The Diagnostic Odyssey: A Guide to Inborn Errors of Metabolism in Adults

Dr Neeraj Manikath , claude.ai

Abstract

Inborn errors of metabolism (IEMs), traditionally considered pediatric diseases, increasingly present diagnostic challenges in adult critical care settings. With advances in neonatal screening and supportive care, many patients survive to adulthood, while others manifest symptoms for the first time in their second or third decade of life. The intensivist must maintain a high index of suspicion when confronted with unexplained encephalopathy, recurrent metabolic crises, or multi-system organ dysfunction that defies conventional explanations. This review provides a practical framework for recognizing, investigating, and managing IEMs in adult patients, with emphasis on high-yield clinical pearls and diagnostic pitfalls.

Keywords: Inborn errors of metabolism, metabolic encephalopathy, porphyria, hyperammonemia, mitochondrial myopathy, tandem mass spectrometry

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Introduction

The concept that IEMs are exclusively pediatric diseases represents one of the most persistent misconceptions in modern medicine. While newborn screening programs have revolutionized early detection, three distinct adult populations present to critical care: (1) previously undiagnosed patients experiencing their first metabolic crisis, (2) known IEM patients with acute decompensation, and (3) carriers of metabolic defects unmasked by physiologic stressors such as pregnancy, infection, or surgery.¹

The intensivist's challenge lies not in memorizing the 1,000+ described IEMs, but in recognizing constellation patterns that should trigger metabolic investigation. This review focuses on high-yield presentations most relevant to adult critical care practice.

🔑 PEARL: The "rule of thirds" - approximately one-third of IEM patients present after age 16, one-third have normal routine laboratory investigations between crises, and one-third are precipitated by identifiable stressors (infection, fasting, protein load, medication).²

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The Adult Presenting with Unexplained Encephalopathy & Metabolic Acidosis

Clinical Recognition

Metabolic encephalopathy in adults typically follows a stereotyped pattern: an initial "well interval" followed by progressive neurological deterioration over hours to days, often with accompanying gastrointestinal symptoms (vomiting, anorexia, abdominal pain). Unlike septic encephalopathy, which fluctuates with hemodynamic parameters, metabolic encephalopathy follows a more predictable trajectory unless specific metabolic therapy is instituted.³

The diagnostic clue lies in the pattern of metabolic derangement:

High Anion Gap Metabolic Acidosis (HAGMA) with Elevated Lactate:

• Consider: Organic acidemias, mitochondrial disorders, glycogen storage diseases
• The lactate:pyruvate ratio is crucial: >20:1 suggests mitochondrial dysfunction, <20:1 suggests tissue hypoperfusion⁴

HAGMA with Normal Lactate:

• Consider: Propionic acidemia, methylmalonic acidemia, isovaleric acidemia
• These generate unmeasured organic anions, widening the anion gap without lactic acidosis

Normal Anion Gap with Hyperammonemia:

• Consider: Urea cycle disorders (discussed separately)

The Organic Acidemias: Key Differentiators

Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) represent the most common organic acidemias presenting in adulthood.⁵ Both result from defects in propionate metabolism, a pathway handling odd-chain fatty acids, cholesterol, and amino acids (valine, isoleucine, methionine, threonine).

Clinical Presentation:

• Episodic vomiting, lethargy progressing to coma
• Ketoacidosis disproportionate to degree of starvation
• Bone marrow suppression (neutropenia, thrombocytopenia) - a distinctive feature
• Movement disorders (chorea, dystonia) in chronic cases
• Pancreatitis (particularly MMA)⁶

Laboratory Hallmarks:

• HAGMA with ketonuria
• Hyperammonemia (usually <200 μmol/L, unlike urea cycle disorders)
• Hypoglycemia or normoglycemia (unlike diabetic ketoacidosis)
• Elevated serum propionylcarnitine (C3) on acylcarnitine profile
• Elevated methylmalonic acid (MMA only) and/or methylcitrate (both) in urine organic acids

🔑 PEARL: The "protein aversion" history - many adults with undiagnosed organic acidemias unconsciously develop lifelong aversion to meat and high-protein foods.⁷ Always ask about dietary preferences in unexplained encephalopathy.

⚠️ OYSTER: Metformin toxicity can mimic organic acidemias with lactic acidosis and elevated C3-carnitine. Always check medication history and serum metformin levels.⁸

Acute Management Protocol

When IEM is suspected in the encephalopathic patient:

1. Stop All Protein Intake Immediately

• Initiate high-calorie dextrose infusion (10-15% dextrose, 8-10 mg/kg/min glucose infusion rate)
• Goal: Switch from catabolic to anabolic state⁹

2. Emergency Laboratory Investigations (Before Any Treatment)

STAT Labs (within 1 hour):
- Arterial blood gas with lactate
- Comprehensive metabolic panel including ammonia
- Complete blood count with differential
- Plasma amino acids (fasting if possible)
- Plasma acylcarnitine profile
- Urine organic acids (first morning void preferred)
- Urine ketones

Critical Action: Spin and freeze extra plasma/urine BEFORE starting treatment - 
you cannot recapture the diagnostic window once metabolism is altered.

3. Empiric Metabolic Therapy While awaiting confirmatory tests, consider:

• L-carnitine: 100-200 mg/kg/day IV (divided every 6-8h, max 3g/day) - facilitates excretion of toxic acyl-CoA intermediates¹⁰
• N-carbamylglutamate (Carbaglu®): 100-250 mg/kg/day if hyperammonemia present - provides alternative pathway for ammonia detoxification¹¹
• Sodium benzoate/phenylacetate: If ammonia >150 μmol/L (see urea cycle section)
• Hydroxocobalamin: 1-5 mg/day IM/IV if MMA suspected (cofactor for methylmalonyl-CoA mutase)¹²

4. Hemodialysis Indications

• Ammonia >400 μmol/L
• Rapidly progressive encephalopathy despite medical therapy
• Severe refractory acidosis (pH <7.1)
• Note: Continuous renal replacement therapy (CRRT) is less effective than intermittent hemodialysis for small molecule clearance¹³

🔑 HACK: Create an "IEM Emergency Box" in your ICU pharmacy with pre-packaged L-carnitine, N-carbamylglutamate, sodium benzoate, and arginine hydrochloride. Include a laminated algorithm - you won't have time to look things up during a crisis.

