General metabolism

Last updated: April 26, 2023

Summary

Metabolism is the sum of chemical reactions continuously taking place in the body to maintain its proper function. These reactions include water metabolism, electrolyte metabolism, and the conversion of nutrients into energy and substances (e.g., proteins, lipids, nucleic acids) that can be processed by cells. The conversion of nutrients involves the breakdown of substances (catabolism), which generally releases energy, or the synthesis of substances (anabolism), which generally consumes energy. Metabolic reactions are organized into pathways (e.g., glycolysis, lipolysis), with each step involving a specific enzyme to catalyze the reaction. Dysregulation of these pathways can lead to metabolic disorders such as glycogen storage diseases.

This article provides an overview of the most important metabolic pathways, as well as the most common metabolic disorders.

Water metabolism

General

Percentage of body water ^[1]
- Adults: 50–60% of the total body weight
- Infants: ∼ 75% of the total body weight
Composition ^[1]
- Approx. 65% intracellular fluid volume (ICFV)
- Approx. 35% extracellular fluid volume (ECFV), which is composed of:
  - 75% interstitial fluid volume (ISFV)
  - 25% plasma volume (PV)
Distribution: via osmosis (e.g., through aquaporin channels) and via diffusion (mostly dependent on Na⁺ and Cl^-concentrations)
Tolerance of imbalance: less than 1% difference to physiological osmolality concentration (285–290 mOsm/kg) ^[2]

Homeostasis

Overview
- The balance of osmolality in intra- and extracellular compartments is maintained by osmosis and diffusion.
- Water loss
  - Renal
  - Extrarenal: skin, lungs, gastrointestinal tract
- Water absorption (external water intake): gastrointestinal tract
Regulation
- Stimulation of water intake
  - Hypotension: hypovolemia → stimulation of baroreceptors → stimulation of autonomic nervous system (increased vascular tone, heart rate, and contractility; increased venous return)
  - Endocrine
    - Renin, angiotensin, aldosterone, vasopressin (for further information see “Renin-angiotensin-aldosterone system” in “Physiology of the kidney”)
    - Epinephrine, norepinephrine, adrenocorticotropin, glucocorticoids
  - Osmoregulation: stimulated by extracellular hyperosmolality
- Initiation of thirst ^[3]
  - Neurons in the hypothalamic region stimulate thirst.
  - Stimulation
    - Increase of osmolality → stimulation of osmoreceptors in the hypothalamic region
    - Angiotensin II → direct stimulation of neurons
- Inhibition of water intake
  - Hypertension
  - Osmoregulation: due to extracellular hypoosmolality

Clinical significance ^[1]

Dehydration and hyperosmolality (for further information see “Dehydration and hypovolemia”)
Hypervolemia and hypoosmolality (for further information see “Hypovolemic hypotonic hyponatremia” in “Hyponatremia”)
Diarrhea and/or vomiting
Diabetic ketoacidosis
Diabetes insipidus
Syndrome of inappropriate ADH secretion
Adrenal insufficiency
Uremia

References:^[1]^[2]^[3]^[4]^[5]

Electrolyte metabolism

Electrolytes that play an important role in water metabolism, electrical cell stability, and action potentials in nerves and muscles are sodium (Na⁺), potassium (K⁺), chloride (Cl^-), bicarbonate (HCO₃^-), calcium (Ca²⁺), magnesium (Mg²⁺), and phosphate (H₂PO₄^-, HPO₄^2-). More detailed information about electrolyte imbalances is provided in the following articles:

“Hypernatremia” and “Hyponatremia”
“Hyperkalemia” and “Hypokalemia”
“Hyperchloremia” and “Hypochloremia”
“Bicarbonate buffer system”
“Hypercalcemia” and “Hypocalcemia”
“Hypermagnesemia “ and “Hypomagnesemia”
“Hyperphosphatemia” and “Hypophosphatemia”
“Electrolyte repletion”
“Acid-base disorders”

Pathway overview

This section deals with the most important metabolic pathways.

Carbohydrate metabolism

For details on the individual pathways, see the articles “Carbohydrates”, “Glycolysis and gluconeogenesis”, and “Glycogen metabolism”.

