Overview of the disease
An autosomal recessive lysosomal storage disease with multiple organ involvement, characterized by growth retardation, pallor, and bone pain associated with mutations in the glucocerebrosidase gene.
Definition
Gaucher disease, also known as glucocerebrosidase and cerebroside reticuloendotheliopathy, is the most common form of autosomal recessive lysosomal storage disease, with multiple organ involvement and a wide range of symptomatology, with the earlier the onset of the disease, the more severe the symptoms.
It is a rare disease and cannot be cured. Active treatment can help to improve clinical symptoms and prolong survival time.
Classification
According to whether the nervous system is involved or not, Gosheimer’s disease can be categorized into the following 4 types.
Type I
The most common subtype is the non-neuropathic type. The disease progresses slowly and most patients have skeletal involvement.
It can develop in all age groups, with 2/3 of patients developing the disease in childhood.
The prognosis is good and the long-term survival rate is high.
Type II
It is an acute neuropathic type, which progresses more rapidly and is less common.
It usually develops in the neonatal period to infancy, and most patients die before the age of 2-4 years.
Type III
Chronic or subacute neuropathy, more common in Northeast Asia.
It usually develops in childhood and has a slow progression, with a prognosis between type I and type II.
Rare subtypes
Rare subtypes, such as perinatal lethal type and cardiovascular type, are extremely rare in clinical practice.
Morbidity
Gosheimer’s disease is a rare disease, the prevalence of which varies in different regions of the world. According to a systematic analysis, the incidence of the disease ranges from 0.7 to 1.75 per 100,000 people worldwide, and it is one of the most common lysosomal storage diseases in the world.
The global prevalence of different subtypes varies greatly, with type I accounting for more than 90% of patients in Europe, America, and the Middle East, and type III accounting for more than 30% of patients in Northeast Asia, including China, Japan, and South Korea.
Causes
Causes
Gosheimer’s disease is an autosomal recessive disease, the causative gene is on the autosomes, and the parents of the patients usually do not have symptoms of the disease and are carriers of the causative gene.
The incidence of the disease is increased in children with the disease in their families.
Pathogenesis
The main pathogenesis of the disease is that a mutation in the glucocerebrosidase gene results in a deficiency of β-glucosidase, so that glucosides are deposited in the cytoplasm of the cell to form the typical storage cells called “Gossypol cells”, which accumulate in organs and tissues such as the liver, spleen, lungs, bones, and the brain, resulting in the development of the disease.
Symptoms
Gossypolosis is often characterized by the involvement of multiple organs such as the liver, spleen, bones, lungs and brain, and the characteristics of different types of Gossypolosis vary.
Type I
The onset of this type is insidious and progresses slowly. It is most common in childhood, but there are also cases of adult onset. The severity of symptoms varies greatly, usually the earlier the onset, the more severe the symptoms.
Organ manifestations
Liver and spleen enlargement are prominent manifestations, with splenomegaly being the most obvious.
Clinical manifestations are atypical, often found during physical examination, and there may be epigastric distension and pressure pain when the enlargement is obvious.
Hematologic manifestations
Thrombocytopenia and anemia are the main features.
Anemia is mainly characterized by pallor and fatigue.
Thrombocytopenia may be accompanied by nosebleeds, bleeding gums and skin bruises.
Skeletal manifestations
Acute or chronic diffuse bone pain is often present, which may affect daily activities and may cause disability.
In the early stage, the affected areas mainly include lumbar vertebrae, long bone epiphyses and diaphysis, and in the middle and late stage, epiphyses and metaphyses may be involved.
Other manifestations
Some children may have lung involvement, which mainly manifests as interstitial lung disease, pulmonary solid changes, pulmonary hypertension, etc., often manifested as weakness, cough, dyspnea, etc. Children may also have growth retardation.
Children may also have backward growth and development, about 40% of children are underweight and more than 2/3 of children have slow height growth. Adolescents may experience significant delay in puberty without treatment.
Type II
This type is relatively rare and is characterized by early-onset, rapidly progressive neurologic involvement, often in infancy, with rapid progression and a high morbidity and mortality rate, with death usually occurring between 2 and 4 years of age.
Infants mainly present with bilateral fixed strabismus, eyelid ptosis, restricted eye movement, and difficulty in sucking and swallowing, as well as seizures and corns (body tilted back like a bow).
Infants with severe disease may develop joint contractures with marked limitation of joint movement.
Type III
The disease usually starts in childhood and progresses slowly.
Early manifestations are similar to those of type I. Children gradually develop seizures, horizontal eye movement disorders, and ataxia such as unsteady walking and falling.
In addition, children may have developmental delays and mental retardation.
Where to see a doctor
Department of Medicine
Pediatrics
Children with symptoms such as pallor, fatigue, bleeding from the skin and mucous membranes, bone pain, growth retardation, horizontal eye movement disorders, and unsteady walking are advised to consult a doctor promptly.
Hematology
Children with symptoms such as pallor, fatigue, bleeding from the skin and mucous membranes, bone pain, etc. may also be referred to the Department of Hematology. The treatment of this disease may be coordinated with other departments, so please follow your doctor’s advice.