When to Call the Metabolic Specialist

Absolute indications:

• Confirmed or suspected IEM in any critically ill adult
• Unexplained encephalopathy with HAGMA or hyperammonemia
• Recurrent episodes of unexplained metabolic decompensation
• Before discontinuing life support in "unexplained" multi-organ failure

⚠️ OYSTER: Many metabolic specialists have limited experience with adult presentations. Consider contacting pediatric metabolic centers with adult critical care colleagues for joint consultation.¹⁴

Long-term Considerations

Adults with organic acidemias face specific complications:

• Progressive chronic kidney disease (especially MMA) - consider pre-emptive nephrology referral¹⁵
• Cardiomyopathy (both PA and MMA)
• Optic neuropathy (MMA with vitamin B12 metabolism defects)
• Increased risk of metabolic stroke and basal ganglia injury¹⁶

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Porphyrias: The Triad of Abdominal Pain, Neuropathy, and Psychiatric Symptoms

The Great Masquerader

Acute porphyrias represent quintessential diagnostic challenges, often mistaken for surgical abdomen, Guillain-Barré syndrome, psychosis, or polypharmacy complications. Four types cause acute neurovisceral attacks: Acute Intermittent Porphyria (AIP, most common), Variegate Porphyria (VP), Hereditary Coproporphyria (HCP), and ALAD-deficiency Porphyria (extremely rare).¹⁷

🔑 PEARL: Think porphyria in the "5 Ps": Pain (abdominal), Port-wine urine, Peripheral neuropathy, Psychological symptoms, and Precipitants (drugs, fasting, hormones).¹⁸

Clinical Presentation: The Diagnostic Triad

1. Abdominal Pain (85-95% of attacks)

• Severe, colicky, poorly localized
• No peritoneal signs despite severity
• Often associated with constipation, nausea, vomiting
• Tachycardia disproportionate to pain severity (autonomic involvement)
• CT abdomen characteristically negative¹⁹

2. Neurological Manifestations (60% of attacks)

• Motor neuropathy predominates (unlike GBS, which is sensorimotor)
• Proximal > distal weakness
• Shoulder girdle and upper extremities often affected first
• Can progress to quadriplegia and respiratory failure
• Seizures in 10-20% (often provoked by hyponatremia)
• Posterior reversible encephalopathy syndrome (PRES) reported²⁰

3. Psychiatric Symptoms (40-60% of attacks)

• Anxiety, agitation, hallucinations, confusion
• Depression, paranoia
• Often dismissed as "functional" or drug-seeking behavior
• May precede physical symptoms by days²¹

The "Red Flag" Clinical Signs

Autonomic Dysfunction (Pathognomonic Combination):

• Tachycardia (persistent, often 100-120 bpm at rest)
• Labile hypertension
• Postural hypotension
• Urinary retention
• Profuse sweating
• This constellation in a young patient with abdominal pain is virtually diagnostic²²

⚠️ OYSTER: Hyponatremia in acute porphyria results from SIADH and is exacerbated by vomiting. Aggressive correction with hypertonic saline can precipitate seizures and worsen neurological outcomes. Correct slowly (<6 mmol/L per 24h) and treat the underlying porphyria attack.²³

Diagnostic Approach

Initial Screening:

1. Random urine porphobilinogen (PBG) and delta-aminolevulinic acid (ALA)
   - Collect during attack for maximum sensitivity
   - >5-fold elevation diagnostic during acute attack
   - Can be normal between attacks (sensitivity ~67% in remission)²⁴

2. Total urine porphyrins
   - Markedly elevated during attacks
   - Port-wine or dark red urine (on standing/light exposure) occurs in <50% of attacks

Confirmatory Testing:

• Plasma/fecal porphyrin fractionation (differentiates VP from AIP)
• Erythrocyte hydroxymethylbilane synthase (HMBS) activity (AIP)
• Genetic testing of HMBS, CPOX, PPOX genes
• Family cascade screening once index case identified²⁵

🔑 PEARL: The "sunlight test" - collect urine in a clear container and expose to sunlight or UV light for 30 minutes. Darkening suggests porphyria (PBG polymerizes to porphobilin). Sensitivity ~60%, but immediately available in resource-limited settings.²⁶

Precipitating Factors: Know Thy Enemy

High-Risk Medications (Unsafe in ALL Acute Porphyrias):

• Barbiturates, sulfonamides, rifampin
• Alcohol (especially binge drinking)
• Carbamazepine, phenytoin, valproate
• Ergots, synthetic estrogens/progestins
• Griseofulvin, metoclopramide
• Many anesthetic agents²⁷

Safe Medications for ICU Use:

• Analgesics: Opioids (all), paracetamol, gabapentin
• Sedatives: Propofol, dexmedetomidine, benzodiazepines (most)
• Antiemetics: Ondansetron, promethazine
• Antibiotics: Penicillins, cephalosporins, carbapenems, quinolones
• Antihypertensives: Beta-blockers, ACE inhibitors, calcium channel blockers²⁸

Resource: Drug database for acute porphyria - www.drugs-porphyria.org and American Porphyria Foundation (www.porphyriafoundation.org)

Non-Pharmacological Precipitants:

• Fasting/caloric restriction (physiologic or due to illness)
• Infection/inflammation
• Psychological stress
• Luteal phase of menstrual cycle/pregnancy
• Surgery²⁹

Acute Management

First-Line Therapy: Intravenous Hemin

• Panhematin® (US) or Normosang® (Europe): 3-4 mg/kg/day IV once daily for 4 days³⁰
• Mechanism: Negative feedback on hepatic ALA synthase (rate-limiting enzyme)
• Administration: Dilute in human albumin (avoid saline - causes degradation), infuse via large peripheral or central line over 30 minutes, protect from light
• Initiate within 24-48 hours of symptoms for best outcomes
• Consider second course if incomplete response

⚠️ OYSTER: Hemin causes phlebitis in peripheral veins and can lead to venous thrombosis. Premeditate with phlebitis prevention (albumin carrier, slow infusion, rotate sites). Some advocate for routine central line placement for treatment courses.³¹

Supportive Care:

1. Glucose Loading (4 Pillars of Management)
   - 10% dextrose at 300-500g/day IV (anabolic stimulus, suppresses ALA synthase)
   - Continue until attack resolves
   - Monitor for hyperglycemia (insulin if needed)

2. Pain Management
   - Opioids (morphine, fentanyl, hydromorphone - all safe)
   - Gabapentin for neuropathic component
   - Avoid NSAIDs if possible (most are unsafe)

3. Hypertension/Tachycardia
   - Beta-blockers (propranolol, labetalol preferred)
   - Caution with excessive BP lowering (may worsen neuropathy via hypoperfusion)

4. Seizure Management
   - Magnesium sulfate first-line for prophylaxis/treatment
   - Gabapentin, levetiracetam, vigabatrin if needed
   - Avoid phenytoin, carbamazepine, valproate³²

🔑 HACK: Create a "Porphyria Alert" bracelet system for known patients. Include genetic subtype, emergency contact for metabolic specialist, and "START HEMIN FIRST, ASK QUESTIONS LATER" if presenting with abdominal pain + tachycardia.

