The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease

Gaucher disease（GD）,the commonest lysosomal storage disorder,results from the lack or functional deficiency of glucocerebrosidase（GCase） secondary to mutations in the GBA1 gene.There is an established association between GBA1 mutations and Parkinson＇s disease（PD）,and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD.Impaired lysosomal-autophagic degradation of cellular proteins,including α-synuclein（α-syn）,is implicated in the pathogenesis of PD,and there is increasing evidence for this also in GD and GBA1-PD.Indeed we have recently shown in a Drosophila model lacking neuronal GCase,that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration.In addition,we demonstrated alterations in mechanistic target of rapamycin complex 1（mTORC1） signaling and functional rescue of the lifespan,locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mT OR inhibitor rapamycin.Moreover,a number of other recent studies have shown autophagy-lysosomal system（ALS） dysfunction,with specific defects in both chaperone-mediated autophagy（CMA）,as well as macroautophagy,in GD and GBA1-PD model systems.Lastly we discuss the possible therapeutic benefits of inhibiting mT OR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.

Gaucher disease:New developments in treatment and etiology

Gaucher disease (GD) is an autosomal recessive disease which if undiagnosed or diagnosed late results in devastating complications. Because of the heterozygous nature of GD, there is a wide spectrum of clinical presentation. Clinicians should be aware of this rare but potentially treatable disease in patients who present with unexplained organomegaly, anemia, massive splenomegaly, ascites and even cirrhosis of unknown origin. The treatment options for adult type GD include enzyme replacement treatment (ERT) and substrate reduction treatment (SRT) depending on the status of the patient. Future treatment options are gene therapy and "smart molecules" which provide specifi c cure and additional treatment options. In this review, we present the key issues about GD and new developments that gastroenterologists should be aware of.

Compound heterozygous p.L483P and p.S310G mutations in GBA1 cause type 1 adult Gaucher disease:A case report

BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD.CASE SUMMARY Here,we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen,thrombocytopenia,and bone pain,diagnosed by enzymatic and genetic testing.Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C(p.L483P)and exon 7 c.928A>G(p.S310G)of GBA1.The latter was first reported in patients with GD.Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site.The p.S310G mutation in domain 1 may decrease stability between theα2 andα3 helices of GBA1.The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminalβ-sheet.The patient was treated with imiglucerase replacement therapy,and her condition was stable.CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function.This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.

Retinal detachment in a boy with Gaucher disease

Dear Editor,I am Dr.Fang Fang, from the Department of Ophthalmologyof the Second Xiangya Hospital of Central South University in Changsha, Hunan Province, China. I write to present a case report of retinal detachment with Gaucher disease（GD）.GD is a chronic, progressive, autosomal recessive lipidstorage disease caused by mutations in the lysosomal enzyme β-glucosidase（glucocerebrosidase）.

Relation between Gastrointestinal Adverse Effects in Gaucher Disease Patients and Intestinal Disaccharidases Activity Evaluated by Methane Hydrogen Breath Test

The aim of this paper is to study the disaccharidase profile in GD （Gaucher disease） patients treated or not with miglustat and compare it with a healthy control group. Miglustat is an iminosugar used as substrate inhibitor in the therapy of some lysosomal disorders, its main side effects resembling carbohydrate maldigestion symptoms and cause more than 50% of medication discontinuation among GD patients. In-vitro studies have revealed that miglustat can act as an inhibitor of some digestive enzymes. An exploratory non-interventional study was designed to compare the disaccharidase profile assessed by MHBT （methane hydrogen breath test） and to analyze the correlation with the reported gastrointestinal symptoms in GD patients （40） and healthy subjects （20）. MHBT was performed following the ingestion of lactose, sucrose and maltose on different days. Each participant completed two detailed surveys about dietary habits, medications and gastrointestinal symptoms previous and during the test. Twenty-one GD were receiving miglustat, 10 （47.6%） of them reported gastrointestinal side effects, and 7/10 （70%） recorded a positive MHBT （lactose 5, maltose 2, and sucrose 1）. In 6/19 （31.6%） patients that never been exposed to miglustat and 7/20 （35%） controls a positive MHBT were detected. The comparison of the malabsorption phenotype between GD patients exposed and not exposed to miglustat （p = 0.028） and control group （p 〈 0.04） showed high statistical significance for the group of patients treated with miglustat. These results suggest that miglustat therapy induces persistent changes in digestive enzyme activity in GD patients.

