Approach to inborn errors of metabolism (acute): Clinical sciences

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Introduction0:00–0:35

Inborn errors of metabolism or I ems are genetic conditions that result from alterations within a biochemical or metabolic pathway.
I es that present with acute onset during infancy are typically caused by single gene defects that impair enzymes involved in the urea cycle.
Amino acid and carbohydrate metabolism, blockage and storage or peroxisomal or mitochondrial activity. When you suspect an acute IE M, you can use results of an initial laboratory evaluation to guide confirmatory testing.
Now, if a pediatric patient presents with a chief concern, suggesting an IE with acute onset first, perform an ABCD E assessment to determine if they are stable or unstable.

Unstable0:35–1:14

If unstable, stabilize their airway breathing and circulation. And you may need to intubate your patient next, obtain intravenous access and consider starting IV fluids, then begin continuous vital sign monitoring and if needed, provide supplemental oxygen.
Finally, since patients with I EMS can present with signs and symptoms that mimic sepsis, consider starting IV antibiotics.
Now, after you've stabilized, your patient obtain a focused history and physical examination and order an A BG CBCC MP ammonia level and urinalysis.

Stable1:14–2:05

Most patients present during infancy with poor feeding, vomiting and irritability affected infants have no obvious infection, no history of trauma and no known central nervous system or other anomalies.
History may also reveal a positive newborn screen, a sibling with an unexplained death or similar symptoms or a family history of a metabolic disorder.
On exam, you're likely to see an altered mental status, rapid deep breathing or apnea and hepatosplenomegaly. With these findings consider an inborn error of metabolism and assess the ABG for respiratory alkalosis If the ABG shows a decreased partial pressure of arterial carbon dioxide or P CO2, which indicates respiratory alkalosis.

Ornithine transcarbamylase deficiency2:05–3:10

This is the first clue that you should consider a urea cycle disorder. Your next step is to check the serum ammonia level.
The presence of marked hyperammonemia indicates that you're dealing with a urea cycle disorder characterized by impaired conversion of neurotoxic ammonia into a more excretable compound called urea.
Initially, hyperammonemia stimulates chemo receptors in the brain resulting in an increased respiratory rate and subsequent respiratory alkalosis.
If left untreated hyperammonemia can lead to encephalopathy, seizures and coma. Now, the most common urea cycle disorder is ornithine, transcarbamylase or OTC deficiency to identify it.
Check plasma amino acid levels if glutamine and alanine are elevated and if citrulline and arginine levels are decreased diagnose otc deficiency.
All right, let's move on to conditions that are not associated with respiratory alkalosis, meaning the P CO2 is not decreased unlike urea cycle disorders.

Pyruvate dehydrogenase complex deficiency3:10–5:21

Many other I ems commonly present with hypoglycemia, metabolic acidosis or a combination of both. So let's look at some other lab findings starting with blood glucose levels.
If the glucose is normal, look at your patient's acid base status to investigate further. Here's your first clinical pearl.
Many I es are characterized by metabolic acidosis with an elevated anion gap. The anion gap is the difference between measured anions and cation ions in the blood and the gap represents unmeasured ions to calculate it.
Take the serum sodium and subtract the sum of serum chloride and bicarbonate. An anion gap above 12 mill equivalents per liter indicates the presence of unmeasured anions such as ketones or lactate.
Now, back to our patient if labs demonstrate an elevated anion gap, metabolic acidosis with elevated serum lactate levels, consider disorders of pyruvate metabolism such as pyruvate dehydrogenase complex deficiency or PDC deficiency characterized by lactic acidosis without organic acid abnormalities.
Patients typically have low birth weight and later develop psychomotor delays. Characteristic exam findings resemble those seen in fetal alcohol syndrome, including short palpebral fissures, a smooth filtrum, a thin vermilion border microcephaly and hypotonia to confirm the diagnosis.
Order a genetic analysis if there's a defect in a gene that codes for one of the three critical enzymes in the pyruvate dehydrogenase complex diagnose PDC deficiency because the pyruvate dehydrogenase complex is part of the citric acid cycle and aerobic respiration disorders of this complex lead to decreased ATP production during times of stress.