Overview of carbohydrate metabolism
Pathway	Precursor(s)	End product(s)	Rate-limiting enzyme	Individual steps	Pathway regulation
Pathway	Precursor(s)	End product(s)	Rate-limiting enzyme	Individual steps	Stimulation	Inhibition
Galactolysis	Galactose	Glucose-1-phosphate UDP-glucose	UDP-galactose 4-epimerase ^[6]	See “Galactose metabolism” for details.	N/A
Fructolysis	Fructose	Dihydroxyacetone-phosphate Glyceraldehyde-3-phosphate	Aldolase B ^[7]	See “Fructose metabolism” for details.	N/A
Glycolysis	Glucose	Pyruvate	Phosphofructokinase-1	See “Glycolysis” for details.	Insulin AMP Fructose 2,6-bisphosphate Fructose 1,6-bisphosphate (feed-forward stimulation)	Glucagon Glucose-6-phosphate (feedback inhibition) Fructose 6-phosphate (feedback inhibition) ATP Citrate Low pH Alanine
Gluconeogenesis	Glucogenic amino acids Lactate Propionyl-CoA Glycerol 3-phosphate	Glucose	Fructose 1,6-bisphosphatase	See “Gluconeogenesis” for details.	Glucagon Acetyl-CoA Cortisol Citrate ATP Fructose 1,6-bisphosphate (feed-forward regulation) Glucose-6-phosphate (feed-forward regulation)	Insulin ADP Fructose 2,6-bisphosphate AMP
Glycogenesis	Glucose	Glycogen	Glycogen synthase	See “Glycogenesis” for details.	Insulin Cortisol Glucose-6-phosphate ATP	Glucagon Epinephrine AMP
Glycogenolysis	Glycogen	Glucose-6-phosphate	Glycogen phosphorylase	See “Glycogenolysis” for details.	Glucagon Epinephrine Cortisol AMP	Glucose-6-phosphate Insulin ATP

Galactose metabolism Mechanisms of fructose intolerance Glycolysis Comparison of glycolysis and gluconeogenesis Glycogen storage diseases

Lipid metabolism

For details on this topic, see the article “Lipids and their metabolism.”

Overview of lipid metabolism
Pathway	Precursor(s)	End product(s)	Rate-limiting enzyme	Individual steps	Pathway regulation
Pathway	Precursor(s)	End product(s)	Rate-limiting enzyme	Individual steps	Stimulation	Inhibition
Lipogenesis	Acetyl-CoA	Palmitic acid NADP	Acetyl-CoA carboxylase	See “Fatty acid synthesis” for details.	Insulin ↑ Glucose ATP Citrate	Glucagon ↓ Glucose Catecholamines AMP Acyl-CoA and palmitoyl-CoA
Lipolysis	Acyl-CoA	Acetyl-CoA Ketone bodies NADH⁺ FADH₂	Carnitine palmitoyltransferase 1	See “Fatty acid degradation” for details.	Glucagon (indirectly)	Malonyl-CoA Insulin (indirectly)
Ketogenesis	Acetyl-CoA	Acetoacetate β-hydroxybutyrate Acetone	HMG-CoA synthase	See “Ketogenesis” for details.	Prolonged fasting Alcohol consumption	N/A
Ketogenolysis	β-hydroxybutyrate Acetoacetate	Acetyl-CoA	Thiophorase	See “Ketogenolysis” for details.	N/A
Cholesterol synthesis	Acetyl-CoA	Cholesterol	HMG-CoA reductase	See “Cholesterol synthesis” for details.	Insulin Thyroxine Estrogen	Glucagon Cholesterol (feedback inhibition via SREBP)

Fatty acid metabolism (overview) Ketone metabolism Degradation of ketone bodies Cholesterol

Protein metabolism

For details on this topic, see the article “Amino acids”.