Emerging Therapies

Givosiran (Givlaari®) - RNAi therapeutic targeting hepatic ALAS1 mRNA

• Subcutaneous injection 2.5 mg/kg monthly
• Reduces attack frequency by 74% in clinical trials
• Approved 2019 for AIP prophylaxis in adults
• Game-changer for recurrent attacks (>4 per year)³³

Liver Transplantation

• Curative for hepatic porphyrias (AIP, HCP, VP)
• Reserved for severe recurrent disease unresponsive to medical therapy
• Excellent long-term outcomes if performed before irreversible neurological damage³⁴

ICU-Specific Considerations

Respiratory Failure:

• Motor neuropathy can progress rapidly (12-24h) to diaphragmatic paralysis
• Low threshold for intubation if declining FVC (<20 mL/kg) or NIF (<-30 cmH₂O)
• Recovery follows treatment but may take weeks to months (similar to GBS trajectory)
• Consider tracheostomy if not improving by 2-3 weeks³⁵

Autonomic Crisis:

• Hemodynamic instability can mimic septic shock
• Beta-blockade essential (esmolol infusion for labile BP/HR)
• Avoid aggressive fluid resuscitation (increases risk of SIADH/hyponatremia)

⚠️ OYSTER: Acute porphyria can mimic brain death with unresponsive coma, absent brainstem reflexes, and respiratory arrest. NEVER declare brain death without excluding reversible metabolic causes. Hemin therapy can result in dramatic neurological recovery even from deep coma.³⁶

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Urea Cycle Disorders: Hyperammonemia Without Liver Disease

Understanding the Urea Cycle

The urea cycle converts toxic ammonia (from protein catabolism) to water-soluble urea in hepatocytes. Six enzymatic steps exist, with deficiencies classified as proximal (ornithine transcarbamylase deficiency [OTC], carbamoyl phosphate synthetase deficiency [CPS1]) or distal (argininosuccinic aciduria [ASA], citrullinemia [ASS]).³⁷

Key Epidemiology:

• OTC deficiency (X-linked): Most common, affects 1:60,000 births
• Female OTC carriers may present in adulthood (lyonization effects)
• 50-70% of adult-onset cases present after age 16³⁸

The Clinical Spectrum

Classic Presentation:

• Progressive encephalopathy (lethargy → confusion → delirium → coma)
• Vomiting, anorexia (protein aversion)
• Hyperventilation (respiratory alkalosis) - attempts to compensate for cerebral edema
• Ataxia, seizures in later stages
• Absence of hepatomegaly or jaundice (key differentiator from hepatic encephalopathy)³⁹

Precipitants:

• High-protein meal (especially after period of reduced intake)
• Postpartum period (dramatic catabolism post-delivery)
• Post-surgical state (catabolic stress, steroid use)
• Valproate therapy (inhibits urea cycle enzymes)
• Chemotherapy (tumor lysis)⁴⁰

🔑 PEARL: The "postpartum hyperammonemia syndrome" - women with undiagnosed OTC heterozygosity may present 24-72h post-delivery with unexplained encephalopathy. Ammonia levels >200 μmol/L in this context should prompt immediate metabolic workup.⁴¹

Diagnostic Approach

Laboratory Patterns by Disorder:

Disorder	NH₃	Glutamine	Citrulline	Arg	Orotic Acid
OTC	↑↑↑	↑↑	↓ or N	↓	↑↑↑
CPS1	↑↑↑	↑↑	↓	↓	Normal
ASS (Citrullinemia)	↑↑	↑	↑↑↑	↓	↑
ASL (ASA)	↑	↑	↑↑	↓	↑
Arginase	↑	↑	N	↑↑↑	N

Critical Investigations:

Diagnostic Panel:
- Plasma ammonia (arterial or free-flowing venous, analyzed within 15 min)
- Plasma amino acids (fasting preferred but not essential during crisis)
- Urine orotic acid (spot urine)
- Liver function tests (AST, ALT, INR - typically normal in UCD)
- Blood gas (respiratory alkalosis common early)

Pitfall Prevention:
- Venous stasis falsely elevates ammonia (no tourniquet, free-flowing sample)
- Delay in processing causes falsely elevated ammonia (RBC ammonia production)
- Smoking/hemolysis falsely elevates ammonia

🔑 HACK: The "ice pack method" for ammonia samples - immediately place blood specimen in ice-water slurry and run to lab. Ammonia rises 5-10% per minute at room temperature.⁴²

⚠️ OYSTER: Normal ammonia does NOT exclude urea cycle disorder. Some patients maintain levels <100 μmol/L between crises but develop neurotoxicity from chronic modest elevations (50-100 μmol/L). Consider plasma amino acid pattern even with borderline ammonia.⁴³

Acute Management: The Race Against Cerebral Edema

Hyperammonemia >200 μmol/L constitutes a medical emergency. Ammonia freely crosses the blood-brain barrier, where it is converted to glutamine in astrocytes, causing osmotic cerebral edema and intracranial hypertension.⁴⁴

Multi-Pronged Strategy:

1. Stop Ammonia Production

- NPO (zero protein intake)
- High-dose dextrose (10-15% at 8-10 mg/kg/min)
- Target: Reverse catabolism, switch to anabolic state
- Insulin if needed (hyperglycemia exacerbates cerebral edema)

2. Activate Alternative Pathways (Ammonia Scavenging)

Intravenous:
- Sodium benzoate: 250 mg/kg IV loading over 90-120 min, then 250 mg/kg/day continuous
  (Conjugates with glycine → hippurate → renal excretion)
  
- Sodium phenylacetate: 250 mg/kg IV loading over 90-120 min, then 250 mg/kg/day continuous
  (Conjugates with glutamine → phenylacetylglutamine → renal excretion)
  
Available as combination: Ammonul® (10% sodium phenylacetate + 10% sodium benzoate)
Dose: 2.5 mL/kg (max 55g) IV over 90-120min, then same dose as continuous infusion over 24h⁴⁵

Caution: Causes hypernatremia, hyperosmolality - monitor electrolytes closely

3. Provide Missing Substrates

- L-arginine (or L-citrulline): 200-600 mg/kg/day IV
  Role: Substrate for citrulline synthesis (bypasses proximal blocks)
  Exception: Avoid in arginase deficiency (worsens hyperargininemia)
  
- N-carbamylglutamate: 100-250 mg/kg/day PO/NG
  Role: Allosteric activator of CPS1 (especially effective in OTC, CPS1 deficiency)⁴⁶

4. Extracorporeal Ammonia Removal

Indications for Emergency Dialysis:

• Ammonia >500 μmol/L (absolute indication)
• Ammonia >350 μmol/L with encephalopathy
• Rapidly rising ammonia despite medical therapy
• Clinical deterioration (declining GCS, seizures)⁴⁷

Modality Selection:

• Intermittent hemodialysis: BEST choice (ammonia clearance 10x higher than CRRT)
• Continuous venovenous hemodialysis (CVVHD): Acceptable alternative if IHD unavailable
• CVVH (hemofiltration): POOR choice (inadequate small molecule clearance)
• Peritoneal dialysis: INADEQUATE for acute hyperammonemia⁴⁸

