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Lysosomal storage disorders are a group of diseases which occur due to accumulation of glucosylceramide/glucocerebroside and some related compounds within the lysosomes. Gaucher disease (GD) is the most common amongst the various disorders under this group. GD is a model for applications of molecular medicine to clinical delineation, diagnosis, and treatment. The prevalence of GD is approximately 1/75,000 births worldwide, but the disease is more prevalent in individuals of Ashkenazi Jewish descent in whom the incidence is 1/1000 births. There is a paucity of reported cases in the literature with reference to the Indian subcontinent possibly due to the rarity of this disease in this part of the world.
Here we present a young female who presented to our outpatient department with breathlessness, massive splenomegaly and congenital ear abnormalities. Further evaluation revealed anaemia, thrombocytopenia, and bone marrow infiltration with Gaucher cells and deficient enzyme activity. She was initiated on enzyme replacement therapy, and is awaiting response to it.
25 yr old lady with no known previous medical comorbidities presented to our OPD services with complaints of easy fatiguability, early satiety, dragging sensation and lump like feeling in the left upper abdomen. The symptoms were of about 1 yr duration with insidious onset and progressive course. A history of bleeding from the gums during brushing of teeth was present. There was no history of any other mucocutaneous bleed or petechial/ purpuric rashes. Examination revealed tachypnoea, tachycardia, normal blood pressure, raised JVP, bilateral pitting pedal edema, pallor, bleeding gums, sterna tenderness, microtia right ear, preauricular tags and sinuses in the left ear appendage. Abdomen was distended with a liver span of 20 cms and a massive splenomegaly measuring upto 19 cms below the left subcostal margin. There was a systolic flow murmur in the pulmonic area. Further evaluation revealed revealed anaemia, thrombocytopenia and raised LDH levels (Table 01). Sonological evidence revealed a hepatomegaly (20cms) with splenomegaly (29.5 cms). Bone marrow studies revealed sheets of histiocytes which stained positive with PAS (Fig 01). X Ray Skull revealed osteopenia (Fig 02), X ray pelvis revealed benign osteolytic lesion in the proximal left femur (Fig 03), X ray knee AP view showed the typical Ehrlenmeyer flask deformity (Fig 04).
Enzyme analysis done on peripheral leucocytes revealed deficiency of the enzyme β-glucosidase with values < 0.37 nmol/hr/mg (normal values > 4 mol/hr/mg).
She was started on management of complications and enzyme replacement therapy and is awaiting response.
Lysosomes are reservoir of enzymes responsible for the degradation of mucopolysaccharides, sphingolipids, and glycoproteins. Deficiency of specific enzymes activity leads to progressive accumulation of partially degraded material in the cell followed by disruption of cellular function.
GD was first described by Phillippe Gaucher in 1882, two decades prior to the dictum of 'Inborn errors of metabolism' given by Sir Archibald Garrod. Gaucher observed large cells in a splenic aspirate during the evaluation of a large spleen and he thought that it was evidence of a primary neoplasm of the spleen. In 1924, Epstein first recognized the storage of glucocerebroside while Brandy et al delineated that the metabolic defect was due to the deficiency of the enzyme β-glucosidase.
GD is inherited as an autosomal recessive disorder. The protein saposin C presents glucocerebroside to β-glucosidase (GBA) and directly activates the enzyme. Deficiency of saposin C, which is even rarer, results in a severe disorder similar to GD. The GBA gene is located on chromosome 1q21. More than 300 distinct mutations of the GBA gene have been described in which 80 percent are single nucleotide substitutions while rare or unknown alleles account for the remaining 20 percent.