Overview of protein metabolism
Pathway		Precursor(s)	End product(s)	Rate-limiting enzyme	Individual steps
Urea cycle (ammoniagenesis)		HCO₃^- NH₃	Urea Ornithine	Carbamoyl phosphate synthetase 1	See “Urea cycle reactions” for details.
Amino acid catabolism	Glucogenic amino acids	Arginine Proline Glutamine Histidine Glutamate	α-Ketoglutarate	See “Overview of the amino acid carbon skeleton metabolism” for details.
		Aspartate Asparagine	Oxaloacetate
		Glycine Alanine Serine Cysteine Threonine	Pyruvate
		Methionine Valine	Succinyl-CoA
	Ketogenic amino acids	Lysine Leucine	Acetyl-CoA
	Mixed glucogenic/ketogenic amino acids	Tyrosine Phenylalanine	Fumarate Acetyl-CoA
		Tryptophan	Alanine Acetyl-CoA
		Isoleucine	Succinyl-CoA
		Threonine	Glucogenic routes Propionyl-CoA Pyruvate
		Threonine	Ketogenic routes Acetyl-CoA Glycine and acetyl-CoA
Synthesis of nonessential amino acids		α-Ketoglutarate	Glutamate	Glutamate dehydrogenase	See “Synthesis of nonessential amino acids” for details.
		Ammonia	Glutamine	Glutamine synthetase
		Oxalacetate	Aspartate	Aspartate aminotransferase
		Glutamine	Asparagine	Asparagine synthetase
		Glutamate	Arginine/proline	N/A
		α-Ketobutyrate	Cysteine	Cystathionine synthetase Cystathionase
		3-Phosphoglycerate	Serine	N/A
		Serine	Glycine	N/A
		Pyruvate	Alanine	Alanine aminotransferase

Metabolic functions of vitamins B6 and B12 Pyruvate metabolism Catabolic pathways of serine, cysteine, glycine, alanine, and threonine Methionine cycle Catabolic pathways of glutamate, arginine, proline, glutamine, and histidine Reaction of glutamate dehydrogenase Metabolism of methionine, isoleucine, valine, and threonine Reaction of aspartate aminotransferase (AST) Catabolic pathway of amino acids phenylalanine and tyrosine Catabolic pathway of tryptophane

Metabolism of exercise and starvation

Metabolism of exercise

The energy required for physical activity is derived from a combination of aerobic and anaerobic metabolism. Short-duration high-intensity exercise promotes anaerobic energy production while long-duration lower-intensity exercise favors aerobic energy production. For more information, see “Pathways of ATP synthesis.”

ATP sources during exercise ^[8]^[9]^[10]
Duration of exercise	Primary source of ATP	Characteristics
1–3 sec	Freely available stored ATP	Immediate energy release Highly limited total capacity
1–6 sec	Phosphagen system	Immediate energy release Highly limited total capacity
6–30 sec	Phosphagen system in progression to anaerobic metabolism	High-rate but low-yield ATP-production End product: lactate Anaerobic metabolism is limited by and depletion of carbohydrate stores. Fuels: blood glucose, liver and muscle glycogen
30–120 sec	Anaerobic metabolism
120–180 sec	Anaerobic metabolism in progression to aerobic metabolism (oxidative phosphorylation)	Low-rate but high-yield ATP-production End product: pyruvate, which is metabolized aerobically Fuels: blood glucose, muscle and liver glycogen, fat (β-oxidation)
> 180 sec	Aerobic metabolism

Metabolic states of the body

There are 3 different metabolic states of the body: postprandial state, fasting state, and starvation.

During fasting and starvation, metabolic processes provide the energy vital for protein preservation and normal cell and tissue function.
The metabolic processes during fasting and starvation are primarily regulated by the following:
- Insulin promotes the storage of energy in the form of glycogen, lipids, and protein.
- Glucagon and epinephrine stimulate the conversion of stored substrates to glucose.
The greater the substrate stores (e.g., adipose tissue), the longer physical function and, ultimately, life can be maintained.

Postprandial and fasting state

Postprandial vs. fasting state of metabolism
	Postprandial (fed or absorptive state)	Fasting (in between meals or postabsorptive state)
Hormone involved	Insulin	Glucagon
Hormone-sensitive tissue	Adipocytes Myocytes Hepatocytes	Adipocytes Hepatocytes
Pathway involved	Glycolysis Aerobic metabolism Glycogenesis and glucose uptake in fat, muscle, and liver Fatty acid synthesis Protein anabolism	Glycogenolysis (predominantly) β-oxidation of free fatty acids released by adipose tissue (to a lesser extent) Gluconeogenesis Protein catabolism
Hormone-resistant tissue	Brain RBCs

