Definition/General
Introduction:
Storage diseases represent a group of inherited metabolic disorders characterized by accumulation of undegraded substrates in lysosomes
They result from deficiency of specific lysosomal enzymes
Bone marrow shows characteristic storage cells with pathognomonic morphology
These include Gaucher cells, Niemann-Pick cells, and foam cells.
Origin:
Result from genetic mutations affecting lysosomal enzyme function
Lead to substrate accumulation in macrophages and other cells
Autosomal recessive inheritance pattern in most cases
Enzyme replacement therapy available for some types
Progressive organ dysfunction due to storage material accumulation.
Classification:
Sphingolipidoses: Gaucher disease, Niemann-Pick disease, Fabry disease
Mucopolysaccharidoses: MPS I (Hurler), MPS II (Hunter), MPS VI (Maroteaux-Lamy)
Glycogen storage diseases: Pompe disease (GSD II)
Other storage diseases: GM1 gangliosidosis, Krabbe disease
Multiple sulfatase deficiency.
Epidemiology:
Gaucher disease: most common lysosomal storage disease (1:40,000-60,000)
Ashkenazi Jewish population: increased prevalence (1:450)
Niemann-Pick disease: rare (1:150,000)
MPS disorders: combined incidence 1:25,000
Regional variations in India with specific founder mutations.
Clinical Features
Presentation:
Hepatosplenomegaly (most common presentation)
Bone pain and bone crises
Growth retardation in children
Neurological symptoms (in neuronopathic forms)
Bleeding tendency due to thrombocytopenia
Respiratory symptoms from pulmonary involvement.
Symptoms:
Easy fatigability and weakness
Abdominal distension from organomegaly
Bone and joint pain
Developmental delay (neuronopathic forms)
Recurrent infections
Coarse facial features (mucopolysaccharidoses)
Cherry-red spot on fundoscopy (some types).
Risk Factors:
Consanguineous marriage
Family history of storage diseases
Ethnic predisposition (Ashkenazi Jewish, French Canadian)
Carrier status in parents
Previous affected sibling
Prenatal screening in high-risk pregnancies.
Screening:
Enzyme assays on dried blood spots or leukocytes
Molecular genetic testing for specific mutations
Biomarker assessment: chitotriosidase (Gaucher), lysosphingomyelin (Niemann-Pick)
Prenatal diagnosis by chorionic villus sampling or amniocentesis
Newborn screening programs in some regions.
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Gross Description
Appearance:
Bone marrow shows increased cellularity with scattered large cells
Gaucher cells: large cells with wrinkled tissue paper cytoplasm
Niemann-Pick cells: foamy macrophages with abundant cytoplasm
Sea-blue histiocytes may be present.
Characteristics:
Storage cells have characteristic morphology specific to disease type
Abundant cytoplasm filled with storage material
Well-preserved cell membranes and nuclei
Variable distribution throughout bone marrow spaces.
Size Location:
Large storage cells measuring 20-100 micrometers
Scattered distribution in bone marrow spaces
Perivascular location common
Increased concentration in areas of active hematopoiesis.
Multifocality:
Systemic involvement: liver, spleen, lungs, bones
CNS involvement in neuronopathic forms
Corneal clouding (mucopolysaccharidoses)
Cardiac involvement (Fabry disease, Pompe disease)
Renal involvement (Fabry disease).
Microscopic Description
Histological Features:
Gaucher cells: large macrophages with striated, wrinkled cytoplasm resembling crumpled tissue paper
Niemann-Pick cells: foamy macrophages with abundant, vacuolated cytoplasm
PAS-positive storage material in many types
Preserved hematopoiesis with normal maturation.
Cellular Characteristics:
Enlarged macrophages with specific cytoplasmic characteristics
Single or multiple nuclei depending on disease type
Abundant cytoplasm filled with storage material
Distinct cell membrane well-preserved
Variable PAS, Sudan, and toluidine blue staining.
Architectural Patterns:
Scattered distribution of storage cells throughout marrow
Normal hematopoietic architecture maintained
No disruption of normal cell maturation
Occasional clustering of storage cells
Reticulin fibrosis generally absent.
Grading Criteria:
Storage cell density: mild (<5%), moderate (5-20%), severe (>20%)
Morphological preservation of storage cells
Background hematopoiesis assessment
Associated features: fibrosis, hemosiderin deposits
Clinical correlation with enzyme levels essential.
