Lysosomal Storage Diseases (PDF)

## A look at some lysosomal storage diseases ### Learning Outcomes * Explain the molecular defects in, clinical symptoms of, and current treatments for the following common lysosomal storage diseases: * **SPHINGOLIPIDOSES** * Fabry disease (X linked) * Tay-Sachs disease * Gaucher...

## A look at some lysosomal storage diseases ### Learning Outcomes * Explain the molecular defects in, clinical symptoms of, and current treatments for the following common lysosomal storage diseases: * **SPHINGOLIPIDOSES** * Fabry disease (X linked) * Tay-Sachs disease * Gaucher disease * Sandhoff disease * Niemann-Pick disease, Types A, B, and C * Metachromatic leukodystrophy ### Lysosomal Storage Diseases (LSDs) * LSDs comprise 50-70 unique monogenic autosomal recessive or X-linked diseases with an estimated combined incidence of 1 in 7,000 to 8,000 live births. * Defects in degradative enzymes result in accumulation of specific macromolecular compounds within lysosomes in multiple tissues and organs, causing progressive damage that can become life-threatening. * Many LSDs have a significant CNS component. ### Management of Lysosomal Storage Diseases * **Supportive care measures** tailored to disease stage, organs and systems involved, and degree of impairment * Could include blood transfusion, bed rest, analgesia, anti-inflammatory agents, hyperbaric oxygen, and surgery. * **Treatment directed at the biochemical deficiency** * Enzyme replacement therapy * Substrate reduction therapy * Pharmacological chaperones to assist in folding and trafficking * Stem cell therapy (bone marrow transplant) ### Enzyme Replacement Therapy * Possible treatment when patient has an enzyme deficiency. * Treats symptoms but not underlying disease. * Given by infusion on a regular basis (biweekly). * Produced recombinantly in mammalian cell culture and purified for use. * How are these replacement enzymes targeted to the lysosome? * Proteins don’t normally cross the BBB (Blood Brain Barrier). * True of any biologic that you add. * There is always some efficiency issue. * Cost and availability are always an issue. * It is not a cure. ### Small Molecule Chaperones * Normalize enzyme folding and transport * Cross blood-brain barrier ( >10% residual activity is target in brain * Avoid immune surveillance * Easier to synthesize and more stable than biologics * Can be taken orally * **Three types:** * Competitive inhibitors (1st generation) * Allosteric ligands (or coenzymes for metabolic enz) * Inducer of endogenous chaperones (Hsp) ### Tay-Sachs Disease * Issue with β-Hexosaminidase-A * Classically found in Jews. * **Second step in ganglioside degradation** * Deficiency in hexosaminidase A caused by defect in HEXA gene which codes for alpha subunit of the aβ heterodimer * More prevalent in intermarried populations * Symptoms include upper and lower motor neuron deficits (developmental delay, exaggerated startle response), visual difficulties that can progress to blindness, seizures, and increasing cognitive dysfunction. Most die by age 5. * No treatment or cure with ERT because hexA-ERT can't get through the blood-brain barrier where the main problem lies. ### Tay-Sachs Disease * **Enzyme Deficiency**: Hexosaminidase A * **Accumulation**: GM2-Ganglioside * **Findings**: Cherry-Red Macula, Onion skin lysosomes, NO hepatosplenomegaly ### Jay Sachz (from Marks) * 9 month old male * Ashkenazi Jewish parents – (Jews from area of Germany) * At 5 month of age exhibited mild, generalized muscle weakness * 7 months worse – poor head control, slowed motor skills, inattentive * Unusual eye movements and staring ### Tay-Sachs Disease * Patients can have cherry-red macula on the retina of the eye * Three types of disease: classic (infantile), juvenile onset, or late onset (rare) * These correlate with amount of enzyme produced, i.e. none, little, or variable. * The highest concentration of GM2 ganglioside is found in neuronal cells, thus Tay-Sachs primarily affects the nervous system ### Sandhoff Disease * Common to both Hexosaminidase Enzymes * First step in globoside degradation * Deficiency in both hexosaminidase A (αβ) & hexosaminidase B (B2) caused by defect in beta subunit which is common to both enzymes. * Symptomwise considered a variant of Tay-Sachs * No treatment or cure because hexA-ERT can't get through the blood-brain barrier where the main problem lies. Death usually before age 5. * + Cherry-Red Macula ### Hexosaminidase A & B * **Hexosaminidase A**: α-β dimer * **Hexosaminidase B**: ββ * **Activator protein** * **Defect in beta chain affects both enzymes** * **Defect in alpha chain or activator protein only affects Hex A** ### Sandhoff Disease * **Hexosaminidase A (αβ)** * Block in Sandhoff disease * Block in Tay-Sachs Disease * **Hexosaminidase A or B (B2)** * Block in Sandhoff Disease ### Fabry Disease * X-linked * Early neuropathy: peripheral burning sensation. * Second step in globoside degradation * Deficiency in alpha-galactosidase A (X-linked) * Affects 1,500-2,000 people in US (1 in 40K) * Clinical presentation: neuropathy of hands and feet, angiokeratomas on skin, decreased sweat, GI symptoms, renal and