‘Non‐neuronopathic’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature

Abstract

Gaucher disease is a lysosomal storage disorder, which is classically divided into three types. Type I Gaucher disease is differentiated from types II and III disease by the absence of nervous system involvement. However, an increasing number of reports has emerged on neurological manifestations in patients with type I Gaucher disease. Whether a strict division in three different phenotypes is still valid has been the subject of debate. The main objective of this study was to provide scientific arguments whether a distinction between type I (non-neuronopathic) and types II and III (neuronopathic) Gaucher disease should be maintained. We investigated retrospectively a large Dutch cohort of type I Gaucher disease patients for the prevalence of neurological manifestations and provide an overview of the literature on this topic. A diagnosis of a neurological disease was made 34 times in 75 patients. Forty-five patients reported at least one neurological symptom during the median follow-up time of 11 years. The literature search revealed 86 studies in which type I Gaucher disease patients or carriers of a glucocerebrosidase mutation were described with a neurological disease or a condition which is known to be associated with neurological disease. In conclusion, the term non-neuronopathic Gaucher disease does not seem to be an appropriate characterization of type I Gaucher disease. However, the neurological signs and symptoms in type I Gaucher disease are of a totally different kind from and, in the majority of cases, of much less severity than the signs and symptoms associated with types II and III disease Therefore, type I disease should be classified as a separate phenotype.

How I treat Gaucher disease

“…In addition, it should be clarified that the neurologic features in type I GD are different from those reported in the neuronopathic forms (type II and III), consisting mainly of peripheral neuropathy, Parkinsonism, and neurologic changes secondary to bone complications. 12 …”

Neuronopathic Forms in Subjects with Mutations in GBA Gene

“…A recent systematic review of published literature identified 86 studies in which patients with GD1, or carriers of a glucocerebrosidase gene mutation, had some form of neurological manifestation (Biegstraaten et al, 2008;Cherin et al, 2010) contrary to the classical neuronopathic phenotypical description. Peripheral nervous system manifestations appear to be of particular relevance in GD1.…”

“…However the precise mechanisms by which glucosylceramide storage originate them is still unclear. The frequency of neurological GD cases is ranging between 7% and 17%, according to different series (Biegstraaten et al, 2008;Chérin et al, 2010). …”

Review of the safety and efficacy of imiglucerase treatment of Gaucher disease

“…Although the N370S mutation was considered to confer protection from neurological involvement, patients with this mutation may be at increased risk for parkinsonism 12,13 and/or may develop peripheral nerve abnormalities. 14,15 Type 2: acute perinatal lethal neuronopathic form Type 2 is a lethal neuronopathic form usually associated with compound heterozygosity for a severe mutation and a null mutation, [16][17][18] characterized by hypertonic posturing, strabismus, trismus, and retroflexion of the head during the first 6 months of life and death following aspiration pneumonia and/or apnea/laryngospasm by 2 years. 19 Massive hepatosplenomegaly and lung involvement are usually seen.…”