1. INBORN ERRORS OF METABOLISM (IEM)

3. Firstly…
In the appropriate clinical context consider IEM in parallel with other more conditions.
Be aware that symptoms that persist and remain unexplained after initial treatment and after usual investigations for more common disorders have been performed may be due to an IEM
Suspect that any neonatal death may possibly be due to an IEM, particularly those that have been attributed to sepsis.
Remember that an IEM can present at any age, from fetal life to old age.
Be aware that although most genetic metabolic errors are hereditary and transmitted as recessive disorders, the majority of individual cases appear sporadic.
Initially consider inborn errors that are amenable to treatment, particularly in patients who are acutely unwell.
Obtain help from specialized centers

4. Classification Disorders that give rise to intoxication
A.a. catabolism (PKU, MSUD, homocystinuria, tyrosinemia)
Organic acidurias (MMA, PA, IVA)
Urea cycle defects
Sugar intolerance (galactosemia, HFI)
Metal intoxication (Wilson, Menkes, hemochromatosis) and porphyrias
Disorders involving energy metabolism
Congenital lactic acidemias (pyruvate carboxylase, pyruvate dehydrogenase)
Mitochondrial respiratory chain disorders
Fatty acid oxidation and ketone body metabolism
Glycolysis, glycogen metabolism, gluconeogenesis
Creatine metabolism, pentose phosphate pathways
Disorders involving complex molecules
Lysosomal storage disorders, peroxisomal disorders
Disorders of intracellular trafficking and processing (CDG), cholesterol synthesis

5. Clinical Presentation
Early symptoms in the antenatal and neonatal period
Later onset acute (and recurrent) attacks of symptoms
Coma, ataxia,
Vomiting, acidosis,
Exercise intolerance,
Cardiac, renal, liver or other organ failure
Chronic and progressive neurological symptoms
Developmental delay, mental retardation, epilepsy,
Neurological deterioration and psychiatric signs
Specific and permanent organ/system presentations (cardiology, dermatology, etc.)

6. Clinical Presentation
Early symptoms in the antenatal and neonatal period
Antenatal
1. True malformations (skeletal dysplasia, cong. heart disease..)
2. Dysplasias (post fossa abnorm, polycystic kidneys, liver cyst)
3. Functional manifestations (IUGR, hydrops fetalis, HSM, microcephaly)
(1) O-glycosylation, cholesterol synthesis, respiratory chain, glutamine synthetase defects
(2,3) Lysosomal, peroxysomal and N-glycosylation defects
* Intoxication disorders (a.a and organic acid catabolism defects) do not disrupt normal fetal development

7. Clinical Presentation
Early symptoms in the antenatal and neonatal period
Neonatal and early infancy
Term, AGA (usually)
After a normal period (from hours to weeks)

8. Poor sucking and feeding, Respiratory abnormalities
Intoxication group
Poor sucking and feeding, Respiratory abnormalities
Apnea, bradycardia, hypotermia
In comatose state:
-Muscle tone change and involuntary movements
-Axial hypotonia and limb hypertonia with tremor and myoclinic jerks
* MSUD (maple syrup urine disease)
Generalised hypertonic episodes with opisthotonus
Boxing or pedalling movements
Slow limb elevations
-Abnormal urine/body odour
(maple syrup, sweaty feet odour (IVA,type II glutaric acidemia))
Energy deficiencies group
Clinical presentation is less suggestive and No symptom-free interval
Severe generalized hypotonia,
Rapidly progressive neurological deterioration (letargy/coma rare)
Hyperlactatemia with or without metabolic acidosis is very frequent
Complex molecules group
Only a few Lysosomal storage disorders
Conversely, most non-metabolic causes of coma are associated with hypotonia, so that the presence of ‘normal’ peripheral muscle tone in a comatose child reflects a relative hypertonia.
Another neurological pattern observed in organic acidurias is axial hypotonia and limb hypertonia with fast large-amplitude tremors and myoclonic jerks, which are often mistaken for convulsions.

