NOTES NOTES SPHINGOLIPIDOSIS GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Lysosomal storage diseases ▪ Metabolic disorders characterized by dysfunctional metabolism of sphingolipids ▪ Sphingolipids accumulate within various tissues’ cell lysosomes → affected organ damage ▪ Causes genetic defects → lysosomal enzyme deﬁciency ▪ Inheritance mode autosomal recessive, except in Fabry disease (X-linked recessive) SIGNS & SYMPTOMS ▪ Vary depending on organs affected, sphingolipid storage extent DIAGNOSIS ▪ Clinical presentation, family history ▪ Enzymatic assays ▪ Mutation analysis TREATMENT ▪ Enzyme replacement therapy ▪ Gene therapy FABRY DISEASE osms.it/fabry-disease PATHOLOGY & CAUSES ▪ Lysosomal enzyme alpha galactosidase A (a-GAL A) deﬁciency ▪ → Accumulation of a sphingolipid, called glycoglobotriaosylceramide (Gb3/ceramide trihexoside), within lysosomes ▪ Gb3 most commonly deposits in vessels, ganglions, kidneys, heart ▪ X-linked recessive inheritance pattern COMPLICATIONS SIGNS & SYMPTOMS ▪ Early presentation ▫ Acroparesthesias (severe peripheral neuropathic pain in extremities) ▫ Angiokeratomas (painless red to blue papules with hyperkeratosis), Telangiectasias (dilated vessels) presenting on the skin ▫ Gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting) ▫ Corneal opacities ▪ Affected organ dysfunction, vascular occlusions, infarctions OSMOSIS.ORG 295
▪ Later symptoms ▫ Progressive renal failure, cardiovascular disease, heat/cold intolerance, hypohidrosis (decreased sweat production), hearing loss DIAGNOSIS LAB RESULTS ▪ Enzymatic assay for alpha galactosidase ▪ Genetic testing TREATMENT OTHER INTERVENTIONS Figure 52.1 Numerous angiokeratomas on the skin of an individual with Fabry disease. ▪ Symptom management (e.g., analgesics) ▪ Enzyme replacement therapy ▪ Gene therapy GAUCHER'S DISEASE osms.it/gauchers-disease PATHOLOGY & CAUSES ▪ Most common lysosomal storage disease ▪ Lysosomal enzyme glucocerebrosidase deﬁciency ▪ → Accumulation of sphingolipid glucocerebroside in cellular lysosomes, particularly macrophages resembling crumpled tissue paper (AKA Gaucher cells) ▪ Glucocerebroside also deposits in liver, spleen, bone marrow, bones, kidneys, lungs, central nervous system (CNS) ▪ Autosomal recessive pattern of inheritance TYPES ▪ Three types based upon CNS involvement ▫ Type I: absence of CNS involvement ▫ Type II: acute neuronopathic form ▫ Type III: subacute or chronic neuronopathic form 296 OSMOSIS.ORG COMPLICATIONS ▪ Thrombocytopenia, anemia, bone disease, neurological deﬁcits SIGNS & SYMPTOMS ▪ Hepatosplenomegaly ▪ Pancytopenia, due to bone marrow inﬁltration with Gaucher cells, hypersplenism, leads to ▫ Easy bruising (thrombocytopenia) ▫ Fatigue (anemia) ▪ Bone disease (e.g., osteoporosis, aseptic necrosis of various bones); most commonly affects the femur ▪ Neurological complications (e.g. seizures, hypotonia, cognitive/olfactory abnormalities) present only in types II, III
Chapter 52 Sphingolidosis DIAGNOSIS LAB RESULTS ▪ Enzymatic assay to conﬁrm glucocerebrosidase deﬁciency ▪ Genetic testing ▫ Prenatal diagnosis available TREATMENT OTHER INTERVENTIONS ▪ Enzyme replacement therapy Figure 52.2 A section of bone marrow demonstrating numerous crinkled paper macrophages, or Gaucher cells, in an individual with Gaucher’s disease. KRABBE DISEASE osms.it/krabbe-disease PATHOLOGY & CAUSES ▪ AKA globoid cell leukodystrophy ▪ Lysosomal enzyme galactocerebrosidase deﬁciency ▪ Lipids galactocerebroside and psychosine buildup → ▫ Globoid cell formation (multinucleated macrophages) ▫ Oligodendrocyte destruction → demyelination ▪ Autosomal recessive inheritance pattern ▪ Progressive damage to nervous system → fatal SIGNS & SYMPTOMS ▪ Usually present within ﬁrst six months of life ▪ Peripheral motor, sensory neuropathy, loss of sensation, muscle atrophy in extremities ▪ Central nervous system dysfunction ▫ Irritability, developmental delay, spasticity, optic atrophy, seizures, weakness DIAGNOSIS LAB RESULTS ▪ Enzymatic assay to measure galactocerebrosidase activity in leukocytes ▪ Microscopy shows demyelination, characteristic globoid cells (i.e, multinucleated macrophages containing ↑periodic acid-Schiff (PAS) positive materials) ▪ Genetic testing TREATMENT OTHER INTERVENTIONS ▪ Affective therapy not yet available ▪ Hematopoietic stem cell transplantation is beneﬁcial, especially in early onset of symptoms OSMOSIS.ORG 297
