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Case Histories. Case 1: Positive Newborn Metabolic Screen. History : NMS test result shows elevated Phenylalanine (0.75 umole/l; normal


  • Case Histories

  • Case 1: Positive Newborn Metabolic ScreenHistory: NMS test result shows elevated Phenylalanine (0.75 umole/l; normal
  • Results of investigationsResultsPlasma PHE=1.2umole/l; tyrosine = 0.05 umole/l

    Urine organic acids increased PPA,PLA,PAA

    QuestionsWhat other tests need to be done to be sure this baby needs diet treatment?

    2.What is the basis of the diet treatment?

  • Metabolism of PhenylalaninePHEDietary ProteinBody ProteinTyrosinePPAPLAPAAPhenylactetyl- glutamineBH4qBH2(PAH)6-pyruvoyl-BH4GTP

  • PHE levels in the Newborn with PKUPHEDays of Age1234NORMALRANGEScreening Possible

  • Untreated PhenylketonuriaSigns / Symptoms mental retardationhypopigmentationeczema-like rashautistic-like behaviorautosomal recessivehigh blood phenylalanine levels

  • PKU: Diagnostic work-up Confirm that PHE level is elevatedRule out biopterin deficiency disordersUrine pterin levelsDihydrobiopterin reductase activityBiopterin load test (optional)If present start DOPA/carbiDOPA/5HTPIf BH4 disorder not diagnsosed & PHE above 0.4 mM/l, start low PHE diet

  • Natural FoodsContains some normal nutrients and all those being restrictedNutritional Treatment of PKUDiet has two components:

    Must meet all nutritional needs + limit intake of restricted nutrients to amts sufficient for growthMedical Formula Contains all nutrientsexcept those being restricted+

  • Case 2: Hepatomegaly with Abnormal Liver PathologyHistory:The pathologist in your hospital calls to discuss an abnormal liver biopsy result8 month old boy with (R) abdominal mass extending down into the iliac fossaSeen by Oncology re: ? Tumor; taken to OR for open biopsyQuestionWhat do you see in the following biopsy?

  • Case 2: patient & liver biopsy

  • QuestionsWhat types of disorders might cause this appearance?

    What further historical information may be of help?

    What further studies should you request from the pathologist?

  • QuestionsWhat types of disorders might cause this appearance?Glycogen storage disorders (types 1a & 1b, 3, 6 lysosmal storage disorders (Gaucher, Niemann-Pick, MPS, oligosaccharidoses, tyrosinemia, B-oxidation disorders (MCAD, LCHAD, VLCAD)

    What further historical information may be of help?Symptoms of hypoglycemia (relationship to fasting including timing)Mother indicates baby can only go about 2-4 hours without a bottle

    What further studies should you request from the pathologist?PAS staining +/- pretreatment with diastaseElecton microscopy

  • Diagnostic testingFasting challenge +/- feeding challengesEnzyme assays Need fresh liverNeed to choose specific enzymes to target based on historyMolecular testingNow have bank of mutations but expensive


  • Glycogen Storage Disease IBControlled Fast

    Time After Feed (min) 0306090120150180Glucose (mM) (mM)

  • GSD IA &IBClinical featuresearly onset hypoglycemialactic acidosishepatomegalyFanconi syndromehyperuricemiahyperlipidemiaDiagnosis controlled fast (test BS & LA)enzyme (liver biopsy)DNA testingTherapy provide 5 - 10 mg glucose/kg/mincontinuous .nocturnal infusion of CHO as polycose or formulafrequent meals during dayscorn starch days &/or nightsdont over treat with CHONeutropenia in Type IBprophylactic antibioticsGCSFEmergency protocols for illness, surgery etc.

  • Case 3: 18 month boy with hepatomegaly and obtundationHistory:stuporous on admission found pale & sweaty and unarousable by parentsHad been ill for about 18 hours with no significant intakeSeizure in ambulance

    Initial studies:Blood sugar = 0.2 mM/l, Na+=145, K+ =3.5, Cl- =104, TCO2 = 10Urinalysis = NormalAll other testing including lactate, NH4 & LFEs normal

  • Key observationsSevere hypoglycemia with hepatomegaly and no ketonuria on setting of history of prolonged fasting

    Needs urgent treatment of hypoglycemia Route?How much glucose?? Significance of no ketones in urine?diagnostic testing

  • Trifunctional proteinVLCAD,MCAD, SCAD

  • Diagnostic InvestigationsPlasma acylcarnitnes suggest Medium Chain Dehydrogenase deficiency (MCAD)Plasma free carnitine levels low while acylcarnitines high14C- palmitic acid oxidation in leucocutes quite reducedMolecular diagnosis indicates homozygosity for the common caucasian mutation.

