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BAWAAN
( INBORN ERRORS OF
METABOLISM)
J. S. LISAL
Sub Bagian Gizi & Metabolik
BIKA FK UNHAS/RSWS
MAKASSAR
SEJARAH
1908 : Sir Archibald Garrod pertama
kali menggunakan istilah inborn
error of metobolism untuk kelainan
alkaptonuria,pentosuria benigna,
albinism, cystinuria (inherited
disorders by Mendel Law)
1934 : Følling menemukan PKU
1995 : ditemukan 400 inborn error of
metabolism (Scriver et al., 1995)
Kelainan metabolisme bawaan
(inborn errors of metabolism = IEM)
5
Membrane -
1 2
Aoutside Ainside B C
Holoenzyme
3
4
D Apoenzyme
+
cofactor
E F
6
Klasifikasi IEM
Manifestasi Klinis
sindrom neurologis
asidosis metabolik
sindrom hati
sindrom jantung
storage syndrome & dysmorphism
gangguan metabolik akut (neonatus)
Jenis/lokasi kelainan metabolisme
Small molecule disease
Organelle diseases (lysosomal,
peroxisomal, mitochondrial)
Sindrom Neurologis
Ensefalopati kronik
Gray matter or white matter diseases
Ensefalopati akut
Hiperamonemia, reye-like ensefalopati
akut, hipoglikemia
Kelainan gerak (movement disorders)
Miopati
Mioglobinuria, mitochondrial miopati
Problem psikiatrik dan perilaku
Autism, hiperaktifitas
Sindrom Hati
Jaundice :
Unconjugated hyperbilirubinemia
- G6PD deficiency, Gilbert syndrome
Crigler – Najjar syndrome
Conjugated hyperbilirubinemia
- Rotor or Dubin Johnson syndrome
Hepatomegaly : glycogenosis
Hypoglycemia :
Glygogenosis, gluconeogenesis defect
Hepatocellular dysfunction :
Galactosemia, tyrosinemia,
1-antitrypsin deficiency
Clinical Differentiation
Feature Organelle Small molecule
disease disease
Onset Gradual Often sudden, even
catastrophic
Course Slowly Characteristic by
progressive relaps & remmision
Physical Characteristic Non spesific
Findings & features
histology
Response Poor Brisk
to therapy
Clinical Characteristics
Lysosomal Peroxisomal Mitochondrial
Disease limited in Multisystem disease Multisystem disease
nervous system & RES
Chronic course FTT FTT
Hepatomegaly, Profound hypotonia Cerebral dysgenesis
variable
Leucodystrophy, often Cerebral dysgenesis Sensorineural hearing
severe loss
Cerebral atrophy Hepatocellular Periphreal neuropathy
marked dysfunction
Skin lesion Sensorineural hearing Myopathy
(angiokeratomata) loss
Cherry red macular Nueropathy Extraocular
spot opthalmoplegia
Behaviour/psychiatric Cyctic disease of Cardiomyopathy
problems kidneys
Seizures, late Seizures, early & Retinitis pigmentosa
intractable seizures, variable
Klasifikasi Kelainan
Metabolisme Bawaan
Kelainan metabolisme asam amino & peptida (PKU)
Kelainan metabolisme asam organik
Hiperamonemia & defek siklus urea
Kelainan metabolisme karbohidrat (glikogenosis,
galaktosemia, fruktosemia, dll)
Kelainan oksidasi asam lemak (MCAD, LCHAD, dll)
Kelainan metabolisme badan keton
Lysosomal storage disorders
{mukopolisakaridosis (MPS), dll}
Kelainan metabolisme lipoprotein & lemak
Kelainan peroksisomal (adrenoleukodistrofi, dll)
Kelainan metabolisme purin & pirimidin
Klasifikasi Kelainan
Metabolisme Bawaan
Kelainan metabolisme kalsium
Kelainan metabolisme logam (penyakit Wilson,
sindrom Menkes, dll)
Asidosis laktat kongenital dan miopati metabolik
Porfiria
Kelainan metabolisme kolesterol, sterol & asam
empedu
Kelainan metabolisme vitamin (biotin,
cobalamin, dll)
Defek transport membran (lysinuric protein
intolerance, dll)
Defek glikosilasi
Defek jaringan ikat
Indikasi Kemungkinan
Kelainan Metobolisme
Bawaan
Konsanguinitas
Riwayat penyakit yang tidak dapat
diterangkan (sepsis, ensefalopati,
SIDS) pada saudara sekandung
Riwayat penyakit keluarga (PKU
maternal, riwayat stroke dini, dll)
Malnutrisi atau gagal tumbuh
Gagal Tumbuh dan IEM
Intrauterine growth retardation
Lysosomal storage disorders
Kelainan peroksisomal
Defek biosintesis kolesterol
(Smith-Lemli – Opitz)
Respiratory chain disorders
Bayi dari PKU maternal yang tidak
diterapi
Gagal Tumbuh dan IEM
GAGAL TUMBUH, ANOREKSIA, SULIT MAKAN
HEPATOSPLENOMEGALI (-)
HEPATOSPLENOMEGALI(+) ANEMIA MEGALOBLASTIK (+)
ANEMIA MEGALOBLASTIK (-)
absent present
preterm full-term
anion gap
THAN PDHD
PCD
elevated normal GA II
organic acidopathy
(see fig. 2)
plasma citrulline
The hyperammonemic disorders can be biochemically distinguished by measuring the anion gap, plasma acids (including citrulline and
argininosuccinate), and urinary orotic acid.
THAN, transient hyperammonemia of the newborn; PDHD, pyruvate dehydrogenase deficiency; PCD, pyruvate carboxylase deficiency;
GA II, glutaric aciduria type II; ASASD, argininosuccinic acid synthase deficiency (citrullinemia); CPSD, carbamylphosphate synthase
deficiency; NAGSD, N-acetylglutamate synthase deficiency; OTCD, ornithine transcarbanoylase deficiency; LPI lysinuric protic
intolerance; ASALD, argininosuccinic acid lyase deficiency (argininosuccinic aciduria).
Diagnostic algorithm, for Questions to ask :
Hypoglycaemia • Age of onset
Patients presenting with • Timing (fasting, postprandial)
hypoglycaemia Consider SGA, IDM, sepsis, poisoning, • Severity (glucose infusion needed)
• Physical exam (liver size, growth)
severe systemic disease
Emergency screening tests :
ketosis • Confirm hypoglycemia !
• Urine - dipstick for ketones
absent present
- amino, organic acids & acylglycines
• Blood - free fatty acids & 3-hydroxybutyrate
- amino acids, lactate & pyruvate
urinary nonglucose urine aa & oA - insulin, cortisol & growth hormone
reducing substances plasma aa, NH4 - ammonium
abnormal
positive negative organic acidophaty normal
amino acidopathy
Galactosemia
ketolysis defect
HFI blood lactate
tyrosinemia hepatomegaly
present absent
normal raised
gluconeogenic defects
respiratory chain defects
blood lactate plasma GH, cortisol, insulin
Plasma FFA
SGA, small for gestational age; IDM, infant of a diabetic mother; HFI, hereditary fructose intolerance,
aa, amino acids; oa, organic acids, HN4+, ammonium; FFA, free fatty acids; GH, growth hormone;
FAOD, fatty acid -oxidation defect; GSD, glycogen strorage disease.