Dialysis Protocol:

• High-efficiency dialyzer (high flux)
• Blood flow rate 300-400 mL/min
• Dialysate flow rate 500-800 mL/min
• Duration: 8-12 hours initially
• Target: Ammonia <200 μmol/L
• Continue medical therapy during dialysis (synergistic effect)

🔑 PEARL: The "ammonia rebound phenomenon" - after stopping dialysis, ammonia redistributes from tissues and can rebound to 70-80% of pre-dialysis levels within 4-6 hours. Check ammonia 2-4h post-dialysis and be prepared for repeat session.⁴⁹

5. Neuroprotection and ICP Management

- Head of bed elevation 30°
- Therapeutic hypothermia (32-34°C) if refractory ICP elevation
- Avoid hypertonic saline (exacerbates sodium load from scavenger drugs)
- Mannitol acceptable if needed for ICP crisis
- Consider ICP monitoring if GCS ≤8 and ammonia >300 μmol/L
- Target CPP >60 mmHg⁵⁰

⚠️ OYSTER: Lactulose is INEFFECTIVE and potentially HARMFUL in hyperammonemic crisis from UCD. It works by reducing colonic bacterial ammonia production (not the problem in UCD) and can cause dehydration/electrolyte disturbances that worsen cerebral edema. Only use in concurrent hepatic encephalopathy.⁵¹

Prognostic Factors and Outcomes

Poor Prognostic Indicators:

• Peak ammonia >1,000 μmol/L
• Duration of coma >48 hours
• Delay to dialysis >12 hours from presentation
• Cerebral edema on neuroimaging
• Age <30 days (neonatal presentations)⁵²

Neurological Sequelae: Even with aggressive treatment, survivors of severe hyperammonemic crises (ammonia >500 μmol/L) face:

• Cognitive impairment (60-70%)
• Attention deficit/executive dysfunction (40-50%)
• Cerebral palsy-like syndrome (20-30% of pediatric cases)
• Epilepsy (15-20%)
• MRI findings: T2 hyperintensity in insular cortex, cingulate gyrus (characteristic pattern)⁵³

Long-term Management Principles:

1. Protein restriction (individualized, typically 1.2-1.8 g/kg/day for adults)
2. Nitrogen scavengers (oral sodium benzoate, sodium phenylbutyrate)
3. Essential amino acid supplementation
4. Medical foods (low-protein formulas)
5. L-arginine or L-citrulline supplementation
6. Avoid valproate, corticosteroids (exacerbate hyperammonemia)
7. Emergency protocol card for patients/families
8. Liver transplantation discussion for severe recurrent cases⁵⁴

🔑 HACK: Develop an institutional "Code Ammonia" protocol with pre-printed order sets, direct metabolic consultant phone line, and immediate nephrology/PICU notification. Minutes matter in preventing irreversible brain injury.

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Mitochondrial Myopathies: The "Red Flag" Symptoms

Understanding Mitochondrial Disease

Mitochondrial diseases encompass >350 distinct genetic disorders affecting oxidative phosphorylation. Unlike other IEMs, they follow maternal inheritance (mtDNA defects) or autosomal recessive/dominant patterns (nuclear DNA defects affecting mitochondrial function). Heteroplasmy - the percentage of mutant mtDNA in different tissues - explains the extraordinary phenotypic variability.⁵⁵

Key Concept: Mitochondrial disorders are multi-system diseases with preferential involvement of high-energy organs: brain, skeletal muscle, heart, eyes, ears, kidneys, endocrine organs.

The Classic Triad: "Red Flag" Symptoms

1. Ptosis (Drooping Eyelids)

• Bilateral, symmetric, slowly progressive
• Often first symptom noticed (years before other manifestations)
• Results from levator palpebrae superioris weakness
• Distinguishing feature: Patient maintains normal frontalis function (no compensatory forehead wrinkling in early stages)⁵⁶

2. Progressive External Ophthalmoplegia (PEO)

• Painless, bilateral limitation of eye movements
• Patient often unaware until severe (brain adapts by turning head rather than eyes)
• Complete ophthalmoplegia in advanced stages
• NO diplopia (unlike cranial nerve palsies - weakness is symmetric)⁵⁷

3. Exercise Intolerance

• Disproportionate fatigue with physical activity
• "Second wind" phenomenon often absent (unlike glycogen storage diseases)
• Myalgias, cramping (but rarely rhabdomyolysis)
• Post-exertional malaise lasting days

🔑 PEARL: The "ophthalmologic triad" - ptosis + PEO + pigmentary retinopathy (salt-and-pepper retinal degeneration) is virtually pathognomonic for Kearns-Sayre Syndrome (KSS), a specific mitochondrial disorder requiring cardiac evaluation.⁵⁸

Expanded Clinical Phenotypes

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes)

• Recurrent stroke-like episodes (focal deficits, seizures) in non-vascular distributions
• Typically presents age 5-15 but adult-onset cases described
• Lactic acidosis (often mild baseline elevation, worsens during crises)
• Short stature, sensorineural hearing loss
• Migraine headaches (90%)
• m.3243A>G mutation most common (80% of cases)⁵⁹

MERRF (Myoclonic Epilepsy with Ragged Red Fibers)

• Myoclonus (sudden, brief muscle jerks)
• Generalized seizures
• Ataxia, peripheral neuropathy
• Deafness, dementia
• m.8344A>G mutation (~80% of cases)⁶⁰

CPEO (Chronic Progressive External Ophthalmoplegia)

• Isolated or predominant eye muscle involvement
• Ptosis + PEO without systemic features (early stages)
• May progress to KSS if onset <20 years with cardiac conduction defects
• Single large-scale mtDNA deletion most common⁶¹

Leigh Syndrome (Adult-Onset)

• Subacute brainstem/basal ganglia degeneration
• Ataxia, dystonia, ophthalmoparesis
• Respiratory failure (central hypoventilation)
• MRI: Bilateral symmetric T2 hyperintensities in basal ganglia, brainstem
• Multiple genetic causes (mtDNA and nuclear DNA)⁶²

ICU Presentations of Mitochondrial Disease

1. Acute Metabolic Decompensation

Triggers:
- Infection/sepsis (most common)
- Surgery/anesthesia
- Medications (valproate, linezolid, aminoglycosides)
- Fasting/catabolism

Clinical Features:
- Lactic acidosis (lactate often 4-15 mmol/L, sometimes higher)
- Hypoglycemia (impaired gluconeogenesis)
- Rhabdomyolysis (CK elevation, myoglobinuria)
- Acute liver failure (Reye-like syndrome)
- Encephalopathy (seizures, coma)⁶³