GD with a worldwide incidence of 1/75,000 births with predilection in the Ashkenazi Jews. It is considered a rare entity in Asia and the Indian subcontinent only a few cases have been reported in the literature. A series of 07 cases from Malabar region in Kerala showing increased incidence in the tribal population of Mappila Muslims has been published. GD has three phenotypic variants depending on the age and presence of the neurological deficit (Table 02). However, the growing recognition of substantial populations with type 1 disease in Asia, South America, the Indian subcontinent, and other demographic areas has elucidated the range of phenotypes in this variant. Similarly, with the broader recognition of types 2 and 3, widespread variation and range of involvement from early onset has become increasingly evident.,
The main manifestation in the different visceral organs involved is the excess accumulation of the glucosylceramide in the macrophages. Type 1 is the most common, and occurs predominantly in the Ashkenazi Jewish population. Types 2 and 3 are less common. Type 2 is panethnic while type 3 is limited to the Norrbottnian population in Sweden.
Type 1(GD1): Adult onset (non neuronopathic type) GD1 is characterized by variability in signs, symptoms, severity, and progression even among siblings with the same genotype. The most common visceral involvement is a splenomegaly which may vary from moderate to massive in volume. Liver enlargement is seen with two - three times the normal volume. Hepatic fibrosis occurs commonly, but liver failure, cirrhosis, or portal hypertension is uncommon. The degree of anaemia and thrombocytopenia in patients with GD is often related to whether or not they have had splenectomy. In a study done among patients with an intact spleen, mean hemoglobin concentration was 11.2 gm/dL and the mean platelet count was 99,000/µL compared to patients who had undergone splenectomy, the mean haemoglobin concentration was 11.9 gm/dL; and mean platelet count was 242,000/µL. Skeletal disease is manifested as bone pains with painful crises in some, similar to the crises seen in sickle cell anemia (esp. if the diagnosis is before 10 yr of age). Osteolytic lesions, pathologic fractures, vertebral compression, and osteonecrosis (avascular necrosis) of the proximal and distal femur, proximal tibia, and proximal humerus also occur. The X ray of the lower end of femur shows the Ehrlenmeyer flask deformity.
Many affected children grow poorly and have delayed puberty. In a series, puberty was delayed in 60% of the 57 patients in whom a primary endocrine abnormality was excluded. Enzyme replacement therapy (ERT) started before puberty, improved growth and appeared to normalize the onset of puberty. Association have also been shown with Parkinsonism, particularly of the akinetic rigid type. The clinical course and life expectancy of GD1 is variable. Phenotypic expression cannot be reliably predicted by genotype, since severity may vary among siblings, even identical twins.
Type 2 (GD 2): Infantile cerebral GD (acute neuronopathic GD) is the rarest form, with an estimated incidence at 1 in 150,000. It is characterized by early onset, typically in infancy, and by a rapidly progressive neurologic deterioration. Visceral involvement is also extensive and severe. Oculomotor dysfunction, strabismus, saccade initiation abnormalities and bulbar palsy or paresis are common. Death occurs before the child reaches 02 yrs of age with a median age of 09 months. Histopathologic examination of brain at autopsy of patients with GD 2 shows neuronal loss, gliosis, periadventitial Gaucher cells, neuronophagia and free Gaucher cells. Variable involvement of the frontal cortex, thalamus, caudate, globus pallidus, pons, and cerebellum has been described.
Type 3 (GD 3): subacute or chronic neuronopathic form consists of three different subtypes. Type 3A or Norrbottnian Gaucher was first described in the Norrbottnian region of Northern Sweden, it is characterized by progressive dementia, ataxia, and myoclonus. Patients with type 3B have a pan-ethnic distribution and have extensive visceral and bone involvement with central nervous system involvement limited to supranuclear gaze palsy. Type 3C is rare and characterized by supranuclear gaze palsy, corneal opacity, and cardiovascular calcification, with little visceral disease. Neurologic involvement may begin late, with a variable progession.
The advent of DNA testing has improved the diagnostic accuracy for affected individuals, and also for the detection of the carriers. However detection of insufficient enzyme activity is the gold standard for the diagnosis of all variants of GD. DNA sequencing can identify sequence variants in the GBA gene; but enzyme diagnosis is still needed to show the association of new nucleotide variants with enzymatic deficiency.
