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Gaucher disease (GD) is a rare autosomal recessive genetic disease, which causes the body's glucocerebrosidase activity to lack activity due to GBA gene mutations, causing its substrate glucocerebrosidase to accumulate in macrophage lysosomes in the liver, spleen, bones, lungs, brain and other organs, forming "Gaucher cells", resulting in lesions of affected tissues and organs. About 50% of GD patients develop in childhood, delay in diagnosis and treatment will cause irreversible serious complications, such as bone crisis, pathological fractures, etc., usually the earlier the onset, the more serious the symptoms [1], so early diagnosis and treatment of GD is particularly critical to improve efficacy and prognosis.
The incidence of GD varies from region to region of the world, with the highest incidence among Ashkenazi Jews[2], and Israel has extensive experience in the early diagnosis and treatment of GD in Israel, which has the largest Shaare Zedek medical ward in the world. Therefore, Professor Shoshana Revel-Vilk from Shaare Zedek Medical Center in Israel was invited to share the early diagnosis and management experience of GD.
Wary! Could these symptoms be Gaucher disease?
After the GBA gene mutation, glucocerebrosidase is misfolded in the lysosome, eventually leading to a lack of enzyme activity and substrate storage in the lysosome, forming "Gaucher cells". When the bone marrow is involved, it can lead to bone marrow suppression, resulting in thrombocytopenia, anemia, and platelet dysfunction, and patients show symptoms such as bleeding tendency, purpura, and fatigue; When internal organs are involved, it can cause hepatosplenomegaly, further exacerbate anemia and thrombocytopenia, and cause pulmonary infiltration or pulmonary hypertension when involving the lungs; Bone pain, bone crisis, osteoporosis, bone thinness, osteonecrosis, or pathological fractures may occur when bone is involved, and bone symptoms often develop into irreversible lesions and should be foreseen as early as possible.
Children with GD will also have growth and development delay, which is manifested as short stature, weight loss, delayed tooth germination, delayed bone age, delayed menarche, etc. In addition, patients with GD may also find inflammatory manifestations such as hyperferritinemia, increased immunoglobulin levels, and decreased levels of high-density lipoprotein cholesterol. Therefore, GD is not only a lysosomal storage disease, but also an inflammatory disease. It is worth mentioning that in recent years an association between GD and Parkinson's disease has been found [3], so a family history of Parkinson's disease can provide clues to the diagnosis of GD.
Fig. 1 Clinical manifestations of GD patients
The above symptoms mainly appear in the non-neuropathy type (type I.) in GD, in addition to GD can also appear nervous system involvement, according to the speed of disease progression can be divided into acute neuropathy type (type II.) and subacute or chronic neuropathy type (type III.), of which type III can be divided into three subtypes: III.a, III.b, and III.c. Gaze paralysis is a very important sign in the manifestations of nervous system involvement, and Professor Shoshana Revel-Vilk showed the specific manifestations of this sign in the process: the patient has codirectional gaze dyskinesia in both eyes, and the patient can only go straight when detour is required during the examination, this gaze paralysis can often be overcome by smooth tracking or vestibulo-ocular reflexes, and in severe cases, the child can have eye fixation. In addition to eye movement disorders, some patients with neuropathy GD may also have cognitive impairment, motor and coordination disorders, ataxia, stuttering, dysphagia, behavioral abnormalities, and in severe cases, progressive myoclonic epilepsy and kyphosis [4].
Apply biomarkers to help achieve early diagnosis of GD
Early diagnosis and classification can better treat and manage patients with GD. In the process of diagnosing GD, because most patients have non-specific clinical symptoms, the diagnosis can be confirmed by glucocerebrosidase levels, genetic analysis, and biomarkers in the blood. The use of dried blood paper method (DBS) can perform the above three tests, which are less invasive, rapid, simple and sensitive, so they are widely used in clinical practice, while bone marrow aspiration is an invasive test, complex to operate, and not highly sensitive, so it is not recommended for the diagnosis of Gaucher disease.
