Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of Gaucher disease, acid beta-glucocerebrosidase deficiency, familial splenic anemia, glucocerebrosidase deficiency, glucosylceramide lipidosis, histiocytosis, and Norrbottnian disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Gaucher disease is a storage disorder caused by mutations in the GBA1 gene, which codes for lysosomal acid beta-glucocerebrosidase (glucocerebrosidase), resulting in accumulation of glucosylceramide (glucocerebroside). Type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) Gaucher disease are in a phenotypic continuum of neurologic abnormalities with variable courses. Sudden unexpected death and unusual behavior may occur in Gaucher type 3, particularly in Egyptian patients. Enzyme replacement therapy has no effect on the neurologic complications of the disease. CSF glycoprotein nonmetastatic B (GPNMB) may be used to quantify neurologic involvement in Gaucher disease. Mutations in the GBA1 gene are the most common genetic risk factor for adult-onset, isolated Parkinson disease; multiple system atrophy; and dementia with Lewy bodies. Substrate reduction therapy, pharmacological chaperone therapy, and gene therapy for neuronopathic Gaucher disease are currently being tested or are in the advanced planning stages.
• Neuronopathic Gaucher disease has a very wide clinical spectrum--from congenital and early infantile Gaucher disease type 2 to very mild with horizontal supranuclear gaze palsy as the only neurologic abnormality and normal or even superior intelligence.
• Current treatment for the non-neuronopathic and for the chronic neuronopathic forms of the disease includes enzyme replacement, which targets only the non-neurologic aspects of the disease.
• Substrate synthesis reduction has shown to be effective in controlling the non-neurologic aspects of Gaucher disease, and the approach is being tried in Gaucher disease type 3 patients.
• Adult-onset, isolated Parkinson disease; multiple system atrophy; and dementia with Lewy bodies are not features of neuronopathic Gaucher disease. Rather, GBA1 mutations are a risk factor for developing these neurodegenerative diseases.
The first example of Gaucher disease was documented in a patient with hepatosplenomegaly. The case was described in the doctoral thesis of Philippe C E Gaucher (51). The disorder was diagnosed as an epithelioma of the spleen. The characteristic appearance of storage in reticuloendothelial cells was noted as early as 1907 (83). The first step toward the description of the chemistry of the material accumulating in these cells evolved from the identification of its "lipoid" character by morphologists. Later, Epstein demonstrated that spleens from Gaucher patients yielded considerable amounts of an alcohol-soluble substance (40). In 1924, Lieb characterized this material as a cerebroside akin to the compounds described earlier by Thudichum (126; 79). The correct identification of the sugar in the sphingolipid compound was not achieved until 1934, when Aghion demonstrated that the lipid accumulating in the tissues of patients with Gaucher disease was a glucosyl, not a galactosyl, a derivative of ceramide (03).
The discovery of the lysosome as an organelle in 1955 by De Duve and colleagues changed the definition of the storage disorders. Within a short time, the first lysosomal storage disorder was described and was shown to be due to a deficiency of acid alpha-1,4-glucosidase (alpha-glucosidase) in a patient with Pompe disease (57). Other storage disorders quickly became recognized as diseases resulting from the lack of a degradative capacity—notably a lysosomal enzyme--with the expected lysosomal accumulation of substrate (58; 34). The accumulation of acid beta-glucocerebrosidase (glucocerebroside) was already well known in patients with Gaucher disease. Attention was focused on the possibility that the material accumulated because of a specific deficiency in its degradative pathway, leading to the description of the enzyme deficiency in 1965 (19; 100). It had been recognized that a variety of clinical disorders were related to glucocerebroside storage. Although these subtypes were originally thought to be distinguished by the relative amount of residual enzyme present (118; 141), experience has shown that this is incorrect.
The discovery of the enzyme deficiency led to the development of several approaches to understand the biology of the lysosomes and to the development of enzyme replacement therapy to replace the missing gene product. The development of this treatment and the steps that have been taken toward gene transfer in Gaucher disease will be reviewed later in this summary.
Note on nomenclature. This summary follows the current guidelines for gene and protein nomenclature and for mutation description. Please see Gene and mutation nomenclature for those guidelines. The enzyme, acid beta-glucocerebrosidase (GBA) is often referred to as glucocerebrosidase in the literature. The description of mutations in the older literature refers to the processed protein after excision of the 39 amino acid leader peptide. The current guidelines for mutation nomenclature stipulate that numbering begins with the leader peptide.
Based on clinical signs and symptoms, Gaucher disease has been divided into 3 subtypes: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (chronic neuronopathic) (74). All 3 types of Gaucher disease are caused by a deficiency of acid beta-glucocerebrosidase that results in the accumulation of glucocerebroside within the cells of the reticuloendothelial system. The principal differences between the subtypes are the presence of neurologic manifestations caused directly by glucocerebrosidase deficiency. Neuronopathic Gaucher disease is defined as the presence of neurologic involvement in a patient with biochemically proven Gaucher disease for which there is no explanation other than Gaucher disease (130). Because symptoms in all of the 3 different types may begin in infancy, and the discrimination of subtypes depends on the evolution of clinical manifestations, especially nervous system involvement, this classification is more appropriate than one that includes reference to age of onset (ie, "adult," "infantile," and "juvenile" forms of Gaucher disease). The assignment of type, especially in children, should be made only after a careful examination for the presence and progression of related neurologic abnormalities or if a genotype study shows the presence of the N370S allele that typically is associated with Gaucher disease type 1.
Type 1: Chronic non-neuronopathic Gaucher disease. The age of onset and the severity of symptoms within this subtype vary widely and are not completely explained by the genotype. Although the genetic defect is present from conception, the diagnosis is frequently made later in life. It is likely that many patients with type 1 disease are not diagnosed because of a lack of significant clinical manifestations.
Although exceptions occur, painless splenomegaly with thrombocytopenia, anemia, and leukopenia are the usual initial signs. In many patients, these complications are not life threatening and may go unrecognized for years.
Visceral features. Although hepatomegaly is often noted at the time splenomegaly is observed, the liver may not become enlarged until later in the course of the disease. Moderate hepatic dysfunction is discerned by elevation of liver enzymes in serum. Histologically, all patients have some degree of hepatic fibrosis (66). Hepatic failure can occur in untreated patients. Portal hypertension leading to esophageal varices is a known complication, occurring in patients with severe type 1 and type 3 disease.
Hematological features. Patients may have platelet counts below 50,000 without an accompanying bleeding diathesis. Conversely, some patients with Gaucher disease who have a normal prothrombin time, partial thromboplastin time, and platelet count (greater than 100,000) may have abnormal clotting times, excessive bruising, and unexpected perioperative bleeding. This variability in hematological features provides little guidance to the practitioner and necessitates an individualized approach that may require the administration of platelets and fresh frozen plasma prior to and after surgical procedures.
Skeletal features. Degenerative changes in the skeleton are the leading cause of disability in patients with type 1 disease. Some degree of osteopenia and osteolysis occurs in virtually all patients. However, the extent of bone disease is variable (142; 65). Very few patients have neither radiographic nor scintigraphic evidence of bone involvement. Most affected individuals have a substantial burden of bone disease that is progressive and leads to clinical presentation. Others have such severe involvement that they are confined to a wheelchair early in life because of pain, pathologic fracture, or skeletal instability. Many patients experience episodic pain lasting for days to months in the hips, legs, back, and shoulders. These episodes have been referred to as "bone crises."
