9/18/14

INBORN ERRORS METABOLISM

dr. R. Sutomo, Sp.A(K), Ph.D

Developmental & Behavioral Pediatrics
H u m a n M o l e c u l a r G e n et i c s
rsutomo.id@gmail.com,  rsutomo@ugm.ac.id  

Inborn  errors  metabolism  (IEM)  

•  Inherited  biochemical  disorders  

•  Muta8ons  affec8ng  proteins  involved  in  the  
many  metabolic  pathways  of  the  body  
•  Disorders  involving  deficiencies  of  enzymes  
 à  mostly  autosomal  recessive  

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IEM  –  clinical  features  

•  OEen  normal  at  birth  
•  May  show  signs  early  
– Metabolic  acidosis,  poor  feeding,  vomi8ng,  
lethargy,  and  convulsion  
– Mental  retarda8on,  organomegaly,  unusual  
bodily  odors,  episodic  decompensa8on  

IEM  -­‐  diagnosis  

•  Many  IEMs  can  be  detected  in  neonatal  
period  or  infancy  
•  Some  IEMs  are  included  in  newborn  screening  
•  Diagnosis  of  IEM  usually  involves  laboratory  
studies  

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IEM  -­‐  treatment  

•  Treatment  varies  among  different  IEMs  
– OEen  suppor8ve/symptoma8c  
– Frequently  includes  dietary  modifica8ons  

IEMs  -­‐  classifica:on  

1.  Defects  of  amino  acid  metabolism  
2.  Defects  of  lipid  metabolism    (lysosomal  
storage  diseases)  
3.  Defects  of  carbohydrate  metabolism  
(glycogen  storage  diseases)  
4.  etc  

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Defect  of  amino  acid  metabolism  

Phenylketonuria  (PKU)  

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PKU  –  basic  defect  

•  Inherited  disorder  of  AA    
•  metabolism  

•  Inability  to  convert  Phenylalanine  to                                    

tyrosine  

•  Deficiency  of  phenylalanine  hydroxylase  

(or  its  cofactor  tetrahydrobiopterin,  BH4,  
THB))  

PKU  –  basic  defect  

•  Accumula8on  of  phenylalanine  and  its  
phenylketone  metabolites  à  brain  damage  
•  Phenylketone  (in  urine)  
–  Phenyl-­‐acetate  
–  Phenyl-­‐lactate  
–  Phenyl-­‐pyruvate  
•   Thus,  tyrosine  becomes  essen8al  amino  acid  

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PKU  –  epidemiology  &  clinical  

•  Inherited  as  autosomal  recessive  
trait  
•  Incidence:  1/10,000  -­‐  20,000  live  
births  
•  Normal  at  birth  (asymptoma8c)  
•  Mental  retarda8on,  fair  hair  and  
skin,  blue  eyes,  eczema,  mousy/
musty  body  odor  

PKU  -­‐  diagnosis  

•  Serum  tested  72  hours  aEer  ini8a8on  of  first  
protein  feed  (test  may  be  nega8ve  prior  to  72  
hours).  
•  Without  neonatal  screening,  diagnosis  usually  
made  at  4  to  6  months  of  age.  
•  Prenatal  and  carrier  tes8ng  are  available  

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PKU  -­‐  treatment  

•  Limit  dietary  phenylalanine  (e.g.,  in  ar8ficial  

sweeteners)  
•  Increase  dietary  tyrosine  
–  Chicken,  turkey,  fish,  milk,  yogurt,  cheese,  peanuts,  
almonds,  pumpkin  seeds,  sesame  seeds,  soy  products,  
avocados,  banana  

Homocys:nemia/  
Homocys:nuria  

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Basic  defect  
•  Inherited  disorder  of  AA  metabolism  (AR)  
•  Homocysteine  is  present  in  greater  than  trace  amounts  
in  urine  
•  Homocysteine  is  not  remethylated  to  methionine  
•  Mostly  deficiency  of  cystathionine  synthase  
•  Other  possible  defects:  
–  defect  of  methylcobalamin  forma8on  
–  deficiency  of  methyltetrahydrofolate  reductase  (MTHFR)  

