Transcript Metabolic Disease in Childhood

Does this ill child have a
metabolic disease?
►General
Intro
►Disease
Presentation & Investigation
Acute Neonatal
Recurrent Encephalopathy
Hyperammonaemia
Hypoglycaemia
Inherited Metabolic Diseases
► Individually
rare diseases
 collectively ‘common’
 ?1 in 800
► Ubiquitous
presentation
 Modern TB
► Likely
to present in
 general paediatric
 neonatal
 speciality paediatric practice
Collection of diagnoses
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6
4
1
1
4
6
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2
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3
1
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2
1
PKU
► 7
Urea cycle
► 1
MSUD
► 1
Tyrosinaemia
► 2
Organic acidaemia
► 1
Fatty acid oxidation
► 1
disorders (5 MCAD)
► 2
X linked & 1 neonatal ► 1
adrenoleucodystrophy
► 1
Galactosaemia
► 5
L 2 hydroxyglutaric
► 2
aciduria
Ketothiolase deficiency ► 2
Transient neonatal
hyperammonaemia
Mucopolysaccharidoses
GSD
Mucolipidosis
Ceroid lipofuscinosis
Gauchers disease
Refsums disease
Steroid sulphatase def’y
Cystinuria
Orotic aciduria
Hypercholesterolaemia
Mitochondrial cytopathy
Segawa disease
The Metabolically ill
Infant and Child
If You Don’t Think You Won’t Look
If You Don’t Look You Won’t Find
If You Don’t Find You Can’t Treat
Acute presentations
►
Neonatal
 Apparent sepsis
 Neurological
deterioration
 Hypoglycaemia
 Liver dysfunction
 E coli septicaemia
Inborn Metabolic Errors
Are easy!
IEMs
A
B
C
X
Y
D
IEMs
E
A
B
C
X
Y
D
► Accumulation
/ excess storage metabolites
 Antenatal or postnatal
► Toxicity
of metabolites
► Energy insufficiency
► Specific deficiency
► Combination
Genetics
► All
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types of inheritance
Recessive
X linked
Dominant
Mitochondrial DNA
► Mutation/s
+ genetics define level of enzyme
activity
► Enzyme activity informs severity and timing of
presentation
 e.g. OCT deficiency, PKU
Four Basic Clinical Groups
 Acute neonatal symptoms
►Present at birth
►Symptom free interval
 Later onset acute/intermittent
 Chronic progressive general
 Specific symptoms of a disorder
History Clues
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Age onset
Disease progression
Precipitating factors
 Milk feeds
 Weaning
 Infection
 Fasting
Sibling death
Maternal HELLP and AFLP syndromes
Acute neonatal symptoms
► Present
► Toxic
at birth
type
► Energy
deficient
► Hypoglycaemia
Acute neonatal symptoms
►
From birth
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Facial dysmorphism
Profound hypotonia
Seizures
Liver disorder
 ? Peroxisomal disorder
 ? Respiratory chain
 ? Carbohydrate Deficient
Glycoprotein disorder (CDG)
 Zellwegers syndrome
Zellweger
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►
Zellweger disease - antenatal onset
 Neurological - disorder neuronal migration
 Hepatic - jaundice, bleeding, ^ ALT, mild cirrhosis on
biopsy
 Cardiac anomaly - 32% VSD : 22% aortic
 Renal cysts
 Calcific stippling of patella
 Eyes - ERG always abnormal
 Death in 1-2 yrs
Diagnosis
 ^VLCFA
 ^pristanic, phytanic acids & some bile acids
 hypoprothrombinaemia
IEMs
E
A
B
C
X
Y
D
Acute Neonatal Symptoms
Toxic Type
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Symptom free interval
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Unexpected/”mysterious” deterioration
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Poor sucking / feeding
►
Encephalopathy
►Hiccups,
apnoea
►Bradycardia,
►Relative
hypothermia
hypertonia, Opisthotonus
►Pedalling/boxing
►Tremors
/ jerks
 True seizures rare
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Odour eg MSUD/IVA
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Coma
Acute neonatal symptoms
► Energy
deficient
 non specific symptoms
►+/-
symptom free interval
►severe
generalised hypotonia
►then
rapidly progressive neurological
deterioration
►cardiomyopathy
►lactic
acidosis common
► Hypoglycaemia
►hepatomegaly
►liver
dysfunction
Acute neonatal symptoms
Watch out for
► initial respiratory alkalosis
► neutropaenia
► thrombocytopaenia
► pancytopaenia
► clotting disturbance
► vomiting
► abdominal distention
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IMD may mimic infection
Acute Neonatal Symptoms
Initial Investigations
► Blood
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FBC, clotting
U&E, (anion gap)
Glucose
Gases
Uric acid
LFT
Ammonia
Lactate
Calcium
Anion Gap
►=
►8
( Na+K ) - (Cl+HCO3)
to 16 mmol/L when not including [K+]
► 10 to 20 mmol/L when including [K+].
