Disorders of Ketone Body Metabolism

 Disorders of Ketone Body Metabolism:

A State-of-the-Art Clinical Review with Bedside Pearls, Oysters, and Practical Hacks

Dr Neeraj Manikath , claude.ai

Target Audience: Postgraduate Trainees & Consultants in Internal Medicine and Metabolic Medicine

 

Abstract

Disorders of ketone body metabolism represent a clinically heterogeneous group of inborn errors of metabolism with devastating consequences if unrecognized. The five conditions reviewed herein — Succinyl-CoA:3-Oxoacid CoA Transferase (SCOT) deficiency, Mitochondrial HMG-CoA Synthase (mHS) deficiency, Beta-Ketothiolase (T2) deficiency, Mevalonate Kinase Deficiency (MKD), and HMG-CoA Lyase deficiency — each carry distinct biochemical fingerprints, clinical phenotypes, and therapeutic imperatives. While these conditions are classically described in the paediatric literature, adult-onset presentations, diagnostic delays, and evolving management paradigms increasingly place them within the purview of the internist and metabolic medicine specialist. This review synthesizes contemporary evidence, clinical nuances, and bedside strategies to equip clinicians with the tools necessary for timely diagnosis and optimal management.

 

Introduction: Why Every Internist Must Know Ketone Body Biochemistry

Ketone bodies — acetoacetate (AcAc), 3-beta-hydroxybutyrate (3-OHB), and acetone — serve as critical alternative fuel substrates during fasting, prolonged exercise, and states of carbohydrate restriction. Their synthesis occurs exclusively in hepatic mitochondria through a tightly regulated pathway, and their utilization occurs in extrahepatic tissues, particularly the brain, heart, and skeletal muscle. The master biochemical arc proceeds as follows: fatty acids undergo beta-oxidation yielding acetyl-CoA, which condenses via mitochondrial HMG-CoA synthase (mHS) to form HMG-CoA, which is then cleaved by HMG-CoA lyase to yield acetoacetate and acetyl-CoA. Acetoacetate is reduced to 3-OHB (stored form) or spontaneously decarboxylated to acetone. Peripheral utilization requires succinyl-CoA:3-oxoacid CoA transferase (SCOT) and mitochondrial acetoacetyl-CoA thiolase (T2, beta-ketothiolase).

 

Enzymatic defects at any node of this pathway produce distinctive metabolic crises. Critically, these disorders do not behave uniformly — some produce hyperketosis, some cause hypoketosis, some mimic diabetic ketoacidosis (DKA), and others masquerade as Reye syndrome, recurrent encephalopathy, or autoinflammatory disease. The internist who grasps the underlying biochemistry gains not just diagnostic acumen but the ability to prevent life-threatening errors.

 

🔴 The Biochemical Mantra In any child or young adult with unexplained metabolic acidosis, encephalopathy, or recurrent crisis — always interrogate the relationship between ketones and blood glucose. The ketone-glucose axis is the master key to differentiating these disorders.

 

1. Succinyl-CoA:3-Oxoacid CoA Transferase (SCOT) Deficiency: The Severe Ketoacidosis Without Hypoglycemia

Biochemical Basis

SCOT (encoded by OXCT1 on chromosome 5p13) catalyzes the rate-limiting step in extrahepatic ketone body utilization: the transfer of a CoA group from succinyl-CoA to acetoacetate, yielding acetoacetyl-CoA and succinate. This step is the metabolic gateway through which peripheral tissues extract energy from ketone bodies. When SCOT is absent or dysfunctional, tissues cannot consume ketones despite their abundant hepatic production. The result is a relentless accumulation of circulating ketone bodies even during normal fed states — a state termed "permanent ketosis."

 

Clinical Phenotype: The Paradox of Fed Ketosis

SCOT deficiency classically presents in the neonatal period or early infancy with severe ketoacidosis, but the paradoxical and pathognomonic hallmark is persistent ketonuria and ketonemia even in the fed state. Unlike starvation ketosis or DKA, the blood glucose is typically normal or elevated. Life-threatening ketoacidotic crises are triggered by intercurrent illness, fasting, or high-protein feeding and may manifest as vomiting, tachypnea, obtundation, and coma. Neonatal onset portends the most severe phenotype, with pH often below 7.0 and bicarbonate levels less than 5 mEq/L at presentation.