  • MS/MS Analysis of plasma acylcarnitines (?= MCAD)

  • Phases of Glucose Homeostasis1.Glucose absorptive phase: 3 - 4 hrs after glucose ingestion (high insulin)2.Post absorptive/early starvation: 3-12 hrsglucose (from hepatic glycogen) to brain, RBC, renal medulla3.Early / Intermediate Starvation: 14+ hrsgluconeogenesis & (later) lipolysis

  • TreatmentAvoid fasting L-carnitine if free carnitine lowEmergency protocol & letterSick day managementAdmission to ER/hospital to maintain blood glucose with IV infusion to prevent excessive lipolysis the would overload the B-oxidation pathway

  • Case 4: Neonatal Presentation5 d.o. maleWell for 72 hrs then became lethargic, fed poorly, began vomiting & developed alternating flaccidity & opisthotonic posturing.Became comatoseDeveloped hyperpnea and respiratoy alkalosis progressing to respiratory failureO/E: hepatomegaly, hypothermiaTest ResultsNormal: CBC, lytes, bld glucose, lactic acid, urinalysisnot acidoticnot ketoticnot hypoglycemicNH3 (350 umole/l) ? Differential Diagnosis? Further testing

  • Case 4: Investigation Results5 d.o. maleWell for 72 hrs then became lethargic, fed poorly, began vomiting & developed alternating flaccidity & opisthotonic posturing.Became comatoseDeveloped hyperpnea and respiratoy alkalosis progressing to respiratory failureO/E: hepatomegaly, hypothermiaTest ResultsNormal: urine amino acids & organic acidsLow: urea, arginine, ornithine, High: citrulline (1.21 mM) glutamine (1.4 mM) asparagine ? Probable Diagnosis

  • Detoxification of NH3 by Urea Cycle Benzoate Dietary ProteinGut Bacteria Endogenous Protein Catab Buphenyl NH4 PAA NH4 + CO2 GLNCarbamoyl PhosphateGluA PhAcGluNH2Hippuric AcidOrnithineCitrullineMITOCHONDRIONAspartateUreaArginineArgininosuccinic AcidFumarate


  • Approach To Differentiation of Urea Cycle Disorders Causing Neonatal HyperammonemiaHyperammonemiaBefore 24 hrs After 24 hrs Metabolic acidosisPreterm FulltermYes No plasma citrullineTHAN PDH PAA abs/tr >1000uM GAII MMA 100-300uM etc. etc. Ur. Orotate uOAlow high ASACPS OTC Citrullinemia

  • Approaches to Therapy of Urea Cycle DisordersAcute Mgmt(based on NH3 level)NPODialysis ( prefer. Hemodialysis)IV: CHO (68 mg Glc/kg/min) Lipid (3 gm / kg)Alternate Pathway TherapyOral (Phenylbutyrate + L-Arg)IV (Phenylacetate + benzoate + L-arginineChronic MgmtLow protein diet 1.0 to 1.5 gm/kg/d-Cyclinex (ess. AAs) (up to 50 % of prot)Phenylbutyrate (Buphenyl) (450-650mg/kg/d)Arg / ornith / citrullineRegular monitoring

  • Case 5: 5 year old girl with hearing loss and macrocephalyRelatively normal global development otherwiseFamily history negative & parents unrelated

    S/S hepatomegaly, mild contractures-hands, knees & elbows

  • HM: Radiologicaal study

  • Case History: HMYou were asked to see this girl for assessment regarding macrocephaly and hearing lossInitial investigations showed an abnormal urine metabolic screen that positive for both CTAB & Toluidine blueAll other initial metabolic studies normalWhat would you do next?

  • Coursened FeaturesLaboratory Screening ParadigmCourse faciesMPS in urineYesNoMPS Storage DiseaseUronic acid MPS by TLCEnzyme AssaysTotal HexMLS II or IIIOligosaccharidosesEnzyme AssaysOligoscreen

  • How do you measure mucopolysaccharide excretion?Uronic acidGAG electrophoresisWhat are the useful GAGS in diagnosing a particular MPS disorder?How is this testing done?

  • How do you measure mucopolysaccharide excretion?Uronic acidGAG electrophoresisAcid Hydrolysis to freemonosaccharide subunits+ Colorimetric detection of the uronic acid (A or B) AB

  • Additional testingUrine MPS excretion

    Uronic acid by acid hydrolysis /carbazole

    Uronic acid is 52 ug/ml

    (Normal < 16.7)

    Other methods

    GAG electrophoresis ( HM spec)

  • Diagnosis & ManagementMucopolysaccharidosis Type III San Filippo syndromeFour different enzyme deficiencies all leading to inadequate breakdown of heparin sulfateShe had deficiency of heparin-N-sulfatase (MPS-IIIA)

    No definitive treatment at presentextensive social/psychological/educational supportappropriate for child with neurodegenerative disorder

  • Case 6:Recurrent Abdominal Pain in 6 yo Male

  • HistoryThe mother of a six year old boy tells you that her son has had three episodes of abdominal pain without any flu-like symptoms or other systemic problems.During the last episode, blood but no bacteria or pus cells were seen in his urine. The urine did not smell, look cloudy or have an unusual color.Her husbands had had similar episodes as a child but these had stopped once he followed the advice of a pediatrician to drink lots of water at nights.

  • Your initial investigations showed that this boy had a