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Case Scenarios Case Scenarios IEM IEM Majid Alfadhel Geneticist and Pediatrician Geneticist and Pediatrician MD,MHSc,SSC MD,MHSc,SSC - - Ped Ped , ABHS(CH), FCCMG , ABHS(CH), FCCMG

Case Scenarios IEM - National Guard Health Affairsngha.med.sa/.../GeneticsDivision/Documents/IEMCaseScenario.pdf · How IEM happened • Monogenic disease results from the absence

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Case ScenariosCase ScenariosIEM IEM

Majid AlfadhelGeneticist and PediatricianGeneticist and Pediatrician

MD,MHSc,SSCMD,MHSc,SSC--PedPed, ABHS(CH), FCCMG, ABHS(CH), FCCMG

Genetics

Clinical Genetics (dysmorphology)

Biochemical Genetics (metabolic)

MolecularClinical  Cytogenetics MolecularClinical  Biochemical

How IEM happened

• Monogenic disease results from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite.

CofactorSubstrate Product

A outside A inside

A inside A outside

How IEM happened

• Monogenic disease result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite.

CofactorSubstrate Product

A outside A inside

A outside A inside

Inborn Errors of Metabolism

A CB

D

BB BB

A1. deficiency

of product

accumulation of substrate

formation of unusual metabolites

(s)

Classification

• Acute vs chronic• Newborn, infancy, childhood, adult• Small molecules vs large molecules

Classification: one approach 

Lysosomes

Mitochondria Peroxisomes

E.R. / Golgi

Cytosol

Inborn Errors of Metabolism:a functional classification

I: Disorders of intermediary metabolism that give rise to “intoxication”(aka "small molecule" disorders)

II: Disorders of energy generation

III: Disorders of complex molecules

Reference: Inborn Metabolic Diseases, 3rd Ed. Fernandes...Saudubray

I. Disorders of intermediary metabolism that give rise to “intoxication”

• Degradative pathways of amino acids

• Organic acidemias

• Urea cycle disorders

• Carbohydrate (“sugar”) intolerances

• Purine and pyrimidine disorders

II: Disorders of energy generation– Glycogen storage disorders– Gluconeogenesis defects (rare)– Mitochondrial respiratory chain disorders– Pyruvate metabolism disorders – Fatty acid oxidation disorders (eg MCAD)– Ketone metabolism disorders (rare)

Glycogen

Glucose

Pyruvate

NADHATP

Fatty acids

III: Disorders of Complex Molecules

• Symptoms are permanent, progressive • Symptoms not related to food intake• Few abnormalities seen on "routine" chemistry

• Classification– Lysosomal storage disorders– Peroxisomal disorders– Congenital disorders of glycosylation (CDGS)– Inborn errors of cholesterol synthesis

Facts• IEM very heterogeneous groups of disorders

– Same disorder can present in neonate, infant, childhood and adult

– Same disorder has different outcome in 2 siblings– Poor correlation between clinical phenotype and genotype

• IEM not limited to pediatrics• IEM can be limited to a single organ and commonly

involves multiple organs• Many IEM disorders are treatable• Clinicians should have high index of suspicion to

recognize such disorders

Case ScenariosIEM

Case #1

• 3 days old infant presented to ER with poor feeding, vomiting, lethargy.

Case #1

• Product of FT NSVD.• Completely well until 3rd day of life.• Antenatal history: unremarkable.• Normal growth parameters.• History of fever but not documented.• Family history: unremarkable.• O/E : growth parameters: normal, CNS

:deep coma.

Case #1

• Investigations:– CBC: benign– Bun: <1, Creatinine:62, Na: 140 , K: 4 , Cl: 100,

co2: 18– Blood gas: PH: 7.48 (7.38-7.44)

Pco2: 20 (23-28 mmol/l)HCO3: 22 (21-28 mmol/l)

– Ammonia: 1000

Questions?

• What is ammonia?• How is it produced?• How to detox from the body ?• What are normal reference ranges?