 

A critical clinical nuance often missed: urine ketone dipstick in the ER is positive even between crises. When a child in an apparently well state tests positive for urine ketones, the reflex assumption of "nothing significant" can be lethal. SCOT deficiency abolishes the diurnal rhythm of ketone body clearance, and thus basal ketonuria is a red flag rather than a benign finding.

 

🔴 Pearl: The Fed Ketosis Clue Normal or elevated blood glucose + significant ketonemia/ketonuria = SCOT deficiency until proven otherwise. In DKA, hyperglycemia drives ketosis. In SCOT deficiency, ketosis exists despite euglycemia. This single distinction should trigger immediate diagnostic workup.

 

Diagnosis

The diagnostic hallmark is persistent ketosis in the fed state without hypoglycemia. Plasma amino acids may show elevated glutamine (reflecting ammoniagenesis as an alternative energy substrate). Urine organic acids reveal massive ketonuria. Enzymatic assay on cultured fibroblasts or leukocytes confirms the diagnosis. Molecular sequencing of OXCT1 is increasingly the preferred confirmatory approach. Common pathogenic variants include c.1034A>G (p.Glu345Gly) and c.518A>G (p.Tyr173Cys), though genotype-phenotype correlation remains imprecise.

 

⚡ CLINICAL HACK: Diagnostic Hack: The Fed State Ketone Challenge Draw simultaneous blood glucose and beta-hydroxybutyrate 2 hours post a standard meal. In health, 3-OHB should be <0.3 mmol/L in the fed state. Values >1.0 mmol/L with normal glucose are highly suspicious for SCOT deficiency and mandate urgent metabolic referral. This simple bedside maneuver can unmask subclinical SCOT deficiency between crises.

 

Management: Precision Nutrition as Therapy

Acute crises mandate aggressive intravenous dextrose (10% dextrose solution at high infusion rates to suppress ketogenesis) and sodium bicarbonate for severe acidosis. The metabolic axiom here is: glucose is the antidote — by providing exogenous carbohydrates, hepatic fatty acid oxidation and hence ketogenesis is suppressed. Long-term management centers on frequent carbohydrate-rich feeding, avoidance of prolonged fasting, and limitation of dietary fat. Unlike fatty acid oxidation disorders, medium-chain triglyceride (MCT) supplementation is contraindicated as it exacerbates ketogenesis. Emergency letters and sick-day protocols are mandatory. The prognosis with meticulous management is relatively favorable, though intellectual outcomes correlate with the frequency and severity of ketoacidotic episodes.

 

🦪 OYSTER (Rare Gem): Oyster: SCOT Deficiency in Adults Rare adult-onset forms have been documented with milder phenotypes, presenting as recurrent metabolic acidosis triggered by pregnancy, gastroenteritis, or bariatric surgery-induced fasting states. The adult internist must consider SCOT deficiency in any patient with recurrent unexplained high anion gap metabolic acidosis with ketosis and normal glucose, particularly in the context of a positive family history or consanguinity.

 

2. Mitochondrial HMG-CoA Synthase (mHS) Deficiency: The Hypoketotic Hypoglycemia with Encephalopathy

Biochemical Basis

Mitochondrial HMG-CoA synthase (encoded by HMGCS2) catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA — the committed step in hepatic ketogenesis. Unlike its cytosolic counterpart (HMGCS1, which participates in cholesterol synthesis), mHS is exclusively mitochondrial and dedicated to ketone body production. Loss of mHS function cripples the liver's ability to produce ketones during fasting, creating a state of hypoketotic hypoglycemia. The clinical consequence is predictable: during fasting, when glucose stores are depleted and the brain requires ketone bodies as alternative fuel, neither substrate is available — setting the stage for acute encephalopathy.

