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= all chemical reaction involved in maintaining the living state of the cells and the organism

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= single-gene defect which cause a significant block in metabolic pathway

Inborn errors can manifest at any age, affect any organ system and mimic many common pediatric problems

- Prevalence: 1:15.000 children
- Many are effectively treated

Pathology usually results from:
- Accumulation of enzyme substrate behind a metabolic block
o The enzyme is diffusible and has adverse effects on distant organs
o The enzyme may also accumulate locally
- Deficiency of a reaction product

Difference inborn error and congenital error of metabolism:
They are the same.

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Anion gap
= balance between anions and cations

normal: loss of HCL3
elevated: increased production of acid (metabolic diseases)

Important to know for differentiating the cause of acidosis:
- metabolic or respiratory acidosis
- or organic acidosis

Increase: fall in cations or rise in anions (albumin)
decrease: rise in the cations (hypercalaemia) or fall in anions

Why do symptoms appear after birth?
Due to the fact that they don't have the mother to help them. The symptoms are vague, but similar to almost all inborn errors of metabolism.

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Enhance the reduced enzyme activity: Gene-replacement is long-term goal
- Enzyme-replacing therapies (administration of recombinant enzymes)
- Enzyme-substitution therapy (modified bacterial enzyme)
- Organ transplant (liver, kidney, heart or bone marrow) may provide source of enzyme
- Pharmacological doses of a cofactor (vitamins), may restore enzyme activity
- Pharmacologically promoting transcription (upregulation)

Cope with consequences of enzyme deficiency / avoid substrate accumulation
- Restriction of precursor in diet
- Removal of accumulated substrate (e.g. by dialysis)

Supplement inadequately produced metabolite

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Definition = disorders of amino and fatty acid metabolism in which non-amino organic acids accumulate in serum and urine

Types
1) Isovalaeric
2) Methylmalonic - MA (due to defect in methylmalonyl-CoA mutase)
3) Proprionic (due to defect in biotin-containing enzyme propionyl-CoA carboxylase)
4) 3-methylcrotonyl-CoA carboxylase deficiency (Isolated pyruvate carboxylase deficiency presents with lactic acidosis and hyperammonemia in early infancy. Poor neurological outcome)
5) Multiple carboxylase deficiency
6) Glutaric acidaemia

PA & MA:
-       Ketotic, metabolic acidosis and hypercalaemia
- Dysfunction in proprionyl carboxylase and methyl malonyl mutase
- Severe neonatal presentation
- Acidosis during metabolism
- Restricted diet of the amino acid.
- Can predispose to: cardiomyopathy, pancreatitis, seizures, developmental delays.

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Maple Syrup Urine Disease
Deficiency of the enzyme complex that catalyzes the oxidative decarboxylation of ketoacid derivates of leucine, isoleucine and valine

It is a “build-up” disease of leucine, which can be neurotoxic (CNS dysfunction)
- Accumulation of ketoacids of leucine and isoleucine (converted to sotolone), cause characteristic sweet odor.

You need to reduce the substrate

Treatment:
- Restricted diet
- Orthotopic liver transplant is “cure”
o The liver is involved in most of these reactions and thus a new liver would have a normal metabolism

PKU
= Phenylalanine Hydroxylase Deficiency (PAH)
PKU is best-known disorder of a.a. metabolism
- Hereditary: autosomal recessive
- Incidence (Caucasians): 1:10.000

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the enzyme phenylalanine-4-hydroxylase (PAH), which is mainly active in the liver. PAH converts the essential amino acid phenylalanine (Phe) into tyrosine using the cofactor tetrahydrobiopterin (BH4). A deficiency of the enzyme leads to increased Phe and normal to decreased tyrosine concentrations in blood and tissues. Untreated, this results in progressive and irreversible neurological damage (among others mental retardation and epilepsy)

PKU is caused by decreased activity of phenylketonuria, no phenylalanine hydroxylase activity --> elevated phenylalanine levels (hyperphenylalaninemia) --> severe intellectual disability, hyperreactivity, seizures, light complexion and eczema
- Enzyme deficiency of phenylalanine hydroxylase, leads to build up of phenylalanine, which is neurotoxic
- Leads to microcephaly and severe cognitive impairment
- First disease to be screened in newborn testing

If a pregnancy woman has PKU, the baby won’t necessarily get the disease (autosomal recessive), but high levels of Phe can become teratogenic to the fetus.

