Understanding genetic factors seen key to personalized therapy
Coexistent conditions may contribute to unusual Gaucher symptoms
Coexistent genetic conditions may contribute to unusual symptoms in people with Gaucher disease, potentially affecting disease progression and management, a study suggested.
Researchers found that 17 Gaucher patients with atypical symptoms all had other genetic conditions, showing that understanding genetic factors is important for developing personalized treatments.
“This study reframes the search for a singular genetic modifier in GD [Gaucher disease], instead highlighting the intricate interplay of multiple genetic and [clinical] factors that shape disease expression,” the researchers wrote. “This [comprehensive] approach not only refines diagnosis and enhances therapeutic decision-making but also uncovers biologically plausible interactions between GD and coexisting genetic conditions.” Genetic modifiers are genes that can affect the clinical outcome of disease-causing gene mutation.
The study, “Precision genomic profiling in Gaucher disease: insights from atypical presentations,” was published in Frontiers Genetics.
Gaucher is caused by mutations in the GBA1 gene that result in missing or defective glucocerebrosidase (GCase), an enzyme needed to break down certain fatty molecules. The lack of functional GCase results in the accumulation of these fatty molecules within cells, affecting various cellular, immune, metabolic, and inflammatory functions, which ultimately leads to the development of Gaucher symptoms.
Genetic testing reveals conditions
While there is some correlation between genetic mutations and disease presentation, people with the same mutations may exhibit different symptoms and varying disease severity. This suggests that additional genetic, epigenetic, and environmental factors may also contribute to Gaucher outcomes. Epigenetic factors are those that influence gene activity without altering the DNA sequence.
The team of researchers in the U.S. set out to integrate whole-exome sequencing (WES), a genetic test that analyzes the protein-coding regions of all genes, with detailed clinical information on Gaucher patients whose symptoms were not fully explained by Gaucher.
Among 275 people with Gaucher enrolled at the Yale Gaucher Disease Center, 17 (6.2%) had atypical symptoms and were included in the study. Most were women (58.8%), with a mean age of 43.75.
The majority (64.7%) carried the p.Asn409Ser mutation in both GBA1 gene copies, which is classified as a homozygous mutation. All but one patient had Gaucher type 1, with the remaining person having Gaucher type 3.
The most common treatment approach was substrate reduction therapy (SRT, 52.9%) followed by enzyme replacement therapy (ERT, 47.1%).
WES revealed additional genetic conditions in all 17 participants, including hereditary hemochromatosis-associated variants (five patients), familial Mediterranean fever (four patients), hereditary cancer predisposition (two patients), and polycystic kidney disease (two patients).
The five patients who carried HFE gene mutations related to hemochromatosis, or excessive iron levels, also had variants in the SLC40A1 gene, which codes for a protein that regulates iron levels.
In terms of Gaucher-causing mutations, all but one had homozygous p.Asn409Ser. Despite good response to ERT, these five patients had persistent iron overload, and two switched from ERT to SRT.
In the four participants with familial Mediterranean fever, an inflammatory disease, the condition was caused by mutations in the MEFV gene. Their symptoms eased with a treatment combination of the SRT Cerdelga (eliglustat) and colchicine, a medication to prevent or treat gout.
The researchers said the findings suggest that SRT “may exert ancillary benefits on coexisting genetic disorders such as [familial Mediterranean fever], likely through shared biological pathways.”
Working toward personalized treatment
Two patients carried mutations in the PKD1 gene related to polycystic kidney disease, which may cause kidney failure. A woman had homozygous p.Asn409Ser in the GBA1 gene, while an adolescent boy was diagnosed with Gaucher type 1 through family screening. Both had preserved kidney function, with their disease well controlled with ERT or SRT.
Two siblings with Gaucher caused by homozygous p.Asn409Ser had a type of blood cancer associated with a homozygous c.3822dupA mutation in the MSH6 gene.
An adolescent girl with Gaucher type 3 and myoclonic epilepsy, a condition marked by seizures characterized by involuntary jerking or twitching of muscles. She carried the p.Leu363Pro and Gly416Ser mutations, one in each copy of the GBA1 gene, and a p.Arg294His mutation in the EFHC1 gene that was previously implicated in epilepsy.
Treatment involved a combination of the ERT Cerezyme (imiglucerase), the SRT Zavesca (miglustat), and several anti-seizure medications.
Three patients carried mutations associated with other rare diseases, including metachromatic leukodystrophy, a condition that results in fat-related neurodegeneration; fibromuscular dysplasia, a condition that affects blood vessel walls; and Brugada syndrome, a heart rhythm disorder.
“Together, these observations support a model in which concurrent genetic variants may modulate [Gaucher disease mechanisms] via shared immune, metabolic, or neuroinflammatory pathways, with implications for personalized therapeutic strategies,” the researchers wrote. “This study contributes to advancing precision medicine strategies that aim to optimize patient outcomes. Future research into genetic and epigenetic modifiers of GD [Gaucher disease] will further refine this framework and enhance individualized therapeutic approaches.”