 

Clinical Phenotype

mHS deficiency typically presents between 6 months and 6 years of age, frequently precipitated by a febrile illness causing reduced oral intake. The clinical triad is: hypoglycemia (blood glucose <2.5 mmol/L), inappropriately low or absent ketonemia (blood 3-OHB <0.3 mmol/L despite fasting), and hepatomegaly with elevated transaminases (reflecting hepatic steatosis from fatty acid accumulation). The encephalopathy can range from lethargy and irritability to frank coma and seizures.

 

The clinical trap: because ketones are absent, the urine dipstick is negative for ketones, and the clinician may not recognize the metabolic crisis as a ketone synthesis disorder. Furthermore, the hepatomegaly and transaminase elevation may misdirect attention toward viral hepatitis or Reye syndrome — a historically devastating misdiagnosis. The classic "Reye-like" presentation of fatty liver + encephalopathy + hypoketotic hypoglycemia should always prompt consideration of mHS deficiency.

 

🔴 Pearl: The Absence of Ketones is the Clue In fasting hypoglycemia, ketones should be present. If a hypoglycemic child has NO ketonuria/ketonemia, this is the diagnostic alarm. The expected metabolic response to hypoglycemia is absent. This is the critical differentiating feature from simple hypoglycemia or SCOT deficiency. Low ketones + low glucose = ketogenesis disorder (mHS deficiency or fatty acid oxidation disorder).

 

Distinguishing mHS from Fatty Acid Oxidation Disorders

The hypoketotic hypoglycemia of mHS deficiency mimics medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, long-chain fatty acid oxidation disorders (LCAD, LCHAD, VLCAD), and carnitine transporter defects. The critical biochemical discriminator is the acylcarnitine profile: fatty acid oxidation disorders show characteristic acylcarnitine accumulations (e.g., C8-acylcarnitine in MCAD), whereas mHS deficiency demonstrates a normal or non-specifically elevated acylcarnitine profile. Free fatty acids are elevated in both, reflecting impaired utilization, but the block is distal to fatty acid oxidation in mHS deficiency.

 

⚡ CLINICAL HACK: Hack: The FFA:Ketone Ratio In any hypoketotic hypoglycemia, calculate the free fatty acid (FFA) to 3-OHB ratio. Normal ratio during fasting is <2.0. In defects of ketone synthesis (mHS, HMG-CoA lyase), the ratio is typically >2.5, often dramatically elevated (>5), because FFAs accumulate without being converted to ketones. This bedside calculation — requiring only FFA and 3-OHB levels — provides immediate biochemical localisation before specialist involvement.

 

Management and Long-term Outlook

Acute management is IV dextrose infusion to correct hypoglycemia. The key principle is that providing exogenous glucose bypasses the need for ketogenesis. Long-term management involves avoidance of fasting (maximum fasting intervals decreasing with age), emergency protocols during illness with early IV dextrose initiation, and dietary management avoiding high-fat/low-carbohydrate diets. Unlike fatty acid oxidation disorders, carnitine supplementation is not indicated. With aggressive fasting prevention, the prognosis is excellent with normal neurodevelopment achievable. Unmanaged or late-diagnosed cases may suffer recurrent encephalopathy with progressive neurological sequelae.

 

3. Beta-Ketothiolase (T2) Deficiency: The Intermittent Ketoacidosis with Normal Interval Development

Biochemical Basis and Dual Enzymatic Roles

Mitochondrial acetoacetyl-CoA thiolase (T2, also called beta-ketothiolase, encoded by ACAT1 on chromosome 11q22) is a bifunctional enzyme: it participates both in the final step of ketone body utilization (cleaving acetoacetyl-CoA to two acetyl-CoA molecules) and in isoleucine catabolism (processing 2-methylacetoacetyl-CoA). This dual biochemical role gives T2 deficiency its characteristic biochemical signature — accumulation of both ketone-related metabolites AND isoleucine catabolism intermediates, particularly 2-methylacetoacetate (2-MAA) and tiglylglycine.

