Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases

The glycolipid storage diseases are hereditary disorders in which one or more tissues become engorged with specific lipids, because of deficiencies of the lysosomal enzymes required for hydrolysis of one of the glycosidic bonds. Figure 72–1 shows the catabolic pathway of glycosphingolipids and lists the diseases that are involved in impaired degradation because of specific enzyme deficiencies. The type of lipid and its tissue distribution have a characteristic pattern in each disorder. This chapter deals mainly with Gaucher disease, in which glucocerebroside is stored. It is a common lysosomal storage disorder and also the one with the most hematologic features. The second storage disorder with some hematologic features is Niemann-Pick disease, in which the accumulated material is sphingomyelin and/or cholesterol. The remaining lysosomal diseases (Fabry disease, Wolman/cholesteryl ester storage disease, and GM₁- and GM₂-gangliosidoses), in which there is hepatosplenomegaly but few hematologic abnormalities, are not reviewed in this chapter.

HISTORY AND DEFINITION

Gaucher disease was first described by P.C.E. Gaucher in 1882, who thought that the large splenic cells of a young woman seen postmortem were evidence of a primary neoplasm.¹ The term Gaucher disease appeared first in 1905, when the autosomal recessive genetic nature of the disorder was elucidated.² In 1934, it was shown that glucocerebroside is the storage material in Gaucher disease,³ and in 1965, the primary defect was recognized as a deficiency of glucocerebrosidase resulting in an impairment of degradation of glucocerebroside.^4,5 Enzymatic purification ultimately led to the cloning of the gene in 1985,^6,7 unraveling of its structure, and identification of many glucocerebrosidase mutations.⁸ Disease-specific enzyme replacement therapy (ERT) was first introduced in 1991.⁹

EPIDEMIOLOGY

Gaucher disease is inherited as an autosomal recessive disorder. Although panethnic, type 1 is most common among the Ashkenazi Jews, with a carriership prevalence of 1 in 17 and an expected frequency of the disease in 1 in 850 livebirths.¹⁰ Two distinct forms of Gaucher disease, type 3b and type 3c, are also relatively common in Norrbottnia in northern Sweden,¹¹ and near the Palestinian town of Jenin, respectively.¹² In the general population, the estimated frequency (based on large-scale neonatal screening projects in three countries is in the range of 1 in 50,000 to 1 in 100,000 persons.¹³

The high prevalence of at least two Gaucher mutation, N370S and 84GG (and possibly R496H¹⁴ and others), among Ashkenazi Jews, and the existence of other lysosomal diseases within this ethnic group, may reflect, in addition to a founder effect, a selective advantage. However, a selective advantage because of greater resistance to tuberculosis¹⁵ or superior intelligence¹⁶ has not been proven. Animal studies suggest that the selective advantage may be the higher circulating serum levels of glucocerebroside that have antiinflammatory and beneficial immunomodulary effects.¹⁷

ETIOLOGY AND PATHOGENESIS

Enzymatic Basis

During normal growth, development, and senescence, parts of or whole cells are continually replaced. Breakdown of complex constituents of cells requires sequential enzymatic degradation. Such degradation occurs largely in secondary lysosomes, organelles formed by the fusion of primary lysosomes with phagocytic vacuoles containing ingested material.

Gaucher disease is the result of a hereditary deficiency in the activity of a lysosomal enzyme, glucocerebrosidase, required for glycolipid degradation. The reduced activity of glucocerebrosidase results in accumulation of glucocerebroside in macrophages engorgement with glucocerebroside induces increased cell size and cytoplasmic striations, leading to the formation of “Gaucher cells” (see Fig. 72–1). Inherent in subsequent lysosomal dysfunction is a dysregulation of metabolites and the consequent lack of coordination of cellular metabolism. These changes may explain the elaboration of various cytokines and other biomarkers because of engorgement of macrophages.

Accumulating evidence indicates that in addition to the glucocerebrosidase enzyme (GBA1), a second, nonlysosomal glucocerebrosidase, GBA2, a cytosolic protein that tightly associates with cellular membranes, may be integral to the pathogenesis of Gaucher disease, affecting its phenotype by potentially interacting with GBA1.^18,19,20

In rare instances, severe forms of Gaucher disease are associated with deficiency of saposin C, a heat-stable glucocerebrosidase co-factor.^21,22

GENETIC BASIS OF GAUCHER DISEASE

The glucocerebrosidase gene is located on chromosome 1q21. A pseudogene, with 96 percent sequence homology, has been identified approximately 16 kb downstream from the functional gene. Nearly 300 point mutations causing Gaucher disease have been described^8,23; most are point mutations, missense, nonsense, frameshift, and splice-site mutations, but there are also insertions, deletions, and recombinant alleles. Some mutations result from recombinant events between the functional gene and its pseudogene.⁸ Since 2000, approximately 20 of these mutated enzymes have undergone crystallography showing the divergence of ligands in the active site and with various degrees of glycosylation.²³