Metabolism of starvation

Energy sources during starvation
		Starvation days 1–3	Starvation after day 3
Biochemical reactions and substrates		Glycogenolysis β-oxidation: Muscle and liver now primarily utilize free fatty acids released by adipose tissue instead of glucose. Gluconeogenesis involves the following substrates: Alanine and lactate, provided by peripheral tissue (i.e., fat and muscle) Glycerol and propionyl-CoA (the only triglyceride component contributing to gluconeogenesis)	Ketogenesis and subsequent ketone body consumption Ketone bodies are synthesized from acetyl-CoA, which is provided by β-oxidation of free fatty acids that are released by adipose stores. Synthesized ketone bodies become the brain's main energy source after 3 days of fasting. Gluconeogenesis When ketone bodies are depleted, vital proteins are degraded even more quickly in order to serve as substrates in gluconeogenesis. This process will eventually result in organ failure and ultimately death.
Source of energy	For brain	Glucose	Glucose Ketone bodies
Source of energy	For rest of body	Triglycerides	Degradation of proteins in muscle and organs after triglyceride stores have been depleted

RBCs rely on glucose as a source of energy and are resistant to both insulin and glucagon.

Fed vs. fasting state Chalk Talk: Energy Metabolism - Part 11

Clinical significance

This section gives an overview of the most common metabolic disorders.

Disorders affecting the carbohydrate metabolism

Disorders that affect the carbohydrate metabolism are predominantly inherited genetic conditions that are inherited in an autosomal recessive fashion. Lactose intolerance, however, is generally caused by a genetic polymorphism of the lactase-coding gene or develops secondary to other conditions (e.g., gluten-sensitive enteropathy). For details, see the article “Lactose intolerance” and “Inborn errors of carbohydrate metabolism”.

Overview of disorders affecting the carbohydrate metabolism
Condition			Enzyme deficiency	Pathophysiology		Clinical features
Lactose intolerance			Lactase	↓ Absorption of lactase in the small intestine → transfer of osmotically active amounts of lactose into the large intestine → the osmotic binding of water		Diarrhea (often watery, bulky, and frothy) Cramping abdominal pain (often periumbilical or in the lower abdomen) Abdominal bloating, flatulence Nausea
Fructose intolerance	Hereditary fructose intolerance		Aldolase B	Accumulation of fructose-1-phosphate → ↓ in available phosphates → inhibition of glycogenolysis and gluconeogenesis → hypoglycemia		Bloating, sweating, vomiting Failure to thrive Jaundice (can progress to cirrhosis) Bleeding tendency Severe hypoglycemia: seizures, hypotonia, poor feeding, cyanosis, irritability Hepatomegaly
Fructose intolerance	Essential fructosuria		Fructokinase	↑ Conversion of fructose to fructose-6-phosphate by hexokinase (hexokinase becomes the main pathway for turning fructose to fructose-6-phosphate) → no entrapment of unphosphorylated fructose in cells → remaining excess fructose → excretion of fructose in urine		Asymptomatic
Galactosemia	Galactokinase deficiency		Galactokinase	↓ Conversion of galactose to galactose-1-phosphate → accumulation of galactitol in tissues		Cataracts Infants often do not track objects with their eyes and show no social smile on physical examination. Pseudotumor cerebri
	Classic galactosemia		Galactose-1-phosphate uridyltransferase	↓ Conversion of galactose-1-phosphate to UDP-galactose → accumulation of toxic substances in tissues (e.g., galactitol in the lens)		Poor feeding Failure to thrive Vomiting, diarrhea Jaundice, hepatomegaly Cataracts Cognitive impairment ↑ Risk of E. coli sepsis (esp. in neonates) Hypoglycemia
	Uridine diphosphate galactose-4-epimerase deficiency		Uridine diphosphate galactose-4-epimerase	↓ Conversion of UDP-galactose to glucose-1-phosphate		Mostly asymptomatic
Glycogen storage diseases	Type I (von Gierke disease)	Type 1a	Glucose-6-phosphatase	↓ Hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate	Abnormal accumulation of glycogen	Renomegaly and hepatomegaly (with hepatic adenomas) Severe fasting hypoglycemia, mild ketosis Severe hyperlipidemia (especially triglycerides) → doll-like facies Hyperuricemia (↑ risk of gout) Lactic acidosis Anemia Failure to thrive Dysfunctional glycogenolysis and gluconeogenesis
	Type I (von Gierke disease)	Type 1b	Glucose-6-phosphate translocase	↓ Transport of glucose-6-phosphate into the endoplasmic reticulum
	Type II (Pompe disease)		Lysosomal acid maltase (α-1, 4-glucosidase)	↓ Hydrolyzation of α-1,4- and α-1,6-linkages in the acidic environment of the lysosome → impaired glycogenolysis		Hypertrophic cardiomyopathy, conduction blocks, cardiomegaly Macroglossia Failure to thrive Proximal myopathy and hypotonia leads to respiratory insufficiency and early death.
	Type III (Cori disease)		Glycogen debranching enzyme	↓ Function of glycogen debranching enzyme (i.e., ↓ function of α-1,6-glucosidase and 4-α-D-glucanotransferase) → impaired glycogenolysis		Clinical presentation is similar to that of type I, though symptoms tend to be less severe. Generalized muscle weakness and/or cramps Possibly cirrhosis (ascites, hepatomegaly, and splenomegaly) Mild fasting hypoglycemia and ketosis Hyperlipidemia Cytosolic accumulations of limit dextrin-like complexes Blood lactate levels are normal. Gluconeogenesis is functional. Type III may result in cardiomyopathy.
	Type IV (Andersen disease)		Glycogen branching enzyme	↓ Function of glycogen branching enzyme → impaired glycogenesis		Symptoms in early infancy (usually leading to death early in childhood) Failure to thrive Hepatosplenomegaly Cirrhosis (possibly causing ascites) Proximal myopathy Cardiomyopathy, hypotonia Late symptom: hypoglycemia A number of neuromuscular forms have been described that can manifest at any age
	Type V (McArdle disease)		Myophosphorylase (skeletal muscle glycogen phosphorylase)	↓ Function of myophosphorylase → impaired glycogenolysis		Generalized muscle weakness, exercise intolerance (with a second wind phenomenon) Demanding physical exercise may cause rhabdomyolysis and myoglobinuria. Electrolyte imbalances can trigger cardiac arrhythmias. Normal serum glucose levels Flat venous lactate curve with exaggerated elevations in blood ammonia during exercise Glycogen accumulates in muscles, but can not be metabolized because of enzyme deficiency.
	Type VI (Hers disease)		Liver phosphorylase	↓ Function of liver phosphorylase → impaired glycogenolysis		Hepatomegaly Fasting hypoglycemia and ketosis Hyperlipidemia

