficking of the wild-type enzymes commonly used for ERT [109]. The combination of PCs with ERT has been explored for Gaucher, Fabry, and Pompe disease [156–158]. While the exact synergistic mechanism between them is not fully understood, PCs were reported to preserve infused enzymes from partial degradation in the bloodstream or during its trafficking to the lysosome. It has been suggested that reversible binding of chaperones can protect the enzymes against neutralizing antibodies, modulating the immune system responses [2]. This approach gained much attention for the combinational therapy of LSDs using PCs/ERT. More information on the efficacy and safety of PCs/ERT can be found at the trials, including NCT00214500 and NCT01196871 (see ClinicalTrials.gov database).
A new compound heterozygous mutation in adult-onset Krabbe disease
Published in International Journal of Neuroscience, 2020
Xianghe Meng, Yingjiao Li, Yajun Lian, Yujuan Li, Liyuan Du, Nanchang Xie, Cui Wang
Krabbe disease (KD), also known as globoid cell leukodystrophy, was first described by the Danish neurologist, Knud Krabbe, in 1916 [1]. KD is characterized by extensive demyelination, axonal injury and the formation of multinucleated macrophages (globoid cell) [2]. KD can be divided into four different forms, which could be distinguished based on the age at onset of neurological symptoms: early-onset or early infantile (onset in the first 6 months), late-onset, including late infantile (onset 6 months to 3 years), juvenile (onset 3‐8 years), and adult (≥9 years) [3]. The prevalence of Krabbe disease is 1/100,000‐1/250,000 [4,5], with the early infantile and late infantile forms accounting for 85–90% of cases. The late-onset adult form is clinically rare with a prevalence of less than 1 in a million [6] and it exhibits heterogenous clinical features [7]. Therefore, the diagnosis of adult-onset KD is challenging and often delayed.