Immunohistochemistry
Positive Markers:
CD68 (macrophage marker, positive in storage cells)
Lysozyme (positive in macrophages)
Alpha-1-antitrypsin (positive)
PAS stain (positive in glycogen and mucopolysaccharide storage)
Sudan stains (positive in lipid storage diseases).
Negative Markers:
CD1a (negative, excludes Langerhans cell histiocytosis)
S-100 (negative in most storage cells)
Cytokeratin (negative)
Melanoma markers (negative)
Lymphoid markers (negative).
Diagnostic Utility:
Specific enzyme histochemistry: acid phosphatase (Gaucher cells strongly positive)
Toluidine blue staining: metachromatic material in some types
Iron stain: hemosiderin deposits in some cases
Electron microscopy: characteristic ultrastructural features
Combined morphology and staining patterns diagnostic.
Molecular Subtypes:
Gaucher disease: Types 1 (non-neuronopathic), 2 (acute neuronopathic), 3 (chronic neuronopathic)
Niemann-Pick disease: Types A (severe), B (mild), C (neurological)
MPS disorders: classified by enzyme deficiency and clinical severity
Fabry disease: classic and late-onset variants.
Molecular/Genetic
Genetic Mutations:
GBA gene mutations (Gaucher disease): L444P, N370S most common
SMPD1 gene mutations (Niemann-Pick A/B)
NPC1/NPC2 mutations (Niemann-Pick C)
IDUA gene mutations (MPS I)
IDS gene mutations (MPS II, X-linked)
GAA gene mutations (Pompe disease).
Molecular Markers:
Chitotriosidase levels: markedly elevated in Gaucher disease (>10-fold normal)
CCL18/PARC levels: elevated in Gaucher disease
Lysosphingomyelin: elevated in Niemann-Pick disease
Glycosaminoglycans: elevated in urine (MPS disorders)
Globotriaosylceramide: elevated in Fabry disease.
Prognostic Significance:
Genotype-phenotype correlation: specific mutations predict clinical severity
N370S homozygotes: mild Gaucher disease, no neurological involvement
L444P homozygotes: severe disease with neurological complications
Compound heterozygotes: variable phenotype
Early diagnosis allows timely enzyme replacement therapy.
Therapeutic Targets:
Enzyme replacement therapy: imiglucerase, velaglucerase (Gaucher disease)
Substrate reduction therapy: miglustat, eliglustat
Pharmacological chaperones: for specific mutations
Gene therapy: experimental approaches
Hematopoietic stem cell transplantation: for selected cases
Symptomatic treatment: bisphosphonates for bone disease.
Differential Diagnosis
Similar Entities:
Reactive foamy macrophages (infection, atherosclerosis)
Hemophagocytic syndrome (activated macrophages with hemophagocytosis)
Rosai-Dorfman disease (S-100 positive, emperipolesis)
Langerhans cell histiocytosis (CD1a+, Langerin+)
Malignant histiocytosis (cytological atypia).
Distinguishing Features:
Gaucher cells: characteristic wrinkled, striated cytoplasm, acid phosphatase positive
Niemann-Pick cells: foamy cytoplasm, sphingomyelin storage
MPS cells: metachromatic granules, toluidine blue positive
Reactive macrophages: lack characteristic morphology, normal enzyme levels
Clinical context and enzyme studies crucial for diagnosis.
Diagnostic Challenges:
Atypical morphology in some storage diseases
Mixed storage patterns in multiple enzyme deficiencies
Pseudodeficiency alleles giving false enzyme results
Carrier state detection requiring molecular analysis
Variant forms with atypical presentations.
Rare Variants:
Pseudo-Gaucher cells: seen in chronic myelogenous leukemia, multiple myeloma
Sea-blue histiocyte syndrome: inherited and acquired forms
Cholesteryl ester storage disease: foamy macrophages with cholesterol esters
Farber disease: ceramide storage with joint involvement
Multiple sulfatase deficiency: combined features of different storage diseases.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Cellularity
Bone marrow cellularity: [percentage]% (age-adjusted normal: [range]%)
Storage Cells
[Storage cell type] present, constituting [percentage]% of nucleated cells
Morphological Features
Storage cells show [specific morphological characteristics] with [cytoplasmic features]
Special Stains
PAS: [result], Sudan stains: [result], Toluidine blue: [result]
Immunohistochemistry
CD68: [result], Acid phosphatase: [result], supporting [storage disease type]
Hematopoiesis
Background trilineage hematopoiesis with [maturation pattern]
Final Diagnosis
Bone marrow with storage cells consistent with [specific storage disease]
Recommendations
Recommend enzyme assays and molecular genetic testing for confirmation. Clinical correlation advised