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• When to investigate suspected metabolic disease
• Dr Nagi Barakat
• Consultant Paediatrician
• Hillingdon Hospital

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Metabolic disorders

• Usually inherited as autosomal recessive
• Presentation can be at any age but usually in
  first year of life
• It is important to make diagnosis even no
  treatment(why)
• Few neonatal screening (PKU in England).
  Galactosaemia, Homocystinurea, and tyrosinaemia
  in some regions
• Can be diagnosed from single blood test
• More incidence in some ethnic groups
• The out come can be very good

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Metabolic disorders

• Organic acidaemia
• Propionic acidaemia
• Methylmalonic acidaemia
• Isovaleric acidaemia
• Aminoacidopathies ( MSUD, Type I tyrosinaemia,
  non-ketotic hyperglycinaemia NKH)
• Urea cycle defect (Orinthine carbamoyltransferase
  (OCT), carbamoyl phosphate synthase
  (CPS),argininosuccinate synthase (AS),
  Argininosuccinate lyase deficiency (AL))
• Disorders of fatty oxidation (Medium Chain acyl
  CoA dehydrogenase (MCAD) deficiency
• Long chain hydroxy acyl CoA dehydrogenase
  (LCHAD) deficiency,
• Carnitine palmitoyl transferase (CPT II)
  deficiency
• Disorders of glucose and galactose metabolism
  (Glycogen storage disease type I(GSD I),
  Galactosaemia, Fructose 1,6 biphosphatase
  deficiency)
• Disorders of Mitochondrial energy production
  (Pyruvate dehydrogenase deficiency, Pyruvate
  decarboxylase deficiency, Mitochondrial
  respiratory chain deficiency)
• Others (glucose transport protein )

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When to suspect metabolic disease in
newborn/early infancy

• Most children born at term and appear normal at
  birth
• Clinical manifestation will start appear within
  first 24-72 hours after birth, but some may
  appear later.
• Progressive encephalopathy is the commonest
  presentation
• Initial symptoms may be difficult feeding with
  vomiting and lethargy
• This may followed up by severe apnoea, fits, and
  coma
• Metabolic acidosis is not prominent feature in
  many metabolic disorders and may absent
• Few may started in uteri like peroxisomal
  disorder (Zellweger syndrome and rhizomelic
  chondrodysplasia punctata, Mitochondrial energy
  production like Pyruvate dehydrogenase
  deficiency, disorders of cholesterol biosynthesis
  like Smith-Lemli-Optiz syndrome, glycolisation
  like carbohydrate deficient glycoprotein
  syndromes, Lysosomal disorders mucolipidoosis II.
• Fits in utero or immediately after birth
  characteriscally seen in non-ketotic
  hyperglycinaemia and pyridoxine deficiency.

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Presentation in Late infancy and early childhood

• It is usually presented after episode of
  metabolic stress, like intercurrent infection or
  prolonged fasting
• Fatty oxidation defect is one of them (MCAD),
  organic acidaemias (Glutharic aciduria,
  isovaleric aciduria)
• Lysosomal enzymes deficiency will lead to slow
  accumulation of toxic materials over months and
  years (neurological and organomegaly)

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When to start

• Children can be suspected of having metabolic
  disorder If they have
• Hypoglycaemia
• Acid/base balance disturbances
• Lactic acidaemia
• Progressive encephalopathy
• Liver disease
• Developmental regression
• Seizures in first days of life
• Unusual dysmorphic features
• Family history of metabolic disorders.
• Progressive neurological disorders
• Unexplained multi organ or single organ unusual
  illness with history of non or/and consanguinity

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First line investigation

• Blood gas
• Metabolic acidosis
• Respiratory alkalosis
• Blood sugar
• Hypoglycaemia
• Electrolytes
• Increased anion gap (12 16)
• Liver function tests
• Raised transaminase
• Infection screen
• Usually negative but sometimes positive like
  E-Coli septicaemia in Galactosaemia, Glutharic
  aciduria)

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Second line of Investigations

• Blood ammonia Encephalopathy
• Blood Lactate Encephalopathy,acidosis
  ,multiorgans problem
• Urine/plasma amino acids Encephalopathy,?
  NH4,?glucose,metabolic acidosis
• Urine organic acids Encephalopathy,?
  NH4,?glucose,metabolic acidosis
• Urine Orotic acid ? NH4, Liver disease
• Acylcarnitines Encephalopathy,?
  NH4,?glucose,metabolic acidosis
• Plasma carnitine Encephalopathy,?
  NH4,?glucose,metabolic acidosis
  ,cardiomypathy, liver disease
• Alpha I-antitrypsin Liver disease
• Urine succinylacetone Liver disease
• CSF lactate, glucose and amino acids
  Encephalopathy, seizures
• Very long chain fatty acids Peroxisomal
  disorders
• Transferrine iso-electric focusing Unexplained
  multisystem problems
• Urine GAGs(Glycosate aminoglycan) Chronic
  progressive neurological disorders,
  organomegaly and dysmorphic features)
• Insulin, c-peptides,growth hormones,cortisol
  Hypoglycaemia
• Urine reducing substances Liver disease
• Urine ketones Encephalopathy,?glucose,metabolic
  acidosis

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Third line of Investigation which usually done at
tertiary centre