Among Ashkenazi Jews, the predominant mutation is N370S which accounts for approximately 75 percent of mutant alleles among Jewish patients and approximately 30 percent of the alleles among non-Jewish patients. Homozygosity for N370S is characterized by relatively milder phenotypes (although the phenotype is very heterogenous and severe cases are seen²⁴). N370S has heretofore been considered “protective” against the development of neuronopathic features. The second common mutation found almost exclusively among Ashkenazi Jews is one that usually causes a severe phenotype. Five or six common mutations account for approximately 97 percent of alleles among Jews, but account for less than 75 percent of alleles among non-Jews.^8,25,26,27 Although controversial, premarital/prenatal screening for common mutations has become frequent among Ashkenazi Jews.^28,29,

The second most common mutation is L444P, which when homozygous accounts for most patients with the neuronopathic type 3 disease, and is the most prevalent mutation in Asians, Arabs, and Norrbottnians. Patients with the unique variant of progressive calcifications of cardiac valves, type 3c, are uniformly homozygous for a point mutation D409H.¹²

Despite some relationship between specific mutations and the clinical course, genotype–phenotype correlation is imperfect. Elucidation of the three-dimensional structure of the glucocerebrosidase by crystallography has also not improved prediction of disease severity based on the location of mutations in the native protein.³⁰

The majority of the mutations cause glucocerebrosidase misfolding, which may lead to early degradation of the enzyme in the endoplasmic reticulum.^31,32 The investigation of the proteotoxic effect of the misfolded mutant enzyme in the endoplasmic reticulum has led to the development of the new therapeutic modality of pharmacologic chaperones (PCs). PCs are targeted to stabilize the mutated glucocerebrosidase and allow its appropriate trafficking from endoplasmic reticulum to Golgi and, finally, to the lysosome.

CLINICAL FEATURES

Three major types of Gaucher disease are differentiated clinically based on absence (type 1) or presence of neurologic features (types 2 and 3).³³ Table 72–1 summarizes key clinical, genetic, and demographic features. Although it has been suggested that there is a phenotypic continuum,^34,35 it is still useful to think of Gaucher disease as three distinct forms to facilitate genetic counseling and management decisions.

There is variability in disease severity of all types of Gaucher disease. Type 1 disease may be asymptomatic and be discovered in the course of population surveys of Ashkenazi Jews,²⁸ or incidentally during evaluation of an unrelated hematologic disorder.

Fatigue

Fatigue is a common complaint, usually not invariably related to anemia, but also quite common in nonanemic patients and may be a result of elevated inflammatory cytokines.³⁶

Organomegaly

In symptomatic patients, the spleen is typically enlarged,³⁷ whether barely palpable or massively enlarged causing positional symptoms, such as early satiety or abdominal discomfort. Splenic infarction and subcapsular hematoma are uncommon. Hepatomegaly is usually asymptomatic, but it may cause abdominal discomfort and in splenectomized patients or others with very severe disease, liver fibrosis and later cirrhosis,³⁸ with or without portal hypertension, may occur; hepatocellular carcinoma may evolve.³⁹ An increased incidence of nonalcoholic fatty liver disease has been observed.⁴⁰

Lymphadenopathy

Lymphadenopathy has been described,⁴¹ including a severe protein-losing form,⁴² which is a clinical management problem.

Hemorrhagic Events

Epistaxis, easy bruising, and hemorrhage after surgical or dental procedures and bleeding during labor are common presenting symptoms. These manifestations usually are related to thrombocytopenia as the result of hypersplenism or marrow replacement by Gaucher cells, but platelet dysfunction and decreased levels of coagulation factors have also been described and hence should be assessed prior to surgical procedure or before delivery.^43,44,45 Coagulation factor deficiencies may result from liver disease or consumption coagulopathy.

Anemia

Reduced hemoglobin levels are also primarily a result of hypersplenism and marrow replacement by Gaucher cells, but additional causes include iron deficiency, vitamin B₁₂ deficiency, and autoimmune hemolysis.^46,47

Gaucheromas

“Gaucheromas” (Fig. 72–2), which are possibly extraosseous in origin⁴⁸ and/or may mimic a malignant process,^49,50 appear idiosyncratically, but possibly after some invasive procedure such as hip surgery; these have been described to be at increased risk of hemorrhaging when manipulated.