2. Stroke-Like Episodes (MELAS)

• Acute focal neurological deficits (hemiparesis, hemianopia, aphasia)
• Seizures (focal or generalized status epilepticus)
• Altered consciousness
• Cortical blindness
• MRI: Hyperintense lesions on DWI/T2 crossing vascular territories, cortical involvement
• CSF lactate elevated (>2.5 mmol/L) - key diagnostic clue⁶⁴

3. Cardiomyopathy and Sudden Cardiac Death

• Hypertrophic or dilated cardiomyopathy
• Heart block, pre-excitation syndromes (especially KSS)
• Sudden death risk in KSS - requires pacemaker placement⁶⁵

⚠️ OYSTER: Mitochondrial patients are exquisitely sensitive to propofol. Propofol infusion syndrome (PRIS)Mitochondrial Myopathies: The "Red Flag" Symptoms (continued)

⚠️ OYSTER: Mitochondrial patients are exquisitely sensitive to propofol. Propofol infusion syndrome (PRIS) - characterized by metabolic acidosis, rhabdomyolysis, cardiac failure, and death - occurs at lower doses and shorter durations in mitochondrial disease patients. Avoid prolonged propofol infusions (>48 hours) and consider alternative sedatives (dexmedetomidine, benzodiazepines).⁶⁶

Diagnostic Approach in the ICU

Initial Screening ("Mitochondrial Panel"):

Blood:
- Arterial/venous lactate (fasting preferred, but not essential in acute setting)
- Lactate:pyruvate ratio (>20:1 suggests mitochondrial dysfunction)
- Plasma amino acids (alanine elevation reflects transamination of pyruvate)
- Creatine kinase (CK)
- Comprehensive metabolic panel (assess renal, hepatic function)
- TSH, free T4 (hypothyroidism common)
- HbA1c (diabetes mellitus in 20-30%)

Urine:
- Organic acids (lactate, Krebs cycle intermediates)
- Urine amino acids

CSF (if neurological symptoms):
- Lactate >2.5 mmol/L (highly specific for mitochondrial CNS involvement)
- Protein (often elevated)
- CSF:blood glucose ratio

🔑 PEARL: The "lactate-pyruvate dissection" - collect lactate and pyruvate simultaneously from same sample. Normal L:P ratio with elevated lactate suggests tissue hypoperfusion (sepsis, shock). Elevated L:P ratio (>25:1) with lactate >2.5 mmol/L suggests mitochondrial dysfunction or severe thiamine deficiency.⁶⁷

Advanced/Confirmatory Testing:

1. Muscle Biopsy (Gold Standard)

• Histochemistry: Ragged red fibers (RRF) on Gomori trichrome stain
• COX (cytochrome c oxidase) staining: COX-negative fibers
• Electron microscopy: Abnormal mitochondria (paracrystalline inclusions)
• Respiratory chain enzyme analysis
• mtDNA analysis from muscle tissue⁶⁸

Biopsy Technique Pearls:

• Open biopsy preferred over needle biopsy (larger sample, better morphology)
• Biopsy moderately affected muscle (not end-stage or unaffected)
• Quadriceps or deltoid typical sites
• Fresh frozen tissue essential (not formalin-fixed for enzyme analysis)
• Coordinate with specialized neuromuscular pathology lab

2. Genetic Testing

First-Tier:
- mtDNA sequencing from blood (detects common mutations: m.3243A>G, m.8344A>G)
- Note: Blood heteroplasmy may be low; muscle biopsy more sensitive

Second-Tier (if mtDNA negative):
- Nuclear gene panel (POLG, TWNK, RRM2B, etc.)
- Whole exome/genome sequencing

Functional Testing:
- Fibroblast respiratory chain enzyme assays
- Oxygen consumption studies⁶⁹

3. Neuroimaging

Brain MRI Features by Syndrome:
- MELAS: Stroke-like lesions (posterior temporal-parietal-occipital), do NOT respect vascular territories, cortical involvement, basal ganglia calcification
- Leigh syndrome: Symmetric T2 hyperintensity in basal ganglia, thalami, brainstem, "lactate peak" on MR spectroscopy
- KSS: White matter changes, cerebellar atrophy
- MERRF: Cerebellar/cerebral atrophy, dentate nucleus involvement

MR Spectroscopy:
- Elevated lactate peak (doublet at 1.3 ppm)
- Reduced NAA (neuronal loss)⁷⁰

⚠️ OYSTER: Normal lactate does NOT exclude mitochondrial disease. Up to 30% of patients have normal baseline lactate levels. Consider provocative exercise testing (forearm ischemic exercise test) or post-exercise lactate measurements if high suspicion despite normal resting levels.⁷¹

Acute ICU Management

Unlike other IEMs, mitochondrial diseases have NO specific curative therapy. Management is supportive with avoidance of mitochondrial toxins and optimization of remaining respiratory chain function.

General Supportive Measures:

1. Avoid Mitochondrial Toxins

Absolute Contraindications:
- Valproate (severe hepatotoxicity risk, respiratory chain inhibition)
- Barbiturates (respiratory chain inhibition)
- Linezolid (inhibits mitochondrial protein synthesis - limit use to <28 days)
- Aminoglycosides (mtDNA mutation agents, ototoxicity risk)
- Metformin (lactic acidosis risk)
- Propofol (PRIS risk - avoid prolonged infusions)

Relative Contraindications:
- Statins (myopathy risk)
- Chloramphenicol
- Tetracyclines⁷²

2. "Mitochondrial Cocktail" Therapy Despite limited evidence, cofactor supplementation is standard practice. Theoretical rationale: bypass impaired complexes, scavenge free radicals, provide alternative electron donors.

Standard Cocktail Components:
- Coenzyme Q10: 300-600 mg/day PO (divided doses with meals)
  Role: Electron carrier in respiratory chain
  
- L-carnitine: 1-3 g/day PO or 100-200 mg/kg/day IV
  Role: Fatty acid transport into mitochondria
  
- Riboflavin (B2): 100-400 mg/day
  Role: Cofactor for complexes I and II
  
- Thiamine (B1): 100-300 mg/day
  Role: Cofactor for pyruvate dehydrogenase
  
- Alpha-lipoic acid: 600-1200 mg/day
  Role: Antioxidant, cofactor for PDH complex
  
Additional Considerations:
- Creatine monohydrate: 5-10 g/day (improves muscle energy buffer)
- Vitamin C: 1-3 g/day (antioxidant)
- Vitamin E: 400-800 IU/day (antioxidant)⁷³

Evidence Reality Check: Controlled trials show minimal benefit for most components. However, individual patients report subjective improvement, and harm is minimal. Continue if pre-existing regimen; consider initiating in newly diagnosed patients.⁷⁴

3. Treat Metabolic Decompensation

For Lactic Acidosis:
- IV dextrose (anabolic switch, reduce gluconeogenesis lactate production)
- Avoid aggressive bicarbonate (worsens intracellular acidosis via CO2 production)
- Dichloroacetate (DCA) controversial - some benefit in pyruvate dehydrogenase deficiency, no clear benefit in respiratory chain defects⁷⁵