Enzyme analysis is the basis of confirmation of the diagnosis of GD. The finding of reduced glucocerebrosidase activity in peripheral leukocytesconfirms the diagnosis. The enzyme activity varies in each white cell type, decreasing from monocytes to lymphocytes to granulocytes in that order. The diagnosis also can be made by measuring glucocerebrosidase activity in cultured skin fibroblasts, or other nucleated cells. The peripheral leukocyte assay requires an artificial substrate, 4-methylumbilliferyl-beta-glucoside and a residual enzymatic activity (10 to 15 percent of the control enzyme activity) is considered to be deficient. Patients with type 2 and 3 GD generally have much lower activity but cannot be reliably distinguished from each other. Activity in heterozygote carriers and normal individuals show overlap and hence, enzyme analysis cannot be used alone to distinguish carriers from noncarriers.
Mutation analysis is an effective method for patient classification and carrier diagnosis as it detects the common mutations. Sporadic and uncommon alleles occur more often in the non-Ashkenazi than in Ashkenazi ethnic groups. DNA sequencing of the entire GBA coding region is clinically available as a second-tier test when targeted mutation analysis fails to identify both mutant alleles in a patient with deficient glucocerebrosidase activity.
Identification of causal mutations provides an opportunity to develop genotype and phenotype correlations for prognostication. It is useful in two situations: first is correlation with GD1 where the N370S allele in affected individuals, even in combination with a different GBA mutant allele, is predictive of the disease. The second situation is correlation with neuronopathic GD, various alleles containing the L444P substitution are strongly, although not exclusively, associated with the development of neuronopathic disease. Many of these GBA alleles contain additional mutations and are termed complex alleles, with adverse clinical implications., The combination of two complex alleles, or a complex allele and the L444P allele, are strongly associated with type 2 disease. By comparison, L444P homozygosity is strongly associated with type 3 variants. The presence of complex alleles and findings of additional nucleotide mutations on the N370S alleles, full gene sequencing of GBA is now the standard for mutation analysis in GD.
Other tests like the demonstration of the Gaucher cells in the involved organs such as the bone marrow, liver and spleen is no longer considered essential for the diagnosis of this disorder. However in resource poor countries and evaluation for visceromegaly it may be the first clue derived from HPE of the involved organs.
Prenatal diagnosis can be performed by enzyme analysis of foetal cells obtained by chorionic villus sampling or amniocentesis. Knowledge of the DNA mutations in the proband or in the heterozygous parents would also allow DNA mutation analysis to be used together with enzyme analysis for prenatal diagnosis and is a recommended confirmatory assay.
The advent of the ERT in the early 1990's changed the outlook of management of a patient with GD. In addition to that, development of substrate reduction, pharmacological chaperone, and gene therapies has broadened the horizon for this rare disease. Enzyme replacement therapy (ERT) consists of infusions of mannose-terminated glucocerebrosidase which have helped in the regression of many visceral manifestations of the disease. Imiglucerase (Cerezyme) and velaglucerase alfa (VPRIV) are produced by recombinant DNA technology and are currently marketed for use in enzyme replacement therapy for GD. The usual starting dose is 30 - 60 U/kg administered intravenously over two hours every two weeks.
Indications for ERT developed by consensus of international experts, using data from the Gaucher registry are: 1) Symptomatic children (including those with malnutrition, growth retardation, impaired psychomotor development, and/or fatigue). 2) Patients with severe disease (i.e. platelet count <60,000/µL, liver >2.5 times normal size, spleen >15 times normal size, radiologic evidence of skeletal disease).
In a double centre study done in Amsterdam (Netherlands) and Dusseldorf (Germany) low-dose enzyme therapy was compared to high-dose. The high-dose group had a better response of the bone marrow burden scores and reductions in bone marrow and the biomarker chitotriosidase than did the low-dose group. Other studies have studied different doses (15, 30, and 60 U/kg / fortnight) and found incremental differences in responses to enzyme therapy. An initial response was more rapid in the higher-dose group (60 U/kg) than in the other groups, other markers of response such as the haemoglobin concentration, platelet count, and decrease in hepatic and splenic volumes were greater in the group given 60 U/kg at during follow up at 60 months.