353336994 Mechanisms of fructose intolerance Galactose metabolism Glycogen storage diseases Comparison of glycolysis and gluconeogenesis Glycogenolysis through cleavage of α-1,6-glycosidic bond Branching enzyme in glycogen synthesis Chalk Talk: Energy Metabolism - Part 10

Disorders affecting the fatty acid metabolism

Medium-chain acyl-CoA dehydrogenase deficiency, primary carnitine deficiency, and carnitine palmitoyltransferase II deficiency are all genetic conditions that are inherited in an autosomal recessive fashion. For details on these conditions, see “Disorders of fatty acid metabolism”.

Overview of disorders affecting the fatty acid metabolism
Condition	Deficiency	Pathophysiology		Clinical features
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency)	Medium-chain acyl-CoA dehydrogenase	Defective breakdown of medium-chain fatty acids into acetyl-CoA → elevated concentrations of fatty acyl-CoA in the blood	Hypoketotic hypoglycemia	Onset within the first years of life Vomiting Lethargy, seizures, coma Cardiopulmonary collapse
Primary carnitine deficiency	Carnitine transporters	Impaired entry of long-chain fatty acids into mitochondria via carnitine-dependent shuttle → ↓ fatty acid metabolism via beta-oxidation Accumulation of fat (long-chain fatty acids) in the cytosol of the liver and cardiac and skeletal muscle cells → toxicity		Weakness, lethargy Dilated cardiomyopathy, hypotonia
Carnitine palmitoyltransferase II deficiency (CPT II deficiency)	Carnitine palmitoyltransferase II	Carnitine cannot be removed from long-chain fatty acids → no fatty acid oxidation → no substrate for gluconeogenesis and ketogenesis Accumulation of fatty acids and long-chain acylcarnitines → damage to liver, heart, and muscles		Myalgia, hypotonia Hepatomegaly, liver dysfunction Cardiomyopathy

Fatty acid metabolism (overview) Chalk Talk: Energy Metabolism - Part 5 (with molecular structures)

Disorders affecting the amino acid metabolism

All conditions that affect the amino acid metabolism are genetic conditions that are inherited in an autosomal recessive fashion. For details on these conditions, see the article “Inborn errors of metabolism”.