Pulmonary Disease

Severe pulmonary disease with cyanosis and clubbing occurs in some patients with advanced liver involvement, and is usually a consequence of hepatopulmonary syndrome with or without infiltration of the lungs by Gaucher cells.^51,52 Mild pulmonary hypertension may be detected by echocardiography,⁵³ but may (rarely) be severe especially among splenectomized patients⁵⁴; it has not been reported in children.⁵⁵ Pulmonary function tests may reveal abnormalities, such as reduced diffusion capacity in approximately two-thirds of patients.⁵⁶

Bone Disease

Bone involvement is usually the main cause of morbidity in symptomatic patients and can occur in any long bone.⁵⁷ Patchy areas of bone demineralization and infarction are seen (Fig. 72–3A), and asymptomatic widening of the distal femur known as Erlenmeyer flask deformity is very common (Fig. 72–3B). Bone metabolism markers indicate that bone resorption predominates,⁵⁸ but the overall mechanisms underlying development of bone lesions are poorly understood. Children may have delayed bone age and delayed eruption of the teeth.⁵⁹ Bone pain is probably the most troublesome symptom of Gaucher disease. Bone pain may be related to the pathologic processes evident by radiography, magnetic resonance imaging (MRI), and computerized tomography, or have the character of a “crisis,” which is a self-limiting, albeit exquisitely painful event, associated with signs of acute local and/or systemic inflammation (Fig. 72–3D). Aseptic necrosis of large joints, mainly the femoral heads but also the shoulders and knees (and rarely even in smaller joints) and vertebral collapse are particularly common typically among untreated patients with genotypes resulting in more severe phenotypes (Fig. 72–3C and E).

Gynecologic Manifestations and Fertility

Gynecologic and obstetric problems are common and are mainly related to bleeding tendency,⁶⁰ which may explain why females are more likely to be diagnosed. Delayed menarche and menorrhagia are common, and increased risk of recurrent abortions has been reported.⁶¹ Fertility is unaffected in males and females.

Ophthalmologic Disorders

Organs other than the spleen, liver, bones, and lungs may be affected. Many patients have pinguecula and a few a pterygium at the corneoscleral limbus.⁶² Additional findings include uveitis and preretinal white spots in rare cases.⁶³

Kidney Disease

Renal manifestations are rare and limited to case reports of nephrotic syndrome and renal cell carcinoma.⁶⁴ Nonetheless, many patients seem to have benign urinary hyperfiltration.⁶⁵

Neurologic Findings

Neurologic symptoms constitute the hallmark of types 2 and 3 diseases.⁶⁶ Particularly notable and pathognomonic are oculomotor abnormalities, especially supranuclear gaze palsy (SNGP), which is typically noted horizontally,⁶⁷ but might occur in the vertical plane as well. Patients with type 2 disease develop hypertonia of the neck muscles with extreme arching of the neck (opisthotonus), bulbar signs, limb rigidity, seizures, and sometimes choreoathetoid movements. In these patients, the SNGP becomes a fixed convergent squint, often facilitating differentiating between type 2 patients, who are terminal by 2 to 3 years of age, and the severe type 3a patients, who may survive longer. Patients with type 3a disease exhibit progressive neurologic abnormalities such as myoclonus and dementia.⁶⁸ Patients with type 3b disease display aggressive visceral and skeletal involvement but neurologic manifestations are largely limited to horizontal SNGP.⁶⁸ Patients with type 3c disease exhibit SNGP, mild visceral involvement, and fatally progressive calcifications of mitral and tricuspid valves and of the large arteries.^12,68,69,70

Several neurologic abnormalities have been observed in patients with type 1 disease, including peripheral neuropathy^71,72 and an increased prevalence of Parkinson disease (the latter also among carriers of a single mutation).^{73,74,75,76,77} Carriers of severe mutations (e.g., null alleles) were reported to have a 13.6-fold increased risk of Parkinson disease compared to controls, whereas carriers of the more benign mutations have a 2.2-fold increased risk.⁷⁸ A meta-analysis of patients with Parkinson disease has confirmed this strong association between mutations in the glucocerebrosidase gene and Parkinson disease, which is marked by an earlier age of onset and higher prevalence of cognitive changes.^78,79

Predisposition to Infections

An increased tendency to infections is sometimes seen, occurring among splenectomized patients or severely affected patients, some of whom may have defective neutrophil chemotaxis.^80,81 Bacterial osteomyelitis is most often iatrogenic following surgical intervention at the site of a bone crisis. In children, linear growth retardation is common regardless of disease severity,⁸² but a compensatory “catch-up” growth may occur by early adulthood.⁸³

Predisposition to Neoplasia

There is a higher prevalence of neoplastic disorders in patients with Gaucher disease.^84,85 Myeloma has been established to be more prevalent.^84,85 Other hematologic malignancies,⁸⁶ hepatocellular carcinoma, and renal cell carcinoma, may also have increased prevalence.⁸⁷ Although elevated levels of interleukin-6 in patients with Gaucher disease may link Gaucher disease and myeloma,⁸⁸ there is no explanation at present for increased incidence of other types of cancer. Some malignancies may be less common.⁸⁷ The impact of ERT on either an increased or decreased development of malignancies has not been determined.

