In GD1, the most common and least serious form of the inherited disorder, the absence of neurological symptoms is considered mandatory for a diagnosis.
Nonetheless, evidence suggests that half of patients with GD1 report neurological issues, and 30% of patients without neurological symptoms show abnormalities upon examination.
In fact, some Gaucher disease (GD) patients might develop Parkinson’s-like symptoms, including muscle rigidity, resting tremor, and slowed, affected movements.
“The increased risk of primary parkinsonism symptoms among individuals affected with GD and carriers for the disorder is well-documented in the literature. However, these risks and case reports often reflect patients with classical Parkinson’s disease (PD) symptoms,” the investigators said.
Atypical motor symptoms, such as involuntary twitching of a muscle and abnormalities affecting horizontal gaze, have been reported among GD1 patients.
Mutations in the GBA1 gene have been associated with both Gaucher disease and Parkinson’s disease. However, a study has demonstrated a stronger association between people with GBA1 mutations and dementia with Lewy bodies — a form of atypical parkinsonism — than spontaneous Parkinson’s disease.
Investigators from Duke University Medical Center in North Carolina described the case of a 62-year-old man who was diagnosed with GD at 14 years old based on his complaints of frequent nose bleeds and easy bruising, in addition to an enlarged liver and spleen.
Genetic testing revealed two distinct mutations in both copies of the GBA1 gene, consistent with GD1.
To correct the underlying enzyme deficiency that causes GD symptoms, when he was 49, the patient started intravenous enzyme replacement therapy (ERT) with Cerezyme (imiglucerase, by Sanofi Genzyme) to which he responded well.
“The patient enrolled in the ENCORE trial (NCT00943111, Sanofi Genzyme) at age 55 years and began receiving oral Cerdelga (eliglustat), which stabilized his systemic Gaucher symptoms,” the researchers wrote.
ENCORE was a randomized Phase 3 trial that was aimed at evaluating the efficacy and safety of oral Cerdelga, a substrate reduction therapy that degrades the excess fat molecules in GD, in GD1 patients who have reached therapeutic goals with ERT.
When he was 58, the patient complained of cognitive decline including long-term memory impairment, slurring of speech, and difficulty finding words. Brain magnetic resonance imaging (MRI) showed enlargement of the brain’s fluid collecting system and advanced cortical atrophy.
Neuropsychological assessment revealed that the patient’s memory was unaffected despite his executive function as well as his lexical and semantic retrieval being compromised.
The patient also exhibited a reduced degree of facial expression and reduced left arm rapid alternating movements. Researchers note that Cerdelga does not cross the blood-brain barrier, meaning theoretically it could not alter cognition.
One year later, at the end of the ENCORE trial, the patient was continuing to receive Cerdelga. He then mentioned an episode where he had acted out a dream while he was asleep. A sleep study revealed sleep maintenance insomnia and possible REM sleep behavior disorder, in which patients act out vivid, often violent dreams.
At 60 years of age, the patient was examined by a clinical team at the National Institutes of Health (NIH). Results showed asymmetric rigidity associated with muscle pain and cramping, left hand tremor, plus asymmetric slowness of movement (bradykinesia). All motor manifestations were notably worse on his left side. The patient also demonstrated abnormally small and cramped handwriting.
Dementia, difficulty performing tasks (apraxia) with his left hand, and vertical gaze palsy (the inability to move the eyes up and down) were also reported; these symptoms are not typically seen with classical Parkinson’s.
Imaging revealed generalized cerebral and cerebellar volume loss, enlargement of the brain’s fluid collecting system, and changes in both superficial and deep white matter.
At the time, the patient was diagnosed with atypical parkinsonism, but carbidopa/levodopa treatment had no clear impact on his motor symptoms, and he started complaining of hallucinations.
When he was 61, the patient was diagnosed with clinically probable corticobasal syndrome (CBS) due to his predominantly left-sided motor symptoms, signs and symptoms of cortical dysfunction, including apraxia and inability to identify objects by touch despite intact sensation, and lack of response to levodopa.
CBS is a nonspecific diagnosis of unknown cause that’s associated with changes in movement and/or language skills.
In some people with corticobasal syndrome, there is a large buildup of a protein called tau; in others, there’s an accumulation of amyloid plaques similar to those seen in Alzheimer’s disease. Simply put, large amounts of these proteins compromise brain function and lead to neuronal death.
Scientists could not confirm a definitive diagnosis since a brain tissue analysis is necessary to do so and can only be carried out after death.
“Our case highlights the need to consider forms of atypical parkinsonism such as CBS in addition to PD in the differential diagnosis of cognitive and motor changes in patients with GD type 1. We also recommend careful assessment and routine monitoring of cognition, mood, behavior, sleep patterns, olfaction, and memory in patients with GD type 1 to identify early symptoms indicative of neurological involvement,” the investigators concluded.