Overview of disorders affecting the amino acid metabolism
Condition		Deficiency	Causes	Pathophysiology		Clinical features
Phenylketonuria		Phenylalanine hydroxylase	Inherited genetic (autosomal recessive)	Impaired conversion of phenylalanine to tyrosine → accumulation of phenylalanine		Growth restriction Psychomotor delay (starting as early as 4–6 months of age) Seizures Blue eyes, pale hair Eczema Musty odor (due to an increase in aromatic amino acids)
Homocystinuria		Methionine synthase		Impaired conversion of homocysteine into methionine	Accumulation of homocysteine	Ectopia lentis Progressive intellectual disability, psychiatric and behavioral disorders Light skin Marfanoid features Osteoporosis Cardiovascular complications
		Cystathionine synthase		Impaired conversion of homocysteine into cystathionine
		Methylenetetrahydrofolate reductase (MTHFR)		Impaired reduction of N5,10-methylenetetrahydrofolate to methyltetrahydrofolate
Hartnup disease		Na⁺-dependent neutral amino acid transporters on enterocytes and proximal renal tubular cells		Decreased renal and intestinal absorption of tryptophan → inability to synthesize vitamin B3		Pellagra Cerebellar ataxia
Alkaptonuria		Homogentisic acid dioxygenase		Impaired conversion of homogentisate to 4-maleylacetoacetate → accumulation of homogentisate → tissue discoloration and organ damage		Ochronosis Calcifications (cartilage, kidneys)
Maple syrup urine disease		Branched-chain alpha-ketoacid dehydrogenase		Impaired degradation of BCAA (valine, leucine, isoleucine) → ↑ α-ketoacid formation		Vomiting, lethargy, poor feeding Sweet-smelling urine (maple syrup or burnt sugar odor) Intellectual disability
Cystinuria		Impaired renal reabsorption of dibasic amino acids		Accumulation of cystine in the urine → frequent formation of hexagonal cystine stones		Recurrent nephrolithiasis
Organic acidemias	Propionic acidemia	Propionyl-CoA carboxylase		Impaired conversion of propionyl-CoA to methylmalonyl-CoA → ↑ propionyl-CoA and ↓ methylmalonate → conversion into propionic acid, which accumulates in serum and urine	Urea cycle inhibition → hyperammonemia Gluconeogenesis inhibition → hypoglycemia during fasting	Manifests in the neonatal period Vomiting, poor feeding Failure to thrive Lethargy Seizures Hypotonia Intellectual disability, developmental delay Hepatomegaly
Organic acidemias	Methylmalonic acidemia	Methylmalonyl-CoA mutase		Accumulation of methylmalonic acid
Cystinosis		Defective transport of cystine out of lysosomes		Accumulation of cystine within lysosomes		Failure to thrive Vomiting, weakness, dehydration Polyuria, polydipsia Progressive renal failure Photophobia (due to corneal crystal formation)
Histidinemia		Histidase		Impaired histidine breakdown → accumulation of histidine		Mostly asymptomatic
Pyruvate dehydrogenase complex deficiency		Pyruvate dehydrogenase complex	Inherited genetic (X-linked recessive or autosomal recessive)	Impaired conversion of pyruvate to acetyl-CoA → reduced production of citrate → impaired citric acid cycle → energy deficit (especially in the CNS) → neurological dysfunction		Onset: early neonatal period Poor feeding, lethargy Tachypnea Developmental delay Progressive neurological symptoms

Disorders affecting the purine metabolism

For details, see “Purine salvage deficiencies”.

Overview of disorders affecting the purine metabolism
Condition	Enzyme deficiency	Causes	Pathophysiology	Clinical features
Lesch-Nyhan syndrome	Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)	Inherited genetic (X-linked recessive)	Impaired conversion of hypoxanthine to IMP and guanine to GMP → excess uric acid and ↑ de novo purine synthesis	Orange sand-like sodium urate crystals can be found in the diapers of infants with hyperuricemia. Developmental delay and cognitive impairment Pyramidal and extrapyramidal symptoms (e.g., dystonia, spasticity) Gouty arthritis, urate nephropathy (due to the accumulation of uric acid in peripheral tissues) Aggression, self-injurious behavior
Adenosine deaminase deficiency	Adenosine deaminase	Inherited genetic (autosomal recessive)	↓ Breakdown of adenosine and deoxyadenosine → ↑ deoxyadenosine (dATP) accumulation → ↓ enzyme activity of ribonucleotide reductase → lymphocyte toxicity → immunodeficiency	Severe, recurrent infections Failure to thrive See “Severe combined immunodeficiency”.