Homocysteine  
 pathway  

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Clinical  features  
•  Depends  on  par8cular  enzyme  deficiency  
•  Mostly   normal   at   birth,   with   subsequent   failure   to  
thrive  and  developmental  delay  
•  Later   à   ectopia   len8s,   marfanoid   body   habitus,  
progressive   mental   retarda8on,   vaso-­‐occlusive  
disease,  osteoporosis,  or  fair  skin  with  malar  flush  

Diagnosis  &  treatment  

•  Diagnosis  
–  Normal  at  birth;  usually  diagnosed  aEer  3  years  old  
–  ↑  homocysteine  in  body  fluids  
–  Prenatal  diagnosis  possible  
•  Treatment  
–  High-­‐dose  vitamin  B6  (may  require  concurrent  folic  acid)  
–  Restric8on  of  methionine  intake  and  supplementa8on  of  cysteine  
–   Betaine  if  unresponsive  to  B6  therapy  
–  Other  types  may  require  vitamin  B12  or  methionine  supplementa8on  

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Maple  Syrup  Urine  Disease  

(MSUD)  

MSUD  -­‐  basics  

•  Autosomal  recessive  trait  
•  Disorder  of  branched-­‐chain  amino  acid  metabolism  
•  ↑  leucine,  isoleucine,  valine,  and  corresponding  
oxoacids  
•  Deficiency  of  branched-­‐chain  ketoacid  
dehydrogenase  
•  Defect  in  the  decarboxyla8on  of  leucine,  isoleucine,  
and  valine  

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MSUD  -­‐  clinical  

•  Incidence:  1/290,000  live  births  
•  Deficiency  of  different  subunits  of  enzyme  account  for  wide  
clinical  variability  
•  Poor  feeding,  vomi8ng  in  first  week  of  life,  proceeding  to  
lethargy  and  coma  
•  Alterna8ng  hypertonicity  and  flaccidity,  convulsions,  
hypoglycemia  
•  Odor  of  maple  syrup  in  urine,  sweat,  cerumen  

MSUD  –  Dx  and  Tx  

Diagnosis  
•  ↑leucine,  isoleucine,  valine,  alloisoleucine  (plasma  &  urine)  
•  ↓  plasma  alanine  
•   Neuroimaging  in  acute  state  à  cerebral  edema.  
Treatment  
•  Chronically,  low  branched-­‐chain  amino  acid  diet  
•  Frequent  serum  level  monitoring  
•  Acutely,  iv  administra8on  of  amino  acids  other  than  branched  chain  

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Defect  of  lipid  metabolism  

(lysosomal  storage  disease)  

Lysosomal  storage  disease  -­‐  lipidosis  

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Lipidosis  
•  Inherited  deficiencies  of  lysosomal  hydrolases  à  
lysosomal  accumula8on  of  sphingolipids  in  brain  and  
viscera  
•  Mostly  AR  inheritance  
•  The  clinical  findings  depend  on  site  of  abnormal  
accumula8ons:  
–  Nervous  system—neurodegenera8on,  ocular  findings  
–   Viscera—organomegaly,  skeletal  abnormali8es,  
pulmonary  infiltra8on  

Lipidosis  
•  Diagnosis  by  measurement  of  specific  
enzyma8c  ac8vity  in  leukocytes  or  cultured  
fibroblasts  
•  Usually  no  specific  treatment  
•  Suppor8ve/symptoma8c  therapy  

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Lysosomal  storage  disease  -­‐  

mucopolisaccharidoses  

Mucopolysaccharidosis  
•  Inherited  deficiencies  of  lysosomal  enzymes  
needed  for  degrada8on  of  glycosaminoglycans  
(GAGs)  
•  Widespread  lysosomal  storage  of  dermatan  
and  heparan  sulfates  and  severe  clinical  
abnormali8es  

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Mucopolysaccharidosis  -­‐  clinical  

•  Normal  at  birth,  diagnosis  at  1+  years  
•  “Gargoyle”  cells  containing  lysosomes  engorged  with  
mucopolysaccharide  
•  Excessive  urinary  excre8on  of  GAGs  
•  Progressive  mental  and  physical  deteriora8on  
•  Coarse  features  
•  Corneal  clouding  
•  S8ff  joints  (abnormal  hyaliniza8on  of  collagen)  
•  Organomegaly  
•  Skeletal  abnormali8es  

Mucopolysaccharidoses  –  Dx  and  Tx  

•  Detec8on  of  enzyme  deficiency  in  leukocytes  or  
cultured  fibroblasts  
•  Ro  à  dystosis  mul:plex  (large  dolichocephaly,  
thickened  calvarium,  ovoid  vertebral  bodies,  flared  iliac  
bones,  shallow  acetabulae,  irregular  widening  of  long  
bones  
•  Urinary  excre8on  of  dermatan  and  heparan  sulfates  
•  Mainly  suppor8ve  therapy  
–  Hurler’s  can  be  treated  with  bone  marrow  transplant.  