Answers

• A compound of nitrogen and hydrogen with the formula NH3. It is a colourless gas with a characteristic pungent odor.

• Transamination of aminoacids and deamination of glutamate.

• Detoxified by:– Glutamine synthesis.– Urea Cycle.

Normal reference ranges

Age Upper limit normal (µ mol/l)

0-7 days 948-30 days 801m-16yrs 48>16 yrs 26

Question

• List 4 metabolic genetics causes of hyperammonemia?

DDxDisorder Clinical hintsUrea cycle disorders Low BUN, Respiratory alkalosisOrganic acidemias Metabolic acidosisLysinuric protein intolerance Present after patient is weaned, variable

finding includes: vomiting, diarrhea, growth failure, aversion to protein, osteoporosis , fractures, progressive interstitial lung abnormalities, hepatosplenomegaly, renal involvement resemble GN.

HHH syndrome Increase Ornithine in PAA, homocitrullinein urine

HIHA Increase insuline and hypoglycemia

DDxDisorder Clinical hintsFAOD 4months-4yrs, acute hypoglycemic

encephalopathy and liver dysfunction precipitated by prolong fasting or URTI

Pyruvate dehydrogenase deficiency Lactic acidosis, psycomotor retardation, hyppotonia, epilepsy

Pyruvate carboxylase deficiency Lactic acidosis, psycomotor retardation, hyppotonia, epilepsy

Transient hyperammonemia of newborn

Preterm, RDS

Clinical differences THAN vs UCD

Clinical finding Clinical finding THANTHAN UCDUCD

HistoryHistory Sick immediately after Sick immediately after birthbirth

Sick after the first daySick after the first day

CXRCXR AbnormalAbnormal NormalNormal

Gestational ageGestational age Preterm Preterm Term Term

Birth weightBirth weight < 2500< 2500 >2500>2500

ComaComa < 48 h< 48 h > 48 h> 48 h

NH3NH3 > 1500> 1500 <1500<1500

Blood gasBlood gas AcidosisAcidosis AlkalosisAlkalosis

• PAA profile :showed decrease citrulline and arginine while glutamine is increased.

• UOA :showed increase orotic acid excretion.

Question?

• What is the diagnosis of the previous case?

Diagnosis

Ornithinetranscarbamylasedeficiency

Urea cycle disorders

• Characterized by the triad of hyperammonemia, encephalopathy and respiratory alkalosis

Question?

• List 4 enzyme deficiencies causing urea cycle disorders?

•• Enzyme deficiency include :Enzyme deficiency include :– N- acetylglutamate synthase (NAGS)– Carbamyl phosphate synthase(CPS)– Ornithine transcarbamylase (OTC)– Argininosuccinic acid synthatase(ASS)– Argininosuccinic acid lyase(ASL)– Arginase.

Genetics

• all are autosomal recessive except OTC deficiency X-linked dominant

Classical neonatal form

• Most babies of normal birth weight and are initially healthy but after short intervals , they become unwell, common early symptoms are poor feeding ,vomiting , lethargy ,irritability that progress to seizure ,deep coma hyperventilation, respiratory alkalosis and even death if not treated .

Classical neonatal form

• the liver may be enlarged and serum level of transaminase are often elevated.

• In OTC deficiency the classical form are more common in male however small number of female may have also similar presentation

Late onset form• Less frequent.• Heterogenous presentation.• Recurrent or cyclic vomiting• Episodic Hyperammonemia• Develop. Delay ,MR,Psychatric sign.• Hepatomegally and elevated transaminase.• Asymptomatic

Additional clinical abnormalities

DiseaseDisease C/FC/F

ASS def.ASS def. Dysmorphic(MicrocephalyDysmorphic(Microcephaly,,brittle hairbrittle hair

ASL def.ASL def. Hepatomegaly,brittleHepatomegaly,brittle hairhair

Heterozygous OTCHeterozygous OTC Post partum Post partum hyperammonemiahyperammonemia

ArginseArginse def.def. Spastic Spastic diplegiadiplegiaAmmonia normal or mild Ammonia normal or mild

elevatedelevatedPMR,SeizurePMR,Seizure

• How to differentiate between different types of urea cycle disorders?

