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Lysosomal storage diseases

lysosomal storage disease in man and animals

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Lysosomal storage diseases

  1. 1. LYSOSOMAL STORAGE DISEASES Presented by PRADEEP. M Submitted to
  2. 2. LSD • To date 51 naturally occurring LSD • Most of them are autosomal recessive gene traits • 9 inherited and 2 acquired mechanisms of LSD known • No sex predilection • Brain lesions are prevalent (2/3rd of LSD)
  3. 3. HISTORY OF LSD • Symptoms of some LSDs were described as early as the 1880s, • Many had been described and classified before the lysosome was discovered in 1955 and before their biochemical and genetic basis was fully understood • This is why they received common names (i.e.: Gaucher disease, name of discovering physician). • Later, an additional, more clinically descriptive name often came into use (glucocerebrosidase deficiency)
  4. 4. HISTORY OF LSD Ernest GAUCHER (1854-1919) Gaucher cell 1882
  5. 5. LSD IN HUMAN IN INDIA (Sheth et.al., 2014) • 387 children (34.8 %) • highest prevalence of • glycolipid storage disorders in 48 %, • mucopolysaccharide disorders in 22 % • defective sulfatide degradation in 14 % of the children. • glycogen degradation defect and protein degradation defect in 5 % each • Lysosomal trafficking protein defect in 4 %, • Transport defect in 3 % of the patients. • Higher incidence of Gaucher disease (16 %) followed by GM2 gangliosidosis that includes Tay-Sachs disease (10 %) and Sandhoff disease (7.8 %) and mucopolysaccharide disorders among all LSDs
  6. 6. Pathways for degradation of cellular materials
  7. 7. BIOCHEMICAL AND CELLULAR BASIS OF LSDS Futerman AH & van Meer G (2004) 5:554- 565 1 catalytic activity 2 activator 3 misfolding 4 multienzyme complex 5 glycosylation 6 M-6-P targetting 7 other transport steps 8 membrane transporters 9 membrane regulators
  8. 8. General outline of LSD dysfunction: • Mutations arising in hydrolytic enzyme, co-factor or factor essential of enzyme delivery to lysosome • Factors essential for lysosome function and biogenesis (membrane proteins, channels and proteins of • Unknown function) plus factors for protein traffic to lysosome • Material (substrate) continues to be delivered to lysosome resulting in ‘stored’ material, usually ‘primary’ and ‘secondary’ leads to swollen lysosomes
  9. 9. Effect of lysosomal storage diseases • Direct consequence of abnormal accumulation of substrates or catabolites in the lysosomes Severe impairment of cellular structures and functions and abnormal extracellular matrix. They include alterations of – Signalling pathways, – Intracellular Ca2+ homeostasis, – Intracellular trafficking, – Dysmyelinogenesis – Formations of ectopic dendrites, – Retarded bone formation, and – Cloudy cornea • Secondary changes are due to disrupted recycling – manifested in abnormal or shortage of cellular and extracellular products – In the brain, there is a compromised recycling of neurotransmitter receptors, altered signalling and dysmylinogenesis
  10. 10. LYSOSOMAL STORAGE DISEASE- DAMAGING EFFECTS IN NERVOUS SYSTEM
  11. 11. LSD- SUB-CATEGORIES 1. Sphingolipidoses 2. Glycoproteinoses 3. Mucopolysaccharidoses (variable nervous system involvement) 4. Mucolipidoses (originally considered an MPS) 5. Glycogen storage diseases 6. Lipid storage disorders 7. Multiple enzyme defects 8. Transport defects 9. Batten Disease (Ceroid lipofuscinoses)- proteinosis (Blue = nervous system involvement)
  12. 12. 1. SPHINGOLIPIDOSES • Sphingolipids- 1. Sphingomyelins ( a phospholipid) 2. Glycosphingolipids (cerebroside, globoside, sulfatides and gangliosides) Ceramide= sphingosine + FA Glycosphingolipid = ceramide + oligosaccharide Cerebroside = glycosphingolipid with one sugar as side chain (gluc or gal) Globoside = glycosphingolipid with more than one sugar.. (glucose, galactose or GalNAc) Ganglioside = glycosphingolipid with one or more sialic acid (NANA) linked to sugar side chain
  13. 13. STRUCTURE AND CATABOLISM OF SPHINGOLIPIDS GM1 Gangliosidosis GM2Gangliosidosis (Tay-Sachs disease, Sandhoff, variant AB) Glucocerebrosidosis (Gaucher disease) Sphingomyelinosis (Nieman-Pick typeA, B) Galactosialidosis Galactocerbrosidosis (Krabbe disease) sialidase αGalactosidase A Sandhoff Fabry disease
  14. 14. 2. GLYCOPROTEINOSES glycoprotein contain hybrid type oligosaccharides Alpha-Mannosidosis Beta- mannosidosis Alpha-L-fucosidosis