Pulmonary hypertension. Pulmonary hypertension is a relatively common complication found in approximately 30% of Gaucher disease patients (Mistry, personal communication). Fortunately, most of the cases are mild and subclinical with pulmonary artery pressures below 25 mm Hg. In less than 1% of the known Gaucher disease patients, pulmonary hypertension is clinically evident. Current data conclude that this complication is a direct consequence of acid beta-glucocerebrosidase storage and is worsened in splenectomized patients by the accumulation of storage cells in the lung. The severe cases of pulmonary hypertension do demonstrate a positive improvement to enzyme therapy (78).
Most patients with type 1 disease do not have clinically symptomatic involvement of the heart or lungs. A small number of patients with types 1 and 3 disease have severe chronic pulmonary disease without cardiac lesions. They have hypoxia, cyanosis, and clubbing secondary to shunting, with extensive liver disease.
Ophthalmological abnormalities. These are rare but variable and include manifestations, involving the vitreous, retina, cornea, uvea, and conjunctiva (35). Vitreous opacities are the most common and seen mostly in patients with Gaucher type 3 and sometimes require vitrectomy to ameliorate visual acuity.
Type 2: Acute neuronopathic Gaucher disease. In contrast to the variability seen within type 1 Gaucher disease, it is evident from the extensive review of type 2 cases by Fredrickson and from our experience with more than 15 cases that type 2 Gaucher disease is somewhat more uniform in its presentation. It has no ethnic predilection (45). The average age of onset is 3 months, and the presenting sign is usually massive hepatosplenomegaly.
Neurologic abnormalities. Neurologic complications develop by 3 to 6 months of age. The presenting signs usually indicate cranial nerve nuclei and extrapyramidal tract involvement. The classic triad of trismus, strabismus, convergent squint due to bilateral 6th nerve palsy followed by completed extraocular paralysis, and retroflection of the head appears combined with a typical facial dystonic posture in the majority of patients, accompanied by progressive spasticity, hyperreflexia, positive Babinski signs, and other pathologic reflexes. Dysphagia and difficulty in handling secretions develop, often followed by aspiration pneumonia. Seizures may occur. As neurologic deterioration proceeds, the child usually becomes apathetic and motionless. Death occurs either from apnea or aspiration pneumonia at an average age of 9 months, with a range of 1 month to 2 years.
This form of Gaucher disease exhibits alterations in epidermal ultrastructure which may provide an early and specific diagnostic tool (24).
Neonatal Gaucher disease. A rare and unique form of Gaucher disease presents with hydrops fetalis and collodion skin (125). In an extensive molecular analysis of 31 patients with this type of connatal Gaucher disease, homozygosity for a recombinant allele that included the mutation p.Leu483Pro (formerly Leu444Pro) was associated with early lethality (120).
It must be reemphasized that children with type 1 Gaucher disease are also diagnosed before 2 years of age. They may have rapid progression in bone, liver, and spleen manifestations. Some of these cases have been erroneously diagnosed as type 2. It is essential that central nervous system involvement be documented and established as an associated finding prior to making a diagnosis of type 2 disease.
An extensive review of the clinical and hematological features of neonatal Gaucher disease has been published (86). From that study it can be concluded that neonatal Gaucher disease is diagnosed based on postmortem pathological findings, with familial history suspected in 22%.
Contrary to what is observed in type 2 disease, there is a 22% rate of dysmorphic features in neonatal Gaucher disease characterized by low-set ears, small nose with flat bridge, and anteverted nares.
The characteristics of the clinical phenotype and the pregnancy are somewhat different between those newborns and fetuses affected by non-immune hydrops fetalis, in whom prematurity, fetal demise, and neonatal distress are prominent features. Hepatosplenomegaly is suspected prenatally in most of the cases with non-immune hydrops fetalis. Cardiomegaly has also been observed in some fetuses with Gaucher disease associated with non-immune hydrops fetalis (86).
Type 3: Subacute or chronic neuronopathic Gaucher disease. The clinical features of type 3 Gaucher disease, apart from those referable to the nervous system, are common to Gaucher disease type 1. Hepatosplenomegaly is often the presenting feature rather than the neurologic abnormalities.
In well-documented and biochemically proven cases, there is marked variation in age of onset and severity of organ involvement.
Neurologic abnormalities. The neurologic hallmark of Gaucher disease type 3 (and type 2) is horizontal supranuclear gaze palsy. It is present in all patients with neuronopathic Gaucher disease (130; 15). In addition to slow saccades, other oculomotor abnormalities were identified in these patients, including decreased gain of smooth pursuit and of the vestibulo-ocular reflex (21). Other manifestations include various degrees of intellectual disability, ataxia, dystonia (especially nuchal and facial), and, more rarely, grand mal or psychomotor seizures and dementia. Less commonly, a syndrome of progressive myoclonic epilepsy, dementia, and variable degrees of supranuclear ophthalmoplegia with relatively mild systemic disease occur. Certain GBA1 mutations are associated with myoclonic encephalopathy (eg, N188S), whereas L444P/L444P rarely, if ever, is (99; 75). There is significant variation in neurologic pattern among different ethnicities. A unique oppositional behavioral abnormality is seen in Egyptian patients with Gaucher type 3 (02).
In general, patients may have any combination of systemic and neurologic abnormalities, including mild systemic disease with a progressive neurologic course or underlying severe skeletal and hematological abnormalities with a non-progressive neurologic course and dominated by horizontal supranuclear gaze palsy (15). Patients who are otherwise stable medically and neurologically who usually have the p.Leu483Pro/p.Leu483Pro (previously L444P homozygote) phenotype and who are on long-term enzyme replacement therapy may develop partial complex seizures of temporal lobe origin that should not be confounded with progressive myoclonic encephalopathy (06; 99). Sudden unexpected death often with epilepsy has been rarely observed, but it is particularly frequent in Egyptian patients (01).
A group of patients with a neurodegenerative course and valvular heart calcification and stenosis are homozygous for the mutation in the acid beta-glucocerebrosidase (GBA1) gene (p.Asp409His, now annotated as NM_000157.3: c.1342G > C; p.Asp448His) (27; 76). These cases have been classified as type 3c. The neurologic features occur at an older age and are no different than the typical Gaucher disease type 3. Finally, one report described a neuronopathic variant characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules in a patient with 1 p.Asp409His allele (64). The onset of presentation at 4 months and the peculiar symptomatology differentiated this variant from the type 3c and more closely mimics Gaucher disease type 2. A description of novel patients and a comprehensive review of the literature has been published (76). The pathogenesis of the cardiovascular abnormalities in this homozygous genotype is not known, but likely not related to acid beta-glucosidase deficiency per se, but rather to other functions or interactions of this protein.
The clinical features of the neuronopathic phenotypes of Gaucher disease appear to be part of a continuum of disease severity, as described by Goker-Alpan in a series of patients that presented intermediate phenotypes between type 2 and type 3 diseases (54). An intermediate phenotype, ie, presenting characteristics of type 2 and type 3 with associated dysmorphic features, has also been described in a patient from Pakistani origin (16).