Preparation
Preparation for consultation: registration, preparation of documents, common problems
Tips for the doctor
It is recommended to wear clothes that can be easily put on and taken off for the doctor to conduct a physical examination.
Parents can keep a detailed record of the symptoms that the child has experienced for the doctor’s reference when making a diagnosis.
Preparation Checklist
Symptom list
Particular attention should be paid to the time of onset of symptoms, special manifestations, etc.
Any symptoms of pallor and fatigue?
Are there symptoms of nosebleeds, bleeding gums and bruised skin?
Are there symptoms of bone pain?
Is the child eating normally? Is there difficulty sucking and swallowing?
Are there any symptoms such as unsteady walking or falling easily?
Does the child have slow growth in height and weight?
Medical History Checklist
Does anyone in the family have Gosheimer’s disease?
Diagnosis
Basis of diagnosis
medical history
There is a family history of Gosheimer’s disease.
Clinical manifestations
Patients often present with pallor, fatigue, bleeding from the skin and mucous membranes, and bone pain.
In children, it may be accompanied by growth retardation, epilepsy, horizontal eye movement disorder, and unsteady walking.
Physical examination may reveal hepatosplenomegaly, slightly pale mucous membranes of the lips and mouth and conjunctiva of the lids, and children’s growth and development lagging behind that of their peers.
Laboratory Tests
Enzyme activity test
Glucosaminidase activity test is the gold standard for the diagnosis of Gosheimer’s disease.
The diagnosis of Gosheimer’s disease is confirmed when the activity of glucosinolates in peripheral blood leukocytes or skin fibroblasts decreases to less than 30% of the lower limit of normal values.
Genetic testing
Even in patients whose diagnosis is confirmed by enzyme activity, improved genetic testing is recommended to clarify the type of mutation.
The glucosinolase gene is located at 1q21, and genetic analysis of the mutant type can be used to determine the prognosis of the disease.
Bone marrow examination
Morphologic examination of the bone marrow may reveal characteristic cells, known as “Gosher cells”, which may help in the diagnosis of the disease.
“Gosher cells are large, have an eccentric nucleus, concentrated chromatin and cytoplasm, and have an “onion-skin” appearance.
Biomarker Tests
Chitosanase and glucosylsphingosine are important biomarkers for Gossyposis, and can be used to assist in the diagnosis of Gossyposis and for follow-up monitoring.
Tests may reveal elevated glucosylsphingosine concentrations and chitosanase may increase to hundreds or even thousands of times, which can be used as an aid in the diagnosis of Gosheimer’s disease.
Electroencephalography
Electroencephalography allows early detection of neurologic infiltration.
Those with neurologic involvement may have a slow wave background, spike waves, and sharp waves.
Increased thresholds of auditory brainstem evoked potentials and ocular motility disorders on neuro-ophthalmologic examination in persons without neurologic symptoms may be indicative of early neurologic involvement.
Others
Blood routine and blood biochemistry tests usually show decreased hemoglobin, thrombocytopenia, dyslipidemia (e.g., decreased blood cholesterol, decreased high-density lipoprotein and apolipoprotein A), and elevated serum ferritin.
Imaging
Ultrasound
Helps to assess the size of the liver and spleen.
An enlarged liver and spleen can be seen on abdominal ultrasound.
CT
Quantitative CT of the skeleton can accurately assess the bone density of the lumbar spine and the response to treatment in children.
Abdominal CT may reveal hepatosplenomegaly, changes in liver and spleen density, and lymph node involvement.
CT of the chest may show signs of thickening of the interlobular septa of the lungs, ground glass-like changes, reticular nodular infiltrates, air trapping and bronchiectasis.
X-ray film
The main examination sites are the spine and the long bones of the lower limbs.
The examination shows thinning of bone, flask-like deformity and reduced density of long bone epiphysis, thinning of bone cortex, etc.
Magnetic resonance imaging (MRI)
MRI examination of the spine and femur can see early bone marrow T1-weighted imaging, T2-weighted imaging signal reduction, T2-weighted imaging fat suppression sequence signal increase.
Abdominal MRI can see hepatosplenomegaly and lesions, lymph node involvement, etc.
Differential diagnosis
Thalassemia
Similarities: both have pallor, hepatosplenomegaly.
Differences: Children with thalassemia have the special features of thalassemia, such as mild jaundice, enlarged skull, elevated forehead, high zygomatic cheekbones, collapsed nasal bridge, and widened distance between the eyes. Laboratory tests, enzyme activity tests, and other tests are helpful in the differential diagnosis of the disease.
Chronic granulocytic leukemia
Similarities: both have pallor, fatigue, weight loss, splenomegaly.
Differences: Bone marrow examination of children with chronic granulocytic leukemia has extremely active proliferation of nucleated cells, with predominantly granulomatous hyperplasia, and cytogenetic testing can find the marker chromosome Ph chromosome of chronic granulomatous leukemia in more than 90% of children.
Treatment
Aim of treatment: to reduce symptoms, control disease progression and improve quality of life through treatment.