Glucocerebrosidase detection using DBS is not very accurate, so Professor Shoshana Revel-Vilk said that they are increasingly using biomarkers to diagnose GD in the clinic. Chitotriglycosidase is a valid diagnostic biomarker, but this biomarker has great limitations, some patients (5%-6%) have loss of chitotriglycosidase expression [5], so glucosphingosine (lyso GB-1) is currently used for newborn screening, lyso Gb-1 detection in DBS sensitivity is 100%, specificity is 92%, which can minimize the missed rate, and monitoring the level of lyso GB-1 can be used for follow-up monitoring of treatment effect. The International GD Working Group (IWGGD) provides the diagnostic process for GD in the guidelines [6]:
Figure 2 GD diagnostic process
How to achieve scientific management of GD in Israel?
Early diagnosis of GD can avoid unnecessary invasive tests, such as bone marrow biopsy and liver biopsy, and help to make treatment decisions in advance and avoid irreversible complications. More importantly, when a child with GD is diagnosed, it can help the couple of the child not to have another child with GD. According to statistics, one in six GD patients reports that it takes at least seven years from the first consultation to the final diagnosis, and more than eight doctors need to be consulted before diagnosis [7, 8].
At Shaare Zedek Medical Center, about half of GD patients are diagnosed as children/adolescents. When obvious symptoms are diagnosed and the disease is diagnosed, the disease has often progressed to a very serious point, but the condition of children diagnosed by neonatal screening is not so serious, so neonatal screening is very important for early diagnosis and treatment. Once GD is diagnosed through neonatal screening, the child is periodically followed up and the symptoms of each system can be scored so that symptoms can be treated as soon as they first appear. When a child has neurological involvement, health care providers help them with language learning.
In order to achieve the purpose of early diagnosis, in addition to carrying out education and raising disease awareness, Professor Shoshana Revel-Vilk said that they are currently researching algorithms or scoring systems based on various symptoms and detection results, or developing machine learning to assist diagnosis to achieve early warning of diseases. Professor Shoshana Revel-Vilk mentioned that only by thinking more on the basis of mastering the clinical characterization and detection methods of GD can GD patients be identified and accurately diagnosed from the population, improve the quality of life of patients, and manage them scientifically.
参考文献：[1]中华医学会儿科学分会内分泌遗传代谢学组, 中华医学会儿科学分会血液学组, 中华医学会医学遗传学分会,等. 中国儿童GD诊治专家共识(2021)[J]. 中华儿科杂志, 2021, 59(12):7. [2] Mistry P K, Cappellini M D, Lukina E, et al. A reappraisal of Gaucher disease-diagnosis and disease management algorithms[J]. Am J Hematol, 2011,86(1):110-115. [3] PMcMahon B, Aflaki E, Sidransky E. Chaperoning glucocerebrosidase: a therapeutic strategy for both Gaucher disease and Parkinsonism[J]. Neural Regen Res, 2016,11(11):1760-1761. [4] Schiffmann R, Sevigny J, Rolfs A, et al. The definition of neuronopathic Gaucher disease[J]. J Inherit Metab Dis, 2020,43(5):1056-1059. [5] Boot R G, Renkema G H, Verhoek M, et al. The human chitotriosidase gene. Nature of inherited enzyme deficiency[J]. J Biol Chem, 1998,273(40):25680-25685. [6] Dardis A, Michelakakis H, Rozenfeld P, et al. Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1[J]. Orphanet J Rare Dis, 2022,17(1):442. [7] Mehta A, Belmatoug N, Bembi B, et al. Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians[J]. Mol Genet Metab, 2017,122(3):122-129. [8] Mistry P K, Sadan S, Yang R, et al. Consequences of diagnostic delays in type 1 Gaucher disease: the need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention[J]. Am J Hematol, 2007,82(8):697-701.
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