By PAA and orotic acidsEnzyme def. Plasma aminoacids Urine

oroticacids

Tissue for enzyme diagnosis

NAGS Increase glutamine and alanine N LiverCPS Increase glutamine and alanine,

decrease citrulline and arginineN Liver

OTC Increase glutamine and alanine, decrease citrulline and arginine

Increase liver

ASS Increase citrulline, decrease arginine

Increase Liver/fibroblast

ASL Increase citrulline, increase ASA, decrease arginine

Increase RBC/liver/fibroblast

Arginase Increase arginine Increase RBC/liver

Management

• A,B,C: The patient with urea cycle should have multilumen central line placed or umbilical catheter.

• Hydration • High caloric intake• Hyperammonemia scavengers• Dialysis

• It is crucial to take blood for plasma aminoacids and urine for orotic acids before start treatment

Question?

• What do we mean by high caloric intake?

Answer

• Covering 110% of the recommended daily allowance (RDA) in order to shut down endogenous protein breakage ( RDA: for newborn and infant: 110-120 kcal/kg/day, for 1-3 yrs:100, for 4-6yrs: 90, for 7-10yrs: 70, for 11-14 yrs: 50-55).

Questions

• How did you achieve high caloric intake?• Calculate the required fluids and lipids for

an infant if his weight: 10 kg?

Answers

• Dextrose + intralipids 20%• 60 X 0.34X 24/10= 50 kcal• 20gram of lipid= 200Kcal/10= 20 Kcal• Total= 60 Kcal• Is this enough?

• What are the indications for dialysis ?

Dialysis

Services Services Once you suspect to start Dialysis in next few hour please Once you suspect to start Dialysis in next few hour please consult ICU and Nephrology team immediatelyconsult ICU and Nephrology team immediately

IndicationIndication If Ammonia doesnIf Ammonia doesn’’t decrease tot decrease to< 200 < 200 umol/lumol/l within 4 hour from start therapywithin 4 hour from start therapy

HypeammonemicHypeammonemic comacomaAmmonia >400 initiallyAmmonia >400 initially

DiscontinueDiscontinue oo Ammonia < 200 Ammonia < 200 mmol/lmmol/loo Risk of rebound overcome by use of Risk of rebound overcome by use of

hemofiltrationhemofiltration..

MethodMethod Depends on the available expertise and equipment.Depends on the available expertise and equipment.

Best recommended Best recommended methodmethod

PumpPump--driven dialysis technique : continuous driven dialysis technique : continuous hemofiltrationhemofiltration with the same pump system, with the same pump system, egeg. CVVH. CVVH

Removal of Removal of cathetercatheter

After the plasma ammonia level has been stable for at After the plasma ammonia level has been stable for at least a day. least a day.

However, this should be balanced by the risk of However, this should be balanced by the risk of maintaining the patient in an maintaining the patient in an anticoagulatedanticoagulated statestate

Questions

• What are hyperammonemia scavengers?• Dosages?• Side effects?

ArginineArginine hydrochloride (200hydrochloride (200--600mg/kg) diluted in 600mg/kg) diluted in D10w given as bolus over 90 minute followed by D10w given as bolus over 90 minute followed by continuous IV infusion as maintenance.continuous IV infusion as maintenance.

ArginineArginine hydrochloride vial: 30 ml.hydrochloride vial: 30 ml.AmmonulAmmonul ((Sodium benzoate and Sodium Sodium benzoate and Sodium phenylacetatephenylacetate)) (250mg/kg or 5.5mg/m(250mg/kg or 5.5mg/m22 followed by followed by 250250--500mg/kg as continuous IV infusion as 500mg/kg as continuous IV infusion as maintenance.maintenance.Potassium can be given in the same line of Potassium can be given in the same line of AmmonulAmmonulinfusion*.infusion*.Reloading only in neonates with severe disorders or Reloading only in neonates with severe disorders or those who are undergoing dialysis, and should be those who are undergoing dialysis, and should be spaced at least 6 hours.spaced at least 6 hours.