  15. 15. MPS I (Hurler, Hurler-Scheie, Scheie) MPS II (Hunter) MPS III (San filipo Types A,B,C and D) MPS IV (Morquio type A and B) MPS VI (Maroteaux-Lamy) MPS VII (Sly) MPS IX (Hyaluronidase deficiency) Multiple Sulfatase deficiency 3. MUCOPOLYSACCHARIDOSES Defective metabolism of glycosaminoglycans
  16. 16. MUCOPOLYSACCHARODOSIS- CLASSIFICATION
  17. 17. 4. MUCOLIPIDOSES • Features of both sphingolipidosis and mucopolysaccharidoses Disease Enzyme deficient signs Species affected Mucolipidoses I αNuraminidase Neurological signs, organomegaly, and skeletal abnormalities. cats ML II (I cell disease) phospho- N-acetylglucosamine transferase -do- cat Pseudo-Hurler polydystrophy (ML-III) phospho- N-acetylglucosamine transferase -do-
  18. 18. MUCOLIPIDOSES II – (I cell disease) • Face; cat, 8 months of age. Left. Note the broad face with hypertelorism, thickened eye lids, and small ears. Right. Note frontal bossing
  19. 19. 5. GLYCOGENOSES • Glycogen storage disease type II (Pompe disease) – α1,4-glucosidase deficiency (Only lysosomal enzyme in glycogen catabolism others are metabolic pathways (type III- Amylo1,6 glucosidase defiency- Cori disease; type IV- Polyglucosan body disease) )
  20. 20. OTHER LYSOSOMAL STORAGE DISEASES • Ceroid-lipofuscinoses – Neuronal ceroid-lipofuscinoses (Batten disease) – Autofluorescent neurons • Laffora disease – Storage of polyglucosan
  21. 21. GENETICS OF LSD • X linked diseases in human – Fabry disease (alpha- galactosidase dificiency)- affect both sex – MPS II – Adult lipofuscinoses • All other are autosomal recessive
  22. 22. INDUCED STORAGE DISEASES • Swainsonine toxicosis – An indolizidine alkaloid – Seen in plants- locoweeds, broom weed etc. – Inhibit αMannosidase- αMannosidoses – “locoism” , “pea-struck” – identical to genetic form • Trachyandra poisoning – Ingestion of Trachyandra sps plants – Lipofuscinosis- central & peripheral neurones – sheep, horse, goat, pig – Reason not known • Phalaris poisnoing – By ingestion of Phalaris sp - grass – Accumulation of granular pigment material – Sudden death form- by cardio toxic compounds – Stagger form
  23. 23. Phalaris poisoning • A. Pigmentation in lateral geniculate body (arrow) • B. Neuronal accumulation of granular pigmented material (arrow head) B
  24. 24. Drug induced LSD • Amiodarone and chloroquine, • Induce phospholipidosis and MPS.
  25. 25. TAY-SACHS DISEASE • Mutation- chromo 15- Hex A gene- hexaminidase deficiency- accu of GM2 ganglioside
  26. 26. Typical signs and symptoms of Fabry disease Typical time at onset Signs and symptoms Childhood and adolescence (≤16 years) Neuropathic pain(burning sensation) Ophthalmological abnormalities (cornea verticillata and tortuous retinal blood vessels) Hearing impairment Dyshidrosis (hypohidrosis and hyperhidrosis) Hypersensitivity to heat and cold Gastrointestinal disturbances and abdominal pain Lethargy and tiredness Angiokeratomas Onset of renal and cardiac signs, e.g. microalbuminuria, proteinuria, abnormal heart rate variability Early adulthood (17–30 years) Extension of any of the above Proteinuria and progressive renal failure Cardiomyopathy Transient ischaemic attacks, strokes Facial dysmorphism Later adulthood (age >30 years) Worsening of any of the above Heart disease (e.g. left ventricular hypertrophy, angina, arrhythmia and dyspnoea) Stroke and transient ischaemic attacks Osteopenia and osteoporosis
  27. 27. LSD IN DOGS Abnormality Breeds affected (RARE) Special tests Clinical features Ceroid lipofuscinosis (Batten disease) many breeds - Australian cattle dog, border collie, chihuahua, cocker spaniel, dalmatian, wire- haired dachshund, English setter, Tibetan terrier none, diagnosis confirmed on post- mortem signs usually start around 1 to 2 years of age, vary between breeds (see resources below), may include diminished eyesight, abnormal behaviour, incoordination, seizures Fucosidosis English springer spaniel measure enzyme levels signs by 6 to 12 months, include slow learning, anxiety and behaviour changes, which gradually progress over the next 18 months or so, to severe incoordination, dementia, visual problems Glucocerebrosidosis (Gaucher's disease) Australian silky terrier measure enzyme levels signs by 4 to 8 months, include incoordination, tremors, hyperactivity, stiff gait Glycogen storage disease type III (Cori's disease) Akita, German shepherd measure enzyme levels signs