Infantile Pompe disease5:21–6:21

Ok. Now, let's talk about cases with no acidosis and a normal serum lactate.
Here, consider infantile pompe disease, also known as glycogen storage disease. Type two history typically reveals profound muscle weakness and inadequate growth.
While the exam demonstrates severe generalized hypotonia, an enlarged tongue and hepatomegaly labs typically demonstrate elevated LFT S to confirm the diagnosis.
Order a creatinine kinase or CK level chest X ray and echocardiogram. The CK is typically elevated.
The chest X ray reveals massive cardiomegaly and the echocardiogram often demonstrates hypertrophic cardiomyopathy. These results confirm infantile pompe disease, which is also considered a lysosomal storage disease due to glycogen accumulation within lysosomes.
You can remember the characteristics of this disease by using the pneumonic mighty heck. Ok.

Hypoglycemia timing6:21–6:36

Let's switch gears and discuss conditions that are characterized by hypoglycemia. Many I es can cause hypoglycemia but you can narrow your differential by assessing the timing of hyperglycemia in relation to feedings, postprandial hypoglycemia should make you consider an inborn error of carbohydrate metabolism to pinpoint the underlying cause check urine, non glucose reducing substances or N GR S and order a galactose one phosphate uil transferase or GALT activity assay as well as molecular genetic testing.

HFI6:36–7:13

If N GR S are elevated and you identify an ad ob gene mutation, diagnose hereditary fructose intolerance, infants with this condition typically experience hypoglycemia when they first consume fruits and vegetables.
On the other hand, if the N GR S are elevated and no GALT activity is detected, diagnose classic galactosemia here, galactose containing foods such as breast or cow's milk trigger hypoglycemia.

Classic galactosemia7:13–7:38

Patients with classic galactosemia have an increased susceptibility to e coli sepsis and may develop hepatomegaly jaundice and cataracts.

Fasting hypoglycemia7:38–7:55

Now, let's switch our focus to conditions associated with fasting hypoglycemia. Here you can further differentiate I MS according to the predominant substrate causing an elevated anion gap.
Let's start by assessing for lactic acidosis. The presence of lactic acidosis should make you consider conditions that impair gluconeogenesis such as fructose, 16 diphosphatase deficiency and glucose, six phosphorylase deficiency also called glycogen storage disease.

Fructose 1,6 diphosphatase deficiency7:55–8:30

Type one or GSD. One.
Both conditions present with hypoglycemia within two hours of fasting and poor weight gain. So to differentiate the two perform molecular genetic testing, an F BP one gene mutation confirms fructose 16 diphosphatase deficiency.
On the other hand, in addition to hypoglycemia within two hours of fasting and poor weight gain, patients with GSD, one have characteristic exam findings including dull like facies, hepatosplenomegaly, hypotonia and xanthomas.

GSD I8:30–8:54

If molecular genetic testing identifies a G six PCG mutation, diagnose GSD type one. Now, if your patient does not have lactic acidosis, you can look for evidence of ketoacidosis by checking for urinary ketones, organic acidemias and some amino acidopathies are characterized by ketoacidosis.

Hypoglycemia/ketonuria8:54–9:13

So if ketonuria is present, assess the CBC results to investigate further. If the CBC reveals neutropenia or thrombocytopenia, consider an organic acidemia such as propionic or methylmalonic acidemia.

Propionic acidemia9:13–9:39

In both conditions, propionic acid levels are elevated and glutamine levels are normal or decreased. So, to tell them apart, obtain a plasma amino acid level and check the methylmalonic acid level if it's normal diagnose propionic acidemia.
However, if they're elevated diagnose methylmalonic acidemia. Now, on the other hand, if the white blood cell and platelet levels are normal, consider maple syrup, urine disease, caregivers often report a distinctly sweet odor of the cerumen, sweat and urine.