METACHROMATIC LEUKODYSTROPHY osms.it/metachromatic-leukodystrophy PATHOLOGY & CAUSES ▪ Lysosomal enzyme arylsulfatase A (ARSA) deﬁciency → ↑ cerebroside sulfate storage in various tissues, progressive demyelination ▪ Metachromatic leukodystrophy (MLD) also caused by saposine deﬁciency (i.e. protein that normally stimulates ARSA) ▪ Autosomal recessive inheritance pattern COMPLICATIONS ▪ Central, peripheral nervous system dysfunction, paralysis, coma ▪ If untreated, fatal in 5–6 years SIGNS & SYMPTOMS ▪ Usually develops in late infancy, but can also present later in life ▪ Infantile onset ▫ Gait difﬁculties ▫ Developmental delay ▫ Muscle tone, strength abnormalities ▫ Ataxia ▫ Peripheral neuropathy ▫ Progressive vision loss ▪ Late onset ▫ Behavioral difﬁculties ▫ Psychiatric disorder ▫ Dementia DIAGNOSIS LAB RESULTS ▪ Enzymatic assay for ARSA ▪ Sulfatides measurement in urine to conﬁrm diagnosis ▪ Genetic testing TREATMENT OTHER INTERVENTIONS ▪ Hematopoietic stem cell transplantation ▪ Gene therapy ▪ Enzyme replacement NIEMANN–PICK DISEASE osms.it/niemann-pick_disease PATHOLOGY & CAUSES ▪ Group of disorders caused by defects in sphingomyelin storage ▪ Types A, B are characterized by enzyme acid sphingomyelinase deﬁciency → sphingomyelin accumulation in macrophage lysosomes in various tissues 298 OSMOSIS.ORG ▪ Type C is characterized by impaired cellular processing, low-density lipoprotein (LDL)cholesterol transport ▪ Autosomal recessive inheritance pattern
Chapter 52 Sphingolidosis COMPLICATIONS ▪ Progressive neurodegeneration, developmental delay, interstitial lung disease SIGNS & SYMPTOMS ▪ Hepatosplenomegaly, hypersplenism → thrombocytopenia ▪ Various neurologic deﬁcits ▫ Ataxia, dysarthria, dysphagia, dystonia ▪ Developmental delay ▪ Interstitial lung disease, recurrent respiratory infections ▪ Lipid abnormalities ▪ Dementia/depression/bipolar disease/ schizophrenia (in adults) ▪ Macular cherry red spot seen on fundoscopy examination ▫ Fovea appears bright red compared to rest of retina where lipids are accumulated TREATMENT ▪ No treatment proven to modify onset/ progression of disease MEDICACTIONS ▪ Miglustat (glycosphingolipids biosynthesis inhibitor) may be beneﬁcial for type C OTHER INTERVENTIONS ▪ Physical/occupational therapy, nutritional assessments DIAGNOSIS LAB RESULTS ▪ Types A, B ▫ Enzymatic assay for sphingomyelinase ▪ Type C ▫ Impaired response to LDL-cholesterol in cultured ﬁbroblasts ▪ Histology shows large lipid laden macrophages in reticuloendothelial system (AKA foam cells) ▪ Genetic testing Figure 52.3 Numerous lipid-laden macrophages in the spleen of an individual with Niemann–Pick disease. OSMOSIS.ORG 299
TAY–SACHS DISEASE osms.it/tay-sachs_disease PATHOLOGY & CAUSES ▪ Hexosaminidase A deﬁciency → glycolipid GM2 ganglioside buildup in neuronal lysosomes ▪ Autosomal recessive inheritance pattern TREATMENT OTHER INTERVENTIONS ▪ Symptom reduction/infection prevention COMPLICATIONS ▪ Progressive neurodegeneration ▪ Mental/physical ability deterioration ▪ Death at ages 2–5, primarily → pneumonia SIGNS & SYMPTOMS ▪ Typically presents at 2–6 months of age ▪ Progressive motor skill loss with hyperreﬂexia, hypotonia ▪ Physical ability deterioration ▫ Blindness, deafness, dysphagia, dysarthria ▪ Milder symptoms in late onset Tay–Sachs disease ▪ Cherry red spot macula sign a characteristic ﬁnding on fundoscopy DIAGNOSIS LAB RESULTS ▪ Enzymatic assay for hexosaminidase A ▪ Genetic testing 300 OSMOSIS.ORG Figure 52.4 A cherry red spot on the retina of an individual with Tay–Sachs disease.