Diagnosis:
- Based on finding elevated plasma phenylalanine and elevated Phe/Tyrosine ratio
o Plasma Phe > 20 mg/dL

Treatment: lower Phe (<6 mg/dL)
- Dietary restriction of Phe (vegetarian; permits normal growth and development), special formula (restricted in phenylalanine, but completes the other a.a. that are necessary for growth and development)
- Increase enzyme activity with pharmacological doses of R-tetrahydrobiopterin
- Interfere with phenylalanine absorption or breakdown Phe

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Definition = Urea cycle disorders (UCDs) represent a group of rare inherited metabolic disorders resulting from a partial or complete deficiency of one of the urea cycle components, thereby resulting in accumulation of ammonia, as well as other nitrogenous products, including glutamine and alanine.

Hyperammonemia results in cerebral edema and neurologic injury. These disorders may present at birth, childhood, or adulthood and may range from a relatively mild encephalopathy to profound developmental disability (due to later metabolic stress). Early diagnosis and treatment may prevent some of the adverse outcomes, which are primarily neurological.

Involves mainly the excretion of nitrogen (in the form of urea and ammonia).

Problem: you can’t complete the cycle and you have build-up of ammonia, which is neurotoxic.

General principles:
- Disorders in the pathway of nitrogen excretion
- Build-up of ammonia is neurotoxic
o Encephalopathy and death
- Can present as:
o Catastrophic neonatal illness (3-10d old baby)
o Childhood/teen onset
o After significant stress (pregnancy)
- Treatment: lifelong protein restriction (formula)

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Definition = Inability to process fatty acids through mitochondria

Fatty Acid Oxidation Disorder
Fatty acid oxidation disorders are disorders of the transport and catabolism of fatty acids in the mitochondria
- Presents with hypoketotic hypoglycemia
-      and, depending on the specific disorder, may include mild hyperammonemia, hepatopathy, encephalopathy, and/or skeletal myopathy or cardiomyopathy.

Diagnosis:
All disorders of fatty acid oxidation have reduced ketogenesis in response to fasting. The analysis of acylcarnitine esters (via an acylcarnitine profile) is a first-line diagnostic test used in newborn screening because it reveals diagnostic metabolites regardless of clinical status.

Treatment:
Management of all disorders of fatty acid oxidation involves prevention of hypoglycemia by avoiding prolonged fasting (> 8–12 hours). This includes vigorous treatment of fasting associated with illness with glucose.

Carnitine
Carnitine is an essential nutrient found in highest concentration in red meat.
- Its function: transport long-chain fatty acids into mitochondria for oxidation

Treatment:
is aimed at maintaining normal carnitine levels: Oral or intravenous L-carnitine
-   also prevent fasting

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Galactosaemia
--> enzyme deficiency

- Defect in GALT (galactose 1 phosphate uridyltransferase)
- Prevents proper breakdown of galactose into glucose
-     Build up of galactosephase-1
- Treatment: lactose restriction/free sugars

Classic:
total deficiency of GALT-1, where the galactose-phosphate accumulates which causes hepatic parenchymal disease and affects the kidneys.
Child presents with jaundice, hepatomegaly, liver insufficiency and vomiting. Without treatment, death can occur due to E. coli or sepsis.
Increased risk for speech and language problems. Or intellectual disabilities.

