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Inborn Errors of Metabolism

The metabolic emergency:

In the neonate, the early clinical features of acute metabolic decompensation are almost always non-
specific; they include “unwell”, lethargy, feeding problems, vomiting, abnormal breathing, hypotonia
and seizures.

Asymptomatic interval with clinical manifestations from the second day of life onwards (“intoxication
type”) are typical in newborns.

The baby’s general condition will usually deteriorate rapidly despite normal or non-specific findings in
routine investigations (laboratory signs of infection, lumbar puncture, chest X-ray, cranial ultrasound)
and antibiotic therapy.

Metabolic disorders after the neonatal period may present with recurrent vomiting and lethargy
progressing to coma without focal neurological signs or typical patterns of organ dysfunction.

A metabolic disorder should be considered, along with other diagnoses (e.g. infection, CNS
pathology) …
… in all neonates with unexplained, overwhelming or progressive disease particularly after normal
pregnancy and birth
… in all children with acute deterioration of the general condition and/or reduced consciousness,
particularly when preceded by vomiting, fever or fasting
… in all children with symptoms and signs of acidosis or hypoglycemia
Appropriate diagnostic and therapeutic measures must be initiated as soon as possible to avoid long-
term damage

Hyperammonemia:

NH3 values

Neonates: healthy < 110 umol/l, sick up to 180 umol/l, suspect metabolic disease >200 umol/l

After the neonatal period: suspect metabolic disease >100 umol/l

It is essential to measure ammonia early in every sick child in whom a metabolic disease may be the
underlying diagnosis. Hyperammonemia may be missed otherwise and the child may be deprived of
efficient treatment.

Causes:

- Urea cycle disorders: most common cause of severe hyperammonemia presenting with
progressive or chronic relapsing encephalopathy. May initially be associated with respiratory
alkalosis but acidosis can occur. Short time-span from first symptoms to irreversible brain
damage – rapid and efficient management is of utmost importance!
- Organic acidurias (e.g. propionic aciduria)- approx. 30% of severe neonatal
hyperammonemias: Blocked urea synthesis due to its inhibition by organic acids and due to
deficiency of acetyl-CoA (required in urea cycle). Usually associated with (lactic) acidosis at an
early stage.
- Severe liver failure (secondary hyperammonemia!!!)
- Transient hyperammonemia of a newborn due to open ductus venosus

Emergency management:

- Stop protein intake, reduce catabolism


o Glucose 10mg/kg/min (add insulin if necessary)
- Remove ammonia (drugs, extracorporeal detoxification)
o Na-benzoate; if available: Additional Na-phenylacetate or Na-phenylbutyrate
o Extracorporeal detoxification: Start urgently if NH3>500 umol/l. Use
haemodiafiltration if available, otherwise haemofiltration or haemodialysis.
Peritoneal dialysis is less efficient. Exchange transfusion increases the protein and
ammonia load and should not be used.
- Replenish urea cycle intermediates with arginine or citrulline, support mitochondrial
metabolism with carnitine in organic acidurias
- Support urinary ammonia excretion by generous fluid intake; consider forced dieresis

Classical organic acidurias

Disorders with characteristic accumulation of carboxylic acids identified by GC/MS analysis of urine.
The most important acidurias are caused by disorders involving the complex metabolism of branched-
chain amino acids. The most common acidurias: propionic aciduria, methylmalonic aciduria, isovaleric
aciduria.

Clinical:

- Neonatal form: Metabolic encephalopathy “intoxication type”. Lethargy, feeding problems,


dehydration, truncal hypotonia/limb hypertonia, myoclonic jerks, neurovegetative
dysregulation  cerebral oedema, coma, multi-organ failure; unusual odour

- Chronic intermittent form (manifestation up to adulthood): Recurrent episodes of


ketoacidotic coma, lethargy and ataxia, focal neurological signs, stupor  coma, Reye
syndrome-like

- Chronic progressive form: Failure to thrive, chronic vomiting, anorexia, osteoporosis,


psychomotor retardation, hypotonia, recurrent infections (particularly candida)

Lab:

- Ketosis/ ketoacidosis,  lactate,  NH3, neutropenia, thrombopenia, pancytopenia

Diagnosis:
- Organic acids (specific metabolites) in urine (GC/MS analysis), amino acids in plasma

Therapy:

- Acute: Interrupt catabolic state with high-dose glucose infusion, counteract acidosis, stop
protein intake, remove toxins, give carnitine

- Long-term: Diet – protein restriction; supplementation of unaffected amino acids, minerals,


vitamins, trace elements, carnitine

Complications:

- Demyelinisation, brain necrosis (basal ganglia), nephritis, pancreatitis, dermatoses 


epidermolysis, osteoporosis, cardiomyopathy

Phenylketonuria (PKU)

PKU was one of the first neurogenetic disorders identified, the first successfully treated inborn error
of metabolism (diet) and the disorder that was instrumental for the introduction of neonatal
population screening (dried blood spots). A deficiency of the enzyme phenylalanine hydroxylase
(PAH) causes the accumulation of phenylalanine leading to severe brain damage with mental
retardation if untreated. Average incidence 1:8000.

Diagnosis:

- Neonatal screening (filter paper card), amino acids in plasma:  Phe, n- Tyr

Therapy:

- Phe-restricted diet, supplementation of essential amino acids + trace elements

- Treatment option in mild PKU – BH4 (tetrahydrobiopterin) supplementation

Prognosis:

- Normal development and intelligence with immediate and efficient treatment

Maternal PKU syndrome

- Fetopathy in pregnant mothers with PKU (brain underdevelopment, congenital heart defects
in the fetus)

- Strict diet treatment must be started before conception and maintained throughout
pregnancy!!!
Galactosemia

Patients develop clinical symptoms only after intake of lactose (milk, milk products) in the diet.
Galactose-1-phosphate which accumulates in classical galactosemia is toxic for the liver, kidneys and
brain.

Clinical:

- Progressive symptoms after start of milk feeds, usually starting on the 3 rd or 4th day of life

- Vomiting, diarrhea, jaundice, disturbances of liver function, sepsis death from hepatic and
renal failure

- Bilateral cataract

Diagnosis:

- In many countries neonatal screening;  galactose and galactose-1-phosphate (serum,


erythrocytes, dried blood spots)

Therapy:

- Lactose-free infant formula (may be life-saving), lactose-free diet throughout life

Prognosis:

- Complications: in many patients sub-normal mental development despite diet, ovarian


dysfunction with abnormal pubertal development (girls)

Reference:

Zschocke J, Hoffmann GF. Vademecum Metabolicum. Manual of Metabolic Pediatrics. Milupa,


Schattauer. 3rd. ed. 2011

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