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Neonatal presentations of Inborn Errors of Metabolism

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... syndrome Dysmorphism at birth Congenital defects of glycosylation Inborn errors presenting at birth Severe hypotonia Peroxisomal disorders Congenital ... – PowerPoint PPT presentation

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Title: Neonatal presentations of Inborn Errors of Metabolism


1
Neonatal presentations of Inborn Errors of
Metabolism
  • Andrew Morris
  • Royal Manchester Childrens Hospital

2
Time of presentation
  • Deterioration after initial period of health
  • At birth
  • In utero

3
Presentations in utero
  • Family history - proven or suspected IEM
  • Hydrops fetalis on U/S scan
  • Occasionally due to lysosomal disorders
  • Maternal AFLP or HELLP syndrome
  • Occasionally fetus has a fat oxidation disorder,
    usually LCHAD deficiency

4
Presentations at birth
  • Dysmorphic syndromes
  • Severe hypotonia
  • Seizures / apnoea

5
Dysmorphism at birth
  • Peroxisomal disorders
  • e.g. Zellweger syndrome

6
Dysmorphism at birth
  • Lysosomal disorders
  • e.g. Mucolipidosis type II

7
Dysmorphism at birth
  • Disorders of cholesterol
  • synthesis
  • e.g. Smith-Lemli-Opitz syndrome

8
Dysmorphism at birth
  • Congenital defects
  • of glycosylation

9
Inborn errors presenting at birth
  • Severe hypotonia
  • Peroxisomal disorders
  • Congenital defects of glycosylation
  • Non-ketotic hyperglycinaemia

10
Presentions at birth (or later)
  • Seizures / apnoea
  • Peroxisomal mitochondrial disorders
  • Non-ketotic hyperglycinaemia
  • Molybdenum cofactor deficiency
  • Pyridoxine dependency
  • Hypoglycaemia hyperammonaemia

11
Pyridoxine dependent seizures
  • Deficiency of a-aminoadipic semialdehyde
    dehydrogenase (antiquitin)
  • accumulation of a chemical which inactivates
    pyridoxal phosphate
  • Pyridoxal-P is a cofactor in neurotransmitter
    metabolism
  • Diagnosis can be confirmed by measuring a-AASA in
    urine

12
Pyridoxal-P responsive seizures
  • Resembles pyridoxine dependency but requires
    pyridoxal phosphate (NG)
  • Deficiency of pyridoxine 5-phosphate oxidase
    (involved in converting pyridoxine to pyridoxal-P)

13
Clues to an Inborn Error
  • Deterioration after an initial period of health
  • Hypoglycaemia
  • Acid-base disturbance
  • Encephalopathy
  • Liver disease
  • Cardiac problems / sudden death

14
Deterioration after an initial period of health
  • Hypoglycaemia
  • Usually due to prematurity, IUGR, hypothermia etc
  • If severe, recurrent, other features of IEM
  • Fat oxidation disorders
  • Organic acidaemias
  • Glycogen storage disease type I
  • Fructose bisphosphatase deficiency
  • Hyperinsulinism
  • Adrenal insufficiency

15
Deterioration after an initial period of health
  • Acid-base disturbance
  • Metabolic acidosis
  • Usually due to sepsis, heart disease etc
  • If primary
  • Organic acidaemias (esp. if ketonuria)
  • Defects of gluconeogenesis (with hypoglycaemia)
  • Congenital lactic acidoses
  • ( multisystem disease or brain
    malformation)

16
Deterioration after an initial period of health
  • Acid-base disturbance
  • Respiratory alkalosis (self ventilating)
  • Hyperammonaemia

17
Deterioration after an initial period of health
  • Encephalopathy
  • Conditions with Hyperammonaemia
  • Hypoglycaemia
  • Acidosis
  • Seizures
  • MSUD

18
Deterioration after an initial period of health
  • Liver disease
  • Neonatal haemochromatosis
  • Mitochondrial disease
  • Galactosaemia
  • Tyrosinaemia type I
  • Niemann-Pick type C
  • a-1-antitrypsin deficiency
  • etc.