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Defect  of  carbohydrate  

metabolism  
(glycogen  storage  disease)  

Glycogen  storage  diseases  

Disease Glycogen Deficiency Type
accumulation
Von Gierke’s Liver, kidney, and Glucose-6-phosphatase I
intestine
McArdle’s Skeletal muscle Skeletal muscle glycogen II
phosphorylase

Pompe’s Cardiac and α-1,4-glucosidase (acid III

skeletal muscle maltase)

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Von  Gierke’s  Disease  

•  Inherited  disorder  of  glycogen  metabolism  
characterized  by  deposi8on  of  glycogen  in  liver,  
kidney,  and  intes6ne  
•  Deficiency  of  glucose-­‐6-­‐phosphatase.  
•  Glycogen-­‐to-­‐glucose  metabolism  stops  at  glucose-­‐6-­‐
phosphate  
•  Autosomal  recessive  inheritance  

Von  Gierke’s  Disease  -­‐  clinical  

•  Massive  hepatomegaly  
•  Hypoglycemia  
•  ↑lactate,  uric  acid,  cholesterol,  triglycerides  in  
serum  
•  Renal  complica8ons  (Fanconi’s,  nephrocalcinosis,  
focal  segmental  glomerulosclerosis)  

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Von  Gierke’s  Disease  -­‐  clinical  

•  Normal  at  birth,  diagnosis  usually  at  5  months.  
•  Administra8on  of  epinephrine,  glucagons,  galactose,  
fructose,  or  glycerol  does  not  provoke  normal  
hyperglycemic  response  
•  Tests  may  precipitate  acidosis  
•  Liver  biopsy  à  accumula8on  of  glycogen  in  cells  

Von  Gierke’s  Disease  -­‐  treatment  

•  Suppor8ve  therapy  
•  Frequent,  high-­‐carbohydrate  meals  
•  Avoid  fas8ng  
•  Macrophage  colony  s8mula8ng  factors  to  combat  
neutropenia  and  inflamma8on  
•   Allopurinol  to  lower  urate  levels  
•   Transplant/hemodialysis  for  renal  failure  

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McArdle’s  Disease  -­‐  basics  

•  Inherited  disorder  of  glycogen  metabolism  
characterized  by  deposi8on  of  glycogen  in  skeletal  
muscle  
•  Deficiency  of  muscle  glycogen  phosphorylase  
(myophosphorylase)  
•  Autosomal  recessive  

McArdle’s  Disease  -­‐  clinical  

•  Temporary  weakness  and  cramping  of  skeletal  
muscles  aEer  exercise  
•   No  rise  in  blood  lactate  during  ischemic  exercise  
•   Characteris8c  “second  wind”  with  ini8a8on  of  faoy  
acid  metabolism  

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McArdle’s  Disease  –  Dx  &  Tx  

Diagnosis  
•  Asymptoma8c  during  infancy.  
•  Muscle  biopsy  and  assay  à  deficiency  of  enzyme  
•  Myoglobinuria,  elevated  CK  aEer  exercise  
Treatment  
•  Dietary  modifica8on  (high  fat  and  protein)  
•  Suppor8ve  therapy  

Pompe’s  Disease  
•  Inherited  disorder  of  glycogen  metabolism  
characterized  by  deposi8on  of  glycogen  in  
cardiac  and  skeletal  muscle.  
•  Deficiency  of  acid  α-­‐1,4-­‐glucosidase  
•  Generalized  glycogenesis  because  the  defect  is  in  
all  cells  
•  Results  in  inability  to  convert  mannose  to  glucose  
•  Autosomal  recessive  

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Pompe’s  Disease  -­‐  clinical  

•  Rapid,  progressive  cardiomyopathy  with  
massive  cardiomegaly  
•  Macroglossia,  hypotonia,  hepatomegaly  
•  Death  by  1  to  2  years  
•  Juvenile  form  milder,  slowly  progressive  
myopathy,  liole  to  no  cardiac  abnormality  

Pompe’s  Disease  –  Dx  &  Tx  

Diagnosis  
•  Electrocardiogram  (ECG),  electromyogram  
(EMG).  
Treatment  
•  No  specific  treatment;  suppor8ve  therapy.  