Treatment principle: Symptomatic treatment is the mainstay, and in recent years, enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction therapy, molecular chaperone therapy and other therapeutic techniques have also been developed.
Drug therapy
Enzyme replacement therapy
It can significantly improve the symptoms of type I and type III patients, relieve bone pain, maintain normal growth and development, and improve the quality of life, and the earlier the treatment, the better the efficacy.
At present, imiglucerase and vilaglucerase alfa have been approved and marketed in China.
Doctors will choose the appropriate drugs and medication regimen, etc. according to the patient’s age, severity of the disease, and progression of the disease.
Antiepileptic drugs
According to the type of epileptic seizure and EEG changes in children, appropriate anti-epileptic drug treatment will be chosen.
Commonly used drugs include valproic acid, lamotrigine, carbamazepine, oxcarbazepine and so on.
Others
Children with severe bone disease and low bone density may be considered for treatment in combination with bisphosphonates (e.g., alendronate, clodronate, etc.). Calcium and vitamin D3 may also be used in children.
Those with significant pain may be treated cautiously with nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen and ibuprofen, as prescribed by the physician.
Surgery
Splenectomy
Splenectomy is generally not recommended for children with Gosheimer’s disease.
Splenectomy can be life-saving in children who cannot be treated with enzyme replacement therapy when they develop severe symptoms of splenic compression, have life-threatening cytopenias, and other complications.
Cutting-edge treatments
Hematopoietic Stem Cell Transplantation
Successful hematopoietic stem cell transplantation can correct enzyme deficiencies, improve bleeding and anemia, and reduce liver and spleen size in children with Gosheimer’s disease.
There are reports of successful hematopoietic stem cell transplantation in children with Gosheimer’s disease in China, but the experience needs to be further accumulated. The risks associated with the treatment are high, and there may be serious complications in the follow-up, which need to be fully weighed in terms of advantages and disadvantages, and the benefits and risks.
Substrate reduction therapy
The mechanism of action of substrate reduction therapy is to inhibit substrate formation and directly reduce substrate accumulation in cells.
Currently, this treatment is only available for adults and not for children.
Molecular Chaperone Therapy
A molecular chaperone is a small molecule compound that can bind to misfolded proteins and help them to revert or mature correctly, with the characteristics of uniform tissue distribution and penetrating the blood-brain barrier.
Some clinical studies have reported the potential efficacy of Ambroxol hydrochloride as a drug molecular chaperone in the treatment of Gosheimer’s disease, which can increase glucosinolates activity, but the application is still immature and is still being explored.
Prognosis
Cure
Gosheimer’s disease is difficult to cure. Type I Gosheimer’s disease has a favorable prognosis, with some children surviving into adulthood after treatment.
The prognosis for type II Gosheimer’s disease is poor, and children with severe disease usually die before the age of 2 to 4 years.
The prognosis for Type III Gosheimer’s disease is between Type I and Type II.
Hazards
People with Gosheimer’s disease experience bone pain, fatigue and weakness, and seizures, which can seriously affect daily life.
Children may suffer from growth retardation and mental retardation, which may affect their studies and life afterward.
Some children may suffer from epilepsy, growth retardation and intellectual backwardness which affects their study and life, and the condition can be life-threatening in serious cases.
Daily
Daily Management
Exercise management
You can do appropriate exercise, such as walking, but do not do strenuous exercise to avoid triggering epilepsy.
Those who have a history of seizures should avoid dangerous activities such as climbing heights and swimming.
If you have bone pain or osteoporosis, it is better not to do strenuous exercise to avoid fracture.
Dietary management
Give patients light and easy-to-digest soft food, avoid eating too hard and too hot food to avoid stimulating or damaging the gums and oral mucosa to aggravate the bleeding symptoms.
Children can choose vitamin D fortified food to supplement vitamin D, such as vitamin D fortified milk.
Life management
It is best to choose clothes that are easy to put on and take off, cotton, soft and loose.
Avoid cleansing the skin with soap or shower gel containing fragrance to avoid skin irritation.
Parents may cut children’s nails short to prevent skin scratching.
Do a good job of oral care, rinse the mouth after eating and in the morning and evening, and brush the teeth with a soft-bristled toothbrush to avoid damage to the oral mucosa.
Follow-up
Symptomatic patients
Regular checkups and assessments will be conducted depending on whether the patient receives enzyme replacement therapy and whether the treatment goal is achieved.
Neurological, pulmonary and cardiovascular checkups should be performed on time as recommended by the doctor.
Asymptomatic patients
For asymptomatic patients, monitoring and evaluation at least once a year is recommended.
Asymptomatic patients diagnosed with Gosheimer’s disease due to a sibling’s disease should be monitored at least once every 6 months.
Prevention
There is no effective prevention for this disease. The following ways can reduce the birth rate of children with Gosheimer’s disease.
Gosheimer’s disease is a genetic disorder. Parents of children who are carriers need to undergo prenatal diagnosis as soon as they know they are pregnant in order to avoid the birth of a child with Gosheimer’s disease.
Members of the child’s family need to undergo genetic counseling before giving birth.