For Seizures/Stroke-Like Episodes:
- IV arginine: 500 mg/kg over 30 minutes, then 500 mg/kg/day continuous infusion
  Mechanism: Improves nitric oxide-mediated cerebral vasodilation
  Evidence: Small studies show reduced stroke-like episode severity/duration in MELAS⁷⁶
- Antiepileptics: Levetiracetam preferred (avoid valproate, carbamazepine)
- Status epilepticus management per standard protocols (midazolam, propofol with caution)

4. Specific Organ Support

Cardiac:
- Pacemaker for KSS patients with ANY conduction abnormality (PR >200ms, any AV block)
- Standard heart failure management for cardiomyopathy
- Avoid beta-blockers if severe heart block risk⁷⁷

Endocrine:
- Screen for diabetes mellitus, hypothyroidism, hypoparathyroidism
- Insulin as needed (mitochondrial diabetes often insulin-dependent)

Renal:
- Fanconi syndrome (proximal tubular dysfunction) common
- Monitor for progressive renal failure (Pearson syndrome, other mtDNA deletions)⁷⁸

🔑 HACK: Create a "Mitochondrial Safe Drug List" laminated card for your ICU. Include safe sedatives (dexmedetomidine, midazolam), analgesics (fentanyl, morphine), antibiotics (beta-lactams, fluoroquinolones), and antiepileptics (levetiracetam, lacosamide). Attach to chart of known mitochondrial patients.

Anesthetic Considerations

Mitochondrial patients require special perioperative planning:

Pre-operative Assessment:

• Cardiac evaluation (ECG, echocardiogram, consider EP study if KSS)
• Pulmonary function tests (vital capacity, forced expiratory volume)
• Baseline lactate, CK
• Glycemic control assessment
• Temperature regulation assessment (malignant hyperthermia risk debated)⁷⁹

Intra-operative Management:

Safe Anesthetic Agents:
- Induction: Propofol (single dose acceptable), etomidate, ketamine
- Maintenance: Volatile anesthetics (sevoflurane, desflurane) - SAFE despite theoretical concerns
- Neuromuscular blockade: Rocuronium, cisatracurium (avoid prolonged infusions)
- Reversal: Sugammadex preferred over neostigmine

Monitoring:
- Temperature (risk of postoperative hypothermia)
- Glucose (frequent checks)
- Lactate (q2-4h)
- ECG (continuous, conduction abnormalities)⁸⁰

Post-operative Care:

• Prolonged monitoring (24-48h minimum)
• Early enteral nutrition (avoid fasting)
• Aggressive treatment of infections
• Continue home medications including "cocktail"

⚠️ OYSTER: The succinylcholine debate - while traditionally avoided due to malignant hyperthermia concerns, large retrospective series show NO increased MH risk in mitochondrial disease. However, prolonged neuromuscular blockade and hyperkalemia from muscle membrane instability remain concerns. Use with caution and monitoring.⁸¹

Prognostic Considerations

Prognosis varies dramatically by genetic subtype and organ involvement:

Relatively Favorable:

• Isolated CPEO: Near-normal lifespan with quality of life impact from vision
• Single mtDNA deletions: Variable, often adult-onset

Intermediate:

• MELAS: Median survival to 40s, highly variable
• MERRF: Median survival to 30s-40s, progressive neurological decline

Poor:

• Leigh syndrome: Median survival <6 years for infantile-onset; adult-onset better but progressive
• Pearson syndrome: Median survival <3 years
• Severe multi-system involvement: Often childhood death⁸²

Factors Predicting ICU Mortality:

• Cardiac involvement (arrhythmias, cardiomyopathy)
• Respiratory failure requiring mechanical ventilation
• Acute liver failure
• Refractory status epilepticus
• Severe lactic acidosis (lactate >15 mmol/L)⁸³

🔑 PEARL: The "maternal inheritance clue" - obtain detailed maternal family history. Mothers with MELAS may be minimally symptomatic (migraine, diabetes) while offspring have severe stroke-like episodes due to higher mutant heteroplasmy. This pattern should prompt genetic counseling and cascade testing.⁸⁴

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The Role of Tandem Mass Spectrometry in Metabolic Screening

Revolution in Metabolic Diagnostics

Tandem mass spectrometry (MS/MS) has transformed metabolic disease diagnosis from a weeks-long odyssey to a hours-long targeted investigation. This technology simultaneously quantifies dozens of metabolites from a single dried blood spot or plasma sample, enabling pattern recognition across multiple metabolic pathways.⁸⁵

Technical Principles (Simplified for Clinicians)

Basic Concept:

1. Sample ionization creates charged molecular fragments
2. First mass spectrometer (MS1) separates fragments by mass-to-charge ratio
3. Selected ions undergo fragmentation
4. Second mass spectrometer (MS2) analyzes daughter fragments
5. Computer matches patterns to known metabolic signatures⁸⁶

What MS/MS Measures:

• Acylcarnitines: Free carnitine (C0) and acylcarnitine species (C2-C18+)
• Amino Acids: Quantitative measurement of 30-40 amino acids
• Ratios: Calculated ratios enhance specificity (e.g., C3/C2 ratio for propionic acidemia)

Clinical Applications in the ICU

1. Acylcarnitine Profiling

Acylcarnitines reflect intramitochondrial CoA ester concentrations. Specific elevation patterns diagnose fatty acid oxidation defects, organic acidemias, and other disorders.

Classic Patterns:

Disorder	Primary Elevation	Ratios	Clinical Context
MCAD deficiency	C6, C8, C10, C10:1	C8/C10 >3	Hypoketotic hypoglycemia
VLCAD deficiency	C14, C14:1, C14:2	C14:1/C2 elevated	Rhabdomyolysis, cardiomyopathy
Propionic acidemia	C3 (propionylcarnitine)	C3/C2 >0.2	Ketoacidosis, neutropenia
Methylmalonic acidemia	C3, C4-DC	C3/C2 >0.2	Similar to PA + methylmalonic acid in urine
Isovaleric acidemia	C5 (isovalerylcarnitine)	C5/C2 >0.5	"Sweaty feet" odor
Glutaric acidemia type 1	C5-DC (glutarylcarnitine)	C5-DC/C16 >0.5	Macrocephaly, striatal injury
Carnitine deficiency	↓C0 (free carnitine)	All acylcarnitines low	Cardiomyopathy, hypoglycemia⁸⁷

🔑 PEARL: The "C3 elevation differential" - elevated C3 (propionylcarnitine) occurs in propionic acidemia, methylmalonic acidemia, vitamin B12 deficiency, malabsorption, and even in patients on total parenteral nutrition. Always correlate with clinical context and urine organic acids.⁸⁸

2. Amino Acid Profiling

Quantitative amino acid analysis identifies disorders of amino acid metabolism, transport defects, and provides clues to organic acidemias and urea cycle disorders.