LABORATORY FEATURES

Blood Counts

The complete blood count in patients with Gaucher disease may be normal or may reflect the effects of hypersplenism. A normocytic, normochromic anemia is frequently present, but hemoglobin levels only rarely fall below 8 g/dL. A modest reticulocytosis is often present in anemic patients. The white cell count may be decreased to as low as 1.0 × 10⁹/L, but milder degrees of leukopenia are more common. The differential count is normal, but splenectomized patients tend to show a lymphocytosis. A defect of leukocyte chemotaxis which may be corrected by ERT,⁸⁹ and in some patients is associated with a tendency to bacterial infections⁸⁰; monocyte dysfunction has also been reported.⁸¹ Thrombocytopenia is typically more prominent than anemia.⁴⁶ In an anemic patient with an intact spleen and normal range platelet counts, there is probably an alternative reason for the low hemoglobin level, unrelated to Gaucher disease. Thrombocytopenia may be quite severe, even in an otherwise mildly affected patient. In splenectomized patients, anemia is more likely in the absence of thrombocytopenia; white cell count and platelet counts are usually higher than normal. Severe anisocytosis and poikilocytosis also occur in splenectomized patients, with many target cells, some nucleated red cells and Howell-Jolly bodies. During bone crises, leukocytosis, thrombocytosis, and elevated erythrocyte sedimentation are seen. Other markers of inflammation have been noted regardless of disease severity: elevated fibrinogen levels, elevated high-sensitivity C-reactive protein, and increased adhesion and aggregation of red blood cells.^90,91

Other Hematologic Findings

Clotting factor abnormalities may be induced by activated macrophages^41,42 or may be found when there is liver involvement. Factor IX deficiency may be a laboratory artifact related to the effect of accumulated lipid on platelet membranes.⁹² Factor XI deficiency is common among Ashkenazi Jewish patients because of its high coincidental prevalence in this ethnic group.⁹³

Bleeding tendency may also result from defective aggregation or adhesion of platelets³³ and therefore platelet function and/or thromboelastography should be tested before surgical and dental procedures and labor.^44,94

Biochemical and Immunologic Findings

In most patients, liver function tests are within normal limits but in conjunction with more severe disease, splenectomy, and/or comorbidities (hepatitic B and/or C, or autoimmune diseases) abnormal liver function tests may be seen. Because of the increased prevalence of cholelithiasis,^95,96 cholestatic findings may occur. Renal function tests are usually normal.⁶⁴

Many patients present with polyclonal gammopathies. Monoclonal gammopathies are found in 1 to 20 percent of patients, particularly older patients.^79,80,81,82 Increased levels of autoantibodies have been reported,⁹⁷ and may indicate coincide with autoimmune diseases such as Hashimoto thyroiditis, rheumatoid arthritis, or immune hemolytic anemia.

Biochemical abnormalities have been used as surrogate markers in Gaucher disease. In the past, increased activities of serum acid phosphatase, angiotensin-converting enzyme, serum ferritin, and other hydrolases, such as β-hexosaminidase or β-glucuronidase, were used. Other biomarkers correlate better with the extent of glucocerebroside storage. The most widely used biomarker is chitotriosidase,⁹⁸ which is undetectable in healthy subjects (its physiologic role is unknown), but is elevated, often several thousand-fold, in patients with Gaucher disease. Chitotriosidase measurement is useful for monitoring both untreated patients, to assess stability versus deterioration, and treated patients, to assess response to therapy. A change in chitotriosidase levels rather than absolute values is used for monitoring. In approximately 6 percent of people, it is undetectable, and for those patients, measurements of chemokine CCL18/PARC which is predominantly produced by Gaucher cells, can be used.⁹⁹

A potentially more sensitive and more specific biomarker has been identified: the lyso-glucosylsphingosine (lyso-Gb1),¹⁰⁰ which may be preferred as a more reproducible biomarker, using a more operator-friendly assay.

Serum iron levels may be low in patients because of iron deficiency related to bleeding or chronic inflammation. Deficiencies of vitamin B₁₂¹⁰¹ and vitamin D¹⁰² have been described, albeit these are also very common in the general population. Serum ferritin levels are usually elevated.

Gaucher Cells

Gaucher cells, found mainly in the marrow, spleen, and liver (Fig. 72–4), have small, usually eccentrically placed nuclei and cytoplasm with characteristic crinkles or striations. The cytoplasm is stained by the periodic acid-Schiff technique. Electron microscopy demonstrates cytoplasmic spindle- or rod-shaped, membrane-bound inclusion bodies 0.6 to 4 μm in diameter, consisting of numerous small tubules, 130 to 750 Å in diameter, that are composed of twisted multilayers in negatively stained preparations.¹⁰³

DIFFERENTIAL DIAGNOSIS

Diagnosis

The diagnosis of Gaucher disease should be considered in (1) any patient who presents with unexplained splenomegaly, thrombocytopenia, frequent nosebleeds, anemia, acute or chronic bone pain; (2) children with short stature for their age; and (3) nontraumatic avascular necrosis of a large joint at any age, especially if is associated with any of the above features.