Gaucher and parkinsonism. Over the past few years it has become clear that Parkinson disease or other forms of parkinsonism (synucleinopathies) occur more frequently than expected by chance in patients with Gaucher disease but also in carriers of GBA mutations (108). Patients with Gaucher disease and parkinsonism were found to have typical Lewy bodies in hippocampal regions susceptible to Gaucher-related neurodegeneration, thus confirming pathologically the co-occurrence of the Gaucher and the Parkinson pathologies (143). A large meta-analytic study demonstrated conclusively that the odds ratio for any GBA1 mutation in patients versus controls was 5.43 overall (116). Patients with a GBA1 mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Thus, GBA1 mutations are the largest genetic risk factor for Parkinson disease (116). Importantly, patients with type 1 Gaucher are also at a higher risk (22). The mechanism by which GBA1 mutations are a risk factor for parkinsonism is not clear, but because there is a clear relationship between the severity of the mutation and the likelihood and the age of onset of developing Parkinson disease, it is likely that loss of function of acid beta-glucocerebrosidase is involved (49). Indeed, glucocerebrosidase activity measured in peripheral blood was found to be lower in patients with Parkinson disease even when they do not carry GBA1 mutations (05). Glucocerebrosidase deficiency was also found in substantia nigra of Parkinson disease brains that do not have GBA1 mutations (52). These findings were confirmed in another group that identified selective reduction of glucocerebrosidase in Parkinson and diffuse Lewy body disease patients, suggesting the possible role of glucocerebrosidase as a biomarker of synucleinopathy (26). Findings support that glucocerebrosidase deficiency and alpha-synuclein form a positive feedback loop that may lead to a self-propagating disease that ends up causing neuronal death (85). This explanation is further supported by the finding of glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains that do not have GBA1 mutations (52). A competing explanation is that mutated glucocerebrosidase causes endoplasmic reticulum stress in susceptible neurons (82). The 2 mechanisms may act in concert, but in any case, GBA1 mutations are the most prevalent genetic risk factor for synucleinopathies (Parkinson and dementia with Lewy bodies). A prospective study of patients with Gaucher disease and carriers for GBA1 mutations has shown that clinical features associated with premotor Parkinson disease and motor features of Parkinson disease are more prevalent compared to controls and progress over a 2-year follow up (14). These findings support the hypothesis that some GBA1 mutation-positive individuals exhibit clinical features of early neurodegeneration (14). However, other lysosomal enzyme deficiencies may be risk factors for Parkinson disease (106), though these activities were not found to be reduced in blood of carriers and noncarrier patients with Parkinson disease (05).
Death in Gaucher type 1 patients who have never received enzyme replacement therapy occurred at a median age of 66 years and was often caused by liver disease, septicemia, malignancies, and suicide (138).
Spleen. Painless splenomegaly is usually the earliest sign in all types of Gaucher disease. Even when the spleen is not palpable by physical examination, it usually can be demonstrated to be enlarged by diagnostic imaging techniques. The rate of enlargement of the spleen is helpful in judging the rate of progression of the disease. The preferred modality for measuring organ volume is volumetric MRI (25). The rate of splenic enlargement is often consistent for each case, but changes in the rate of progression are known to occur without any precipitating factors. Changes in that rate have been associated with malignancy or other intercurrent disease. Spontaneous rupture of the spleen is uncommon. The majority of cases develop hypersplenism manifested by pancytopenia and a bleeding diathesis. Red cell and platelet survival time is shortened. Splenectomy should be limited to those patients having severe bleeding diathesis, high-output cardiac failure, or mechanical interference of bowel, diaphragm, or kidney. Splenic tissue has been extensively studied. Fibrosis with distortion of the splenic architecture is commonly observed. The spleen is enlarged and firm and contains pale areas caused by infarcts. The process of infarction can lead to abdominal pain and should be considered in the differential diagnosis of an acute abdomen in patients with Gaucher disease. The red pulp of the spleen is replaced by white collections of Gaucher cells. The surface and body of the spleen may contain dark-purple nodules that are foci of extramedullary hematopoiesis. Splenectomy is almost always followed by correction of cardiac and hematologic abnormalities. However, splenectomy poses a risk for severe, overwhelming sepsis that can be fatal within a day. For these reasons enzyme replacement therapy is the treatment of choice.
Liver. Despite the frequent occurrence of hepatomegaly in Gaucher disease, hepatic failure occurs infrequently. Gaucher cells are seen within the sinusoids. In virtually all cases, fibrosis occurs. In the more severely affected cases, fibrosis distorts the architecture, forming small regenerating nodules that are infiltrated by Gaucher cells. These cases have been described as cirrhotic. In contrast to other lipidoses (such as Niemann-Pick disease), hepatocytes are not involved in storage. The enlarged liver may contain sites of extramedullary hematopoiesis. The majority of patients have abnormal liver function tests. Marked portal hypertension and consequent complications such as ascites and esophageal varices do occur and are common in severe disease. Radionuclide scans show a shift in tracer from liver to spleen in the majority of cases, indicating a degree of portal hypertension. Recurrent bleeding from esophageal varices has been successfully treated with a combination of aggressive medical management and sclerotherapy. Jaundice is a serious sign in this disease and represents either intercurrent infectious, chronic active hepatitis, or hepatic failure. In the authors' experience, only 4 cases out of several hundred have died of hepatic failure. In cases with liver involvement, early intervention with enzyme replacement therapy is indicated. Hepatic transplantation is required in patients with end-stage liver disease.
In some patients, lymph nodes may be enlarged and contain Gaucher cells. The thymus, Peyer patches in the intestine, and the pharyngeal tonsils are frequently affected.
Skeletal manifestations. The severity and onset of symptoms are extremely variable. Joint pain and "arthritic" bone pain are common. These pains are caused by deterioration of the skeleton in the periarticular regions of bone and are relieved by analgesics. Particularly useful are nonsteroidal anti-inflammatory agents.
In Gaucher patients types 1 and 3, roentgenographic abnormalities of bone are frequent, occurring in 50% to 75% of all patients. Expansion of the cortex in the distal femur (Erlenmeyer flask deformity) as well as fractures and other abnormalities of the acetabulum and head and neck of the femur are frequent. Prosthetic hip replacement has been invaluable in permitting patients to remain ambulatory. The hip lesions, in some cases, may be confused with Legg-Calve-Perthes disease. Destruction of vertebral bodies may produce collapse and gibbus formation and spinal cord or nerve dysfunction.
Bone pain and bone crises. Infarction of the bone produces the "bone crises." This process affects the femoral heads and distal femur more frequently than other bones. These episodes are usually self-contained and last approximately 2 weeks but may be extended to many months. During the first days of the crisis, analgesia is difficult to accomplish and may require hospitalization. Bed rest is always indicated until the episode is completely resolved. The infarction process sometimes resolves completely, but typically a region of osteosclerosis, bone deformity, or pathologic fracture develops. There is a possibility that the infarcted region will become secondarily reinfected, producing a true osteomyelitis. However, this is not uniform, and the episode should be treated conservatively unless infection is highly suspected. Instrumentation of the infarcted bone should be avoided unless clearly indicated because it may lead to secondary infection and development of a sinus tract. X-rays and technetium scans are usually not helpful in distinguishing infarction from osteomyelitis, but gallium scans may assist in this sometimes difficult decision. As a general measure, one should ensure that adequate calcium intake is maintained. If urinary calcium is low, the diet should be fortified with calcium and vitamin D. In addition, the storage of glucocerebroside in tissue macrophages may alter the generation of competent osteoclasts and result in a failure to maintain a healthy bone matrix. Further research is needed to delineate the pathogenesis of this disorder before entirely effective therapy for bone complications can be developed. A rare occurrence in type 1 disease is the extraosseous extension of Gaucher cells to the surrounding soft tissues, a condition that may mimic a malignant process (102). Because the incidence of several malignancies, including lymphoproliferative disorders, is increased in Gaucher disease (114), a biopsy may be required for an accurate differential diagnosis.