Fructose-1,6-biphospate aldolase deficiency (fructose intolerance)
--> enzyme deficiency
= failure of gluconeogenesis

- Infants present with hypoglycaemia, ketosis and lactic acidosis
- Dietary control leads to normal growth

Glycogen storage disorder:
- GSD 1/ von Gierke disease

Inherited disease that results in the liver being unable to properly break down stored glycogen. This impairment disrupts the liver's ability to break down stored glycogen that is necessary to maintain adequate blood sugar levels.
- can be in accumulation in muscles or brain

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Inborn errors must be considered in the DDX of critically ill new-borns, children with seizures, neurodegeneration, recurrent vomiting, renal insufficiency, unexplained metabolic acidosis, cardiomyopathy, hypoglycaemia, hyperammonaemia
- Failure to thrive, developmental delay and intellectual disability are often present, but have low specificity
-     You don't expect the child to be so sick

Inborn errors should be suspected when:
1. Degree of illness appears out of proportion to history

1. 2. Symptoms accompany changes in diet

3. Child’s development regresses
4. Child shows specific food preferences/aversions
5. Child has family history of parental consanguinity

Ammonia level
Important to measure as ammonia can be (neuro-)toxic.
> 100mcg/dL in neonates and > 80mcg/dL in neonates is seen as elevated levels

High in urea cycle defects.

Lab evaluation
Lab is needed for the diagnosis of inborn errors
- Serum electrolytes and pH: estimate anion gap and acid-base status
- Urine ketones and blood glucose
- Serum lactate, pyruvate and ammonia levels
- Amino acids, acylcarnitine and organic acid studies
- DNA sequencing is more commonly used, to detect the specific gene mutation.

Physical findings
- Alopecia or abnormal hair
- Retinal red spots
- Optic atrophy
- Hepatomegaly or splenomegaly
- Coarse features
- Skeletal changes
- Neurological regression
- Failure to thrive, microcephaly, rash, jaundice, hypotonia and hypertonia

Heel prick test (in NL)
In the first week (preferably between 24-72h) after birth, children are tested for congenital disorders. This is done by drawing some blood from the child’s heel. This test is known as the heel prick or newborn blood spot screening.

The blood collected by means of the heel prick is tested for:
• a disease of the thyroid gland,
• a disease of the adrenal gland,
• a type of anaemia (sickle cell disease),
• a disease of the lungs (cystic fibrosis),
• a number of metabolic diseases (acidopathies, organic acidosis, and fatty acids oxidation disorders, lysosomal disorders).

False negatives and false positives are a possible outcome due to the small time frame.

BH4 test
Used to test for PKU.
The child's life can be very normal if they are tested for PKU and get treated early.

BH4 test: heel prick test, tested within 7 days

PKU converts Phe into tyrosine, using the cofactor BH4 (more info underneath the PKU categorie of inborn errors of metabolism).

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Criteria for screening newborns depends on frequency of disease, its consequences if untreated, the ability of therapy to mitigate consequences, cost of testing and cost of treatment

Newborn screening includes 35 core conditions:
- Amino acidpathies, organic acidurias and disorders of fatty acid oxidation are screened

- Screening tests measure a metabolite (e.g. phenylalanine) that becomes abnormal with time and exposure to diet
o The disease cannot be detected reliably until intake of the substrate is established
- Other tests measure enzyme activity (can be performed at any time)

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Proteins are main building blocks (aid in structure, functions, hemoglobin formation, enzymes, etc.)
- Proteins contain amino acids

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Fats are concentrated sources of energy and produce 2x the energy of carbohydrates/proteins

Function of fat:
- Formation of cellular structure
- Insulation around vital organs
- Helps absorb fat-soluble vitamins
- Reserve storage for energy

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Energy production

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Urea production from ammonia and CO2 in the liver.

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Inborn errors of metabolism: Identifying the specific disorder - UpToDate

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Inborn errors of metabolism: Classification - UpToDate

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Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features - UpToDate

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Level of amino acids in amino acid disorders

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Level of amino acids in amino acid disorders

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https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/urea-cycle-disorder

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Fanconi syndrome is a defect of proximal tubule leading to malabsorption of various electrolytes and substances that are usually absorbed by the proximal tubule.