A definitive diagnosis requires a reduced enzymatic activity of β-glucocerebrosidase in leukocytes,^104,105 cultured fibroblasts, or amniocytes obtained during prenatal diagnosis. Measurement of glucocerebrosidase levels is supplemented by mutational analysis. This is important for prognosis, particularly in children, and for detection of carriers among affected families. While rapid polymerase chain reaction-based tests are often performed for five or seven common mutations, especially among Ashkenazi Jews as a “first-pass,” it is highly recommended to perform whole-genome sequencing¹⁰⁶ to rigorously establish the molecular diagnosis.

Marrow aspiration as a means of diagnosis is only indicated when other hematologic diseases must be considered.^94,105 Gaucher cells are often sparse and thorough examination under low-power may be required to find them. Cells indistinguishable by light microscopy from typical Gaucher cells may also be seen in patients with other disorders such as chronic myelogenous leukemia, Hodgkin lymphoma, myeloma, and acquired immunodeficiency syndrome. The latter patients do not lack the ability to catabolize glucocerebroside, but the great inflow of globoside into phagocytic cells exceeds their capacity to hydrolyze glucocerebroside, forming “pseudo-Gaucher cells.”

Prenatal diagnosis can be established by examining cultured amniocytes obtained by amniocentesis for measurement of glucocerebrosidase activity¹⁰⁴ or by examining amniocytes or chorionic villi DNA for known mutations.

Heterozygote Detection

Heterozygotes for Gaucher disease have neither Gaucher cells in their marrow nor stigmata of Gaucher disease (other than the increased risk of Parkinson disease). Existence of a carrier state can be demonstrated by reduced glucocerebrosidase activity to approximately 50 percent of normal values. However, regardless of methodology, enzyme activity among heterozygotes overlaps the normal range and hence definitive diagnosis of heterozygous status only can be made by mutational analysis. Currently various methodologies are being developed to allow noninvasive prenatal diagnosis of monogenic diseases like Gaucher disease; the most promising of these is molecular analysis of cell-free fetal DNA.¹⁰⁷

THERAPY

Symptomatic Treatment

Symptoms and signs related to massive enlargement of the spleen (e.g., pancytopenia, early satiety, abdominal discomfort, and growth retardation in children) can be resolved by splenectomy. However, because of the efficacy of ERT, splenectomy should only be a last resort as it often induces progressive liver and bony complications, and increases the risk of infection with encapsulated organisms. Partial splenectomy has not proved useful, with both regrowth of the remnant and risk of osteonecrosis.

When bone lesions result in fractures or osteonecrosis (see Fig. 72–3D), orthopedic procedures may be required. Joint replacement is generally uneventful, with good functional outcome and quality of life. The success of arthroplasties is enhanced by adherence to preoperative protocols including assessment of bleeding tendency, prophylactic use of antibiotic therapy, particularly in splenectomized patients, and early post-operative ambulation.¹⁰⁸

Deficiencies of iron, vitamin B₁₂, or vitamin D should be corrected and calcium supplementation is recommended in patients with osteoporosis receiving bisphosphonates.¹⁰⁹ Use of erythropoietin may be required for management of anemia because of marrow failure.¹¹⁰

Enzyme Replacement Therapy

The use of alglucerase,⁹ the first mannose-terminated, placental-derived enzyme, was approved in 1991, and the recombinant form, imiglucerase, albeit with one amino acid R495H that differs from the wild-type protein owing to a cloning artifact in the original complementary DNA (cDNA), was introduced in 1994.¹¹¹ Two intravenous preparations, one with the perfect native-enzyme sequence developed in a human cell line, velaglucerase alfa,¹¹² and the other, a carrot root cell-derived with the imiglucerase core sequence, taliglucerase alfa,¹¹³ have completed phase 3 clinical trials and are available. Phase 2 clinical trials with taliglucerase alfa are currently underway in which the same carrot cells, expressing taliglucerase alfa, are used as vehicle for oral delivery of the enzyme.

The response to ERTs is most gratifying.^{9,111,112,113,114,115,116} Decreased spleen and liver volumes and increased hemoglobin levels and platelet counts usually occur within 6 months of therapy with biweekly doses between 15 and 60 U/kg. Platelet counts in patients with massively enlarged spleens may require longer periods to respond, but improvement continues within the first 2 years of therapy. Thereafter, patients treated with imiglucerase stabilize even while on the same dose.¹¹⁶

The bone response is slower and less predictable. Osteonecrosis and lytic lesions do not respond to ERT. Quantitative chemical shift imaging, a sensitive modality to show changes in the marrow, including response to ERT (Fig. 72–5),¹¹⁷ is a resource available in only one site worldwide and, hence, various other imaging modalities, especially MRI-based modalities, but also bone densitometry and plain radiographs, are used as needed to document skeletal status.

ERT may or may not improve pathologic pulmonary findings. Because the enzyme is a large molecule, it does not cross the blood–brain barrier, and hence, does not impact neuronopathic features.^118,119

All ERTs are safe, having few side effects that are usually transient.^112,113,120 Hypersensitivity reactions have been reported with each type of ERT, but only rare cases of anaphylaxis. Most patients with such reactions may continue ERT with or without premedication; it is advisable to avoid the administration of glucocorticoids for this purpose because of an increased risk of osteonecrosis. For each ERT there is a different percent of patients who may develop antibodies either shortly after initiation of treatment or over time.

