Advances in the Diagnosis and Treatment of Krabbe Disease.

Mohammad A. Rafi,David A Wenger,Paola Luzi

doi:10.3390/ijns7030057

Mohammad A. Rafi, David A Wenger + Show 1 more

Open Access

https://doi.org/10.3390/ijns7030057

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Abstract

Krabbe disease is an autosomal recessive leukodystrophy caused by pathogenic variants in the galactocerebrosidase (GALC) gene. GALC activity is needed for the lysosomal hydrolysis of galactosylceramide, an important component of myelin. While most patients are infants, older patients are also diagnosed. Starting in 1970, a diagnosis could be made by measuring GALC activity in leukocytes and cultured cells. After the purification of GALC in 1993, the cDNA and genes were cloned. Over 260 disease-causing variants as well as activity lowering benign variants have been identified. While some pathogenic variants can be considered “severe,” others can be considered “mild.” The combination of alleles determines the type of Krabbe disease a person will have. To identify patients earlier, newborn screening (NBS) has been implemented in several states. Low GALC activity in this screening test may indicate a diagnosis of Krabbe disease. Second tier testing as well as neuro-diagnostic studies may be required to identify those individuals needing immediate treatment. Treatment of pre-symptomatic or mildly symptomatic patients at this time is limited to hematopoietic stem cell transplantation. Treatment studies using the mouse and dog models have shown that combining bone marrow transplantation with intra-venous gene therapy provides the best outcomes in terms of survival, behavior, and preservation of normal myelination in the central and peripheral nervous systems. With earlier diagnosis of patients through newborn screening and advances in treatment, it is hoped that more patients will have a much better quality of life.

Highlights

Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder resulting in defective myelination in the central and peripheral nervous systems
After noting that the activities of other lysosomal enzymes could be measured in urine, we found we could measure GALC activity in urine
By 1993, before we published on the cloning of the human cDNA, we had already diagnosed over 175 patients with Krabbe disease by enzymatic testing, indicating that molecular analysis is not required for an accurate diagnosis

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder resulting in defective myelination in the central and peripheral nervous systems. It has an incidence of about 1 in 100,000 births in the United States and Northern Europe. Individuals presenting in the late infantile and adult periods are diagnosed They currently make up about 10–20% of the patients diagnosed with Krabbe disease. The earliest published description of patients with globoid cell leukodystrophy was by Dr Knud Krabbe in 1916 [2] He described five infants who clearly showed the phenotype of infantile Krabbe disease. More about the significance of elevated psychosine as a second-tier test in the diagnosis of Krabbe disease has recently been published [17,18]

GALC Purification and Cloning of the Gene

Early Diagnostic Studies and Mutation Analysis

Relationship between Measured GALC Activity and Phenotype

Effect of Mutations Identified and Phenotype

Tables and

Management of Individuals Confirmed to Be at Risk for Developing Krabbe

Findings

Treatment of the Animal Models of Krabbe Disease