by 6 to 12 weeks, muscle tremors, incoordination, hypoglycemia (low blood sugar), seizures, death by 8 months GM1 gangliosidosis Portuguese water dog, English springer spaniel measure enzyme levels signs by 2 to 4 months, include vision problems, lethargy, difficulty in walking, death occurs by 8 months. GM2 gangliosidosis (type B - Tay-Sachs disease, type O - Sandhoff's disease) German short-haired pointer (rare) measure enzyme levels signs by 6 to 9 months, include visual problems, abnormal behavior, incoordination, stiff gait Mucopolysaccharidosis I Plott hound (rare) measure enzyme levels signs often develop later, in adulthood; this is a connective tissue disorder and signs include musculoskeletal abnormalities, and heart disease due to thickened valves. Sphingomyelinosis (Niemann- Pick disease) very rare measure enzyme levels signs by 2 to 5 months, include incoordination, exaggerated gait, dullness
  28. 28. CLINICAL SIGNS 0F LSD • Cerebellar or cerebellovestibular signs such as tremor, ataxia, dysmetria, and nystagmus with progression to paresis and paralysis • Visual impairment, ataxia, hypermetria, tremors, seizures, and behavioral abnormalities. Differ from other LSD by diffuse forebrain disease and central blindness can be among the earliest clinical signs • Gangliosidoses in dogs and cats • Niemann-Pick disease types A and C • Globoid cell leukodystrophy • Canine Gaucher disease • Feline -mannosidosis • Ceroid lipofuscinosis
  29. 29. Lysosomal storage diseases in dogs – MRI STUDY (Hasegawa D, Tamura S, Nakamoto Y, Matsuki N, Takahashi K, et al. (2013) Magnetic Resonance Findings of the Corpus Callosum in Canine and Feline Lysosomal Storage Diseases. PLoS ONE 8(12) • The corpus callosum was ‘not visualized’ or ‘partially visualized’ in all cases of the juvenile-onset group, including the Shiba Inu dogs. It was barely recognized on both the transverse and sagittal images (Figures 1C, D), and in the domestic shorthair cats with GM1 gangliosidosis (data not shown) and GM2 gangliosidosis (Figures 1E, F). In the late juvenile-onset group, visualization of the corpus callosum in the toy poodles (Figures 1G, H) and golden retriever (data not shown) with canine GM2 gangliosidoses was inconsistent (‘partially visualized’ or ‘visualized but atrophic’), although the sagittal plane was not obtained from 2 of the 3 cases. In those 2 groups, if the corpus callosum was evaluated as ‘partially visualized’, the visualized portion was significantly atrophic (Figure 1C) and shortened longitudinally (Figure 1H). On the other hand, the corpus callosum of the early adult-onset group, comprised of those with canine neuronal ceroid lipofuscinosis, was recognized clearly and consistently, although it was thinner than those of normal animals (Figures 1I, J).
  30. 30. Gross pathology • Radial nerve enlargement- fucosidosis in dogs
  31. 31. GM1-gangliosidosis - vertebrae • lumbar vertebrae from a 3-month-old normal Portuguese water dog (A) and his brother with GM1-gangliosidosis (B). In (B) the vertebrae are shorter and the intervertebral disks are irregular and wide.
  32. 32. Ceroidlipofuscinosis- sheep
  33. 33. • Gross appearance of aMiniature Poodle lung with Niemann- Pick disease, showing diffuse nodular appearance of lung on pleural and cut surface
  34. 34. HISTOPATHOLOGY
  35. 35. SPHINGOLIPIDOSIS • GM1 gangliosidosis, type I, II and III • GM2 gangliosidosis (Tay-Sachs type I, II, III and Sandhoff) • Acid sphingomyelinase deficiency (Niemann-Pick A & B) • Fabry disease- (alpha-galactosidase A deficiency) • Farber disease (Ceramidase deficiency) • Gaucher disease, type I, II and III • Krabbe disease (galactosylceramidase deficiency)
  36. 36. GM1 GANGLIOSIDOSIS- CEREBRUM Diffusely, neurons are moderately swollen with finely granular to microvacuolated cytoplasm. Multifocally, glial cells often contain large, discrete, clear vacuoles
  37. 37. GM1 GANGLIOSIDOSIS- CEREBRUM Rarely within the white matter there are spheroids characterized by swollen, hypereosinophilic axons (arrow) X400
  38. 38. GM1 GANGLIOSIDOSIS- CEREBRUM Within the white matter there are rare digestions chambers characterized by swollen axon sheaths containing gitter cells and cellular debris (arrow
  39. 39. GM1-gangliosides- Luxol Fast Blue stain • Paraffin section of the brain of a 7-month-old English Springer Spaniel dog stained with Luxol Fast Blue demonstrating the storage of GM1-gangliosides.