Another side effect is weight gain with some concerns about changes in insulin resistance and the development of metabolic syndrome,¹²¹ including steatohepatitis. Because of the excellent safety profile, many patients receive therapy at home¹²² and many female patients are comfortable continuing with ERT during pregnancy and lactation.^123,124 The effects of treatment are unaffected by switching from imiglucerase to velaglucerase alfa¹²⁵ or taliglucerase alfa.¹²⁶

The two major disadvantages of ERTs are the apparent lifetime dependency on intravenous infusions and the extremely high cost. Guidelines and/or expert opinions usually recommend the use of relatively high doses.^127,128 Yet, it is evident that for most symptomatic patients, there is no justification for doses higher than 30 to 60 U/kg per month, and for patients with asymptomatic type 1 disease, ERT should not be encouraged.¹²⁹

Substrate Reduction Therapy

The possibility that decreasing the formation of glucocerebroside from ceramide and glucose, referred to as substrate reduction therapy (SRT),¹³⁰ might favorably impact disease parameters was proposed in the 1970s.¹³¹ Oral miglustat (N-butyldeoxynojirimycin),¹³⁰ a glucose analogue that inhibits glucocerebroside synthase, has been licensed for treatment of patients for whom ERT is not suitable or not a therapeutic option according to the two preeminent regulatory authorities’ definitions. This circumscribed approval stems from inferior efficacy of miglustat relative to ERT and a problematic safety profile including peripheral neuropathies, tremor, and memory impairment. Miglustat is effective in reducing hepatosplenomegaly in Gaucher disease when given as 100 mg, three times daily.¹³² Response to miglustat is dose-dependent; lower doses yield suboptimal improvement without reducing frequency of side effects.¹³³ Miglustat has also been studied as maintenance therapy in patients previously treated with imiglucerase.¹³³ A practical advantage was that it could be considered in type 3 patients because as a small molecule it crosses the blood–brain barrier and impacts neurologic signs. Unfortunately, a clinical trial failed to achieve the end points and, hence, there is no indication for this drug in neuronopathic Gaucher disease.

Another SRT, a ceramide analogue, eliglustat tartrate,¹³⁴ has been granted FDA approval. However, it has a more problematic safety profile compared to ERT (including cardiac events), the efficacy parameters.¹³⁵ The robust database derived from long-term followup from phase 2 and from three different phase 3 clinical trials¹³⁶ indicates it can be useful. However, unlike miglustat, it cannot cross the blood–brain barrier and should be targeted to type 1 patients only.

Pharmacologic Chaperones

A new approach to lysosomal storage diseases is “chaperone therapy.” PC therapy is based on in vitro experiments showing that some misfolded mutants of glucocerebrosidase are destroyed prior to their export from the endoplasmic reticulum to the lysosome.^137,138 Under these circumstances, a reversible inhibitor stabilizes the mutant enzyme, enabling its passage to the lysosome without losing activity. Clinical trials with the first PC for Gaucher disease, isofagomine tartrate which had been shown to increase mutant enzyme activity in cells, tissues,¹³⁹ and healthy volunteers during the phase 1 trial, failed in the phase 2 clinical trial when only 1 of 18 patients with type 1 showed a beneficial effect.¹⁴⁰

Another PC, ambroxol, an expectorant that is available without prescription in many countries and has decades-long safety experience, was administered in a pilot study to adult type 1 patients¹⁴¹; clinical trials in type 3 patients are planned.

Organ Transplantation

Because the macrophage is a derived from hematopoietic stem cells, allogeneic hematopoietic stem cell transplantation should cure Gaucher disease. Although some enthusiasm was expressed for this approach, the short-term risks of transplantation markedly limit the number of suitable candidates. Effective ERT further limits the appropriateness of transplantation. Liver transplantation has been performed in a few patients with severe hepatic failure.¹⁴²

COURSE AND PROGNOSIS

Age of onset, severity of clinical manifestations, and degree of progression are partially related to genotype. Patients homozygous for the N370S mutation tend to present with symptoms and signs at an older age with relatively milder manifestations, and usually have a relatively stable disease. By contrast, compound heterozygotes for N370S and a “severe” mutation (such as N370S/84GG or N370S/L444P) usually present with the disease during childhood, and if untreated, progress continuously with both visceral and skeletal complications.^108,143,144 Patients homozygous for the L444P mutation will develop neuronopathic disease with deteriorating neurologic signs and symptoms and their life span is reduced.⁶⁵

Although the genotype of the patient provides a benchmark for prognosis, there is much variability in patients with the same genotype, including between siblings with the same genotype. The availability of ERT has changed the natural course of the disease allowing normal growth and development in most patients, even in those with “severe” genotypes. Nevertheless, some patients still develop skeletal complications despite ERT and there is concern regarding development of associated diseases, such as myeloma, other malignancies, or Parkinson disease.¹²⁰

Prior to the availability of ERT, patients with severe type 1 or type 3, died at an early age because of liver disease, bleeding, or sepsis. With the advent of ERT, typical causes of death are malignancy, cardiovascular disease, and cerebrovascular disease.¹⁴⁵ In type 2 disease, death usually results from neurologic complications within the first 4 years of life⁶⁵; there is also a lethal neonatal variant. Total absence of glucocerebrosidase may not be compatible with life.