The hypothesis that bone crises are the result of progressive vascular compromise produced directly by occlusion of vessels by Gaucher cells is not supported by scintigraphic or histologic studies. In fact, perfusion scans of bones are often enhanced. Vascular occlusion by Gaucher cells would not explain the combination of osteopenia, osteonecrosis, and osteosclerosis seen in the disorder. Other vascular complications, such as premature stroke, myocardial infarction, or renal failure, are not features of the disease, making a simple vascular occlusive process a less attractive explanation of the skeletal involvement. Metabolic and endocrinologic studies suggest an imbalance in calcium homeostasis; however, the entire skeleton is not affected uniformly. On the contrary, the lesions consist of collections of Gaucher cells scattered throughout the bone substance. Bone complications probably result from a toxic process around these foci, which then leads secondarily to edema, vascular compromise, and infarction. One study reported a correlation between the severity of type 1 disease and serum levels of macrophage derived cytokines. This correlation suggests that a cytokine imbalance may have a role in the pathophysiology of the bone lesions (60). From existing information, it is not likely that infarction is incited by vascular occlusion by Gaucher cells, but rather by the vascular compromise alluded to above.
Progressive kyphosis (sometimes with scoliosis) without any vertebral body abnormality is commonly observed in patients with Gaucher type 3. It is very rarely seen in patients with Gaucher type 1. Correction and stabilization of the kyphosis is required, and Harrington rods are often placed towards the end of the growth period (late adolescence). The mechanism of this phenomenon is unknown, but studies in a zebrafish model suggest a developmental abnormality of bone (146).
Growth retardation and delay in skeletal maturation occurs in children but is normalized by enzyme replacement therapy (69).
Other organic systems. In the kidney, Gaucher cells can be found in the cortex, medulla, or glomeruli. Renal function in Gaucher patients is usually normal. In a few cases, proteinuria or hematuria has been reported. The cause of these signs is uncertain, but they have been attributed to the infiltration of Gaucher cells.
Focal collections of Gaucher cells are found within Peyer patches and the lamina propria of the gastrointestinal tract. Patients may complain of bloating, cramps, and diarrhea. Abnormal uptake of calcium may be one of several factors affecting bone in the disorder.
The cherry-red spot that appears in the macula in some sphingolipidoses and mucolipidoses does not occur in Gaucher disease; however, white patches containing Gaucher cells have been seen in the vitreous and retina of some Gaucher type 3 patients, and they can develop while the patient is on enzyme replacement therapy (109). A case has been reported in which loss of vision due to uveitis in type 1 disease could be reversed by enzyme replacement therapy (17). There have been many reports suggesting that patients with Gaucher disease are at increased risk of developing malignancies, particularly hematopoietic tumors. A large study of 1525 patients found 2- to 3-fold risks of non-Hodgkin lymphoma, malignant melanoma, and pancreatic cancer in patients with Gaucher disease but no significant association between Gaucher disease and cancer in general or with other specific malignancies, such as multiple myeloma (77).
Because of the different clinical courses of patients with Gaucher disease, researchers have tried to develop a laboratory test that would both discriminate subtype and be useful in determining prognosis. Genotype analysis gives some guidance in this area but is not completely satisfactory. Most individuals with even one p.Asn409Ser allele do not have neurologic involvement, whereas almost all patients with the p.Leu483Pro allele have neurologic involvement. Differences in epidermal cells may provide a means to differentiate type 2 neuronopathic Gaucher disease from types 1 and 3 Gaucher disease (46; 115). Disorganized lamellar membranes in the epidermal stratum corneum are present in type 2 patients but not in type 3 patients (62; 24).
Garvey and colleagues observed that the amplitude of stretch-evoked somatosensory evoked potentials in patients with type 3 Gaucher disease positively correlated with the degree of cognitive deficit and, therefore, with neurologic disease burden (50). It is possible that measurement of somatosensory evoked potentials may be useful to monitor the response of future therapies aimed at correcting the neuropathology of Gaucher disease.
Case 1. Ashley was a 5-year-old who experienced a bladder infection that became obvious when she suddenly began to have toileting accidents. The infection was treated with sulfa drugs and cleared up initially, but reoccurred 6 months later. When the primary care physician examined Ashley, she found splenomegaly and a low platelet count. Ashley was diagnosed with a platelet disorder and treated with prednisone. Several days into the steroid treatment, her platelet count was found to be very low, and a bone marrow biopsy was performed. The biopsy showed Gaucher cells. Follow-up testing showed enzyme assay of 2 (NR 12-17) and genotype p.Asn409Ser/p.Leu483Pro.
Follow up and discussion. The p.Asn409Ser mutation is only associated with type 1 Gaucher disease. When p.Asn409Ser occurs with a second different mutation like p.Leu483Pro, the disease sometimes presents earlier in life. Ashley had 2 brothers, and because neither of them had symptoms of Gaucher disease, they did not have genetic testing. When a genetic condition, such as Gaucher disease, is known in a family, the brothers and sisters of a person with the condition are at higher risk for having the same condition and for being carriers. For this reason, it is important for parents to educate all of the children in their family about the condition. Many parents want and need help with this process. Genetic counseling is recommended for each family member when he or she becomes an adult (or before if indicated).
Case 2. At age 4 months, Justin's parents noted "something not quite right with his eye movement" and mentioned this to their pediatrician at Justin's 6-month well baby visit.
At this visit, the pediatrician noticed splenomegaly and heard a report from the parents that Justin had a choking episode during which he became cyanotic and was taken to the ER. Developmentally, Justin was meeting expected milestones and at 6 months was sitting, reaching for and grasping objects, and responding to his name. The pediatrician ordered a panel of metabolic tests including acid beta-glucocerebrosidase.
• Liver approximately 2 times normal size
• Platelet count 125,000
Follow up and discussion. Justin was treated with enzyme replacement therapy at a dose of 120 U/kg every 2 weeks. He did well for several months; he was walking well and saying a few words. Eventually, he failed to progress and began having more frequent choking episodes. Justin died during the night at age 22 months.
Case 3. Christopher, a 20-month-old Caucasian male, presented with the following history: at his 12-month well-child checkup, the pediatrician noted hepatosplenomegaly. Chris's hepatosplenomegaly was unchanged on follow-up at 15 months, and at 18 months he was seen because of irritability and fever that had persisted for approximately 1 month. At that time, increased hepatosplenomegaly and cervical lymphadenopathy were noted. Christopher was admitted to the hospital, at which time he also had hoarseness and diarrhea. He was evaluated for possible malignancy with results that included the following: chest x-ray, normal; abdominal x-ray, HSM; fragmented right femoral epiphysis; cervical lymph node biopsy, normal; bone marrow aspirate, Gaucher cells.