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Galactosemia  
•  Inborn  errors  of  carbohydrate  metabolism  that  result  
in  elevated  galactose  and  metabolite  levels  in  blood  
and  urine  
•  Remind:  galactose  =  glucose  +  lactose  
•  Autosomal  recessive  
•  Incidence  of  1/60,000  

Galactosemia  
•  3  types:  
– Classic:  Absence  of  galactose-­‐1-­‐phosphate  
uridyltransferase  
– Others:  Galactokinase,  uridine  diphosphate  
galactose-­‐4-­‐epimerase  

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Galactosemia  
•  Inges8on  of  galactose  leads  to  increased  
concentra8ons  in  the  blood  and  urine  
•  Toxic  substances,  including  galac8tol,  cause  
organ  damage.  
•  Cataracts,  hepatosplenomegaly,  mental  
retarda8on  

Galactosemia  

•  Newborn,  infant,  or  child  à  jaundice,  hepatomegaly,  

vomi8ng,  hypoglycemia,  convulsions,  lethargy,  
irritability,  feeding  difficul8es,  poor  weight  gain,  
aminoaciduria,  cataracts,  vitreous  hemorrhage,  
hepa8c  cirrhosis,  ascites,  splenomegaly,  or  mental  
retarda8on  

     Highly  suspected  

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Galactosemia  –  Dx  &  Tx  

Diagnosis  
•  Demonstrate  reducing  substance  in  urine  aEer  
administra8on  of  human  or  cow’s  milk  
•  When  diagnosis  is  not  made  at  birth,  damage  
to  the  liver  and  brain  become  irreversible  
Treatment  
•  Exclude  galactose  and  lactose  from  diet  
•  Elimina8on  of  galactose  from  diet  does  not  
ensure  reversal  of  cataract  forma8on  

Fructosuria  

•  Inborn  errors  of  carbohydrate  metabolism  resul8ng  in  

elevated  fructose  and  metabolite  levels  in  blood  and  urine  
•  Caused  by  deficiency  of  fructokinase  
•  Enzyme  is  normally  found  in  the  liver,  kidney,  and  intes8ne  
•  Ingested  fructose  is  not  metabolized  
•  Autosomal  recessive  trait  

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Fructosuria  
•  Asymptoma8c  un8l  fructose  introduced  into  diet  
•  Fructosemia  and  fructosuria  
•  Presence  of  urinary-­‐reducing  substrate  without  
clinical  symptoms  
•  No  specific  treatment  

Defect  in  purine  metabolism  

Lesch–Nyhan  Syndrome  
•  Disorder  of  purine  metabolism  resul8ng  in  
deposi8on  of  purines  in  8ssues  and  subsequent  
clinical  abnormali8es  
•  Deficiency  of  hypoxanthine–guanine  phosphoribosyl  
transferase  (HGPRT)  
•  X-­‐linked  recessive  trait  

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Lesch–Nyhan  Syndrome  -­‐  clinical  

•  Retarda8on  of  motor  development,  spas8c  
cerebral  palsy,  self-­‐injurious  behavior  
•   Hyperuricemia,  uricosuria,  urinary  tract  
calculi,  nephropathy,  tophi,  gouty  arthri8s  

Lesch–Nyhan  Syndrome  –  Dx  &  Tx  

DIAGNOSIS  
•   Normal  at  birth,  diagnosis  usually  made  at  3  months  when  
delayed  motor  development  becomes  apparent  
•  Serum  uric  acid  levels.  
TREATMENT  
•  No  specific  treatment;  suppor8ve  therapy  
•  Allopurinol  -­‐-­‐  ↓  serum  uric  acid  
•  Preven8on  of  self-­‐injury  

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Some6mes,  
You  have  to  be  confused  first  
to  get  a  beGer  understanding  

It’s  not  for  exam,  

but  for  life,  
you  learn  

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