Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes

• Published in: Molecular genetics and metabolism Vol. 132; no. 2; pp. 49 - 58
• Main Authors: Daykin, Emily C., Ryan, Emory, Sidransky, Ellen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2021
• Subjects: Blood-Brain Barrier - drug effects; Gaucher disease; Gaucher Disease - classification; Gaucher Disease - diagnosis; Gaucher Disease - drug therapy; Gaucher Disease - genetics; GBA1; Genetic Association Studies; Glucocerebrosidase; Glucosylceramidase - genetics; Humans; Neuronopathic; Newborn screening; Next-generation sequencing; Phenotype; Severity of Illness Index; Newborn screening; Neuronopathic; Glucocerebrosidase; GBA1; Gaucher disease; Next-generation sequencing
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2021.01.002

Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic presentations. The more severe forms of the disease, acute neuronopathic GD (GD2) and chronic neuronopathic GD (GD3), also have a continuum of disease severity with an overlap in manifestations and limited genotype-phenotype correlation. In very young patients, assigning a definitive diagnosis can sometimes be challenging. Several recent studies highlight specific features of neuronopathic GD that may provide diagnostic clues. Distinguishing between the different GD types has important therapeutic implications. Currently there are limited treatment options specifically for neuronopathic GD due to the difficulty in delivering therapies across the blood-brain barrier. In this work, we present both classic and newly appreciated aspects of the Gaucher phenotype that can aid in discriminating between acute and chronic neuronopathic GD, and highlight the continuing therapeutic challenges. •Patients with Gaucher disease (GD) are now being diagnosed earlier in life.•Features of GD2 include abnormal swallow, stridor, hydrops fetalis, and ichthyosis.•In GD3, expect slowed horizontal saccades and prominent visceral involvement.•Small molecule chaperones and other brain-penetrant drugs are under development.•There are ongoing gene therapy clinical trials targeting GD.