• These medication should be given through central line, can be given through peripheral line on limited bases.

• Don’t exceed 500 mg/kg/dy of sodium benzoate and phenylacetate.

•• Note:Note:– Ammonul contain 30.5 mg/ml of sodium =1.3meq/ml– Concentration: Na benzoate 100 mg/ml ,phenylacetate 100

mg/ml.– Ammonul vial: 50 ml.

PharmacPharmacokineticsokinetics

NH3 NH3 Removal Removal

MOAMOAusesuses

1.5 hour1.5 hourMetabolism : Metabolism : liverliver

1 mole of 1 mole of sodium sodium benzoate benzoate remove 1mole remove 1mole of ammonia as of ammonia as glycineglycine

conjugate conjugate with glycine with glycine to form to form hippurichippuric acidacid

Acute ,some Acute ,some use it in use it in chronic if PB chronic if PB failfail

Sodium Sodium benzoatebenzoate

2 hour 2 hour Metabolism : via Metabolism : via acetylationacetylation in in liver and kidneyliver and kidney

1 mole of 1 mole of phenylaceatephenylaceateremove 2 mole of remove 2 mole of ammonia as ammonia as glutamineglutamine

conjugate with conjugate with glutamine to glutamine to form form phenylacetylglutaphenylacetylglutaminemine

AcuteAcuteSodium Sodium phenylacetatephenylacetate

1 mole of 1 mole of phenylaceatephenylaceateremove 2 mole of remove 2 mole of ammonia as ammonia as glutamineglutamine

ProdrugProdrug rapidly rapidly convert to PAGconvert to PAGchronicchronicSodium phenyl Sodium phenyl

buteratebuterate

Use in caution with

Congestive heart failureRenal or hepatic dysfunctionHyperbilirubenemiaSodium retention associated with edema

Adverse reaction

Sodium benzoate and sodium phenylacetate :• Cardiovascular: Hypotension (4%)• Dermatologic: Injection site reaction (3%)• Endocrine metabolic: Hyperglycemia (7%),

hypokalemia (7%)• Gastrointestinal: Vomiting (9%) , diarrhoea (3%)• CNS: Altered mental status (6%) , seizure (6%)

,cerebral oedema (5%) • Other: Fever (5%

Case#2

• Mohammed, 7 months old boy with Argininosuccinate Lyase deficiency admitted to PICU while you are luckily on-call that night. He is improving with hyperammonemia scavengers and high caloric intake. You are monitoring electrolytes, ammonia and blood gas q4 hourly. A nurse called you with glucose result of 20 mmol/l. What you will do?

Case#2–– Start Insulin infusion IV :Start Insulin infusion IV :

50 unit diluted in 500 ml NS to be run @ 1/4 -1/2 weight of the patient (0.025-0.05 unit /kg/hour). Usual dilution 0.1 unit/mlOnce infusion started measure glucocheck Q1 hourlyTitrate the insulin infusion rate according to the glucocheck result.The lowest rate through peripheral line is 2 ml/hour and central line 4 ml/hour to keep vein open.

Case#3

• Nojoud, 1 yr old with propionic acidemia. Admitted over the night with acute metabolic crises. Currently, on IVF D10% at 1and1/2 maintenance+ intralipid 20% (2 gram/kg). You are seeing her in the morning. Her electrolytes, ammonia, blood gas within normal. What will you do?

Case#3

• Call metabolic dietitian to start the propiomexformula if not started.

• Titrate IVF and D/C lipids

Case#4

• Saif, 4 years old with argininosuccinatelyase deficiency admitted to the general word with acute metabolic crises 3 days ago. You are preparing him for discharge, what are the parameters you are looking for before discharge?