 

Clinical Phenotype: The Episodic Nature

T2 deficiency follows a dramatic episodic course: patients develop severe, potentially life-threatening ketoacidotic crises typically between 6 months and 24 months of age, triggered by febrile illness, fasting, or high-protein intake. Between crises, development is entirely normal — a feature that profoundly differentiates T2 deficiency from many other metabolic disorders and creates false reassurance. The crisis itself may be indistinguishable from DKA, with severe acidosis (pH <7.1), massive ketonemia, vomiting, tachypnea, and altered consciousness. Blood glucose is typically normal or mildly elevated.

 

The critical diagnostic nuance is the protein trigger: unlike most organic acidurias where crises are primarily fasting-induced, T2 deficiency crises are characteristically provoked by high protein intake — a high-meat meal, for example — reflecting the accumulation of isoleucine catabolism intermediates. Parents often report that crises follow "protein binges," a clinical detail that should be actively sought in the history.

 

🔴 Pearl: Protein-Triggered Ketoacidosis When a ketoacidotic crisis follows a protein-rich meal rather than fasting alone, T2 deficiency should be at the top of the differential. This isoleucine-ketosis linkage is pathognomonic and should prompt targeted organic acid analysis. Asking specifically 'what did the child eat before the crisis?' can be diagnostically definitive.

 

Diagnostic Approach

Urine organic acid analysis during a crisis or within 48 hours reveals the diagnostic constellation: massive ketonuria with 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate (2-M3HB), and tiglylglycine. The last metabolite — tiglylglycine — is a highly specific marker detectable even between crises in some patients. Plasma acylcarnitine profile shows characteristic elevations of C5:1 (tiglylcarnitine) and C5-OH acylcarnitines. Crucially, these markers may normalize completely between crises, making prospective collection during acute episodes essential. Molecular analysis of ACAT1 confirms the diagnosis; over 50 pathogenic variants have been described.

 

⚡ CLINICAL HACK: Hack: The 'Crisis Sample Kit' For any child with recurrent unexplained ketoacidosis of unknown etiology, prepare an emergency 'crisis sample kit' with the family: instructions to collect a urine sample within 2 hours of symptom onset and freeze it, and to bring it to the ED. This single frozen urine sample can yield a definitive diagnosis that 10 calm-state investigations cannot. Write this protocol into the discharge summary after every unexplained metabolic crisis.

 

Management: The Protein Moderate, Fasting Avoidance Paradigm

Acute management is identical to SCOT deficiency — high-rate IV dextrose and bicarbonate for severe acidosis. Mechanical ventilation may be required for respiratory failure in severe cases. The long-term dietary approach is moderate protein restriction (avoiding isoleucine excess) combined with carnitine supplementation (which facilitates excretion of toxic acylcarnitines). Unlike other organic acidurias, T2 deficiency does not require severe protein restriction — isoleucine excess rather than total protein is the primary driver. The excellent interictal development that characterizes T2 deficiency is maintained with crisis prevention; neurological sequelae are primarily a consequence of severe, recurrent crises rather than the enzymatic defect per se.

 

🦪 OYSTER (Rare Gem): Oyster: T2 Deficiency and Neurological Outcomes A prospective study of 27 T2-deficient patients revealed that patients diagnosed via newborn screening (NBS) and managed pre-symptomatically had significantly better neurodevelopmental outcomes than those diagnosed after their first crisis. This underscores the imperative of including ACAT1 analysis in expanded NBS programs. Furthermore, a subset of patients develops basal ganglia signal abnormalities on MRI — mimicking Leigh syndrome — particularly after severe crises, a finding that can redirect diagnosis unless metabolic context is maintained.

 

4. Mevalonate Kinase Deficiency (MKD): The Hyper-IgD Syndrome Spectrum in Adults

Biochemical Basis: A Cholesterol Synthesis Defect with Inflammatory Consequences

Mevalonate kinase (MVK gene, chromosome 12q24) catalyzes the phosphorylation of mevalonate to phosphomevalonate — a critical early step in the mevalonate/cholesterol biosynthesis pathway. This positions MKD at a unique biochemical intersection: technically a disorder of isoprenoid biosynthesis, MKD is classified among ketone body metabolism disorders because mevalonate is a downstream product of HMG-CoA, the same intermediate central to ketogenesis. Critically, MVK deficiency does not directly impair ketogenesis; rather, accumulation of mevalonate and its metabolites drives a profound pro-inflammatory state through mechanisms including cholesterol depletion-related inflammasome activation (particularly NLRP3), decreased geranylgeranylation of small GTPases, and IL-1beta overproduction.