• 85 cm, 10.5 kg
Follow up and discussion. Over the next few months, it became apparent from examination and parents’ observations that Christopher had horizontal supranuclear gaze palsy with compensatory head thrusting. Treatment with enzyme replacement therapy was initiated at a dose of 60 U/kg every 2 weeks. Years later at age 11 years, Christopher had no progression of the slow looping saccadic eye movements and no organomegaly or obvious bone disease; he played baseball and football, was an A and B student, and had the lead in the school play during the previous academic year.
The precise genetic and biochemical reasons for the manifestations of the disease and the phenotypic differences among patients are not completely understood. There is little doubt that other genetic modifiers of Gaucher disease cause marked differences in the presentation of signs and symptoms related to bone marrow, liver, spleen, lung, bone, brain, and other systems involved in the disease (53).
Reticuloendothelial system. It is postulated that the glycolipid storage in the cells of the reticuloendothelial tissue may induce an inflammatory response characterized by the recruitment of proinflammatory cytokines and other cells of the immune system. In turn, extensive tissue damage would ensue, particularly in the liver, spleen and bones. A study of the gene expression profile in Gaucher disease showed enhanced expression of genes associated with inflammatory reactions in the affected spleen (91). In particular, the transcript abundance of the cDNAs representing cysteine proteinases (cathepsins B, K, and S) was greatly increased. These proteins are known to participate in tissue modeling, antigen presentation, and in the case of cathepsin K, bone matrix destruction.
Brain involvement. An understanding of the involvement of the brain in Gaucher disease has increased in the last several years but is far from complete because of the limited number of postmortem cases available for study. Type 1 Gaucher disease patients do not have clinical symptoms or signs referable to the nervous system. In this group, anatomic and biochemical examinations of the brain have been infrequent. Hippocampal gliosis has been found in brains of otherwise neurologically normal patients with Gaucher disease type 1 (143).
In Gaucher disease types 1, 2, and 3, perivascular Gaucher cells have been observed within the Virchow-Robin spaces (33; 143).
Pathologic features of neuronopathic phenotypes. In type 2 patients' brains, free Gaucher cells have been demonstrated within the parenchyma accompanied by gliosis and microglial nodules. These changes are present but much less frequently in type 3 patients' brains. Neuronal storage of lipid has been suggested in several reports, but this has not been confirmed ultrastructurally in any case of Gaucher disease. In type 2 disease, neuronophagia and neuronal cell death in the deeper layers of the cortex, thalamus, basal ganglia, brainstem nuclei, cerebellum, and spinal cord have been reported. Variable degrees of demyelination have been described in brains of type 2 patients. From the available information, one would have to conclude that the accumulation of acid beta-glucocerebrosidase in the brain produces dysfunction in surrounding cells long before discrete pathologic changes are seen (71). Extensive study of 14 brains from type 1 (including patients with parkinsonism), 2, and 3 Gaucher disease showed common neuropathologic findings in all forms of Gaucher disease (143). Unique patterns of gliosis and neuronal loss involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. Although these findings were common to all 3 Gaucher disease phenotypes, the extent of the changes varied depending on the severity of disease (143). Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all Gaucher disease patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as having type 1 Gaucher disease had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated acid beta-glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal 45Ca(2+) uptake autoradiography in rat brain was performed, demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium-release-sensitive (CICR-sensitive). These findings match biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity (101). In 2 patients with type 1 Gaucher disease and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found in hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant acid beta-glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in Gaucher disease (143). Progression of the neuropathology is very predictable in the mouse model including microglial activation and astrogliosis were spatially and temporally correlated with selective neuron loss (44). Glucocerebroside accumulates to a similar extent in most brain areas, and upon reaching a certain threshold of accumulation inflammation and neurodegeneration is initiated in susceptible brain areas (43). The same group found that receptor interacting protein (RIP) kinases-mediated necrosis plays a major role in inducing inflammation and neuronal death in neuronopathic Gaucher disease (132). Ripk3 deficiency (double knockout mice) dramatically improved the clinical course of Gaucher disease mice with increased survival and motor coordination. Therefore, Ripk3 is a new therapeutic target for neuronopathic Gaucher disease (132). Using the mouse model for the most severe form of neuronopathic Gaucher, it was shown that altered lysosomal localization and cytoskeleton disruption precede the neuroinflammatory pathways, axonal dystrophy, and neuronal loss previously characterized in neuronal forms of Gaucher disease (148).
Glucosylsphingosine has been implicated in toxic damage to neural cells. This molecule is a metabolic precursor in acid beta-glucocerebrosidase synthesis that has been shown to accumulate in the cerebral and cerebellar cortex of patients with type 2 and 3 Gaucher disease (92; 92; 93) and in Gaucher mice. Hannun and Bell have shown that lysosphingolipids, including glucosylsphingosine, inhibit protein kinase C, mitochondrial cytochrome c oxidase, and CTP:phosphocholine cytidylyltransferase, which has been postulated to interfere with signal transduction and cellular differentiation (56).
The level of glucosylsphingosine is not increased in patients with type 1 Gaucher disease; however, the level is markedly increased in patients with type 3 (36-fold on average) and type 2 disease (225-fold). The highest levels of this metabolite were found in brain tissue from 2 fetuses with hydrops fetalis (98). However, glucosylsphingosine levels in the brain are too low and do not significantly increase above baseline in the mouse model of Gaucher disease type 2, and therefore glucosylsphingosine is unlikely to participate in the pathogenesis of neuronopathic Gaucher disease (101; 43).
Biochemical abnormalities. Levels of acid phosphatase, angiotensin-converting enzyme, lysosomal hydrolases, lysozyme, and immunoglobulins are elevated in the plasma of Gaucher disease patients (127; 95; 80; 136; 117; 89; 63; 107). Chitotriosidase is a particularly sensitive indicator of macrophage storage in patients with Gaucher disease (61). Because of liver involvement, patients may have prolonged partial thromboplastin, prothrombin, and bleeding times. In addition, it has been suggested that increased amounts of plasma glucocerebroside may interfere with the clotting cascade (18). Acid beta-glucocerebrosidase is elevated in the plasma and may be as high as 10 times normal. Although the level of plasma glucocerebroside has been shown to increase following splenectomy in some Norrbottnian cases, this has not been reported in cases of other subtypes of the disease.
Biochemical abnormalities in neuronopathic Gaucher disease. Patients with Gaucher type 2 and type 3 have the same abnormalities in blood as described above. In an effort to identify biomarkers specific for the neurologic involvement in Gaucher disease, glycoprotein nonmetastatic B (GPNMB) was identified (147). There was a correlation between the severity of neurologic symptoms and GPNMB levels. The same was found in a mouse model of Gaucher disease. These data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy in future treatment trials (147).
The hematologic and skeletal manifestations of Gaucher disease are due to macrophage disorder whereas brain abnormalities are mainly caused by involvement of neurons and astrocytes.
Storage substance. Glucocerebroside is a compound of ceramide and glucose. The glucose moiety is esterified to the C-1 of ceramide in a beta-glucosidic linkage. The compound is similar in structure and properties to the group of sugar-containing lipids isolated from the brain by Thudichum (126).