Effect of enzyme therapy on the lung (pulmonary hypertension or interstitial or alveolar disease) has not been demonstrated. The CNS and lymph nodes also are inaccessible to intravenously administered enzyme that is mannose terminated. The commonest adverse effects of the ERT are immune hypersensitivity mediated. The shortcoming of the ERT is the high cost (US$100 000 to >$200 000 per year). The rarity of the disease has inhibited large-scale randomised trial for the optimum dose and, therefore controversies have developed about the appropriate dose and dosing schedules. Large numbers of RCT's have begun to evaluate these issues.
Substrate reduction therapy (SRT) may be offered to patients who are either unwilling or unable to afford the cost of ERT. It reduces glycolipid accumulation by decreasing the synthesis of glucocerebroside, the substrate of the deficient enzyme. Miglustat an FDA approved therapy is an oral agent (N-butyldeoxynojirimycin) which has shown decreases in hepatic and splenic volumes, and increases in platelet counts during 1-3 years in affected adults.,, Another oral formulation, eliglustat tartrate, is under phase III trials. Ceramide analogues were developed as alternatives to the deoxynojirimycin derivatives by Shukla et al. Short-chain-ceramide analogues are being tested preclinically in mouse models of GD.
An alternative approach called the pharmacological chaperone has been devised to modify in situ the endogenous mutant enzyme with the use of specific agents that interact with these dysfunctional enzymes. This counter-intuitive approach used competitive inhibitors of the enzyme to improve lysosomal activity. The range of mutations that might be responsive to one chaperone needs further investigation. In the era when ERT was not available splenectomy was considered a treatment option in the face of life threatening anaemia and thrombocytopenia. Bone marrow transplantation (BMT) has the potential and has been demonstrated to provide a definitive cure for GD., However, this procedure is associated with substantial morbidity and mortality and thus has been effectively replaced by ERT in clinical practice. Progress in gene therapy has slowed because of issues of gene delivery and expression, especially in stem cells derived from bone marrow. Concerns about toxic effects are related to insertional mutagenesis and malignant-cell transformation.
Conclusion: Advances in the management of this disorder continues to be hindered by the individual financial burden and staggering emotional support required for its successful cure. Development of optimal doses, treatment goals, improved staging systems and expert guidance in the use of these agents are essential in the care of patients affected with GD.
Table 01 Investigations done at the admission
Serum bilirubin (mg/dl)
Severe Microcytic Hypochromic anemia No hemolysis, haemoparasites
F/2 hour PP
K19 (kalazar antigen)
Serum LDH (IU/L)
Beta glucosidase assay (normal >4.0 nmol/hr/mg )
Onset of disease
Childhood or adolescence
Age at death
Median 9 months
Childhood or early adulthood
Hepatic fibrosis, pulmonary hypertension, lymphoma
Cardiac and vascular calcifications
Panethnic and Ashkenazi Jews
Panethnic and Norrbottnian type from Sweden
Table 03: Treatment goals for GD type 1
Improve and maintain haemoglobin at normal values (age, sex-dependent levels) 12-24 months
Increase and maintain platelet count sufficient to avoid bleeding difficulties
(1) Splenectomised patients normalise
2) Intact spleen increase 1.5-2 fold and then to low normal
(3) Avoid splenectomy
Hepatomegaly Decrease and maintain liver volumes at 1-1.25 times normal volumes
1) Decrease by 20-30%
2) Decrease by 30-40%
About 36 months
Splenomegaly Decrease and maintain spleen volume <2-8 times normal volumes
(1) Decrease by 30-50%
(2) Decrease by 50-60%
About 24-36 months
(1) Lessen or eliminate bone pain
(2) Prevent bone crises
(3) Attain ideal peak bone mass in chil dren
(1) Achieve normal growth rate
By 36 months
(2) Achieve normal puberty
Pulmonary involvement Reverse hepatopulmonary syndrome, decrease or eliminate pulmonary hypertension, prevent pulmonary failure Needs development
Quality of life
1) Restore daily activities
2) Improve quality-of-life scores on validated tests