Case#4

– Normal clinical status as home before crises.• Ammonia level normal.• Check the dosages of medications .

Case#5

• You are doing your daily morning round and one of your patients has urea cycle disorders. One of the junior residents ask you about the role of carnitine in such disorders?

Case#5

– Not believed to be beneficial

Case#6

– Lyan, 4 years old with argininosuccinate lyasedeficiency. Admitted overnight with metabolic crises, she is currently looking well but a nurse called you from general word with blood gas result of • PH: 7.46 (7.38-7.44) • Pco2: 25 (23-28 mmol/l) • HCO3: 15 (21-28 mmol/l). What you will do?

Case#6

• Check the dose of arginine hydrochloride. It could be side effect of medication

• Check hydration status and type of IVF.• Check electrolytes for hyperchloremia and

hypokalemia.• Repeat blood gas could be lab error.

Case#7

• You are seeing in the clinic a 1 year old boy with developmental delay and seizures. Opon examination: Microcephalic and his complexion is lighter than his brothers. His mother said that his urine smell musty. What is the most likely diagnosis?

Case#7

• Phenylketonuria (PKU)

Question?

• What lab investigations will you order?• Why does his urine smell musty?

Answers

• Plasma aminoacids• Because of increase concentration of

phenyllactic acid.

Abnormal odour

Case#8

• 3 days old newborn product of FT, NSVD, BW: 3Kg and AS: 9, 9, found to have poor feeding, lethargy started today.

• Ammonia: 250 (normal<72), blood gas: PH: 7.2

• PaCO2 : 22, HCO3 : 8. What is the most likely diagnosis

Case#8

• Most likely organic acid disorders:– Propionic acidemia– Methylmalonic acidemia

Question?

• What lab investigations will you order?

Answer

• Acylcarnitine profile (TMS)• Plasma aminoacids.• Urine for organic acids.

Organic acidemiasPoor feeding, vomiting, lethargy

metabolic acidosis , hypoglycemia

Ketosis No ketosis

No skin Skin involvement 1. HMG CO A lyase

deficiency2. FAOD3. GA II4. HMG  CO A synthetase

def.

Multiple carboxylasedef.

No odour odour

MMAPPA

MSUDIVA

Case#9

• You are on-call and a Newborn Screening Lab called for positive newborn screening for Maple Syrup Urine Disease. What will you do?

Case#9

• Ask the lab to fax you the result.• Ask about the date of birth.• Call the family and take detailed history.• Call Biochemical Geneticist on-call.• Accordingly, you will decide to bring the baby

to ER or bring him tomorrow to repeat the test.

Question

• Which disorders are currently included in the National NBS program in Saudi Arabia?

KAMC started NBS at 31 May 201116 disorders:

– Methylmalonic acidemia (MMA)

– Propionic acidemia (PA)

– Maple syrup Urine disease ( MSUD)

– Arginosuccinate lyase Deficiency (ASL)

– Citrullinemia (Cit)

– HMG‐CoA lyase def.

– Isovaleric acidemia (IVA) 

– Glutaric acidemia (GA‐1)

– Betaketothiolase def. (BKT)

‐Medium Chain acyl coAdehydrogenaqse def. (MCAD)

– Phenylketonuria (PKU)– 3‐methylcrotonylcoa 

carboxylase def. (3‐MCC)– Galactosemia– Biotinidase def.– Congenital adrenal 

hyperplasia– Hypothyroidism 

Case#9Case#9

• Baby is 8 days old and has poor feeding and crying all the time since today.

• You received the result from the lab, what amino acids you are looking for in this report?

Answer

• Leucine, Isoleucine and Valine

Case#9Case#9

• Leucine: 3400µmol/l (61-183)• Isoleucine: 900 µmol/l (27-80)• Valine: 780 (78-264)What you will do?

