Dr vidyut 2


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Dr vidyut 2

  1. 1. Storage disorders inchildrenDr Vidyut BhatiaPediatric GastroenterologistIndraprastha Apollo Hospital, New DelhiEditor: Celiac Focus
  2. 2. Inborn error of metabolism—Garrod’s hypothesis C Not enough, substrateA B insufficiency/deficit D Toxic!! Substrate excess
  3. 3. Storage within the cellLysosomal: Lysosomal storage disordersCytoplasmic: Glycogen storage disorders
  4. 4. GlycogenGlycogen is a glucose polymer joined in straight chains by alpha 1,4 linkages and branched by alpha 1,6 linkages. It forms a tree like moleculeGlycogen is the storage form of glucose and is found in abundance in the liver, muscles and kidneys
  5. 5. Glycogen polymer
  6. 6. Cont.Glycogenesis:The conversion of excess glucose to glycogen forstorage
  7. 7. Cont.Glycogenolysis:The degradation of glycogen to glucose.A phosphorylase enzyme splits the alpha 1,4linkage releasing glucose-1-phosphate, adebranching enzyme then splits the alpha 1,6linkage
  8. 8. Glycogen Storage Disease (GSD)GSD as a group reflect an inability to metabolize glycogento glucose in the liver.It mainly occurs because of a number of enzymatic defectsalong the pathwayThere are eleven distinct types of diseases that arecommonly considered to be glycogen storage diseases andall of them are caused as a result of enzymatic defect in thepathway including type I and III.
  9. 9. Cont.The system for glycogen metabolism relies on a complex system of enzymes. These enzymes are responsible for creating glycogen from glucose, transporting the glycogen to and from storage areas within cells, and extracting glucose from the glycogen as needed. Both creating and tearing down the glycogen macromolecule are multistep processes requiring a different enzyme at each step. If one of these enzymes is defective and fails to complete its step, the process halts.
  10. 10. Incidence and mode of inheritanceOverall frequency of all forms of GSD is approximately one in 20,000-25,000 live birthsThe most common forms of GSD are Types I, II, III, V and IX, which may account for more than 90% of all cases
  11. 11. GSD Type I and IIIGSD type I a: caused by a defect in the enzyme glucose1,6 phosphatase which impairs gluconeogenesisPatient is not able to metabolize glycogen stored in theliverGSD type III also referred to as debrancher enzymedefect that prevents glycogen breakdown beyond branchpoints
  12. 12. Symptoms of type I and IIIPoor physical growthHypoglycemiaHepatomegalyAbnormal biochemical parameters especially forcholesterol and triglycerides
  13. 13. Diagnosis of hepatic glycogenosesGlucagon challenge (historical): Intra-muscular administration of glucagon results in poor blood glucose level elevation, and elevates levels of lactateLiver biopsy: The biopsy sample is tested for its glycogen content (which is increased) and assayed for enzyme activity and presence (which is defective or absent) Liver histology reveals ,in addition, steatosis typically with absence of fibrosis
  14. 14. Cont.DNA based gene mutation analysis:The genes for many enzymes , which their defects or deficiencies are responsible for GSD have been encoded and mutations have been identified. Molecular technologies have provided a non- invasive way of diagnosis, and pre-natal diagnosis is being developed as well
  15. 15. Dietary Management in GSDThe therapeutic objective of dietarymanagement for GSD is to provide aconstant source of exogenous glucose tomaintain plasma glucose in a safe range andto “avoid hypoglycemia”
  16. 16. Description and PrecautionsProlonged fasting of <5 to 7 hours must be avoidedSome patients cannot even tolerate fasting for >3.5hoursNormal blood glucose concentration (70-120mg/dl)(2 hours postprandial) must be maintained throughout the day and night to ameliorate biochemicalabnormalities.Therapy with raw cornstarch administered at regularintervals and a high carbohydrate, low fat diet isadvocated
  17. 17. Lysosomal Storage Disorders Sandoff 2% Gaucher Gm1 Gangliosidosis 2% 14%Mucolipidosis II/III 2%Niemann Pick A/B 3%Maroteaux-Lamy 3% MPS I H/S 9% Niemann Pick C 4% Sanfilippo B 4% Metachromatic Leukodystrophy Tay-Sachs 8% 4% Cystinosis 4% Sanfilippo A 7% Morquio 5% Pompe Fabry 5% 7% Krabbe Hunter 5% 6% MPS (For Australia1980-1996; Meikle et al., JAMA 281;249-254 34%
  18. 18. Lysosomal storage disorders general principlesThe single most common Manifestations of neurological disease begin in infancy orLSD is Gaucher disease childhoodMost LSDs are autosomal Initially, there is delay and thenrecessive arrest of psychomotor development, neurologicalA few are X-linked regression, blindness, andPatients are normal at birth seizures. Progression leads to a vegetative state
  19. 19. Presentation and ProgressionHeterogeneous presentation across the LSD categories andoften even within a single diseaseWide clinical variability according to different types ofsubstrate stored and locations of storageClinical manifestations tend to be progressive, as more wastesubstrate accumulates over time
  20. 20. Presentation and Progression
  21. 21. Presentation and ProgressionAs a group, LSDs affect nearly every bodily systemSymptoms vary in severity from relatively mild to severesomatic and rapidly progressive neurologicmanifestations.Even those without formal sub-types based on age ofonset, affected organs/systems, and severity generallyencompass a spectrum of clinical manifestations
  22. 22. "Red Flag" SymptomsWhile no single symptom is an LSD hallmark, severalfrequently present across enough of the disorders thatthey can raise a physicians suspicion and prompt furtherinvestigationLSD symptoms often present in clusters, so theappearance of more than one of these is even moresuggestive
  23. 23. "Red Flag" SymptomsCoarse facial features (sometimes with macroglossia)Corneal clouding or related ocular abnormalitiesAngiokeratomaUmbilical/inguinal herniasShort statureDevelopmental delaysJoint or skeletal deformitiesVisceromegaly (especially liver and spleen)Muscle weakness or lack of control (ataxia, seizures, etc.)Neurologic failure/decline or loss of gained development
  24. 24. Coarse facial features Corneal clouding Umbilical hernia
  25. 25. SkeletalAbnormalities Gaucher MPS I
  26. 26. Angiokeratoma Joint deformities Visceromegaly
  27. 27. "Red Flag" SymptomsParticularly noteworthy are the following signs: Loss of motor skills, Increasing dementia or behavioural abnormalities, Muscular or neurologic deterioration,That suggest a progressive/degenerative disorder.