Cerebrosides are composed of ceramide esterified to a variety of different substituents at C-1. This carbon may participate in reactions with phosphorylcholine to produce the sphingomyelins, an unsubstituted monosaccharide or oligosaccharide to produce the neutral glycosphingolipids, or an oligosaccharide containing 1 molecule to 4 molecules of sialic acid to produce the gangliosides. The common unit among these compounds is ceramide. Ceramide is derived from a long-chain base named sphingosine (D(+)-erythro-1,3-dihydroxy-2-amino-4-transoctadecene, or C18 sphingosine). This lipid is joined by an amide bond at C-2 to a long-chain fatty acid to form ceramide. The fatty acid chain length varies. In general, the neutral glycosphingolipids and sphingomyelins contain C20 and C24 fatty acids, whereas the gangliosides contain C18 fatty acids. It is from sphingosine that the group of disorders of lipid catabolism obtains its name (ie, sphingolipidoses) because the accumulating lipid compounds are derived from it.
Glucocerebroside is at the end of the glycosphingolipid catabolic pathway. The higher glycosphingolipids and gangliosides are degraded in a stepwise fashion by specific acid hydrolases, resulting in the formation of glucocerebroside, which is normally degraded to ceramide and glucose by acid beta-glucocerebrosidase. The compounds that contribute to the pool of glucocerebroside in peripheral organs are globoside, globotriose, and lactosylceramide. These are derived from the degradation of membranes, the major source of which is white blood cells (70).
It is important to note that the glucocerebroside found in spleen, liver, kidney, plasma, and red cells contains fatty acids with chain length of approximately C22 to C24 (45). The glucocerebroside in the brains of patients with type 2 disease is composed primarily of C18 (stearic acid) (121; 93). This conclusion has been confirmed and extended to type 3 cases (92; 29). These data have been interpreted to mean that the glucocerebroside accumulating in brain derives from gangliosides within the brain itself. This is consistent with the known fatty acid content of gangliosides. The suggestion has been made that some of the glucocerebroside, in certain type 3 cases, may be derived from sources outside the central nervous system. If the data are confirmed, they should have important consequences, especially because it has been suggested that levels of plasma and tissue glucocerebroside increase following splenectomy in Norrbottnian cases (93).
Studies on the pathogenesis of neuropathic Gaucher disease suggest that defective calcium homeostasis is a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease (101). Agonist-induced calcium release via the ryanodine receptor was significantly enhanced in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) compared to the subacute (type 3) and the non-neuronopathic (type 1) forms and controls and correlated with levels of GlcCer accumulation (101). The precise mechanism by which glucocerebroside enhances calcium release via the ryanodine receptor is not known, but these findings suggest the use of certain calcium channel blockers in neuronopathic Gaucher disease. Altered expression and distribution of cathepsins in the brain of the neuronopathic Gaucher mouse suggests that inflammation plays a role in the disease and, therefore, may be a target for therapeutic intervention (131). Elevation of GBA2, a non-lysosomal glucocerebrosidase, may play a role in the disease (23).
The wide spectrum of clinical severity in patients with Gaucher disease, but in particular in Gaucher type 3 patients, is often explained by the presence of genetic modifiers. An interesting effort used animal models to identify such genes (73). The authors identify a number of variants that modify the lifespan of the affected mouse. The most interesting was Grin2b, which codes for NR2B subunit of the N-methyl-D-aspartate receptor. Pharmacological blocking of the N-methyl-D-aspartate receptor using memantine led to a significant prolongation of the Gaucher mouse model (73). Effort to identify genetic modifiers in Gaucher type 3 patients is underway.
Acid beta-glucocerebrosidase. In addition to the 5' and 3' untranslated regions, the cDNA of the GBA gene contains 1548 base pairs encoding human acid beta-glucocerebrosidase. The molecular weight of 59,716, calculated from the 536 amino acids deduced from cDNA sequence, is in good agreement with that estimated by SDS-polyacrylamide of the product of in vitro translation of human placental mRNA (42; 41). Five potential glycosylation sites (Asp-X-Ser/Thr) were identified. Quantitative carbohydrate analysis indicates that only 4 are glycosylated (124). This has been confirmed by direct analysis of the amino acid sequence (B Martin, unpublished data). In addition to the amino acid sequence of the structural protein, the reading frame of the cDNA codes for 39 additional amino acids upstream of the amino terminus. This signal polypeptide contains a hydrophobic core, consisting of Gly-Leu-Leu-Leu-Leu and, in addition, has glycine at the peptidase cleavage site. These features are consistent with the properties of signal peptides of other translocated proteins. Furthermore, the cDNA sequence confirms the presence of a 2-kd signal sequence identified by pulse-labeling studies. Based on The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff, there are 332 mutations of the GBA gene described as a cause of Gaucher disease--including 253 missense or nonsense mutations as well as splice mutations, deletions, and complex gene rearrangements.
All types of Gaucher disease are inherited as an autosomal recessive trait. The collective subtypes of Gaucher disease constitute 1 of the most prevalent forms of the sphingolipidoses and the most common lysosomal storage disorder. Gaucher disease type 1, the non-neuronopathic form, occurs with an incidence of about 1 in 40,000 to 60,000 in the general population and 1 in 500 to 1000 among Ashkenazi Jews. Patients with Gaucher type 3 disease (chronic neuronopathic Gaucher disease) constitute about 5% of the population of Gaucher patients in the United States and in Europe, with an estimated incidence of about 1 out of 100,000. However, reports suggest the neuronopathic form of Gaucher disease predominates in countries like China, Japan, Korea, Taiwan, Egypt, and Syria (134; 28; 123; 67; 36; 04; 55). The reason is that the N370S mutation is common in European countries but almost absent in Northern Africa and Asia, whereas the L444P mutation is particularly common in the East (134; 28; 123; 67; 36; 04; 55).
Although it is more frequent among Eastern European Jews, Gaucher disease type 1 is usually less severe in this group. It is more severe among blacks. This generalization is helpful in counseling, but there are exceptions. Therefore, it is important to know the types of complications of the disease that have occurred in a family. In general, the severity of the disorder tends to be similar among siblings. A single exceptional family has been reported in which one type 1 and one type 2 case occurred in full siblings.
Implications for genetic counseling. Testing and genetic counseling of immediate family members of affected patients are recommended. The differences in clinical subtypes and variability of some forms of the disease should be pointed out. Because of the high carrier frequency among the Ashkenazi, wide-scale carrier testing has been suggested. Because the disease among this group is not uniformly catastrophic (in fact, many cases do not come to medical attention until late in life), this kind of testing, if desired, should be done within a system providing careful counseling that includes adequate information about the disorder and an explanation of the limitations of carrier detection. More than 300 mutations have been described in the GBA1 gene, 4 account for the majority of the nucleotide alterations. In the Ashkenazi Jewish population, the p.Asn409Ser mutant allele accounts for about 75% of the abnormal genes (55). In this ethnic group, 4 alleles (p.Asn409Ser [formerly described as Asn370Ser], c.84insG [formerly described as 84GG], p.Leu483Pro [formerly described as Leu444Pro], and IVS2+1G> A) account for more than 95% of the chromosomes, thus, permitting population screening (11). In the general population, many "private" alleles or mutations confined to a single kindred are found. Testing for the 4 mutations listed above results in identification of fewer than 50% of the cases. Thus, except for the Eastern European Jewish group, population screening is not appropriate for this disease with currently available technology.