Disorders affecting the urea cycle

For details, see “Urea cycle disorders”.

Overview of disorders affecting the urea cycle
Condition	Enzyme deficiency	Causes	Pathophysiology	Clinical features
Ornithine transcarbamylase deficiency	Ornithine transcarbamylase	Inherited genetic (X-linked recessive)	Impaired conversion of carbamoyl phosphate and ornithine to citrulline (and phosphate) → accumulation of ammonia	Symptoms commonly manifest in the first days of life but can develop at any age. Nausea, vomiting, irritability, poor feeding Delayed growth and cognitive impairment Metabolic encephalopathy
Arginase deficiency	Arginase	Inherited genetic (autosomal recessive)	Impaired conversion of arginine to ornithine → accumulation of ammonia and arginine in the serum	Acute: episodic hyperammonemia Chronic Delayed growth Poor cognitive development, missed developmental milestones Progressive spasticity (especially of lower extremities) Dystonia, ataxia, seizures
Carbamoyl phosphate synthetase 1 (CPS1) deficiency	Carbamoyl phosphate synthetase 1		Disruptions in urea cycle → hyperammonemia	See clinical features in “Hyperammonemia.”
N-acetylglutamate synthase deficiency	N-acetylglutamate synthase		Disruptions in urea cycle → hyperammonemia	See clinical features in “Hyperammonemia.”

Urea cycle

Miscellaneous

For details, see the article “Inborn errors of metabolism”.

Overview of miscellaneous disorders
Condition		Defect	Causes	Pathophysiology	Clinical features
Alpha-1 antitrypsin deficiency		Alpha-1 antitrypsin deficiency	Inherited genetic (autosomal codominant)	Gene mutation → conformational change in the structure of AAT protein → dysfunctional (or absent) AAT	Pulmonary manifestations (e.g., barrel chest, cough, dyspnea) Hepatic manifestations (e.g., hepatitis, cirrhosis)
Mitochondrial myopathies	Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes (MELAS)	Impaired oxidative phosphorylation	Inherited genetic (defects in mitochondrial DNA)	Impaired oxidative phosphorylation → ↓ production of energy in mitochondria (lack of ATP) → ↑ glycolysis → ↑ pyruvate → accumulation of lactate and alanine	Encephalomyopathy, muscle weakness, tonic-clonic seizures Lactic acidosis Recurring stroke-like episodes
	Myoclonic epilepsy with ragged red fibers (MERRF)				Myoclonic epilepsy with ragged red fibers
	Chronic progressive external ophthalmoplegia (CPEO)				Chronic progressive external ophthalmoplegia (with bilateral ptosis)
	Kearns-Sayre syndrome				Ophthalmoplegia, retinitis pigmentosa Impaired electrical activity of the heart, especially AV block
	Leber hereditary optic neuropathy (LHON)				Painless acute or subacute bilateral vision
	Leigh syndrome				Rapidly progressive psychomotor regression Ophthalmoparesis, nystagmus, optic atrophy
Pyruvate dehydrogenase complex deficiency		Absent pyruvate dehydrogenase complex	Inherited genetic (X-linked recessive or autosomal recessive)	Impaired conversion of pyruvate to acetyl-CoA → reduced production of citrate → impaired citric acid cycle → energy deficit (especially in the CNS) → neurological dysfunction	Onset: early neonatal period Poor feeding, lethargy Tachypnea Developmental delay Progressive neurological symptoms
Orotic aciduria		UMP synthase deficiency	Inherited genetic (autosomal recessive)	Deficiency of UMP synthase → accumulation of orotic acid in serum and urine Defective de novo synthesis of pyrimidine nucleotides	Manifests in early childhood Failure to thrive Delayed physical and mental development Megaloblastic anemia that does not respond to folate and vitamin B12 supplementation Orotic acid crystalluria

Alpha-1 antitrypsin deficiency: serum electrophoresis Panlobular emphysema Chalk Talk: Energy Metabolism - Part 8 Ragged red fibers

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