Answer

• Call the family to bring the baby to ER ASAP.• Call biochemical Genetics specialist.• Prepare IV team for peripheral and central IV

line insertion.• Call the pharmacy to prepare intralipid20%• Call the PICU team and Nephrology team for

dialysis.

Case#10Case#10

• A 9 months old child presented with coarse facial features and developmental delay. Eye examination showed corneal clouding, you ordered skeletal survey which showed:

Answer• Dysostosis Multiplex: :Dysostosis: abnormal development

of the bone , Multiplex: multiple .• Spatulated ribs, Shallow acetabulum, vertebral bodies develop

peak-like projection on the lower anterior margin while upper part remains hypoplastic, tappering of terminal phalnges and widening at distal end and tapering at proximal ends of metacarpals

• What is DDx of dysostosis multiplex

DDx• Galactosialidosis• GM1 ganglisidosis• Mucopolysaccharidosis• Mucolipidosis I (Neuroaminidase Deficiency)• Mucolipidosis II ( I cell disease)• Mucolipidosis III• Multiple Sulfatase deficiency• Fucosidosis• Mannosidosis• Infantile sialic acid storage disorder• Geleophysic Dysplasia

Case#10Case#10

• You ordered urine for mucopolysaccharides as part of work-up for this patient and the result came back positive with high dermatan and heparan sulfatase, what is the most likely diagnosis?

• Hurler syndrome or MPSIH

Case#11Case#11• Lyan, an 18 months old girl with 

severe developmental delay and coarse facial features as in the picture noted since birth.

• skeletal survey showed periostealreactions in the long bone. Lab investigations showed excessive excretion of oligosaccharides in the urine. What is the most likely diagnosis?

Case#11Case#11

• Mucolipidosis II or I cell disease.

Mucolipidosis

• 4 types• All are autosomal recessive disease

MucolipidosisTypes Clinical hints DX

I (Sialidosis) Type I = myoclonus‐cherry red spots without dysmorphism, >50%  ataxia, seizure.Type II: congenital: hydrops, ascitis, MR, still birth, coarse facial features, HSM, inguinal hernia, stippling of epiphysis, periosteal cloacking, severe renal involvmentInfantile: normal at birth, present in 1st year of life with dysostosismultiplex, cherry red spot, corneal clouding, psychomotorregressionand seizure

Urine for oligosaccharides

BM: foamy  cells, voculatedlymphocytesEnzyme assay  (neuroaminidase) in C/S fibroblastDNA molecular testing

MucolipidosisTypes Clinical hints Dx

II ( I cell disease) C/F similar to Hurler, however, the earlier onset of sign and symptoms and absence of MPS uria, death between 5‐8 yr of age

Defect in lysosomaltargeting, therefore, all lysosomal enzyme are high in plasma compare to control

III Milder disorder with later onset and more slowly progressive presenting survival into adult hood

Diffrentiated from mucolipidosis II by DNA molecular testing

IV Severe motor developmental delay, corneal clouding, progressive retinal degeneration and  achlorhydria

Increase blood gastrin levelDNA molecular testing

Case#12Case#12

• A 1 year old child presented to the ER with acute hepatic crises which is precipitated by URTI. He is febrile, irritable, has vomiting and hematemesis, his liver is enlarged and has jaundice, his blood glucose level is low and you started him on IVF D10%. He has high liver enzymes and coagulation abnormalities and smells like boiled cabbage.

Questions?

• What is the diagnosis?• What is the treatment of this condition?

Answers

• Tyrosinemia type I• Diet restricted in phenylalanine and tyrosine• NTBC (2-(nitro-4-trifluoromethylbenzoyl)-

1,3-cyclohexanedione).

Case#13Case#13

• A 6 months old girl referred from cardiology clinic with hypertrophic cardiomyopathy based on Echocardiogram finding, EKG showed short PR interval. O/E she has macroglossiaand central hypotonia

Questions?Questions?

• What is the most likely diagnosis?• What is the enzyme deficient in this disorder?