Prenatal diagnosis. Affected fetuses with any form of Gaucher disease can be diagnosed prenatally by enzymatic assay of cultured amniocytes or chorionic villi. This is particularly important in families in whom the neuronopathic subtypes have occurred. Because of the difficulty of the assay for carriers (32) and the lack of appropriate control data, prenatal carrier detection is unreliable by enzyme assay. However, molecular genetic methods permit this identification without difficulty in families where the mutations are known.
Painless splenomegaly is the most common initial presenting sign in Gaucher disease type 1. Lymphoproliferative malignancies are the chief concern in the diagnostic evaluation of patients presenting in this manner. The results of bone marrow biopsies may suggest the presence of Gaucher cells; however, the diagnosis should be made by enzymatic assay of acid beta-glucocerebrosidase in leukocytes or fibroblast cultures. If a patient is Jewish, Gaucher disease should be considered and an enzyme assay performed. Results can usually be obtained within several days. A disease virtually identical to Gaucher can rarely be caused by a deficiency in saposin c, the protein that activates glucocerebrosidase (129; 68). In this case, glucocerebrosidase activity is normal but the patient has clinical features resembling Gaucher disease. In infants with hepatosplenomegaly and a neurodegenerative course, Niemann-Pick disease type A and GM1 gangliosidosis are sometimes similar in presentation but usually can be distinguished by clinical presentation.
The diagnosis of Gaucher disease should be considered in any case of unexplained splenomegaly with or without a bleeding diathesis or other manifestations of the disease in the skeleton or liver. The disorder should be considered likely in any infant with hepatosplenomegaly and a neurodegenerative course. Elevation of tartrate-resistant acid phosphatase in serum is suggestive of the disease. Demonstration of characteristic Gaucher cells in bone marrow biopsies narrows the diagnostic possibilities. The definitive diagnosis is made by assay of acid beta-glucocerebrosidase in leukocytes, fibroblasts, chorionic villi, or urine.
After a diagnosis of Gaucher disease has been established, the burden of the disease should be assessed. Evaluation of the characteristic features of the disease should include hematological, visceral, skeletal, and quality of life parameters, as suggested by the Gaucher Disease Registry.
Hematologic workup. Hemoglobin, platelet count, tartrate resistant acid phosphatase, angiotensin converting enzyme, and chitotriosidase should be measured when the diagnosis is established; follow up measurement is recommended every 3 months for patients on enzyme replacement therapy and at least every 12 months for patients who choose not to receive enzyme replacement therapy.
Visceral studies. Spleen and liver volume should also be assessed at the time of diagnosis. The recommended technique is volumetric CT scan or MRI. These tests are recommended every 12 months in patients receiving enzyme replacement therapy and every 24 months in those patients who achieve a stable state.
Enzymatic diagnosis. A variety of natural and artificial substrates provide accurate assays for homozygotes, but they all have the same limitations when used for heterozygote detection (141; 32). The best substrate employed for the assay is the 4-methylumbelliferyl-beta-D-glucopyranoside. Modifications and improvements in the original description of the assay involving the addition of taurocholate have made it useful as a diagnostic tool and equivalent to assays employing the natural substrate. The assay is easy to use, and the substrate is widely available, making it the method of choice for a diagnostic laboratory. Conduritol B-epoxide is a specific inhibitor of mammalian acid beta-glucocerebrosidase and permits confirmation of the enzyme deficiency in systems where nonspecific beta-glucosidase may be interfering. Leukocytes and fibroblasts may be prepared and shipped to laboratories for assay as whole cells or extracts. High throughput method for newborn screening has been developed (96).
From the time of the introduction of the assay of acid beta-glucocerebrosidase, it has been observed that the values of heterozygotes overlap those of control subjects for the activity of acid beta-glucocerebrosidase in leukocytes and leukocyte subpopulations. This subject has been reviewed extensively. A variety of methods have been developed, but all have the same problem in the detection of heterozygotes. In studies of known heterozygotes, approximately 20% of the carriers fall into the normal range. Fibroblasts have a higher specific activity of acid beta-glucocerebrosidase than leukocytes; however, a wide range of activity in control cells, which varies with time in culture and conditions, makes these cells no more useful in heterozygote detection. In those for whom the genotype is known, carrier detection by molecular methods is completely reliable.
Skeletal assessment. Computerized tomography, radionuclide scan, and magnetic resonance imaging have been useful in assessing the extent of bone abnormalities. The recommended method for routine assessment of bone disease is T1- and T2-weighted MRI of the entire femora (25).
Bone density should also be assessed in patients with Gaucher disease. DEXA studies are useful to determine and assess the risk of pathological fractures. Spine, femur, forearm, and whole body densitometries can be performed in these patients. These studies should be performed at baseline and every 12 months in patients receiving enzyme replacement therapy.
The special case Gaucher disease type 2. This severe form of Gaucher disease poses sometimes significant diagnostic, management and ethical challenges. These are well addressed by 1 review (140).
Cell and organ transplantation. Splenic and renal transplantations have had little or no effect on the disease process in patients with Gaucher disease. Bone marrow transplantation has been reported in both Gaucher disease type 1 and type 3 patients. Rapid resolution of the enzyme deficiency in circulating white cells was achieved, indicating successful engraftment.
The indications for hematopoietic cell transplantation vary according to the subtype of Gaucher disease. In type 1 disease, allogeneic bone marrow transplantation leads to resolution of organomegaly within several months to 2 years. The bone disease is also ameliorated, with disappearance of Gaucher cells from the marrow, regression of bone lesions, improvement in linear growth, and disappearance of bone pain (122; 105; 59). Bone marrow transplantation may, therefore, be curative for type 1 disease, even though this therapeutic option is limited by donor availability and high short-term risks, which include a high percentage of procedure associated morbidity and mortality of about 15%. In type 2 and 3 disease, bone marrow transplantation has no effect on the neurologic disease and should be avoided (130).
Enzyme replacement. The final development of enzyme replacement therapy was a fortunate intersection of scientific disciplines that provided key findings:
• Discovery of receptors for glycoproteins (lectins) (08)
The mannose moieties in the oligosaccharides are the key to successful enzyme replacement therapy. Mannose, rather than mannose-6-phosphate, binds to the mannose receptor on Kupffer cells. There are also mannose receptors on hepatocytes, although some of these are non-endocytic. Acid beta-glucocerebrosidase can, therefore, gain entry into both hepatocytes and Kupffer cells, but the delivery to Kupffer cells is much better for mannose-terminated (modified) acid beta-glucocerebrosidase.
Early studies of enzyme replacement produced great hope and excitement that Gaucher disease might be amenable to therapy by infusions of enzyme (20). The initial encouraging biochemical and clinical reports could not be confirmed. Even though amounts of enzyme in subsequent trials were increased significantly, no changes could be measured in response to enzyme. These trials were unsuccessful because they failed to target the enzyme to the proper cell in sufficient quantity.
A method was devised to improve that aspect of the problem (48). Using enzymatic degradation of the oligosaccharide side chains of acid beta-glucocerebrosidase to expose mannose residues, the enzyme molecule was tailored to bind to the naturally occurring mannose receptors on macrophage plasma membranes. In animal model studies, this engineered acid beta-glucocerebrosidase was delivered to reticuloendothelial cells in quantities 10 times greater than the unmodified native enzyme (48). The function of the oligosaccharide side chains is not fully understood, but they are probably important in maintaining the tertiary structure of the protein during its synthesis and translocation to the lysosome. If addition of the sugar side chains is prevented completely, the protein is not properly folded and has no enzyme activity.
