Gaucher disease is caused by mutations in the GBA1 gene, leading to the production of a glucocerebrosidase enzyme with abnormal structure and reduced activity. The disease has a broad spectrum of symptoms, including an enlarged spleen and liver, low platelet levels, bone disease, and neurological issues.
Classically, Gaucher disease is classified into three types, depending on the presence and progression of neurological symptoms, but distinguishing between subtypes is not always easy.
As a result, identifying which GBA changes are harmless and which cause disease, as well as the symptoms linked to each mutation, is of crucial importance for the correct management of these patients.
Researchers in Italy are now reporting the case of a 17-year-old patient with type 3 disease and epilepsy who had what researchers first thought was a harmless mutation.
The patient was developing normally until she was 11 years old when she first experienced sleep-related convulsions lasting for several minutes.
An initial brain analysis by noninvasive electroencephalography (EEG) revealed generalized abnormal brain activity, but a magnetic resonance imaging (MRI) scan showed no alteration of brain structures.
Epileptic medication kept the patient free of seizures for almost two years, but when she turned 13, the seizures returned and became resistant to all anti-epileptic therapy combinations tried.
Seizures occurred two to three times per month, mostly during sleep and lasting several minutes. Occasionally, the patient required acute treatment with Diastat (rectal diazepam) to manage her symptoms.
During this period, her parents noticed daily episodes of loss of contact and interruption of motor activity with a slight head drop and eyelid fluttering.
A new analysis detected altered brain activity associated with the sleep-related seizures, and also showed sudden involuntary contraction of the muscle before the seizures. The patient was also very reactive to light stimulation, showing an altered response of her eyelid muscles.
After the onset of seizures, the patient started showing signs of cognitive regression, leading to mild-moderate cognitive impairment.
At the age of 16, the patient already had significant physical impairments. She was not able to coordinate her movements or walk on toes, and had tremors on her upper extremities. She also had difficulty articulating speech and had sudden involuntary muscles contractions.
All her clinical features were consistent with a diagnosis of progressive myoclonus epilepsy. But a new MRI evaluation and abdominal ultrasound revealed an enlarged liver and abnormal bone marrow burden, suggestive of a lysosomal disorder.
Blood analysis revealed reduced beta-glucosidase enzyme activity, consistent with a Gaucher disease type 3 diagnosis.
To confirm the finding, the team performed a genetic analysis of the GBA gene, which revealed an Asn188Ser mutation, which has been previously reported, and a Gly82Gly silent mutation.
A silent mutation is a variation of the coding gene that does not alter the amino acid sequence in the protein. These mutations usually don’t have an impact on the function of the protein.
However, additional experiments showed that the Gly82Gly mutation caused changes in RNA — the molecule that comes from the DNA and originates a protein — processing, leading to the production of an abnormal beta-glucosidase enzyme.
“Patients with type 3 Gaucher disease exhibit different clinical manifestations but in recent years a subset of patients who developed a treatment refractory form of progressive myoclonus epilepsy has been identified. These patients shared several alleles including Asn188Ser,” the researchers wrote.
“Our report strengthens the association of Asn188Ser with [this] particular neurological [presentation],” they added, which in combination with variants that seem harmless “at first sight” may contribute to the severe manifestation of Gaucher disease.
The patient started enzyme replacement therapy, but this has had no effect on the neurological symptoms, consistent with the fact that the engineered enzyme cannot pass the brain-blood barrier to reach the brain.
Now 17 years old, the patient has drug-resistant epilepsy with frequent seizures, prominent photosensitivity, mild-moderate cognitive impairment, upper limb tremor, and an abnormal bone marrow burden.