Devin Oglesbee, Ph.D., Director of the Biochemical and Molecular Genetics Laboratories at Mayo Clinic, provides an overview of the lysosomal storage disease panel, when it is appropriate to order this test, what actions the results allow you to take, and how this test improves upon previous approaches.
Lysosomal storage diseases (LSDs) encompass a group of more than 40 inherited biochemical diseases in which genetic mutations cause defective lysosomal functioning. Lysosomes perform catabolic functions for cells, which is accomplished through activity of various proteins such as lysosomal enzymes, transport proteins, and other proteins. Functional deficits in these proteins cause an accumulation of substrates in cells leading to progressive organ dysfunction.
This leads to variable clinical features that can affect the cardiovascular, neurological, ocular, and skeletal systems, among others. Clinical features are dependent on the amount and location of the substrate accumulation, but they may include the following: characteristic facial features (coarse features), hepatomegaly, deafness, vision loss, abnormal skeletal findings, hydrops fetalis, ataxia, hypotonia, developmental delay/regression, and intellectual disability. Age of onset is variable, with symptoms presenting from the prenatal period to adulthood, but generally, LSDs are progressive and cause significant morbidity and mortality with a decreased lifespan. Enzyme replacement therapy and oral substrate inhibitors are therapeutic options for some LSDs.
LSDs are inherited in an autosomal recessive manner with the exception of Hunter, Fabry, and Danon diseases, which are X-linked. There are some founder mutations associated with particular LSDs in the Ashkenazi Jewish and Finnish populations, leading to an increased carrier frequency for some. Overall, the prevalence of LSDs is estimated at 1/7,000 to 1/8,000.
Neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases that involve defective cellular processing of lipids. NCLs are clinically characterized by epilepsy, intellectual and motor decline, and blindness. Electron microscopy typically shows a characteristic accumulation of granular osmophilic deposits (GROD), curvilinear profiles (CVB), or fingerprint profiles (FP). Enzymatic testing may show deficiency in palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl-peptidase 1 (TPP1), or cathepsin D (CTSD). Currently, there are at least 14 genetically distinct forms.
Age of onset and clinical features can be variable, from congenital to adult onset. NCL is typically inherited in an autosomal recessive manner, although one adult onset form (ANCL; DNAJC5 gene) has been shown to be autosomal dominant.
First-tier biochemical testing is available for the two most common types of enzyme deficiency resulting in NCL: TPPTL/Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Leukocytes; and TPPTF/Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Fibroblasts.
This panel includes sequencing of 43 genes related to various LSDs, as well as 15 genes specific to neuronal ceroid lipofuscinosis, for a total of 58 genes.