HISTORY AND CLASSIFICATION

In 1914, Niemann, a Berlin pediatrician, reported the case of an infant who died at age 18 months with a disorder that seemed atypical for Gaucher disease because of its early onset and rapid course.¹⁴⁶ In 1927, Pick identified this as a unique disorder of rapid, progressive neurodegeneration in infants.¹⁴⁷ The first adult patients identified had massive hepatosplenomegaly but no neurologic involvement. The predominant phospholipid accumulating in this disorder is sphingomyelin. In 1966, a deficiency of sphingomyelinase activity was demonstrated in a patient with Niemann-Pick disease.¹⁴⁸ Niemann-Pick is not a single entity; it comprises a group of disorders in which sphingomyelin storage occurs. Type A and type B disease, the classic forms of the disorder, represent an infantile neuronopathic and a later-onset nonneuronopathic form, respectively.¹⁴⁹ Type C, the most common form of Niemann-Pick disease, is a neuronopathic disorder, usually with an onset in early childhood, that results from an abnormality in cholesterol transport.¹⁵⁰ The sphingomyelinase gene is normal in type C disease, but mutations occur in one of two genes which have been designated NPC1 and NPC2; the proteins they code may function in closely related steps of cholesterol transport. The designation type D disease was once applied to a population isolate in Nova Scotia¹⁵¹ but because these individuals also have an NPC1 mutation, this term is no longer used.

EPIDEMIOLOGY

Niemann-Pick type A and type B diseases, also referred to as acid-sphingomyelinase deficiency, are panethnic disorders. There is a relatively high prevalence of type A disease among Ashkenazi Jews with a carrier rate of approximately 1 in 90.¹⁵² Three mutations account for 90 percent of Ashkenazi Jewish patients. Type B is common among individuals from the Maghreb region and the Arabian peninsula,¹⁵³ with three and two mutations accounting for 75 percent and 85 percent of Turkish and Arabic patients, respectively. Type C disease is relatively common in a Nova Scotia isolate,¹⁵¹ in a Hispanic population from the Upper Rio Grande Valley in the United States,¹⁵⁴ and in Western Europe.¹⁵⁵ The prevalence of Niemann-Pick type C disease in European populations is estimated to be 1 in 120,000 to 1 in 150,000 Europeans.¹⁵⁶

ETIOLOGY AND PATHOGENESIS

Type A and type B are autosomal recessive diseases caused by loss of function mutations in the gene for sphingomyelinase,¹⁵⁷ which is required for cleaving the bond between ceramide and phosphorylcholine (see Fig. 72–1). Nonsense mutations seem to cause the more severe type A disease, while missense mutations are found in the milder type B disorder.¹⁵⁷ Although sphingomyelinase is believed to be a part of an apoptosis-signaling pathway by generating ceramide from sphingomyelin,¹⁵⁸ no relationship between disease severity and this pathway has been established.

Type C disease also is an autosomal recessive disorder and is caused by mutations in either the NPC1^159,160 or NPC2¹⁶⁰ gene. The function of the proteins encoded by these genes is unknown, but was suggested to be related to intracellular cholesterol transport.^160,161 The NPC1 gene encodes for a multi-pass transmembrane protein that localizes to the late endosome. The NPC2 protein is soluble. The NPC1 mutations account for more than 95 percent of cases.¹⁶¹ There are only a few cases of NPC2 mutations manifested in neonates by severe liver and lung involvement, and progressive neurologic involvement leading to death by 4 years of age; there is a juvenile form in which there seems to be good genotype–phenotype correlation.¹⁶² NPC1 deficiency is associated with induction of autophagy by the class III-P13K (phosphatidylinositide 3′-kinase)/beclin-1 complex.¹⁶³ A naturally occurring murine model of the disease exists.¹⁶⁴

PATHOLOGY AND CLINICAL MANIFESTATIONS

The most characteristic histopathologic feature of the various forms of Niemann-Pick disease is the presence of foam histiocytes (Fig. 72–6), mainly in lymphoid tissues, but these may be present throughout the body. The foam cells contain largely sphingomyelin and cholesterol, the storage of cholesterol being more prominent in type C disease.

Type A disease presents in infancy. During the first months of life, affected infants gain weight at a diminished rate, the abdomen enlarges, and development is delayed. The patients usually cannot sit and lose physical capabilities already achieved and become blind and deaf. Some infants have a protracted course of jaundice of unknown cause. During the second year of life, the child lies still with nearly flaccid hyporeflexic extremities; there is massive hepatosplenomegaly, mild lymphadenopathy, and often a fine xanthomatous rash. Bone lesions may occur.