19
Deterioration after an initial period of health
  • Cardiomyopathy
  • Fat oxidation disorders (hypertrophic)
  • Mitochondrial disorders (varaible)
  • Pompe disease (hypertrophic)
  • Arrhythmias / sudden death
  • Fat oxidation disorders
  • Mitochondrial disorders

20
Neonatal presentations of IEMs
  • In utero e.g. Hydrops fetalis
  • At birth Dysmorphism
  • Hypotonia
  • Seizures
  • Later Hypoglycaemia
  • Acid / base disturbance
  • Encephalopathy
  • Liver disease
  • Cardiac problems or sudden death

21
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22
Pyridoxine dependent seizures
  • Seizures often start in utero
  • Multiple types, resistant to anticonvulsants
  • Usually dramatic response to IV pyridoxine
  • apnoea for 24 hours
  • Long-term language problems
  • Pyridoxine also non-specific anticonvulsant

23
Non-ketotic hyperglycinaemia
  • Severe hypotonia
  • Lethargy / coma
  • Hiccups
  • Seizures (initially myoclonic)
  • Recurrent apnoea (usually within 1st 2 days)

24
Non-ketotic hyperglycinaemia
  • Investigations
  • EEG - burst suppression
  • CSFplasma glycine gt0.08
  • Low glycine cleavage enzyme in liver or
    transformed lymphoblasts
  • Mutation studies difficult 3 genes

25
Non-ketotic hyperglycinaemia
  • Treatment
  • Sodium benzoate (lowers plasma glycine)
  • Dextromethorphan (NMDA antagonist)
  • Outcome
  • Intractable seizures
  • Almost always profound handicap
  • Few patients with milder handicap reported
  • Few reports of transient NKH

26
Molybdenum cofactor deficiency
  • Intractable seizures
  • Poor development
  • Spasticity
  • Dislocated lenses
  • Investigation
  • Urine sulphite
  • Plasma sulphocysteine, low urate
  • Treament symptomatic

27
Galactosaemia
  • Presentation
  • Usually 412 days
  • Failure to thrive, vomiting
  • Liver failure
  • initially unconjugated jaundice
  • Cataracts
  • Occasionally, Gram ve sepsis

28
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29
Galactosaemia
  • Investigation
  • Urine reducing substances (if on milk)
  • Red cell Gal-1-PUT or Beutler screening test
  • If transfused
  • Red cell Gal-1-P
  • Parental Gal-1-PUT (heterozygous levels?)

30
Galactosaemia
  • Treatment
  • Soya-based formula or pregestamil
  • Minimal galactose diet
  • Long-term complications
  • Learning difficulties
  • esp speech delay, dyspraxia
  • Shy personality
  • Ovarian failure

31
Tyrosinaemia type I
  • Variable presentation (2 weeks adulthood)
  • Liver failure in infancy
  • Prominent coagulopathy
  • Later also rickets or porphyria-like crises
  • Investigation
  • Urine succinylacetone
  • Mutation analysis / enzyme assay

32
Tyrosinaemia type I
  • Treatment
  • Nitisinone (NTBC)
  • Inhibits tyrosine breakdown
  • Low tyrosine diet
  • Outcome
  • Generally good
  • Monitor for hepatocellular carcinoma

33
Management if IEM in family
  • Review diagnosis history in index case
  • Diagnostic tests
  • Prenatal
  • Cord blood (galactosaemia)
  • Later leucine at 12-24 hrs in MSUD
  • serial ammonias in UCD, OAs
  • definitive tests

34
Management if IEM in family
  • Management
  • Drugs from birth e.g. sodium benzoate
  • ? in utero e.g. pyridoxine
  • Diet - no galactose
  • - restrict protein, long-chain fat
  • Energy - enteral or IV
  • - top-ups in MCADD if breast-fed

35
Hydrops fetalis
  • Anaemia isoimmunisation etc
  • Chromosomal / malformation syndromes
  • Congenital infections
  • Lysosomal disorders
  • Histology
  • Amniotic fluid MPS oligosaccharides
  • Chorionic cell culture for enzymology
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