Multidisciplinary Study Based on Clinical, Electrophysiological and Psycological Evaluations Combined with Advanced Neuroimaging in Gaucher Disease Patients

Gaucher Disease (GD) is an autosomal recessive metabolic disorder due to glucocerebrosidase deficit. There are three main clinical phenotypes: type I (GD1: non-neuronopathic form), characterized by a visceral involvement that can mimic a hematologic disease; type II (GD2: acute neuropathic form) and type III (GD3) characterized by a slower and progressive neurological involvement. Hematologists have often involved in diagnosis and management of the GD1 patients. Increasing data and our experience show that patients with GD1 may present manifestations of Parkinson's disease or Parkinsonism symptoms (tremor, bradykinesia and rigidity), frequently combined with cognitive impairment and behavioral alterations.

The aim of this study is to deeply investigate the neurological and neuropsychiatric aspects in GD1 patients in order to identify clinical and subclinical neurological manifestations, including cognitive impairment and behavioral alterations in this category of patients.

This observational, monocentric, and prospective study is planned to enroll 22 GD patients (19 GD1 patients and 3 GD3 patients with or without active neurological signs) aged >12 years. Neurological assessments include: clinical evaluation including Severity Scoring Tool Unified Parkinson's Disease Rating scale and Epworth Sleepiness scale, psycho-diagnostic tests and psychiatric evaluation using cognitive test battery and two psychiatric (BPRS) and psychological (CBA 2.0) questionnaires, Somatosensory and Motors Evoked Potentials, Electroencephalography (EEG) and magnetic resonance (MR) 3Tesla, at baseline, after 12 months and 24 months. Preliminary results concerning the baseline evaluation of first cohort of patients are here reported.

Since June 2019, 11 patients (10 GD1 and 1 symptomatic GD3) have been enrolled. Neurological impairment according to the major features (Gaucher severity score tool) was found in 4/11 patients: signs of Parkinson disease in 1 GD1 patient, motoneuron disease in 1 GD3 patients, abnormalities in ocular motility and psycho-cognitive disturbances in 2 GD1 patients. Minor features of a neurological impairment was found as follows: bradykinesia in 5 GD1 patients, excessive daytime sleepiness in 5 GD1 patients, and saccadic slowness in 1 GD1 patient. EEG revealed focal or diffuse slow waves in 6 patien patients (5 GD1 and 1 GD3). Cognitive and psychological evaluations revealed the presence of significant psychiatric symptoms such as depression, anxiety, and physical concerns. Six patients (5 GD1and 1 GD3) surprisingly had sensorineural hearing loss. Auditory Brainstem Response revealed abnormal disyncrony-like morphology and central speech processing in noise in 3 GD1 and in 4 (3 GD1 and 1 GD3) patients, respectively. Ophthalmological evaluation highlighted a normal visus and intraocular pressure in all patients. Moderate alterations of the fundus were present in 2 patients (1 GD1 and 1 GD3) and superficial corneal dystrophies in 3 (2 GD1 and 1 GD3) patients. An increased latency and moderate reduction in the amplitudes of optic nerve function were found in all tested patients. The retinal responses to the Electroretinogram exam were of excellent quality in all but one GD1 patient, who showed slightly reduced responses. The spectral domain-optical coherence tomography (SD-OCT) examination showed posterior pole alterations in 3 patients (2 GD1 and 1 GD3) and borderline nerve fiber layers of the optic nerve (RNFL) in 3 (2 GD1 and 1 GD3) cases.

Our clinical study represents quite an innovative one, since neurological investigations are focused on GD2 and GD3 phenotypes. Neurological involvement with different phenotypical aspects were also found in GD1 patients. Sensorineural hearing loss and central alteration of auditory processing were present in higher incidence compared to the unaffected population. Psychological data din't show significant cognitive impairments, but pointed out some psychiatric aspects, such as anxiety, depression and somatic concerns.

MR 3Tesla can be an important tool to better understand these data. Evaluation of the remaining cohort of patients and longer follow-up could confirm that neurological involvement is not exclusive of the type 3 GD.