Acute Neonatal Symptoms
Initial Investigations
► Blood
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FBC, clotting
U&E, (anion gap)
Glucose
Gases
Uric acid
LFT
Ammonia
Lactate
Calcium
► Urine
 Odour
 Ketones
► Ketonuria
is an indicator
for a metabolic disease
in the newborn.
 Reducing substances
 Ph
Interpretation
 Ketones+++ NH3 +/►MSUD
 Acidosis++ NH3 +/++ lactate+/- cytopaenia
►Organicacidurias
 Increased Uric acid is indicative for organic aciduria
 Thrombocytopenia and Neutropenia are criteria for severity
in organic aciduria
 NH3++/+++ acidosis - lactate +/►Urea
cycle
►Fatty
acid oxidation
Interpretation
 Lactate +++ acidosis ++ ketones ++
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Respiratory chain
►“Cong
lactic acidosis”
 Liver+++ acidosis++ lactate ++
hypoglycemia++
►GSD
i, iii
 LFT abn Liver +, NH3 +/►Galactosaemia
tyrosinaemia HFI
Acute Neonatal Symptoms
Further Investigations
► Blood
► Urine
 Amino acids
 Carnitine T & Free
 Acyl carnitines
 Amino acids
 Organic acids
► CSF+/-
► Specific
tests
 Eg Gal-1-PUT
 Lactate
 glycine
Recurrent Encephalopathy
► May
be well for years
► Cause not immediately obvious
► Child seems sicker than expected for
apparent illness
► Rarely of sudden onset
► Encephalopathy preceeds hypoglycaemia
► Consider in any type of coma or
encephalopathy
( including DKA)
Recurrent Encephalopathy
► Well
between episodes BUT
 May suffer neurological damage during episodes
(MCAD, OCT)
 Many are treatable
 Early diagnosis is important
► Most
metabolic encephalopathies do not have
focal neuro signs BUT
 Strokes, ataxia,
► It
does not quite fit
►D&V
more ill than expected
► Unexpected
“psychiatric illness”
Recurrent encephalopathy
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“Metabolic” investigations
 glucose
 ketones
 ammonia
 lactate
 blood gases
 FBC
 carnitines
 acyl carnitines
► Urine
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Odour
Ketones
Amino acids
Organic acids
► CSF+/-
 Glucose
 Lactate
 Glycine
Recurrent Encephalopathy
Metabolic causes
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Fatty acid oxidation disorders
 MCAD
Carnitine disorders
Urea cycle disorders
Organic acidaemias
Respiratory chain defects
Recurrent Encephalopathy
Consider also
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Stroke like episodes
 MELAS
 Homocystinuria
►Total homocysteine
 organic acidaemias
 ornithine carbamyl transferase deficiency
 Carbohydrate Deficient Glycoprotein syndromes (CDG)
► (sialotransferrin)
Macrocephaly
 Glutaric aciduria I
►Frontal atrophy
 CDG syndromes
HYPERAMMONAEMIA
Differential diagnosis
► INHERITED
DISORDERS
► ACQUIRED
DISORDERS
Liver disease
► Poisoning
► ‘Reye’s syndrome’ –
acquired – aspirin + viral
infection
► Sodium valproate toxicity
► Asparaginase toxicity
► Urinary tract infection with
stasis
►
Urea cycle disorders
► Organic acidaemias
► Fatty acid oxidation
disorders
► Other inborn errors
(OAT,PC, HHH syndrome,
etc)
►
Hyperammonaemia
Mainly neurological presentation
► Inhibits
► NH3
neurotransmitters
+ glutamate = glutamine
► Osmotic
► Careful
load = cerebral oedema
sampling is important
► Values
of 100 mmol/l may be significant, but
usually >200 mmol/l
► Ammonia
level not a good predictor of severity but
>350 expect neuro sequelae
Hyperammonaemia
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Brain stem stimulant
 tachypnoea