Methylmalonic acidemia9:39–9:44

Classic maple syrup urine disease9:44–10:49

And the physical exam typically reveals altered mental status, hypertonicity and opisthotonus. To confirm the diagnosis measure plasma amino acid levels.
If leucine isoleucine and valine are elevated diagnose classic maple syrup urine disease. This aminoacidopathy is characterized by an accumulation of branched chain amino acids which leads to acute encephalopathy and impaired gluconeogenesis time.
For a clinical pearl amino acidopathies are a heterogeneous group of disorders in which a deficiency of enzymes involved in amino acid deamination leads to accumulation of specific amino acids.
Other examples of amino acidopathies with late or progressive onset include fetal ketonuria, homocysteinuria and alcaptonuria.
Now let's move on and discuss patients with hypoglycemia and no urinary ketones, hypoketotic hypoglycemia is a clue that you're dealing with a mitochondrial fatty acid oxidation disorder to determine the subtype, assess for signs and symptoms of rhabdomyolysis.

FAODs10:49–11:08

Carnitine transporter deficiency (CTD)11:08–11:59

If your patient reports manifestations of rhabdomyolysis such as muscle weakness, stiffness or pain and t colored urine, consider carnitine transporter deficiency or CTD.
These patients typically present after one year of age with weakness, shortness of breath, hypotonia, and possibly hepatomegaly and elevated LFT S to confirm your suspicions, check the plasma ACL carnitine profile plus ACL glycine and organic acid levels.
And order an echocardiogram, decreased total and free carnitine levels with normal levels of acylcarnitine acylglycine and organic acids confirmed the diagnosis of CTD echocardiogram.
Findings of either dilated or hypertrophic cardiomyopathy further support the diagnosis. Ne let's switch gears and talk about patients with hypoketotic hypoglycemia who show no clinical manifestations of rhabdomyolysis, meaning they have no muscle weakness and their urine appears normal.

MCAD11:59–13:39

In this case, consider medium chain ACL coa dehydrogenase or M CAD deficiency. Affected infants typically develop symptoms after an illness or fasting with progressive lethargy, vomiting seizures and in rare cases, sudden unexpected infant death.
The exam may demonstrate hepatomegaly and labs may show elevated LFT S to confirm the diagnosis. Obtain a plasma ac carnitine profile lipid panel and a 12 lead ecg labs typically demonstrate normal or decreased free carnitine levels with increased medium chain fatty acids.
While ECG may reveal a prolonged qt interval. These findings are diagnostic of MCD deficiency.
Let's wrap it up with a few high yield facts when it comes to fatty acid oxidation disorders, the longer the affected carbon chain, the more severe a patient's clinical manifestations defects in long chain and very long chain fatty acid oxidation often present with rhabdomyolysis and severe cardiomyopathy.
Zellweger spectrum disorder is a peroxisomal disorder that causes the accumulation of very long chain fatty acids. These patients have characteristic clinical findings which include atypical facial features, severe weakness and hypotonia, seizures and eye abnormalities.
All right, as a quick recap I es with acute onset can be differentiated according to initial lab results, respiratory alkalosis and markedly elevated serum ammonia.

Review13:39–14:46

Suggest urea cycle defects like ornithine transcarbamylase deficiency. While severe lactic acidosis and normal blood glucose suggest PDC deficiency cardiomegaly without hypoglycemia or acidosis is a sign of infantile pompe disease.
Postprandial hypoglycemia suggests hereditary fructose intolerance or classic lactosa. While fasting hypoglycemia with lactic acidosis suggests fructose 16 diphosphatase deficiency or GSD one fasting hyperglycemia with ketonuria are classic findings of propionic or methylmalonic acidemia as well as maple syrup urine disease.
Finally, hypoketotic hypoglycemia should make you think of fatty acid oxidation disorders such as carnitine transporter deficiency and M CAD deficiency.