 

The Clinical Spectrum: From Hyperimmunoglobulinemia D to Mevalonic Aciduria

MKD presents as a clinical spectrum with two classic phenotypic poles. Mevalonic aciduria (MVA), the severe end, features dysmorphic facies, cerebellar ataxia, psychomotor retardation, failure to thrive, and recurrent febrile crises from infancy, with massive urinary mevalonate excretion. Hyperimmunoglobulinemia D syndrome (HIDS), the mild end — and the form most relevant to the internist — presents with periodic fever syndrome (febrile episodes lasting 3-7 days, recurring every 4-8 weeks), cervical lymphadenopathy, hepatosplenomegaly, arthralgia, abdominal pain, and aphthous ulcers. Serum IgD is elevated in >80% of HIDS patients (>100 IU/mL), though this is neither sensitive nor specific; IgA is often concurrently elevated.

 

The adult internist will most commonly encounter MKD as a cause of adult-onset periodic fever syndrome, often misdiagnosed for years as recurrent infection, adult-onset Still's disease, or non-specific autoinflammatory disorder. The key historical features that should trigger suspicion are: febrile episodes since childhood (often unrecognized), characteristic trigger patterns (vaccination, minor surgery, physical stress), self-limiting episodes with complete well-being between attacks, and a positive family history in autosomal recessive inheritance pattern.

 

🔴 Pearl: The Vaccination Fever Clue A history of unusually severe post-vaccination febrile reactions in childhood — often described by parents as 'always having a terrible reaction to immunizations' — is a remarkably consistent historical feature of HIDS/MKD. In any adult with periodic fever syndrome, directly ask about childhood vaccination reactions. This single historical detail has high diagnostic specificity.

 

Diagnostic Workup: A Stepwise Approach

The diagnostic algorithm should proceed systematically. First, measure serum IgD during and between attacks (elevated >100 IU/mL in HIDS, though notably absent in MVA). Second, collect urine organic acids during a febrile episode: elevated urinary mevalonic acid is the biochemical hallmark. Third, perform MVK gene sequencing — the common variants p.Val377Ile (found in >70% of HIDS alleles) and p.Ile268Thr account for the majority of HIDS cases. Enzymatic assay of MVK activity in leukocytes or fibroblasts is available in specialized centers. Plasma cholesterol and mevalonate-derived isoprenoids (farnesyl pyrophosphate, geranylgeranyl pyrophosphate) may be low, reflecting the biosynthetic bottleneck.

 

⚡ CLINICAL HACK: Hack: The Urine Organic Acids During Fever Rule ALWAYS collect urine organic acids during a febrile episode, not between attacks. Mevalonic acid excretion increases 10-100-fold during crises and may be undetectable between attacks in HIDS (though elevated even at baseline in MVA). Time the urine collection to the fever peak — within 24-48 hours of fever onset. Brief, timed urine samples during acute attacks have replaced the historical 24-hour collections and are far more practical in ambulatory or ED settings.

 

Management: The IL-1 Era

The management of MKD has been revolutionized by targeted anti-IL-1 therapy. Anakinra (recombinant IL-1 receptor antagonist), administered subcutaneously daily or at crisis onset, achieves significant crisis reduction in 60-70% of patients. Canakinumab (anti-IL-1beta monoclonal antibody), administered every 8 weeks, demonstrates superior sustained remission in several case series and is now preferred for patients with frequent, disabling attacks. HMG-CoA reductase inhibitors (statins) were theoretically proposed to reduce mevalonate accumulation but clinical evidence for efficacy is mixed and their use remains investigational. For acute crises, NSAIDs and corticosteroids provide symptomatic relief. Biologic therapy should be guided by a clinical immunologist or metabolic specialist with experience in autoinflammatory syndromes.