  40. 40. GANGLIOSIDOSIS High power electronmicrograph of membranous cytoplasmic bodies (open arrow) and zebra bodies (closed arrow) within a brain stem neuronal cell body
  41. 41. GM1 GANGLIOSIDOSIS- CEREBRUM Intraneuronal concentric lamellar membranous whorls
  42. 42. Globoid cell leukodystrophy (krabb’s disease) PAS - Mulinucleated macrophages ("globoid cells") and loss of myelinated fibers in a case of Krabbe's leukodystrophy (globoid cells are enlarged vacuolated macrophages typically localized around blood vessels)
  43. 43. Krabbe disease ( globoid cell leukodystrophy or galactosylceramide lipidosis) • Globoid cells with electron microscopical view(*) (enlarged lysosomes packed with twisted tubules)
  44. 44. α-Mannosidosis -cow Cow cerebrum with a-mannosidosis illustrating • (A) enlarged neurons with vacuolated cytoplasm, hematoxylin and eosin (H&E). • B, Staining with Con A demonstrating the storage of oligosaccharides with terminal a- mannosyl residues
  45. 45. MANNOSIDOSIS- CALF neuronal cell bodies with vacuolated cytoplasm (arrows)
  46. 46. CEROID LIPOFUSCINOSIS- SPINAL CORD • Frozen section of spinal cord of a 11=2-year-old Australian Blue Heeler dog with neuronal ceroid lipofuscinosis in spinal cord stained with Sudan black revealing the storage of ceroid lipofuscin within the neurons.
  47. 47. DIAGNOSIS • Hematological and routine biochemical assessment is usually unremarkable • Blood smear- storage vacuoles in leukocytes • Lymph node aspirates or biopsies can be diagnostically helpful • Radiograph- bone deformities • CSF analyisis- vacuoles in macrophages / lymphocytes (eg. globoid cell leukodystrophy and fucosidosis) • Peripheral nerve biopsy- Globoid cell leukodystrophyl, g Niemann-Pick type A,47 -mannosidosis,2 and fucosidosis, fucosidosis • Muscle biopsy- glycogen storage disease • MRI
  48. 48. Blood smear examination • Blood smear of a patient with multiple sulfatase deficiency showing a lymphocyte and neutrophil stained with Wright-Giemsa. The cytoplasm of both cells contains metachromatic granules.
  49. 49. • Urine analysis (in MPS) – Fucosidosis - excrete fucoglycoconjugates – Cats with mannosidosis - mannose-rich oligosaccharides – MPS spot test- staining urine on filter paper with toluidine blue- give a crude indication of increased concentrations of glycosaminoglycans in urine
  50. 50. Confirming diagnosis- live animal • Enzyme activity analysis- – homozygotes- 0-5% of normal activity – Heterzygotes- 50% of normal activity (dried blood sample analysis using fluorescent substrate; Sewell et.al., 2012) • 2o increase of activities of other enzyme when one is deficient
  51. 51. ANTI-NIEMANN-PICK DISEASE, TYPE C1 (NPC1) (C-TERM) ANTIBODY • Rabbit antimouse antibody
  52. 52. Flow diagram- LSD diagnosis
  53. 53. Treatment: • BMT (membrane proteins) • Enzyme replacement (BBB?) • Gene therapy • Substrate reduction- Miglustat (monosaccharide • mimetic-imino sugar) • Neuronal stem cells (membrane proteins?) • Chemical chaperone therapy
  54. 54. conclusion • Lysosomal storage diseases are one of the less identified animal diseases in India mainly due to lack of awareness. As these are mainly a genetic disease, early identification will help in taking proper preventive measures like excluding the related animals from breeding. More study needed to be conducted to evaluate the extend of the disease in the animal population
  55. 55. THANK YOU
  56. 56. • Sheth, Mehul Mistri, Frenny Sheth, Raju Shah, Ashish Bavdekar, Koumudi Godbole, Nidhish Nanavaty, Chaitanya Datar, Mahesh Kamate, Nrupesh Oza, Chitra Ankleshwaria, Sanjeev Mehta, andMarie Jackson (2014), Burden of Lysosomal Storage Disorders in India: Experience of 387 Affected Children from a Single Diagnostic Facility JIMD Rep. 2014; 12: 51–63.

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