Key Diagnostic Patterns:

Elevated Phenylalanine (>200 μmol/L):
- Phenylketonuria (PKU) - Phe >>1200 μmol/L, low tyrosine
- BH4 deficiency - Phe elevated, low neurotransmitter metabolites
- Liver failure - moderate elevation, multiple amino acids abnormal

Elevated Tyrosine (>200 μmol/L):
- Tyrosinemia type I - very high Tyr, elevated succinylacetone (diagnostic)
- Tyrosinemia type II - high Tyr, corneal crystals
- Hepatocellular injury - moderate elevation

Elevated Methionine (>50 μmol/L):
- Homocystinuria (CBS deficiency) - high Met, ↑homocysteine
- Methionine adenosyltransferase deficiency - isolated Met elevation
- Liver disease - multiple amino acid elevations

Elevated Citrulline (>100 μmol/L):
- Citrullinemia type I (ASS deficiency) - Cit >>1000 μmol/L
- Citrullinemia type II - Cit 100-300 μmol/L, adult-onset, Asian population
- Argininosuccinic aciduria - Cit moderately elevated, ↑ASA

Low Citrulline (<10 μmol/L):
- OTC deficiency - low Cit, high glutamine, ↑orotic acid
- CPS1 deficiency - low Cit, high glutamine, normal orotic acid⁸⁹

3. Integration with Other Metabolic Tests

MS/MS does NOT replace comprehensive metabolic evaluation. Optimal diagnostic approach combines:

Tier 1 (Rapid Screen - Results in 24-48h):
- Plasma acylcarnitine profile (MS/MS)
- Plasma amino acids (MS/MS)
- Blood gas, lactate, ammonia, glucose
- Urine ketones (dipstick)

Tier 2 (Confirmatory - Results in 3-7 days):
- Urine organic acids (GC-MS)
- Urine amino acids
- Urine orotic acid
- CSF lactate (if neurological symptoms)
- CSF amino acids (if available)

Tier 3 (Specialized - Results in 2-4 weeks):
- Enzyme assays (fibroblasts, leukocytes, liver)
- Molecular genetic testing
- Functional studies⁹⁰

Interpretation Pearls and Pitfalls

🔑 PEARL: The "fasting effect" - many metabolic disorders only manifest abnormalities during physiologic stress (fasting, illness). Sampling during asymptomatic periods may yield normal results. Always state "sample obtained during acute illness" vs "sample obtained when well" on requisition.⁹¹

Common False Positives:

Finding	Benign Causes	Distinguishing Features
Elevated C3	TPN, B12 deficiency, valproate	Normal urine organic acids, clinical context
Elevated C5	Pivampicillin (antibiotic), isovaleryl-CoA dehydrogenase variant	No clinical symptoms, resolves off antibiotic
Elevated tyrosine	Liver disease, prematurity, dietary	Multiple amino acids abnormal, succinylacetone normal
Low carnitine	Vegetarian diet, malabsorption, dialysis	No clinical symptoms, replete with supplementation
Elevated glycine	Valproate therapy	N-methylglycine (sarcosine) also elevated⁹²

Sample Collection Considerations:

Optimal Timing:

• During Crisis: Maximum diagnostic yield for intermittent disorders
• Before Treatment: Glucose infusion alters acylcarnitine profiles; L-carnitine therapy masks carnitine deficiency
• Fasting Status: Document on requisition (affects amino acid interpretation)

Sample Handling:

Blood:
- EDTA or heparin tube (NOT serum separator tubes)
- Spin and separate plasma within 2 hours
- Freeze at -20°C if not analyzed immediately
- Stable frozen for months

Dried Blood Spots:
- Heel/finger prick onto filter paper card
- Dry completely at room temperature (not direct sunlight)
- Stable at room temperature for weeks
- Excellent for remote/resource-limited settings⁹³

⚠️ OYSTER: Hemolysis falsely elevates amino acids and acylcarnitines due to release from erythrocytes. Reject hemolyzed samples and recollect. Venous stasis also elevates amino acids - avoid tourniquet when possible or release before collection.⁹⁴

Newborn Screening Programs

MS/MS is the cornerstone of expanded newborn screening, detecting 30-50+ disorders from a single dried blood spot collected 24-48h after birth. Conditions screened vary by region but typically include:

Core Conditions:

• Amino acid disorders: PKU, MSUD, homocystinuria, citrullinemia, ASA
• Organic acid disorders: PA, MMA, isovaleric acidemia, glutaric acidemia type 1, 3-MCC deficiency
• Fatty acid oxidation defects: MCAD, VLCAD, LCHAD, TFP, CPT-I/II deficiencies
• Others: Biotinidase deficiency, galactosemia⁹⁵

Implications for Adult Critical Care:

• False negative newborn screens occur (~0.5-1% rate depending on disorder)
• Milder variants may screen negative but present in adulthood
• Some screening programs have only existed since 2000s - adults born before program initiation may be undiagnosed
• Always obtain newborn screening results if available when evaluating suspected IEM⁹⁶

🔑 HACK: Contact your state/regional public health laboratory to obtain a "metabolic emergency kit" containing sample collection cards, instructions, and courier information. Store in ICU for rapid deployment. Many labs offer STAT processing (results in 4-8 hours) for critically ill patients.

Emerging Technologies

Next-Generation Metabolomics:

• Untargeted metabolomics: Comprehensive profiling of all detectable metabolites (100s-1000s)
• Increased diagnostic yield in undiagnosed metabolic disorders
• Currently research-based, moving toward clinical application⁹⁷

Point-of-Care MS/MS:

• Miniaturized mass spectrometers for bedside testing
• Potential for rapid (<1 hour) metabolic screening
• Early developmental stages⁹⁸

Dried Blood Spot Panels:

• Expanded panels including very long-chain fatty acids, sterols, bile acids
• Single sample, comprehensive metabolic snapshot
• Facilitates telemedicine consultation for remote centers⁹⁹

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Conclusions and Key Takeaways

The diagnosis of IEMs in adult patients requires vigilance, pattern recognition, and systematic metabolic investigation. The following principles should guide the intensivist:

🔑 Critical Pearls for Practice:

1. Think metabolic in the "unexplained triad": Encephalopathy + metabolic acidosis/hyperammonemia + negative sepsis workup = IEM until proven otherwise

2. Time is brain: Hyperammonemia >200 μmol/L and acute organic acidemia require emergency intervention within hours to prevent irreversible neurological injury

3. Collect samples BEFORE treatment: Freeze extra plasma and urine at presentation - you cannot recapture the diagnostic window once glucose and L-carnitine are started

4. Know your toxins: Valproate, propofol, linezolid, and aminoglycosides are particularly dangerous in specific IEMs. When in doubt, choose alternatives

5. Hemodialysis saves lives: For severe hyperammonemia (>350-500 μmol/L), intermittent hemodialysis is superior to CRRT and should be initiated emergently

