Download Urea cycle defects

INBORN ERRORS OF METABOLISM
(IEM)
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
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
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.)
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
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)
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
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
Hypotonia
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
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)
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
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)
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.)
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
Chronic and progressive neurological symptoms
• 5-15 yrs
Chronic and progressive neurological symptoms
• 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*)
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.)
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)
Treatment
• Supportive care
Hydration, 5-10%Dx, 34-75 mEq/L Na, 20-40 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)
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
Q&A….