9. Non-treatable
Nonketotic hyperglycinaemia, d-glyceric aciduria,
Mitochondrial glutamate transporter defect, GABA transaminase deficiency, glutamine synthetase deficiency,
Peroxisomal biogenesis defects, respiratory chain disorders, Sulfite oxidase deficiency, defects of purine metabolism,
CDGs and Menkes disease
Epilepsy is severe, with an early onset, and can present with spasms, myoclonus and partial or generalised
tonic / clonic crises
Always consider the possibility of an IEM in a neonate with unexplained and refractory epilepsy

10. The most severe metabolic hypotonias are observed
- Hereditary hyperlactataemia
- Respiratory chain disorders
- Urea cycle defects, NKH, sulfite oxidase (SO) deficiency
- Peroxisomal disorders and trifunctional enzyme deficiency
Severe hypotonia is a common symptom in sick neonates. It is generally observed in nonmetabolic inherited diseases (mainly in severe fetal neuromuscular disorders).
Only a few inborn errors of metabolism present with isolated hypotonia in the neonatal period, and very few are treatable.

11. (neonatal haemochromatosis, respiratory chain disorders,
Hepatic presentation
Massive HM with hypoglycemia and seizure (glycogenosis, glyconeogenesis defects)
Liver failure (jaundice, coagulopathy, HC necrosis, hypoglycemia, ascites)
(neonatal haemochromatosis, respiratory chain disorders,
transaldolase deficiency, galactosaemia, hereditary
fructose intolerance and tyrosinaemia type I (after 3 wks).
Cholestatic jaundice with failure to thrive (alpha-1-antitrypsin deficiency, Byler disease, inborn errors of bile acid metabolism, peroxisomal disorders, Niemann-Pick type C disease, CDGs (mostly type 1b)
HSM withh signs of storage (coarse facies, macroglossia, hydrops fetalis, ascites, oedema, dysostosis multiplex, vacuolated lymphocytes)
Lysosomal disorders (GM1 gangli- osidosis, sialidosis type II, I-cell disease, Niemann- Pick A, MPS type VII, galactosialidosis)
At an advanced stage of hepatocellular damage nonspecific abnormalities
Mellituria (galactosuria, glycosuria, fructosuria)
Hyperammonaemia, hyperlactataemia
Hypoglycaemia after a short fast
Hypertyrosinaemia and hypermethioninaemia.

12. Cardiac presentation
Cardiac failure and a dilated hypertrophic CM
(pure dilated cardiomyopathy is very rare),
most often associated with hypotonia,
muscle weakness
failure to thrive
suggests FAO disorders (with hypoglycaemia)
Respiratory chain disorders (with severe LA)
Pompe disease (with suggestive EKG) or
Fatal congenital heart glycogenosis
CDGIa, LCFAO

13. Metabolic Derangements and Diagnostic Tests
As soon as there is a clinical suspicion of an IEM, general supportive measures and laboratory investigations should be undertaken concurrently !!!
Family history, background
Abnormal urine odours
Ketone bodies
Hypocalcaemia and elevated or reduced blood glucose
Neurological dysfunction
Metabolic acidosis (elevated anion gap) (keton, lactate, OA, decreased HCO3)

19. Clinical Presentation
Early symptoms in the antenatal and neonatal period
Later onset acute (and recurrent) attacks of symptoms
Coma, ataxia,
Vomiting, acidosis,
Exercise intolerance,
Cardiac, renal, liver or other organ failure
Chronic and progressive neurological symptoms
Developmental delay, mental retardation, epilepsy,
Neurological deterioration and psychiatric signs
Specific and permanent organ/system presentations (cardiology, dermatology, etc.)