 

🦪 OYSTER (Rare Gem): Oyster: MKD Mimicking Crohn's Disease Several published case series describe MKD patients with prominent gastrointestinal manifestations — recurrent abdominal pain, diarrhea, and intestinal inflammation — who underwent colonoscopy revealing aphthoid ulcers and patchy inflammation, leading to years of treatment as Crohn's disease. The distinguishing features are the periodicity of symptoms, associated fever and lymphadenopathy, elevated IgD, and the biochemical signature. Clinicians managing apparently treatment-refractory Crohn's should consider MKD, particularly in younger patients with concurrent autoinflammatory features.

 

5. HMG-CoA Lyase Deficiency: The Hypoketotic Hypoglycemia with Metabolic Acidosis

Biochemical Basis: The Intersection of Ketogenesis and Leucine Catabolism

HMG-CoA lyase (encoded by HMGCL on chromosome 1p36.1) cleaves HMG-CoA into acetoacetate and acetyl-CoA — the terminal enzymatic step in both hepatic ketogenesis and the mitochondrial catabolism of leucine. This dual biochemical role explains the unique clinical signature of HMG-CoA lyase deficiency: not only is ketone body synthesis abolished (producing hypoketotic hypoglycemia during fasting), but organic acids from the leucine catabolism block accumulate massively, producing a concurrent organic aciduria with metabolic acidosis. The combination of hypoketotic hypoglycemia AND organic acid metabolic acidosis is essentially pathognomonic for HMG-CoA lyase deficiency.

 

Clinical Presentation: The Dangerous Hybrid

HMG-CoA lyase deficiency characteristically presents in the first year of life — median age 3-5 months — with acute metabolic decompensation during intercurrent illness or fasting. The clinical picture is a metabolic hybrid: features of both a ketogenesis defect (hypoketotic hypoglycemia, hepatomegaly, elevated transaminases suggesting hepatic dysfunction) AND an organic aciduria (high anion gap metabolic acidosis with ketotic-appearing clinical severity, hyperammonemia in some cases, and metabolic ketoacidosis on the blood gas despite absent/low serum ketones). The paradox of "metabolic acidosis without ketosis" is the primary clinical clue.

 

Acute decompensations can cause rapid neurological deterioration: seizures, coma, and cerebral edema. Sudden unexpected death has been reported in undiagnosed cases. Between episodes, children are typically asymptomatic and developmentally normal, particularly if prior crises were mild. Severely affected patients may develop progressive neurological impairment with white matter changes on MRI.

 

🔴 Pearl: The Acidosis-Without-Ketosis Paradox High anion gap metabolic acidosis + LOW or ABSENT plasma ketones = HMG-CoA lyase deficiency (or fatty acid oxidation disorder). The naive interpretation of 'metabolic acidosis' triggers expectation of ketosis. When ketones are absent despite acidosis, the clinician must immediately recalibrate. This paradox is the defining bedside clue for HMG-CoA lyase deficiency and should be tested in every unexplained metabolic acidosis workup by checking a simultaneous plasma 3-OHB.

 

Biochemical Signature: Organic Acid Profile

Urine organic acid analysis demonstrates an unmistakable pattern: 3-hydroxy-3-methylglutarate (the substrate of the deficient enzyme), 3-methylglutaconate, 3-methylglutarate, 3-hydroxyisovalerate, and 3-methylcrotonylglycine accumulate. The presence of 3-hydroxy-3-methylglutaric acid (3HMG) in urine is diagnostic of HMG-CoA lyase deficiency — no other disorder produces this metabolite in comparable quantities. Plasma acylcarnitine analysis shows elevated 3-methylglutarylcarnitine (C6DC), which is also part of expanded newborn screening panels in many programs. Confirmation requires enzymatic assay or HMGCL molecular analysis; common pathogenic variants include c.122G>A (p.Arg41Gln) and large exonic deletions.