Answers

• GSD type II• Alpha glucosidase

GSDs

• 14 types• Liver types: I, III, IV, VI, IX, 0, Fanconi-

Bickel syndrome.• Muscle types: V, VII, phosphoglycerate kinase

def., X, XI, XII, XIII, XIV.• Cardiac involvement: II, IIb, III, Muscle

glycogen depletion syndromes.• Neurodegeneration: Lafora disease, adult

polyglucason disease.

GSDs

• Type IX classifications:– X- linked liver phosphorylase Kinase deficiency – Autosomal combined liver and muscle PKD– Autosomal liver PKD– X-linked muscle PKD– Autosomal muscle PKD– Heart limited PKD

Case#14Case#14

• You are on‐call at NICU and you received a baby who was just delivered with profound hypotonia and poor feeding and dysmorphic as in the picture (high forehead, large AF, hypoplastic supraorbitalridge, epicanthal fold, midface hypoplasia), skeletal survey: epiphysealstippling  and renal U/S : renal cyst

Questions?• What is the most likely diagnosis?• Where is the defect located?

Answers

• Zellweger spectrum disorders• Peroxisomal biogenesis

Peroxisomal disorders

• What is peroxisomes?• What are their functions?• What is the classification of peroxisomal

disorders?

Answers• Peroxisomes organelles play a major role in the

oxidation of fatty acids for energy conversation.• Has multiple functions:

– Plasmalogen biosynthesis– FA beta-oxidation– Peroxisomal alpha oxidation– Glyoxylate detoxification– Hydrogen peroxide metabolism– L-pipecolic acid oxidation– Metabolism of bile acids– Cholesterol biosynthesis

Classification– Disorders of peroxisome import:

• Zellweger syndrome.• Neonatal ALD• Infantile Refsum disease• RCDP type I

– Disorders of single peroxisomal enzyme:• X-linked ALD• Bifunctional enzyme deficiency.• Acyl-Co A oxidase deficiency.• 2-methylacyl Co-A racemase deficiency.• Classic Refsum disease• RCDPII• RCDPIII• Acatalasemia• Peroxisomal thiolase deficiency• Glutaric aciduria type III

Questions

• What are the investigations you ordered for diagnosing a patient with suspected peroxisomal disorders?

Answer

• Very long chain fatty acids• Phytanic acid• Pristanic acid• Plasmalogen analysis in RBC• Dihydroxycholestanoic acid and trihydroxy

cholestanoic acid in plasma• Plasma and urine pipecolic acid

Case#15Case#15

• A 3 years old intelligent girl with huge liver and spleen, ophthalmological examination showed cherry red spot and bone marrow biopsy showed foamy histiocytes what is the most likely diagnosis?

Answer

• Niemann-pick disease type B

Niemann-pick vs GaucherNiemann-Pick Gaucher

Types A, B, C I,II,III, Perinatal lethal and cardiac

Enzyme deficient

Acid sphingomyelinase, C due to defect in lipid trafecking

Acid b-glucocerebrosidase

Cherry red spot

Present in A and B Absent

Treatment ERT for C ERT but not effective in neuronopathic form

Dx Enzyme assay in WBC and C/S fibroblast confirmed by DNA molecular testingFor type C: fillipin staining in C/S fibroblast

Enzyme assay in WBC and C/S fibroblast confirmed by DNA molecular testing

Niemann-Pick Gaucher

Clinical Type A: earlier onset, rapidly progressive, involvement of CNSType B: non-neronopathic, later onset, slowly progressiveBoth: HSM, diffuse lung infiltrate, recurrent chest infections, arthrogenic lipid profile and xanthomas.Type C: hydrops, neonatal ascitis, cholestatic jaundice, HSM, at childhood: ataxia, supranuclear vertical gasepalsy

TypeI: at any age, no CNS involvement, bone disease, splenomegaly > hepatomegaly, hematological manifistations and diffuse lung infiltrate.Type II: neronopathic form rapidly progress death by 2 years (supranuclearhorizontal gase palsy).Type III: subacuteneuronopathic form