# Inborn Errors of Metabolism: Newborn Screening and Adult Presentations

## Introduction

**Inborn errors of metabolism (IEM)** encompass over 1,000 genetic disorders affecting biochemical pathways. While traditionally considered pediatric diseases, improved newborn screening and treatments have created a growing population of adults living with IEM. Med-peds physicians are uniquely positioned to bridge the gap between pediatric metabolic care and adult medicine, recognizing both neonatal presentations and late-onset or surviving-into-adulthood phenotypes.

## Newborn Screening

### Principles and Methods

The **Recommended Uniform Screening Panel (RUSP)** includes over 35 core conditions and 25 secondary targets. **Tandem mass spectrometry (MS/MS)** revolutionized screening by enabling simultaneous detection of amino acids and acylcarnitines. Screening is performed on dried blood spots collected at 24-48 hours of life. **Point-of-care screening** for critical congenital heart disease (pulse oximetry) and hearing loss complement metabolic panels. False positives are common; confirmatory testing is essential before initiating treatment.

### Categories of Screened Conditions

| Category | Examples | Detection Method | Acute Presentation |
|----------|----------|-----------------|-------------------|
| Amino acid disorders | PKU, MSUD, homocystinuria | Elevated amino acids on MS/MS | Encephalopathy, seizures |
| Fatty acid oxidation | MCADD, VLCADD | Abnormal acylcarnitine profile | Hypoketotic hypoglycemia, cardiomyopathy |
| Organic acidemias | Propionic, methylmalonic, isovaleric | Abnormal acylcarnitines + organic acids | Metabolic acidosis, hyperammonemia |
| Urea cycle disorders | OTC deficiency, citrullinemia | Elevated citrulline or low citrulline | Hyperammonemia, respiratory alkalosis |
| Other | Galactosemia, biotinidase deficiency, congenital hypothyroidism | Specific analytes | Variable |

**Amino acid disorders**: Phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria. **Fatty acid oxidation disorders**: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) **Organic acidemias**: Propionic acidemia, methylmalonic acidemia, isovaleric acidemia. **Urea cycle disorders**: Ornithine transcarbamylase (OTC) deficiency, citrullinemia. **Other**: Galactosemia, biotinidase deficiency, congenital hypothyroidism, sickle cell disease, cystic fibrosis.

![Overview of newborn screening categories and tandem mass spectrometry workflow](illustration-newborn-screening-categories.jpg)

## Clinical Presentations Across Ages

### Neonatal Presentations

**Acute metabolic crisis**: Poor feeding, lethargy, vomiting, seizures within the first days of life. Key laboratory findings: **metabolic acidosis**, hyperammonemia, hypoglycemia, elevated lactate. Urea cycle defects classically present with **respiratory alkalosis** and markedly elevated ammonia. Organic acidemias present with **anion gap metabolic acidosis** and ketonuria.

### Childhood Presentations

Developmental delay, failure to thrive, hepatomegaly. Recurrent episodes of metabolic decompensation triggered by illness, fasting, or dietary indiscretion. **Lysosomal storage diseases** (Gaucher, Fabry, mucopolysaccharidoses) may present with organomegaly, skeletal abnormalities, and neurodegeneration.

### Adult Presentations

**Late-onset OTC deficiency**: Episodic confusion, psychiatric symptoms, hyperammonemia triggered by stress, surgery, or high-protein meals. **Fabry disease**: Neuropathic pain, angiokeratomas, progressive renal failure, cardiomyopathy. **Wilson disease**: Hepatic and neuropsychiatric symptoms in adolescents and young adults. **Acute intermittent porphyria**: Abdominal pain, neuropsychiatric symptoms, autonomic dysfunction. **Adult-onset MSUD**: Episodic encephalopathy during metabolic stress.

## Diagnostic Approach

**Plasma amino acids**: Elevated phenylalanine (PKU), branched-chain amino acids (MSUD), methionine (homocystinuria) **Urine organic acids**: Characteristic profiles for organic acidemias. **Acylcarnitine profile**: Identifies fatty acid oxidation and organic acid disorders. **Ammonia and lactate**: Critical in acute presentations. **Genetic testing**: Next-generation sequencing panels, whole exome/genome sequencing for definitive diagnosis. **Enzyme assays**: Confirmatory for lysosomal storage diseases and specific enzyme deficiencies.

![Diagnostic algorithm for suspected inborn error of metabolism in acute presentation](illustration-iem-diagnostic-algorithm.jpg)

## Management Principles

### Acute Management

**Stop catabolism**: Provide high-concentration IV dextrose (D10 or higher) with appropriate electrolytes. **Ammonia scavengers**: Sodium benzoate and sodium phenylacetate for hyperammonemia. **Dialysis**: Hemodialysis for ammonia >500 mcmol/L or rapidly rising levels. Avoid prolonged fasting; maintain anabolism with sufficient calories. Specific cofactor therapy: **Carnitine** supplementation, **biotin**, **hydroxocobalamin** as indicated.

### Chronic Management

**Dietary therapy**: Phenylalanine-restricted diet for PKU; protein-restricted diets for urea cycle defects and organic acidemias. **Enzyme replacement therapy (ERT)**: Available for Fabry, Gaucher, Pompe, and select mucopolysaccharidoses. **Substrate reduction therapy**: Miglustat for Gaucher type 1 and Niemann-Pick C. **Liver transplantation**: Curative for some urea cycle defects, MSUD, and propionic acidemia. **Gene therapy**: Emerging for several conditions including aromatic L-amino acid decarboxylase deficiency.

### Transition to Adult Care

Structured transition programs improve outcomes and adherence. Adult providers must understand dietary restrictions, emergency protocols, and monitoring schedules. Pregnancy planning is critical: **maternal PKU syndrome** causes intellectual disability, microcephaly, and heart defects in offspring of women with uncontrolled phenylalanine.

![Transition care pathway for patients with inborn errors of metabolism](illustration-iem-transition-care-pathway.jpg)

## Clinical Pearls

Any neonate with unexplained lethargy, poor feeding, or metabolic acidosis should have ammonia, lactate, and newborn screening results checked urgently. Hyperammonemia with respiratory alkalosis points toward a urea cycle defect; with metabolic acidosis, consider organic acidemia. Adults with unexplained episodic encephalopathy, cardiomyopathy, or renal failure should be evaluated for late-onset IEM. Maternal PKU requires preconception phenylalanine control to prevent teratogenic effects. The growing population of adults with IEM demands internists who understand these conditions.

## References

1. Wasserstein MP, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for IEM. *Genet Med*. 2021;23(5):816-826.
2. Saudubray JM, Baumgartner MR, Walter J. *Inborn Metabolic Diseases: Diagnosis and Treatment*. 7th ed. Springer; 2022.
3. Berry SA, Brown C, Grant M, et al. Newborn screening 50 years later: access issues faced by adults with PKU. *Genet Med*. 2013;15(8):591-599.
4. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. *Orphanet J Rare Dis*. 2019;14(1):32.