• DNA analysis
• ERG/VEP
• Nerve conduction study
• EMG
• Enzyme assays
• White cell enzyme
• Cultured fibroblast Usually from skin
• Liver biopsy
• Muscle biopsy
• Bone marrow biopsy

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Hyperammonaemia

• Liver failure
• Urea cycle defect- OTC, CPS,citrulinaemia,
• Amino acid problems
• Glycine encephalopathy
• Isovaleric acidaemia
• Methylmalonic acidaemia
• Multiple carboxylase deficiency
• Propionic acidaemia
• Transit neonatal Hyperammonaemia

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• A week old baby boy
• Breast milk only
• Lethargic, recurrent vomiting, dehydrated, and
  hypotonic
• RR 40, intercostal recession, and grunting
• CXR- no abnormalities
• Metabolic acidosis, ketotic,NH4 400mmol/l, high
  plasma glycine
• Start fitting and cranial Ct show intracranial
  bleeding
• Thrombocytopenia, neutropenia with normal LFT
• Tissue fibroblast culture show D-methylmalonate
  CoA mutase deficiency
• What is the diagnosis?
• Metylymalonic acidaemia

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Progressive encephalopathyBefore age of 2 years

• Aminoaciduria (Hom, MSUD, PKU)
• Lysosomal enzyme disorders
• Mucolipidosis
• Mucoplysacridoisis
• Sphingolipoidosis
• Glycoprotein degradation
• Mitochondrial disorders
• MELAS
• Alper syndrome
• Leigh disease
• Menkes disease
• Neurocutaneous syndromes (TS,NFI, C-H disease)
• Genetic disorders affecting both white and Grey
  matter)

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Progressive encephalopathyAbove age of 2 years

• Lysosomal enzyme disorders
• Mucopolysaccharidoses
• Sphingolipoidosis
• Glycoprotein degradation
• Genetic disorders affecting Gray matter
• Ceroid lipfuscinosis
• Huntington chorea
• MERRF
• Xeroderma pigmentosa
• Genetic disorders affecting White matter
• Adrenoleukodystrophy
• Alexander disease
• Xanthomatosis
• Infectious diseases (SSPE)

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Phenlyketonuria

• Autosomal recessive
• Phenylalanine hydroxlase deficiency
• 11600 live births
• Normal at birth
• Screening is available to all new born babies
• Develop at age 48-72 hours after milk feeding
• Must odour (phenylacetic in sweat)
• Developmental delay early months
• Second year developmental regression
• Hyperactivity, aggression is common
• 25 may develop seizures- more with
  tetrahydropetrine
• Frequently have blond hair,pale skin and blue
  eyes

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Investigations (PKU)

• Blood Phenylalanine is high
• Phenlyketonuria
• Tyrosine level will be low
• Phenylalanine 1,2,3 Tyrosine Dopa
• 4 6
• Phenylpyruvic acid P-Hydroxyphenylpyruvic acid
• 5
• Phenylacetic acid Homogentisic acid
• 1-Phenylalanine hydroxylase, 2.dihydropteridine
  reducatase, 3.Tetrahydrobiopterin, 4
  Phenylalanine transaminase, 5.P-hydroxyphenylpyruv
  ic acid, 6.Tyrosine transaminase

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Hyperphenylalanaemia

• Classic Phenlyketonuria (6)
• Benign
• Partial hydroxylase deficiency (6-30)
• Transient hydroxylase deficiency
• Phenylalanine transaminase deficiency
• Malignant
• Dihydropteridine reducatase deficiency
• Tetrahydrobiopterin synthesis deficiency
• Tyrosinaemia
• Transient tyrosinaemia
• Tyrosinosis
• Liver disease
• Galactose 1-phosphate uridyltransferase deficiency

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Treatment

• Restricted diet shouldd start with every one
  with blood Phenylalanine concentration of
  30mg/l(1800micromol/l) or greater and some
  recommend for those with 20mg/l (1200micromol/L)
• 3 day challenge after three months with
  Phenylalanine of 180mg/kg/day
• Children with blood Phenylalanine of 20mg/l or
  more should continued on restricted diet all life
  long. Less than 20mg/l should stop.
• Phenylalanine between 5-10mg/l
• Malignant form will have some neurological
  deficit and diet restriction on it is own will
  not enough. Adding Tetrahydrobiopterin will help
  to prevent neurological deterioration.

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Initial management of children with suspected IBM
at DGH level

• Stop protein intake in children with
  hyperammonaemia and metabolic acidosis
• IV glucose of 5-7mg/kg/min to keep blood glucose
  around 7-11.
• Use insulin infusion of 0.05unit/kg/hr to keep
  blood glucose around 7-11mmol/l
• Supportive treatment
• Correct acidosis with bicarbonate
• Specific treatment for hyperammonaemia after
  arrangement with specialist centre
• Treat with antibiotic as often associated with
  septicaemia
• Monitor electrolytes and blood gases
• Intensive care is often required
• Treat cerebral oedema early if present
• Assisted ventilation should be considered early

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Summary Slide

• Key points

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Key points

• IBM are a significant cause of mortality and
  morbidity
• High index of suspicious in cases presented with
  unexplained multi organ or single organ problem
• Always do ammonia and blood gas in children with
  encephalopathy
• Careful planning of investigation is required
• Difficult to interpret results is often the case
• Consult expert before ordering any second or
  third line of investigation
• IBM investigation should be carried as early as
  possible

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