Neonatal presentations of Inborn Errors of Metabolism

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Neonatal presentations of Inborn Errors of
Metabolism

• Andrew Morris
• Royal Manchester Childrens Hospital

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Time of presentation

• Deterioration after initial period of health
• At birth
• In utero

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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

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Presentations at birth

• Dysmorphic syndromes
• Severe hypotonia
• Seizures / apnoea

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Dysmorphism at birth

• Peroxisomal disorders
• e.g. Zellweger syndrome

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Dysmorphism at birth

• Lysosomal disorders
• e.g. Mucolipidosis type II

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Dysmorphism at birth

• Disorders of cholesterol
• synthesis
• e.g. Smith-Lemli-Opitz syndrome

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Dysmorphism at birth

• Congenital defects
• of glycosylation

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Inborn errors presenting at birth

• Severe hypotonia
• Peroxisomal disorders
• Congenital defects of glycosylation
• Non-ketotic hyperglycinaemia

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Presentions at birth (or later)

• Seizures / apnoea
• Peroxisomal mitochondrial disorders
• Non-ketotic hyperglycinaemia
• Molybdenum cofactor deficiency
• Pyridoxine dependency
• Hypoglycaemia hyperammonaemia

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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

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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)

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Clues to an Inborn Error

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

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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

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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)

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Deterioration after an initial period of health

• Acid-base disturbance
• Respiratory alkalosis (self ventilating)
• Hyperammonaemia

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Deterioration after an initial period of health

• Encephalopathy
• Conditions with Hyperammonaemia
• Hypoglycaemia
• Acidosis
• Seizures
• MSUD

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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.

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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

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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

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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

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Non-ketotic hyperglycinaemia

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

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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

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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

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Molybdenum cofactor deficiency

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

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Galactosaemia

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

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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?)

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Galactosaemia

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

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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

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Tyrosinaemia type I

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

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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

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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

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Hydrops fetalis

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