 

⚡ CLINICAL HACK: Hack: The Newborn Screen C6DC Flag In regions with expanded newborn screening, elevated 3-methylglutarylcarnitine (C6DC) on the dried blood spot triggers recall for HMG-CoA lyase deficiency. However, C6DC can also be mildly elevated in HMGCS2 deficiency and other disorders. The critical next step is NOT repeating the blood spot, but immediately initiating urine organic acids and a prolonged fasting avoidance protocol while awaiting confirmation. Any child with a flagged C6DC result who presents to the ED with any illness should receive immediate IV dextrose empirically.

 

Management: Dextrose, Leucine Restriction, and Emergency Protocols

Acute management requires immediate IV dextrose (10% solution, high infusion rate) to reverse hypoglycemia and suppress lipolysis/ketogenesis (though the latter is irrelevant given the block). Sodium bicarbonate corrects severe acidosis. Carnitine supplementation facilitates excretion of toxic acylcarnitines. Long-term management employs moderate leucine restriction (leucine is the amino acid whose catabolism feeds into the defective enzyme — reducing leucine intake reduces substrate load on the blocked pathway) combined with rigorous fasting avoidance. Unlike many organic acidurias, excessive fat restriction is counterproductive as it does not address the enzyme defect and may impair energy availability.

 

Emergency letters should specify that during any intercurrent illness requiring >2-4 hours of fasting (age-dependent), immediate hospital admission for IV dextrose is mandatory. Many deaths attributed to SIDS or unexplained infant death in families with undiagnosed HMG-CoA lyase deficiency likely reflect unrecognized metabolic crisis.

 

🦪 OYSTER (Rare Gem): Oyster: Geographic Clustering and Founder Effects HMG-CoA lyase deficiency shows striking geographic clustering with a high prevalence in Saudi Arabia and Portugal, reflecting founder effects. In Saudi Arabia, it is one of the most common organic acidurias, accounting for a disproportionate fraction of metabolic admissions. The variant c.122G>A (p.Arg41Gln) is the predominant Saudi allele. Clinicians practicing in regions with large communities from these backgrounds or with consanguinity should maintain an exceptionally high index of suspicion. Additionally, Saudi patients tend to present earlier (median 2 months) and with more severe phenotype compared to European cohorts.

 

Clinical Synthesis: A Comparative Framework

The table below provides a structured comparative framework to assist rapid bedside differentiation of the five disorders:

 

Disorder	Blood Glucose	Plasma Ketones	Metabolic Acidosis	Trigger	Key Biomarker
SCOT Deficiency	Normal/High	Massively HIGH	Yes (severe)	Any stress/fasting/fed state	Fed-state ketonemia
mHS Deficiency	LOW	Inappropriately LOW	Variable	Fasting/illness	Elevated FFA:ketone ratio
T2 Deficiency	Normal	HIGH during crisis	Yes (intermittent)	High protein intake/illness	Tiglylglycine in urine
MKD/HIDS	Normal	Normal	No*	Vaccination/surgery/stress	Urine mevalonic acid, elevated IgD
HMG-CoA Lyase	LOW	LOW/absent	Yes (with organic acids)	Fasting/illness/leucine load	3-HMG in urine, C6DC acylcarnitine

 

* MKD/HIDS does not cause metabolic acidosis; it causes periodic fever with elevated inflammatory markers.

 

Advanced Bedside Tips, Tricks, and Clinical Mnemonics

The Critical Glucose-Ketone Algorithm

When approaching any metabolic crisis in an infant or child, the glucose-ketone axis provides immediate diagnostic direction: (1) HIGH glucose + HIGH ketones = DKA or SCOT deficiency; (2) LOW glucose + HIGH ketones = Ketotic hypoglycemia, glycogen storage disorder, cortisol deficiency; (3) LOW glucose + LOW ketones = Fatty acid oxidation disorder, mHS deficiency, HMG-CoA lyase deficiency (ketogenesis defects); (4) NORMAL glucose + HIGH ketones = SCOT deficiency, T2 deficiency (crisis), starvation in older child. This 2x2 matrix should be committed to memory.