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Cyclical vomiting
 Check in all children in
acute episode
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anorexia
Lethargy
Failure to thrive
Delayed development
Faddy eating
Acute encephalopathy
► irritability
► headache
► confusion
► ataxia / slurring of speech
► bizarre behaviour
► focal neurological signs
► fluctuating level of
consciousness
► coma
►
Hyperammonaemia
►
Treatment
 Emergency regimen
► Avoid
catabolism
► High CHO feeds only
 10% dextrose IV+/- insulin IV
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Drugs
 Arginine
 Benzoate
 Phenylbutyrate
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Haemofiltration
Haemodialysis
Treat cerebral oedema
Healthy Children:
Response to fasting
Hypoglycaemia
► May
be the end result
of a metabolic disease
- sick
► May be the primary
symptom
► What is the timing of
hypo
 Fasting
 Postprandial
 Intercurrent illness
► Hepatomegaly?
 Permanent
 Transient
► Ketosis?
► Lactate++?
► Liver dysfunction?
► Short stature?
Hypoglycaemia investigations
When hypo
► lactate
► Ketones
► FFA
► urate
► CK
► lipids
► GH
► insulin
► cortisol
Others
► carnitine
► acyl carnitine
► LFT
► Aminoacids
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Urine (first available)
 aminoacids
 organic acids
 reducing substances
 ketones
Hypoglycaemia - Permanent hepatomegaly
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“All metabolic”
Fasting hypo/ ketosis / lactate +
 Glycogen storage disease
►Trigly > cholesterol I
►Chol > trigly
III
►Urate ++
I
►Creat kinase ++
III
►Lactate ++
I
Liver failure / short fast
 Galactosaemia
 Tyrosinaemia
Postprandial
 Hereditary fructose intolerance
Hypoglycaemia - No Permanent Hepatomegaly
► Ketosis
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Organicaciduria
MSUD
Ketotic hypoglycaemia
Adrenal insufficieny
► Without
ketosis
 Fatty acid oxidation disorder
 Hyperinsulinism
 Growth hormone deficiency
Diagnostic algorithm
METABOLIC ACIDOSIS
yes
Ketonuria
Ketonuria
yes
Major hyperlactatemia
yes
Mitochondrial
defect
no
Organic
aciduria
no
no
Maple Syrup Urine
Disease (MSUD)
yes
Hyperlactatemia
yes
Hypoglycemia
yes
Fatty acid oxydation
Glycogen storage disease
Glyconeogenesis defects
no
Maple Syrup Urine
Disease (MSUD)
Organic aciduria
Pyroglutamic
aciduria
no
Respiratory
chain
no
HYPERAMMONEMIA
yes
no
Hypoglycemia
yes
Fatty acid oxydation
Variant hyperinsulinism
(glutamate dehydrogenase)
Non-ketonic hyperglycinemia
Sulfite oxydase deficiency - XO
no
Urea Cycle
Disorders
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Best Practice Guidelines
Contents
Guidelines for the Biochemical Investigation of Patients with Foetal and
Neonatal Hydrops
Guidelines for Investigation of Fits and Seizures (Instruction Sheet for
CSF sample collection )
Guidelines for the Investigation of Hypoglycaemia in Infants and
Children
Guidelines for the Investigation of Hyperammonaemia for Inherited
Metabolic Disorders
Appendix - Notes on the measurement of ammonia in blood/plasma
Skin Biopsy - Information Sheet for parents/carers
Skin Biopsy - Consent form
Neonatal Jaundice in Inherited Metabolic Disorders
Inherited Metabolic Diseases
Practice points
► More
► Can
common than expected
present in unexpected ways
► If
you do not think about the possibility you
will not make the diagnosis
 Lower threshold to investigate
► Be
aware significance of NH3 level
► Hypoglycaemia
is a late event