A clinical study in one patient demonstrated that this mannose-terminated acid beta-glucocerebrosidase was therapeutic (10). A formal clinical trial confirmed these results (13; 12). The commercial preparation is now widely used in patients and successfully reverses the visceral, hematologic, and skeletal manifestations of the disease.
After several clinical trials of placental derived acid beta-glucocerebrosidase (alglucerase) for the treatment of Gaucher disease, alglucerase was approved in 1991 (12). Production of the same protein using recombinant DNA technology was achieved, and the resultant drug, imiglucerase, received regulatory approval in 1994.
A review of the hepatic, splenic, and hematologic outcome from 175 patients was reported by Weinreb and colleagues (139). The authors concluded that the following 4 responses could be expected after 12 to 24 months of enzyme replacement therapy:
(1) Patients with hepatomegaly will have approximately a 20% decrease in hepatic volume.
The skeletal complications of Gaucher disease respond well within the same time frame as the other signs and symptoms of the disease. Bone pain is relieved, and the incidence of bone infarct is reduced dramatically to near zero in patients treated with 60 U/kg of recombinant human acid beta-glucocerebrosidase every 2 weeks prior to the development of a significant structural abnormality. The radiographic assessment of the skeletal complications, however, remains inadequate as a tool to measure the baseline and improvements in the bone in response to therapy.
Enzyme replacement has the same salutary effect on patients with type 3 Gaucher disease as it has in type 1 patients (111; 06). Treatment is indicated in these patients at a dose of 60 IU/kg of body weight every 2 weeks and should be closely monitored clinically and with laboratory studies to establish the response to the therapy (130). When initiated early in the course of the disease, enzyme replacement normalizes growth, corrects the hematologic abnormalities, and prevents the skeletal complications that occur in patients with type 3 Gaucher disease. There is no doubt that this therapy has markedly ameliorated the course of the disease in this group of patients who used to die in their teens prior to the advent of enzyme replacement. However, in type 2 disease, enzyme replacement therapy may lengthen the course of the illness, but the neurologic deterioration progresses, and the poor prognosis of the disease is unaltered; therefore, enzyme replacement therapy should not be initiated in this group (104).
The adverse effects of enzyme replacement therapy are few and rarely a reason for discontinuing the therapy (90). Antibodies to enzyme replacement therapy have been reported in approximately 15% of patients. The incidence of serious complications is very low.
Effects of enzyme therapy cessation and withdrawal have been evaluated in patients who completely discontinued their therapies. These studies suggest that a complete cessation of therapy will inevitably endanger the patient by deteriorating hematological, biochemical, and skeletal parameters (133; 137). However, successful experiences of enzyme withdrawal for short periods of time have been reported (112).
Early initiation of enzyme replacement therapy is very important in children because it allows prevention of serious, irreversible skeletal complications in children. Children show an important increase in bone mineral density and growth rates (69; 07).
Mouse models of Gaucher disease. The transgenic acid beta-glucocerebrosidase-deficient mouse model obtained by targeted knockout of the acid beta-glucocerebrosidase gene exhibits a severe phenotype with prenatal or perinatal death (128). A number of other mouse models were of limited use and did not represent a genuine model for the neuronopathic form of the disease (144). Two true models of the acute neuronopathic form of Gaucher disease were produced. One of the models had normal enzyme activity in hematopoietic cells but no enzyme activity in neuronal and astrocytic cells. There was no significant mitigation of the neuronal disease in this model, confirming the observation in patients that bone marrow transplantation is not effective in neuronopathic Gaucher disease (39).
Other therapeutic approaches. The success of enzyme replacement therapy has probably led to a diminished motivation to develop a gene therapy approach for the nonneurologic aspects of Gaucher disease. Because there is an unmet need to reverse or prevent the primary neurologic complications of Gaucher disease, research is ongoing to develop approaches that will enable delivery of acid beta-glucocerebrosidase or the normal copy of the GBA1 gene across the blood-brain barrier and into brain cells (119).
Substrate deprivation. N-butyldeoxynojirimycin (OGT-918), an inhibitor of the glucocerebroside synthase, initiates the glycosphingolipid pathway and catalyzes the formation of glucocerebroside (31). The rationale of this therapy is to decrease the formation of glucocerebroside to rates at which the residual acid beta-glucocerebrosidase activity of the patients would be sufficient to catabolize the substrate. Most patients experienced diarrhea, the most frequent side-effect, and 2 patients withdrew from the study because of this complaint. Some patients developed peripheral neuropathy. These results do not compare favorably to those obtained with enzyme replacement therapy, which normalizes or greatly impacts the clinical parameters with negligible side-effects (09; 88).
In a randomized controlled trial, miglustat was found not to be effective for the treatment of type 3 Gaucher disease (110).
A much more specific inhibitor of ceramide glycosyltransferase, the ceramide analogue eliglustat, has shown marked efficacy that is similar to enzyme replacement therapy at the 60 IU/kg/2 weeks dose (Kamath et al 2014; 30). It does not have the side effect of miglustat but its metabolism is susceptible to the genotype of cytochrome P450 CYP2D6. Eliglustat was approved by the FDA in 2014 (103). Eliglustat tartrate is a P-glycoprotein substrate, possibly accounting for its poor distribution into the brain (113). Newer compounds with similar function but with good brain penetration are being developed and are being tested in human patients (84). Venglustat is currently being tested in adults with Gaucher disease type 3 (ClinicalTrials.gov Identifier: NCT02843035).
Pharmacological chaperones. A proposed approach for the treatment of Gaucher disease and other lysosomal storage diseases relies on the administration of active site competitive inhibitors that promote the correct folding and trafficking of the mutant protein (and even wild-type molecules). This process leads to increased level of the mutant enzyme that can then function during drug washout period (145; 135). The only pharmacological chaperone that is currently being clinically tested is ambroxol in high dose (81; 72). It shows some promise in myoclonic forms of Gaucher disease type 3 (72). However, no controlled studies have been performed to confirm the clinical benefit of ambroxol.
Gaucher disease type 2. None of the specific therapeutic approaches described above have been shown to be efficacious in patients with the most severe form of Gaucher disease. The overall management of patients with Gaucher disease type 2 is very difficult and has been reviewed (140).
Gene therapy. Gene therapy using an adeno-associated virus vector injected intrathecally is in the advanced planning stages.
Patients with Gaucher disease can become pregnant and deliver normal healthy infants. Precautions should be taken for women who are anemic or thrombocytopenic during the pregnancy. Excessive bleeding is a frequent complication following delivery. The teratogenic potential of acid beta-glucocerebrosidase has not been evaluated, and patients contemplating pregnancy should be advised of this fact. Prudence suggests that pregnant women should not be treated with enzyme replacement during the first trimester. However, pregnant patients who were treated with at least 2 forms of enzyme replacement have delivered normal babies (37; 38).
Patients with anemia, thrombocytopenia, or pulmonary involvement are at an increased risk for complications related to anesthesia and surgery. A particularly instructive case is a patient who was not diagnosed prior to cardiac surgery (87).
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
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