Gaucher Disease (GD), a metabolic inherited disorder, includes three clinical phenotypes. Type I GD (GD1), that can mimic a hematologic disease, has been classically considered as a non-neuropathic variant; type II (GD2) and type III (GD3) are classified as acute and chronic neuropathic forms, respectively. A protective role of N370S mutation against neurological impairment had been previously hypothesized in GD1, however, clinical signs of parkinsonism have recently been reported in this category of patients.

The aim of our observational, monocentric, and prospective study, called SENOPRO_GAUCHER, was to evaluate in depth the neurological and neuropsychiatric aspects in GD1 patients, using clinical and instrumental investigations, in order to identify clinical and subclinical neurological manifestations, including cognitive impairment and behavioural alterations.

Neurological assessments were scheduled for 22 GD patients (19 GD1 and 3 GD3) aged >12 years. Clinical evaluation, including Severity Scoring Tool Unified Parkinson's Disease Rating scale and Epworth Sleepiness scale; psychological tests and psychiatric evaluation, using a cognitive test battery and two psychiatric (BPRS) and psychological (CBA 2.0) questionnaires; somatosensory, motor and visual evoked potential, spectral domain optical coherence tomography (SD-OCT), standard electroretinogram; electroencephalography (EEG), and magnetic resonance (MR) 3Tesla, were planned at baseline, after 12 and 24 months.

Results at the baseline evaluation of all 22 enrolled patients (9 males and 13 females; median age at the study: 44.5 years, range 17 - 68) are here reported. Regarding genotyping, all but one of the 19 GD1 pts was heterozygous for the N370S mutation.

Parkinsonian motor signs were found in 10/22 patients (9 GD1): 7 pts (6 GD1) had isolated bradykinesia and 3 GD1 patients presented bradykinesia combined with rigidity. Abnormal saccadic movements were found in all GD3 pts and in one GD1. Excessive daytime sleepiness (EDS) was detected in 9/22 patients (8 GD1). EEG revealed focal, or diffuse slow waves in 6 patients (5 GD1).

Significant cognitive impairments in attention, language, memory and executive functions were found in 4/19 GD1 and in 2/3 GD3 patients. Moreover, psychological and psychiatric evaluations underlined anxiety, depression and somatic concerns in 10/22 patients (9 GD1), combined with cognitive impairments in 3/12.

Sixteen patients (13 GD1) showed slight or moderate sensorineural hearing loss (SNHL), and 4 of them had a cookie and reverse cookie bite morphology, typically associated with genetic SNHL.

Ophthalmological evaluation revealed a degree of retinal blood vessel tortuosity in all but one patient, and superficial corneal dystrophies in 3 patients (2 GD1). An increased latency and moderate reduction in the amplitudes of optic nerve function were found in 13/22 patients (10 GD1). The SD-OCT examination showed impairment in retinal nerve fibre layers in 7 patients (6 GD1), combined with macular damage in 2 of them.

Qualitative MR 3Tesla examinations revealed unspecific abnormalities in 7/19 (37%) GD1 patients; in particular, cortical and/or subcortical areas of gliosis (4 patients), vascular ectasia extended from the left frontal surface of the brain to the lateral ventricle (1 patient), dilation of perivascular spaces in the sub-cortical and nucleus-basal area (1 patient), diffuse suffering of the brain white matter due to a chronic ischemic vascular damage (1 patient).

In summary, all GD3 patients showed a wide spectrum of neurological abnormalities, as expected. Surprisingly, however, all GD1 pts also presented at least two, or more, clinical and/or instrumental, neurological signs. The high prevalence of EDS in our population suggests a possible underlying sleep disorder which should be further investigated. The N370S mutation did not impact the likelihood of developing neurological abnormalities in our cohort of GD1 patients. In conclusion, our results have demonstrated that a multidisciplinary, and in-depth approach is necessary in evaluating GD1 patients.


Giona:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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