20. Chronic and progressive neurological symptoms
Early infancy
- with extraneurological features (CM, abnormal hair and cutaneous signs (Menkes,biotinidase), fat pads on the buttocks and thick-sticky skin (CDG))
- with specific or suggestive neurological signs (dystonia, encephalopathy, macrocephaly, recurrent attacks of neurological crisis (stroke-like or encephalopathy)
- with nonspecific developmental delay*
1-5 yrs
- with visceral, craniovertebral, ocular or other somatic abnormalities (retinitis pigmentosa, cataract, blindness, corneal opacities, coarse facies…MPS,ML,perox)
- with progressive paraplegia and spasticity (leukodystrophy, neuroaxonal dystrophy…Schindler, Arginase defc, Cbl-synthesis def)
- unsteady gait and uncoordinated movements (when standing,walking,speaking) due to either ataxia, peripheral neuropathy, myoclonia
- predominant epilepsy and myoclonus (Niemann-Pick C, Gaucher,MERRF,Schindler)
- isolated developmental arrest or regresion
*A large number of inborn errors present with nonspecific early progressive developmental delay, poor feeding, hypotonia, some degree of ataxia, frequent au- tistic features and seizures. Many IEM can masquerade as a cerebral palsy by presenting as a permanent im- pairment of movement or posture.

21. Chronic and progressive neurological symptoms
5-15 yrs

23. Chronic and progressive neurological symptoms
Neuroimaging signs (basal ganglia/brain/white matter hyperintensities, deposits, dysplasia/malformations, posterior fossa hypoplasia/atrophy)
Neuro-ophthalmological signs (retinitis pigmentosa, cherry red spot, optic atrophy, ptosis, ophtalmoplagia, eye movements)
Neurophysiological signs (peripheral neuropathy*)
*lipid storage disorders and energy metabolism defects.

24. Clinical Presentation
Early symptoms in the antenatal and neonatal period
Later onset acute (and recurrent) attacks of symptoms
Coma, ataxia,
Vomiting, acidosis,
Exercise intolerance,
Cardiac, renal, liver or other organ failure
Chronic and progressive neurological symptoms
Developmental delay, mental retardation, epilepsy,
Neurological deterioration and psychiatric signs
Specific and permanent organ/system presentations (cardiology, dermatology, etc.)

25. Specific organ signs and symptoms
Cardiology (cardiac failure, dysrhythmia, CM)
Dermatology (hair-alopecia,brittle hair.., hyperkeratosis, ichtyosis, photosensitivity, xanthoma…)
Endocrinology (diabetes, hyperinsulinism, hyper/hypothyroidism, adrenal failure, hypogonadism)
Gastroenterology (abdominal pain (recurrent), acute pancreatitis, chronic diarrhoea, failure to thrive, osteoporosis, hypocholesterolaemia, HELLP syndrome, constipation, intestinal obstruction)
Hematology (anemia)
Myology (cramps, exercise intolerance, myoglobinuria, elevated CK, myopathy)

26. Treatment Supportive care
Hydration, 5-10%Dx, mEq/L Na, mEq/L K
HCO3 (acidosis)
Nutrition
Protein-free TPN (high calorie, 100 kcal/kg/d) (no more than 2 days)
Specific therapies
Insulin (after improved dehydration and acidosis)
Na-benzoate and/or Na-phenylbutyrate with L-arginine (hyperamonemia)
L-carnitine, biotine
Toxin-removel therapies (HD, HF, PD)
l-arginine is an essential amino acid in all disorders of the urea cycle (except arginase deficiency)
Owing to its own toxicity, arginine supplementation should be reduced to its nutritional requirement as soon as acute hyperammonaemia has abated
As a rule, l-carnitine supplementation is never contraindicated in these disorders. Only if a long-chain FAO defect is suspected should the administration of carnitine be avoided, at least as a bolus,

27. Take home message…
Be aware that symptoms that persist and remain unexplained after initial treatment and after usual investigations for more common disorders have been performed may be due to an IEM
Suspect that any neonatal death may possibly be due to an IEM, particularly those that have been attributed to sepsis, FAMILY HISTORY, SUSPICIOUS DEATH !!
CRİTİQUE SAMPLES…
Acute treatment and obtain help from specialized centers

28. Q&A….