6. Porphyria mimics everything: Abdominal pain + tachycardia + psychiatric symptoms in a young adult = check urine PBG before rushing to surgery or psychiatry

7. Mitochondrial disease is a great masquerader: Ptosis + PEO + exercise intolerance is your diagnostic triad, but multi-system involvement can present in myriad ways

8. MS/MS is a screening tool, not a diagnosis: Always correlate with clinical presentation, urine organic acids, and specialized testing. False positives and false negatives occur

9. Genetics doesn't replace biochemistry: Genetic testing confirms diagnosis but metabolic monitoring guides acute management. Treat the metabolic crisis first, genotype later

10. Call for help early: Most intensivists will encounter <5 acute IEM cases in their career. Metabolic specialists provide invaluable guidance - consult early, consult often

The Diagnostic Algorithm:

Unexplained Encephalopathy/Metabolic Crisis
↓
Emergency Labs: ABG, lactate, ammonia, glucose, amino acids, acylcarnitines, urine organic acids
↓
Pattern Recognition:
├─ HAGMA + elevated lactate → Organic acidemia, mitochondrial disorder
├─ HAGMA + normal lactate → Organic acidemia
├─ Hyperammonemia + normal LFTs → Urea cycle disorder
├─ Abdominal pain + tachycardia + neuropathy → Porphyria
└─ Multi-system + exercise intolerance → Mitochondrial disease
↓
Acute Management:
• Stop protein
• High-dose dextrose
• Disorder-specific therapy (L-carnitine, N-carbamylglutamate, hemin, etc.)
• Consider hemodialysis if severe
• Consult metabolic specialist
↓
Long-term: Confirmatory testing, genetic counseling, chronic management plan

Building an IEM-Ready ICU:

Create systems to facilitate rapid diagnosis and treatment:

• Emergency metabolic kit: Pre-assembled sample collection tubes, requisitions, courier information
• Laminated algorithms: Posted in ICU for unexplained encephalopathy, hyperammonemia, metabolic acidosis
• Pharmacy "IEM box": L-carnitine, N-carbamylglutamate, sodium benzoate/phenylacetate, arginine HCl, hemin (if available)
• Code Ammonia protocol: Automated nephrology notification + metabolic consultation
• Safe drug lists: For mitochondrial disease, porphyria, organic acidemias
• Direct metabolic consultant phone: 24/7 access to pediatric/adult metabolic specialist

Future Directions:

The landscape of adult IEM care is rapidly evolving:

• Expanded therapeutic options: RNAi therapeutics (givosiran for porphyria, others in development), enzyme replacement, substrate reduction therapies
• Gene therapy: Clinical trials for hemophilia (successful), PKU, glycogen storage diseases, mucopolysaccharidoses
• Newborn screening expansion: More disorders added yearly, improving early diagnosis
• Adult metabolic clinics: Growing recognition of need for dedicated adult IEM care¹⁰⁰

The Bottom Line:

Inborn errors of metabolism are no longer "zebras" in adult critical care. With improved survival from pediatric diagnosis and increasing recognition of adult-onset presentations, every intensivist will encounter these disorders. A systematic approach to the patient with unexplained encephalopathy, metabolic acidosis, or organ dysfunction can unmask treatable IEMs and prevent tragic outcomes from missed diagnoses. The key is maintaining suspicion, collecting appropriate samples before treatment, and consulting specialized expertise early in the clinical course.

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Glossary of Key Terms for Postgraduate Trainees

Acylcarnitine Profile: Biochemical test measuring carnitine conjugates of fatty acids and organic acids; diagnostic for fatty acid oxidation defects and organic acidemias

Anion Gap: Difference between measured cations and anions; elevated in organic acidemias, lactic acidosis, and ketoacidosis

Heteroplasmy: Coexistence of normal and mutant mitochondrial DNA within cells; explains variable phenotypes in mitochondrial disease

Lactate:Pyruvate Ratio: Indicator of redox state; elevated ratio (>20:1) suggests mitochondrial dysfunction versus tissue hypoperfusion

Lyonization: Random X-chromosome inactivation in females; explains variable phenotypes in X-linked disorders like OTC deficiency

Organic Acids: Carboxylic acid intermediates of metabolism; urine organic acid analysis detects organic acidemias

Ragged Red Fibers (RRF): Subsarcolemmal accumulation of abnormal mitochondria; pathognomonic finding on muscle biopsy in mitochondrial myopathies

Tandem Mass Spectrometry (MS/MS): High-throughput analytical technique measuring multiple metabolites simultaneously; cornerstone of newborn screening

Urea Cycle: Hepatic pathway converting ammonia to urea; defects cause hyperammonemic encephalopathy

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Appendix: Emergency Contact Information and Resources

24/7 Metabolic Consultation Services:

1. Genetic and Rare Diseases Information Center (GARD)

   • Phone: 1-888-205-2311
   • Website: rarediseases.info.nih.gov

2. National Organization for Rare Disorders (NORD)

   • Website: rarediseases.org

3. American College of Medical Genetics and Genomics (ACMG)

   • Find a biochemical genetics specialist: www.acmg.net

Porphyria-Specific Resources:

• American Porphyria Foundation

  • Phone: 1-866-APF-3635
  • Website: porphyriafoundation.org
  • Drug database: drugs-porphyria.org

• European Porphyria Network

  • Website: porphyria.eu

Newborn Screening Programs:

• State/Regional Public Health Laboratory listings available at:
  • Baby's First Test: www.babysfirsttest.org

Emergency Medications:

• Ammonul® (sodium phenylacetate/sodium benzoate): Horizon Therapeutics, 1-866-479-6742
• Carbaglu® (carglumic acid/N-carbamylglutamate): Recordati Rare Diseases, 1-888-575-8344
• Panhematin® (hemin for injection): Recordati Rare Diseases, 1-800-325-8008
• Givlaari® (givosiran): Alnylam Pharmaceuticals, 1-833-256-2748

Metabolic Formula Companies (for long-term management):

• Nutricia North America: 1-800-365-7354
• Abbott Nutrition: 1-800-986-8510
• Mead Johnson Nutrition: 1-812-429-5000

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Author Disclosure Statement

This review article represents a comprehensive synthesis of current evidence and clinical experience in the diagnosis and management of inborn errors of metabolism in adult critical care settings. The authors have no financial conflicts of interest to disclose.

Acknowledgments: The authors thank the metabolic specialists, intensivists, and genetic counselors whose clinical insights contributed to the practical recommendations in this review.

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Correspondence: For questions regarding this review or specific clinical cases, readers are encouraged to contact their institutional genetics/metabolism service or regional metabolic referral center.

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This review article is intended for educational purposes for postgraduate trainees in critical care medicine. Clinical decisions should be individualized based on patient-specific factors and in consultation with appropriate subspecialty expertise.