  28. 28. Kyphosis Cystine crystal deposits Aspartylglycosaminuria CystinosisLymphadenopathy Ataxia Hypertonia Farber Krabbe Disease
  29. 29. Strabismus Retinitis pigmentosa Cherry red spot Neuronal ceroid lipofuscinosisInfantile Sialic acid SD Small jaw GM2 Gangliosidosis Cardiomegaly Macroglossia PompePicnodysostosis Muscle wasting Hypotonia
  30. 30. LSD Sub-CategoriesWhen a lysosomal enzyme (or another protein thatdirects it) is deficient or malfunctioning, the substrate ittargets accumulates, interfering with normal cellularactivity Healthy cell vs. LSD cell with accumulated substrate
  31. 31. LSD Sub-CategoriesSub-categories are based on the type of enzymatic defectand/or stored substrate product.For example, the mucopolysaccharidoses (MPS) aregrouped together because each results from an enzymedeficiency that causes accumulation of particularglycosaminoglycan (GAG) substrates.
  32. 32. I - Defective metabolism of glycosaminoglycans " the mucopolysaccharidoses" 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
  33. 33. II - Defective degradation of glycan portionof glycoproteins Aspartylglucosaminuria Fucosidosis, type I and II Mannosidosis Sialidosis, type I and IIIII - Defective degradation of glycogen Pompe disease
  34. 34. IV - Defective degradation of sphingolipidcomponentsAcid sphingomyelinase deficiency (Niemann-Pick A & B)Fabry diseaseFarber diseaseGaucher disease, type I, II and IIIGM1 gangliosidosis, type I, II and IIIGM2 gangliosidosis (Tay-Sachs type I, II, III and SandhoffKrabbe diseaseMetachromatic leukodystrophy, type I, II and III
  35. 35. V - Defective degradation of polypeptides Pycnodysostosis VI - Defective degradation or transport of cholesterol, cholesterol esters, or other complex lipidsNeuronal ceroid lipofuscinosis, type I, II, III and IV
  36. 36. VII - Multiple deficiencies of lysosomal enzymes Galactosialidosis Mucolipidosis, type II and IIIVIII - Transport and trafficking defects Cystinosis Danon disease Mucolipidosis type IV Niemann-Pick type C Infantile sialic acid storage disease Salla disease
  37. 37. Progression and outcomeThe LSDs with neurologic involvement can often be themost severe, marked by rapid decline and high mortalityratesBut generally, predicting LSD progression and outcomeis challenging, especially in later-onset patients
  38. 38. Prognosis of LSDsEarly identification and diagnosis is essential forappropriate managementEarly intervention is mandatory for the mostserious and debilitating symptoms (particularlyneurologic and skeletal)Once established these often will not respond toeven disease-specific therapies
  39. 39. Disease ManagementFor most LSDs, no disease-specific therapy is availableClinical manifestations can only be addressed throughpalliative measures such as physical therapy, dialysis orsurgeryThese methods can be effective in managingsymptoms, but they do not affect the biochemicalcause of the disease
  40. 40. Disease-Specific Treatment Options Hematopoietic stem cell transplant (HSCT) Healthy stem cells (from bone marrow or cord blood) are transplanted i.v. to the patient to provide new healthy cells that produce the missing enzyme Enzyme replacement therapy (ERT) A recombinant form of the deficient enzyme is infused i.v. at definite intervals
  41. 41. Disease-Specific Treatment Options Enzyme enhancement therapy (EET) Misfolded enzyme is stabilized during its synthesis by the use of small chemical chaperones Substrate reduction therapy (SRT) The rate of production of the substrate is slowed by drug therapy
  42. 42. Bone marrow transplantFirst attempted in the 1980s and has been most used for MPS IPositive results when performed early in a diseases course,despite its challenges and risks transplant failure or rejection toxicity of the conditioning regimen difficulty finding a good donor matchImproved chance for success in newborns with naturallysuppressed immune systems
  43. 43. Enzyme Replacement TherapyThe first ERT for Gaucher type I went on the marketin 1991ERT is a treatment option for 6 LSDs Gaucher Type I, Fabry, MPS I (Hurler/Scheie) and MPS II (Hunter) Pompe (GSD type II) and MPS VI (Maroteaux-Lamy)
  44. 44. Thank You