Metabolic/Biochemical
for inborn errors of metabolism, newborn screening confirmation, and leukodystrophies with exome sequencing
System Profile
Yield Comparison
Clinical Dimensions
- Hypoglycemia
- Acidosis
- Metabolic crises with illness or fasting
- Vomiting after high-protein meals
- Lethargy
- Urea cycle disorders
- FAODs
- Organic acidemias
- Galactosemia
- MSUD
- Mitochondrial diseases
- Peroxisomal disorders
- Glycogen storage diseases
- Kussmaul breathing
- Hepatomegaly
- Unusual body odor
- Hypotonia with intermittent crisis
- Abnormal fat distribution
- Dysmorphic features typical of metabolic syndromes
- Lethargy with fasting
- Vomiting during illness
- Coma-like episodes
- Seizures triggered by high-protein intake
- Intolerance to exercise
- Unexplained hypoglycemia
- Elevated ammonia
- Anion-gap metabolic acidosis
- Ketosis/hypoketosis
- Abnormal plasma amino acids
- Abnormal urine organic acids
- Abnormal acylcarnitine profile
- Low carnitine
- Abnormal lactate/pyruvate ratio
- Positive newborn screen markers
- MRI with symmetric basal ganglia lesions
- White matter abnormalities
- MR spectroscopy showing lactate
- Concurrent hepatic or renal cystic changes
- Skeletal rickets changes
- Plasma amino acids
- Urine organic acids
- Acylcarnitine profile
- Lactate/pyruvate ratio
- Enzyme assays
- Fibroblast metabolic studies
- Newborn screen confirmatory tests
- Carnitine
- Riboflavin
- Thiamine
- Biotin
- Sodium benzoate
- Bicitra
- Continuous or emergency dextrose infusions
- Tailored metabolic supplements
- Metabolic decompensation triggered by high-protein formula or intravenous feeds
- Intolerance to standard IV solutions
- Adverse responses to fasting or common IV meds
- G-tube placement for metabolic feeding
- Central line placement for metabolic infusions
- Biopsies (liver, muscle, skin) for enzyme or mitochondrial studies
- Metabolic diet therapy (protein/fat restriction, special formulas)
- Sick-day emergency plans
- Caregiver training for decompensation management
- Pumps and feeding devices for continuous metabolic formulas
- Home glucose/ketone monitors
- Metabolic genetics teams
- Biochemical genetics
- Multidisciplinary metabolic clinics
- Recurrent hospitalizations requiring metabolic consults
- Geneticist following long-term
- Known metabolic disorders
- Neonatal deaths of unknown cause
- Recurrent metabolic crises
- Unexplained SIDS
- Consanguinity
- Multiple siblings with similar episodes
- No starvation, fad dieting, or food insecurity explaining hypoglycemia or metabolic crises
- Metabolic decompensation tied to illness rather than environment
- Abnormal newborn metabolic screen
- Persistent metabolic acidosis
- Hyperammonemia
- Hypoglycemia
- Vomiting or lethargy within first days/weeks
Red Flag Combinations
Clinical patterns that should prompt consideration of genetic testing
Hypoglycemia + hyperammonemia
Vomiting + metabolic acidosis
Exercise intolerance + rhabdomyolysis
Recurrent decompensation with illness or fasting
Screening Decision Pathway
When to consider genetic testing for metabolic/biochemical presentations
graph TD
START["Patient Presents with\nMetabolic/Biochemical Concerns"] --> SCREEN{"Screen for\nRed Flags"}
SCREEN --> RF1["Positive newborn metabolic screening"]
SCREEN --> RF2["Abnormal glucose/ketone strips"]
SCREEN --> RF3["Abnormal lactate or ammonia on routine lab screen"]
SCREEN --> RF4["Tandem MS findings"]
RF1 --> EVAL{"Multiple\nFlags Present?"}
RF2 --> EVAL{"Multiple\nFlags Present?"}
RF3 --> EVAL{"Multiple\nFlags Present?"}
RF4 --> EVAL{"Multiple\nFlags Present?"}
EVAL -->|Yes| TEST["Order Genetic Testing\n(ES/GS)"]
EVAL -->|No| MONITOR["Continue Monitoring\nRe-evaluate if New Findings"]
TEST --> DX["Molecular Diagnosis\n88-90% yield"]
style TEST fill:#dcfce7,stroke:#16a34a,color:#14532d
style DX fill:#bbf7d0,stroke:#16a34a,color:#14532d
style MONITOR fill:#fef3c7,stroke:#d97706,color:#92400e
Screening Red Flags
Findings on routine screening that may indicate genetic etiology
- Positive newborn metabolic screening
- Abnormal glucose/ketone strips
- Abnormal lactate or ammonia on routine lab screen
- Tandem MS findings
Exome / Genome Sequencing Indications
Clinical scenarios supporting ES/GS as a diagnostic approach
- Any pattern of recurrent metabolic crises
- Unexplained lactic acidosis
- Hyperammonemia
- Hypoglycemia
- Multisystem involvement where targeted metabolic testing is inconclusive
Key Evidence
Published studies supporting genetic testing for metabolic/biochemical conditions
| Study | Year | Type | Sample | Yield | Key Finding |
|---|---|---|---|---|---|
| Genetic diagnosis by whole exome sequencing is complemented ... | 2018 | Cohort | None | 10-35% | RNA-seq transcriptomics provides 10-35% additional diagnostic yield beyond WES a... |
| Effectiveness of Whole Exome Sequencing Diagnosis in the Cli... | 2018 | Review | None | 16-68% | WES diagnostic yield ranges 16-68% across IEM and neurogenetic disorder cohorts ... |
| A Comprehensive Multiplex PCR Based Exome-Sequencing Assay f... | 2019 | Cohort | None | 89% | 89% concordance between PEARS enzymatic assay and molecular testing for PKU in 8... |
| Genomic Sequencing for Newborn Screening: Results of the NC ... | 2020 | Cohort | None | 88% | 88% (15/17) of metabolic disorders confirmed by exome sequencing in NC NEXUS new... |
| Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops... | 2020 | Cohort | 127 | 29% | Exome sequencing identified a genetic diagnosis in 29% of NIHF cases after stand... |
| Clinical exome sequencing as a first-tier test for the diagn... | 2021 | Cohort | 128 | 55% | CES as first-tier test achieved 55% overall diagnostic yield in 128 pediatric pa... |
| 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Ca... | 2021 | Cohort | 2183 | 25% | 25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs c... |
| Next-Generation Sequencing for Inborn Errors of Metabolism i... | 2022 | Cohort | None | 64.3% | NGS achieved 64.3% diagnostic yield for IEM in Lebanese population; WES yielded ... |
Updated: 2026-02-25
Curated by: human
Status: human reviewed