Abstract
BackgroundThe diagnostic workup in patients with a clinical suspicion of lysosomal storage diseases (LSD) is often difficult due to the variability in the clinical phenotype. The gold standard for diagnosis of LSDs consists of enzymatic testing. However, due to the sequential nature of this methodology and inconsistent genotype–phenotype correlations of certain LSDs, finding a diagnosis can be challenging.MethodWe developed and clinically implemented a gene panel covering 50 genes known to cause LSDs when mutated. Over a period of 18 months, we analyzed 150 patients who were referred for LSD testing and compared these results with the data of patients who were previously enrolled in a scheme of classical biochemical testing.ResultsOur panel was able to determine the molecular cause of the disease in 22 cases (15%), representing an increase in diagnostic yield compared to biochemical tests developed for 21 LSDs (4.6%). We were furthermore able to redirect the diagnosis of a mucolipidosis patient who was initially suspected to be affected with galactosialidosis. Several patients were identified as being affected with neuronal ceroid lipofuscinosis, which cannot readily be detected by enzyme testing. Finally, several carriers of pathogenic mutations in LSD genes related to the disease phenotype were identified as well, thus potentially increasing the diagnostic yield of the panel as heterozygous deletions cannot be detected.ConclusionWe show that the implementation of a gene panel for LSD diagnostics results in an increased yield in comparison to classical biochemical testing. As the panel is able to cover a wider range of diseases, we propose to implement this methodology as a first‐tier test in cases of an aspecific LSD presentation, while enzymatic testing remains the first choice in patients with a more distinctive clinical presentation. Positive panel results should however still be enzymatically confirmed whenever possible.
Highlights
Lysosomal storage diseases (LSD) affect approximately 1 in 5,000–8,000 worldwide
We describe two cases with an unspecific phenotype where implementation of the gene panel resulted in a diagnosis: 1. A patient with an initial suspicion of galactosialidosis was found to have two pathogenic mutations in the GNPTAB gene, namely c.1196C>T and c.3503_3504delTC, causing mucolipidosis II/III, while no mutations in CTSA were present
When looking to the gene panel results of the lysosomal storage diseases (LSD) which are in our biochemical testing list, a yield of 9/150% or 6% could be observed, which is slightly higher, but comparable to the 4.58% of the biochemical tests
Summary
Lysosomal storage diseases (LSD) affect approximately 1 in 5,000–8,000 worldwide. Currently, mutations in over 50 genes have been reported to disrupt the lysosomal metabolism, leading to a wide spectrum of disease phenotypes including neuropathological effects, musculoskeletal abnormalities, dysmorphia, hepatosplenomegaly, and the occurrence of seizures. For any specific LSD, these multiorgan phenotypes can be present in a varying degree and show significant overlaps across different LSDs. And most LSDs manifest themselves during early childhood, certain diseases have a genetically specific late‐onset form (e.g., Pompe) or display only more severe effects later in life (e.g., Fabry). Most LSDs manifest themselves during early childhood, certain diseases have a genetically specific late‐onset form (e.g., Pompe) or display only more severe effects later in life (e.g., Fabry) Given these challenges, the path to a diagnosis for an LSD in an affected patient can be long and is often unsuccessful. We investigated 150 patients with a clinical suspicion of an LSD and evaluated this approach compared to classical sequential biochemical testing based on fluorimetric methodologies
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