cardiac disease, early stroke risk, eye abnormalities (corneal whirling) * Diagnosis: level of alpha-galactosidase A in blood cells, or genetic testing (& family history) ### Fabry Disease Treatment * Enzyme replacement therapy using agalsidase beta (Fabrazyme) or agalsidase alfa (Replagal), both are recombinant human alpha-galactosidase A and differ only in glycosylation * Migalastat (Galafold) approved 2018 - competitive inhibitor (1st gen chaperone) which promotes proper folding of some mutant proteins, dissociates at low pH of lysosome ### Gaucher's Disease * First lysosome one discovered. * Deficiency in glucocerebrosidase * First LSD described (1882, Philippe Gaucher) * Accumulation of glucocerebroside in phagocytes causes swelling into “Gaucher” cells which cause anemia, easy bruising and bleeding problems * Other clinical symptoms: hepatosplenomegaly, bone and joint pain, osteoporosis * Diagnosis by enzyme level and genetic testing * Three broad types * Type I- non-neuronopathic, 95% in western countries * Type II- acute infantile neuronopathic, don’t live long * Type III-chronic neuronopathic, most common worldwide * Defects in glucocerebrosidase are risk factor for Parkinsons ### Gaucher's Disease * Gaucher disease type I. A child 10 years of age showing marked distension of the abdomen due to massive splenomegaly. The spleen was surgically removed and weighed 10 kg; * Gaucher disease. Radiograph of lower extremities showing Erlenmeyer flask deformity of the distal ends of the femur. ### Gaucher's Disease * The "crumpled tissue paper" appearance of the cytoplasm of Gaucher cells is caused by enlarged, elongated lysosomes filled with glucocerebroside. ### Gaucher Treatment * Enzyme replacement therapy * ERT is standard treatment. * New therapy reduces substrate by inhibiting the biosynthetic enzyme glucosylceramide synthase. * Other possible treatments are bone marrow transplant, spleen removal, and osteoporosis drugs. * Treatment should begin as early as possible to prevent disease progression ### Substrate Reduction Therapy * **Gaucher** * Inhibitors of Glucosylceramide Synthesis * Eliglustat * Miglustat * Venglustat ## Comparing Lysosomal Storage Diseases | Disease | Enzyme Deficiency | Accumulated Lipid | Notes | |---|---|---|---| | Fucosidosis | α-Fucosidase | Cer-Glc-Gal-GalNAc-Gal:Fuc H-isoantigen | | | Generalized gangliosidosis | GM1-B-galactosidase | Cer-Glc-Gal(NeuAc)-GalNAc: Gal GM1 ganglioside | | | Tay-Sachs disease | Hexosaminidase A | Cer-Glc-Gal(NeuAc):GaINAC GM2 ganglioside | | | Tay-Sachs variant or Sandhoff disease | Hexosaminidase A and B | Cer-Glc-Gal-Gal:GalNAc globoside plus GM2 ganglioside | | | Fabry disease | α-Galactosidase | Cer-Glc-Gal:Gal globotriaosylceramide | X-linked | | Ceramide lactosidase lipidosis | Ceramide lactosidase (B-galactosidase) | Cer-Glc:Gal ceramide lactoside | | | Metachromatic leukodystrophy | Arylsulfatase A | Cer - Gal : OSO3-sulfogalactosylceramide | | | Krabbe disease | β-Galactosidase | Cer:Gal galactosylceramide | | | Gaucher disease | β-Glucosidase | Cer:Glc glucosylceramide | | | Niemann-Pick disease A & B | Sphingomyelinase | Cer:P-choline Sphingomyelin | | | Farber disease | Ceramidase | Acyl:sphingosine ceramide | | ### Niemann-Pick types A & B * Deficiency in sphingomyelinase * Clinical presentation: difficulty walking, dystonia, sleep disturbances, difficulty swallowing, recurrent pneumonia, cherry red macula - (clue only 2 have this) * Type A occurs in infants showing severe progressive neurodegeneration & early death * Type B has later onset and usually survival into adulthood. * Diagnosis of type B made by presence of hepatosplenomegaly. Both A & B characterized by sphingolipid-laden foam cells. * No current therapy for A or B. ### Niemann-Pick Type C * Third type of Niemann-Pick. * Totally different lipid. * Niemann-Pick disease type C involves primary defect in lipid transport (cholesterol and gangliosides) from lysosome. * Type C is more common than A & B combined. * Characterized by fatal, progressive neurodegeneration including ataxia, dystonia, dementia. May survive into adulthood. * Also characterized by foam cells in visceral organs and nervous system. * No specific treatment. ### Niemann-Pick A & B * Sphingomyelinase deficiency * Enlarged liver and spleen filled with lipid. * Severe intellectual disability and neurodegeneration (Type A). * Death in early childhood (Type A). ### Niemann-Pick type C * Defect in cholesterol transport out of lysosome, usually in the NPC1 gene (~90%) rather than NPC2 (~10%). * Leads to build up of cholesterol in the lysosome. ### Metachromatic Leukodystrophy * Defect in arylsulfatase A * Sulfatide (or lysosulfatide) buildup destroys myelin sheath. (Fatty acid is leaved off of it = toxic) * Clinical symptoms: progressive deterioration of intellectual functions and motor skills, paralysis, blindness, hearing loss, seizures, eventually fatal (~ 4 yrs old for infantile MLD) * Three types MLD depending on age of onset. * Diagnosed by ARSA-A enzyme blood level with confirming urinary sulfatide test and brain MRI. Family history and genetic testing can also be confirmatory. * No effective treatment.