Gaucher Disease with Mesenteric Lymphadenopathy： A Case with 13-year Follow-up

Mesenteric lymphadenopathy is a rare manifestation of Gaucher disease （GD） with only 26 cases reported worldwide and its outcome remains largely unknown.In this manuscript,we described a 17-year-old girl with GD who has been treated with standard enzyme replacement therapy （ERT） for 16 years.The follow-up of her mesenteric lymphadenopathy began 13 years ago,which is one of the longest follow-up for this condition worldwide.

Electroencephalogram and phenotype patterns in neuronopathic Gaucher disease patients-ten years of experience in a single center

Background This study aimed to investigate the unique electroencephalography(EEG)patterns in neuronopathic Gaucher disease(GD)patients and explore the correlations between EEG findings and neurological phenotypes so as to optimize clinical outcomes.Methods A retrospective analysis was conducted on 74 EEG recordings from 50 GD patients between January 2012 and July 2022.Results Twenty-three patients exhibited abnormal EEG recordings,including 11 of the GD1 type(the transitional type)and 12 with neuronopathic GD.Of the 12 neuronopathic GD patients,9 patients with epilepsy were analysed specifically in terms of the clinical course.The primary waveform observed in the neuronopathic EEG recordings was the spike-and-wave complex(SWC)during both awake and sleep states.This was significantly different from sharp waves observed only during sleep in the patients of the transitional type(P=0.0230).The abnormal discharges in the neuronopathic patients were most commonly located in the bilateral Rolandic areas,while the transitional type commonly involved the bilateral frontal regions.Three patients with an epileptic EEG pattern reported their initial seizures years later.Seizures in the neuronopathic patients were effectively controlled with anti-seizure medications(ASMs),despite the ongoing presence of abnormal EEG patterns.The EEG patterns during ocular symptoms were characterized by sporadic or continuous unilateral SWC during sleep.Conclusions Patients with neuronopathic GD exhibit distinct EEG patterns that can help differentiate them from GD1 patients.Early treatment with ASMs can effectively control seizures.EEG plays a crucial role in monitoring seizures and can facilitate prompt intervention for GD patients.

A Novel Functional Missense Mutation p.T219A in Type Gaucher＇s Disease

Background： Gaucher＇s disease （GD） is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase （glucocerebrosidase [GBA]） that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease. Methods： Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene. Sequence alignments of mammalian β-GBA （GCase） and three-dimensional protein structure prediction of the mutation were made. A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro. Results： GCase is relatively conserved at p.T219A. This novel mutation differs from its wild-type in structure. Moreover, it also causes a reduction in GCase enzyme activity. Conclusion： This novel mutation （c.655A〉G, p.T219A） is a pathogenic missense mutation, which contributes to GD.

Autophagy-lysosome pathway as a source of candidate biomarkers for Parkinson's disease

Parkinson's disease(PD)is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1%of the worldwide population.Diagnosis of PD relies on clinical history and physical examination,but misdiagnosis is common in early stages.Despite considerable progress in understanding PD pathophysiology,including genetic and biochemical causes,diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments.Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease-modifying treatments.Increasing evidence suggests that autophagic dysregulation causes the accumulation of abnormal proteins,such as aberrantα-synuclein,a protein critical to PD pathogenesis.Mutations in the GBA gene are a major PD risk factor andβ-glucocerebrosidase(GCase)is also emerging as an important molecule in PD pathogenesis.Consequently,proteins involved in the autophagy-lysosome pathway and GCase protein levels and activity are prime targets for the research and development of new PD biomarkers.The studies so far in PD biological material have yielded some consistent results,particularly regarding the levels of Hsc70,a component of the chaperone-mediated autophagy pathway,and the enzymatic activity of GCase in GBA mutation carriers.In the future,larger longitudinal studies,corroborating previous research on possible biomarker candidates,as well as extending the search for possible candidates for other lysosomal components,may yield more definitive results.