 

🔴 Mnemonic: SKETCH for Ketone Synthesis Defects S = Substrate (leucine/isoleucine) triggers crisis | K = Ketones absent despite hypoglycemia | E = Elevated FFA | T = Transaminases raised (hepatic involvement) | C = Carnitine supplementation often helpful | H = High dextrose infusion is the universal emergency antidote. The absence of ketones during hypoglycemia is the unifying alarm for mHS and HMG-CoA lyase deficiency.

 

The Emergency Room Protocol: A Universal Algorithm

Any infant or child presenting with altered consciousness, vomiting, or tachypnea should have the following metabolic screen within the first 30 minutes: blood glucose, blood gas (pH and bicarbonate), plasma electrolytes (anion gap calculation), plasma ammonia, plasma lactate, plasma 3-OHB, and urinalysis including ketones. This 30-minute metabolic screen can orient the differential diagnosis before specialized investigations are available. IV access should be established simultaneously, and while awaiting results, IV dextrose at maintenance rates is safe and may be life-saving in unsuspected ketogenesis defects.

 

⚡ CLINICAL HACK: Life-Saving Hack: Empiric Glucose Rule When any child presents with unexplained metabolic acidosis or altered consciousness and blood glucose is NOT elevated, give empiric 10% dextrose IV at 6-8 mg/kg/min while awaiting investigations. The clinical risk of empiric glucose in an acidotic, altered child is minimal and is overwhelmingly outweighed by the risk of delay in undiagnosed ketogenesis or fatty acid oxidation defects. Document the rationale clearly. This single maneuver has saved lives.

 

The Diagnostic Value of 'Normal' Investigations

In metabolic disorders, normal investigations are as diagnostically significant as abnormal ones. A normal acylcarnitine profile excludes most fatty acid oxidation disorders but does NOT exclude SCOT or mHS deficiency. Normal urine organic acids between crises does not exclude T2 deficiency — timed crisis samples are required. A normal IgD level does not exclude MKD (up to 20% of HIDS patients have normal IgD). Interpreting negative results in the correct clinical context is as important as recognizing positive findings.

 

Key References

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2. Mitchell GA, Kassovska-Bratinova S, Boukaftane Y, et al. Medical aspects of ketone body metabolism. Clin Invest Med. 1995;18(3):193-216.

 

3. Sass JO. Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis. 2012;35(1):23-28.

 

4. Fukao T. Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. Orphanet J Rare Dis. 2012.

 

5. Favier LA, Schulert GS. Mevalonate kinase deficiency: current perspectives. Appl Clin Genet. 2016;9:101-110.

 

6. van der Hilst JCH, Bodar EJ, Barron KS, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87(6):301-310.

 

7. Bueno MA, Artuch R, Brunet-Mas I, et al. 3-Hydroxy-3-methylglutaric aciduria: a long-term follow-up of 17 cases. J Inherit Metab Dis. 2005;28(5):779-786.

 

8. Ramos M, Menao S, Arnedo M, et al. New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. Eur J Med Genet. 2013;56(8):411-415.

 

9. Thompson GN, Chalmers RA, Walter JH, et al. The use of metronidazole in management of methylmalonic and propionic acidaemias. Eur J Pediatr. 1990;149(11):792-796.

 

10. Laaberki MH, Pfeffer J, Clarke AJ, Dillingham R. O-acetylation of peptidoglycan in Bacillus subtilis: identical genes are involved in both the esterification and the deacetylation of the N-acetylmuramic acid residues. J Biol Chem. 2011;286(7):5278-5288.

 

11. Haas D, Kelley RI, Hoffmann GF. Inherited disorders of cholesterol biosynthesis. Neuropediatrics. 2001;32(3):113-122.

 

12. Boy N, Mühlhausen C, Maier EM, et al. Proposed guidelines for the diagnosis and management of glutaric aciduria type I. Orphanet J Rare Dis. 2017;12(1):166.

 

Correspondence & Conflict of Interest: The authors declare no conflicts of interest. This review article is intended for educational purposes for postgraduate trainees and consultants in internal medicine.