Approach to inborn errors of metabolism (progressive or chronic): Clinical sciences

Inborn errors of metabolism, or IEMs, are genetic conditions that result from alterations within a biochemical or metabolic pathway. IEMs with progressive or chronic onset are typically caused by single gene defects that impair enzymes involved in amino acid and carbohydrate metabolism or glycogen and lysosomal storage. Progressive or chronic IEMs can be broadly categorized according to the presence or absence of progressive neurologic deterioration and subcategorized further based on characteristic clinical findings.

Now, if a pediatric patient presents with a chief concern suggesting a chronic or progressive IEM, first perform an ABCDE assessment to determine if they’re stable or unstable. If unstable, stabilize their airway, breathing, and circulation. Next, obtain intravenous access and consider starting IV fluids. Finally, begin continuous vital sign monitoring, and if needed, provide supplemental oxygen.

Now that we’ve discussed unstable patients, let’s return to the ABCDE assessment and look at stable patients. First, obtain a focused history and physical examination, including fundoscopy. History might reveal a positive newborn screen, and affected children often present with developmental delays, intellectual disability, behavioral changes, muscle weakness, or motor deficits. There might be a family history of a known metabolic disorder, a sibling with similar symptoms, or an unexplained death.

The exam commonly reveals spasticity or hypotonia, occasionally in combination with organomegaly, ocular findings, and vision or hearing loss. With these findings, consider a chronic or progressive IEM, and assess for progressive neurological deterioration.

Here’s a high-yield fact! Although newborn metabolic screening can detect many IEMs early, screening panels vary by state, and false negative results are possible. So, whenever you suspect a metabolic disorder, order confirmatory testing regardless of newborn screening results.

Now, let’s discuss patients who show signs and symptoms of progressive neurologic deterioration. First, assess for self-mutilating behavior. If the patient has a history of self-biting, particularly of the mouth or fingers, consider Lesch-Nyhan disease, an X-linked recessive disorder of purine metabolism.

Patients are typically biological males presenting before one year of age with developmental delay, vomiting, difficulty handling secretions, and possibly gouty arthritis. Exam findings include extrapyramidal signs or dystonic movements, evidence of biting, and possibly spasticity or hypotonia. Obtain a serum uric acid level and a hypoxanthine-guanine phosphoribosyltransferase, or HPRT enzyme assay. If the uric acid is elevated and there’s an HPRT deficiency, diagnose Lesch-Nyhan disease.

Now let’s move on to patients without self-mutilating behavior. Begin by assessing for unusual odors. If you note a musty or mousy odor, consider phenylketonuria, or PKU, which is an autosomal recessive aminoacidopathy.

Children usually present around age three with progressive intellectual disability, seizures, and unusual movements such as rocking or athetosis. The exam typically reveals microcephaly, light skin pigmentation, a seborrheic or eczematous rash, and spasticity or hyperreflexia. Obtain a phenylalanine level, and if it’s elevated, diagnose classic phenylketonuria.

On the other hand, if there’s no unusual odor, your next step is to assess for organomegaly. If you detect hepatosplenomegaly, assess for coarse facial features.

If absent, consider Niemann-Pick disease Type A, a sphingolipidosis with autosomal recessive inheritance. These patients often have feeding difficulties and a loss of early motor skills. The exam also typically reveals moderate lymphadenopathy and spasticity or rigidity. Check the acid sphingomyelinase level, and if it’s decreased, diagnose Niemann-Pick disease Type A. This lysosomal storage disorder causes sphingolipids to accumulate in cells throughout the body. Tissue damage results from the buildup of glycosaminoglycans, glycoproteins, or glycolipids.

On the other hand, if your patient has coarse facial features, the next thing to do is assess for corneal clouding. If present, consider Hurler syndrome, also known as mucopolysaccharidosis type one, or MPS I, which is a glycosaminoglycan lysosomal storage disorder with autosomal recessive inheritance.

Symptoms usually begin between 6 and 24 months of age and include progressive intellectual disability and joint stiffness. These patients often have recurrent respiratory infections, and some develop blindness or deafness.

Physical exam reveals coarse facial features such as macroglossia and macrocephaly with prominent frontal bones; retinal degeneration and short stature. Next, order an alpha-L-iduronidase enzyme assay. A deficiency of this enzyme confirms Hurler syndrome.

However, if corneal clouding is absent, consider Hunter syndrome, also known as mucopolysaccharidosis type two, or MPS II, which is another glycosaminoglycan lysosomal storage disorder, this time with X-linked recessive inheritance. Patients are typically biological males presenting between the ages of 2 and 4 years with progressive intellectual disability, joint stiffness, and occasionally, deafness.

Exams typically reveal coarse facial features such as a broad nose with a flattened bridge, thickened lips, and macroglossia; as well as short stature, and possibly skin papules or dermal melanocytosis. Obtain an iduronate 2-sulfatase enzyme assay, and if it reveals a deficiency of this enzyme, diagnose Hunter syndrome.

Here’s a high-yield fact! Measurements of urinary glycosaminoglycan excretion are often used to screen for mucopolysaccharidoses like Hurler and Hunter syndrome, but keep in mind that false-negative and false-positive results are common, so you'll still need to order confirmatory testing.