Type B disease usually presents in the first decade of life with hepatosplenomegaly, but may not be noted until adulthood. Neurologic manifestations are usually absent. Pulmonary infiltrates are common. The absence of a cherry-red spot in the macula and longer life expectancy differentiate type B from type A. Sea-blue histiocytes are sometimes found in the marrow, and a number of patients had been diagnosed as having sea-blue histiocytosis before a deficiency in sphingomyelinase was demonstrated.¹⁶⁵

Patients with type C disease often have neonatal jaundice, normal early childhood, and then develop hypotonia, dementia, ataxia, dysarthria, dystonia, seizures, gelastic cataplexy, and cognitive decline.¹⁶⁵ Hepatosplenomegaly is common.¹⁴⁹ Presentation may be at any age, even in the seventh decade,¹⁶⁵ but the “classic” description is of juvenile dystonic lipidosis with neonatal icterus and hepatosplenomegaly. In infants and toddlers, hepatosplenomegaly may be the only sign. In patients with a later-onset, there are variable presentations, but psychiatric signs and symptoms (disinhibition and deteriorating executive function) predominate.¹⁶⁵

LABORATORY FEATURES AND DIFFERENTIAL DIAGNOSIS

Hemoglobin values may be normal, or mild anemia may be present. Approximately 75 percent of lymphocytes contain one to nine vacuoles with a diameter of 2 μm. Electron microscopy reveals that these vacuoles are lipid-filled lysosomes.¹⁶⁶ The marrow contains typical foam cells whose diameter ranges between 20 and 100 μm. Small droplets are scattered throughout the cytoplasm (see Fig. 72–6). The cytoplasm of these cells stains only very faintly with the periodic acid-Schiff reagent. Phase microscopy of unstained preparations clearly reveals droplets in the cytoplasm of Niemann-Pick foam cells that distinguish them from Gaucher cells. Sea-blue histiocytes may be present in the spleen and marrow.^158,164

Type A and type B disease can be distinguished from other disorders by identification of the lipid as sphingomyelin and by demonstration of sphingomyelinase deficiency in leukocytes or cultured fibroblasts.^166,167 Patients with type A disease have acid sphingomyelinase activity levels less than 5 percent of normal in in vitro cultures of lymphoblasts or fibroblasts. In type B disease, acid sphingomyelinase activity levels range between 2 and 10 percent of normal levels. Monospecific antibodies against sphingomyelinase are used to differentiate between type A and type B disease.¹⁶⁸ Heterozygotes may be detected by measurement of sphingomyelinase activity of cultured fibroblasts.¹⁶⁹ For patients with type C disease, the presence of foam cells is the only indication of the disease.

Prenatal diagnosis of the three types of the disease is possible, but is difficult in type C.¹⁷⁰

TREATMENT

There is no effective treatment for types A and B disease, but there has been an announcement of a successful phase 1b trial with ERT for type B disease and plans for continuation into a phase 2 trial.¹⁷¹

Splenectomy is only rarely required, because death usually occurs from other manifestations of the disease before hypersplenism becomes clinically important. Liver transplantation in type A disease corrects hepatic pathology but has little long-term benefit¹⁷²; similarly, allogeneic hematopoietic stem cell transplantation does not ameliorate the neurologic deterioration in type B disease,¹⁷³ nor does it affect the course of type C disease.¹⁷⁴ Somatic cell gene therapy has been attempted in knockout type B mice¹⁷⁵ and was effective in ameliorating visceral signs but had no effect on neurologic signs.

SRT was attempted in a patient with type C disease.¹⁷⁶ Depletion of glycosphingolipids by miglustat¹³⁰ despite having no direct effect on cholesterol metabolism, corrected abnormal lipid trafficking¹⁷⁷ and indicated that glycosphingolipid accumulation is a primary pathogenetic event in type C disease.

A clinical trial using miglustat at a dose of 200 mg three times daily in an open-label 12-month trial with extension to 66 months in juvenile and adult patients with type C disease and in some children, resulted in improvement or stabilization.¹⁷⁷ Subsequent long-term exposure in adults, and some children¹⁷⁹ led to its commercial approval and use clinically in many countries. Miglustat improved neurologic manifestations such as ambulation, manipulation, speech, and swallowing; there are some gastrointestinal side effects.^177,178,179

COURSE AND PROGNOSIS

The prognosis in type A Niemann-Pick disease is dire; death nearly always occurs before the third year of life. Patients with type B disease may survive into childhood or longer and there is now hope for a disease-specific ERT. Patients with type C disease usually die in the second decade of life, but some patients with mild disease have a normal life span. New hope for patients with type C emanates from the potential for identification of disease-specific oxysterols as both biomarkers¹⁸⁰ of the disease and as harbingers of PC therapy for misfolded variants.¹⁸¹