Inborn errors of metabolism

Inborn errors of metabolism are a group of inherited disorders characterized by enzyme defects. Clinical manifestations are usually due to the accumulation of toxic substances in the body. While in many cases the disorder cannot be cured, disease outcomes and life expectancy can be improved with supportive care and the appropriate diet.

• Definition: a congenital disorder characterized by the accumulation of defective alpha-1 antitrypsin enzyme
• Epidemiology: more common in individuals of European descent ^[1]
• Etiology: mutations in SERPINA1 gene ^[1]
  • M is the normal allele.
  • S mutation causes a moderate decrease in AAT production.
  • Z mutation causes a significant decrease in AAT production.
  • Order of severity of genotypic expression: PiMS < PiSS < PiMZ < PiSZ < PiZZ ^[2][3]
• Inheritance: autosomal codominant
• Pathophysiology
  • Alpha-1 antitrypsin: a protease inhibitor that is synthesized in the liver and protects cells from breakdown by neutrophil elastase
  • Gene mutation induces a conformational change in the structure of AAT protein. (Another form of AAT deficiency leads to complete absence of AAT synthesis)
    • Effect on the liver: impaired secretion of AAT by hepatocytes → accumulation of AAT in hepatocellular ER → hepatocyte destruction → hepatitis and liver cirrhosis
    • Effect on the lungs: lack of functional AAT → uninhibited neutrophil elastase activity in the lungs → destruction of the pulmonary architecture → panacinar emphysema
• Clinical features
  • Severe form: prolonged neonatal jaundice, hepatitis, cirrhosis, barrel chest, diminished breath sounds, wheezing, and dyspnea
  • Mild form: manifests in adolescence, primarily with pulmonary disease; hepatic symptoms may also be present ^[2]
  • Increased risk of hepatocellular carcinoma (HCC)
• Diagnostics
  • Serum: decreased antitrypsin protein levels
  • Electrophoresis: decreased alpha-1 peak ^[4]
  • Chest x-ray: low and flat diaphragm, widened intercostal spaces, hyperinflation and increased basilar radiolucency of both lungs with rarification of peripheral pulmonary vessels
  • Chest CT: panacinar emphysema (in contrast to centriacinar emphysema in smoking-related emphysema), bronchiectasis, bullae ^[5]
  • Liver biopsy
    • PAS-positive, spherical inclusion bodies in periportal hepatocytes
    • Signs of cirrhosis ^[6]
• Treatment
  • Avoid active and passive exposure to cigarette smoke.
  • Symptomatic treatment: bronchodilators, pulmonary rehabilitation, preventive vaccination, nutritional support if necessary
  • Antitrypsin replacement; : patients with severe AAT deficiency (e.g., ATT < 57 mg/dL or < 11 micromol/L) and evidence of decreased airflow ^[7]
  • Liver transplantation: results in correction of AAT deficiency; considered for end-stage liver disease ^[8]

The diagnosis of alpha-1 antitrypsin deficiency should be considered in all patients with emphysema under the age of 50.

References: ^{[9][7][8][6][5][4][2][6][3][1]}

General considerations

• Epidemiology
  • Prevalence: 13:100,000 ^[10]
• Etiology: caused by defects in mitochondrial DNA, which are maternally inherited
  • All offspring of the affected mother is also affected.
  • Genetic expression is variable due to heteroplasmy.
• General pathophysiology: impaired oxidative phosphorylation → decreased production of energy in mitochondria
  • Organs with a high energy requirement (e.g., retina, brain, inner ear, skeletal, and cardiac muscles) are particularly affected.
  • Common clinical features include external ophthalmoplegia, ptosis, and exertional muscle weakness.
• Clinical features: see “Subtypes of mitochondrial myopathies” below
• Diagnostics
  • Genetic studies (including mitochondrial DNA)
  • Muscle biopsy: immunohistochemistry typically shows "ragged red fibers", which are caused by subsarcolemmal and intermyofibrillar accumulation of mitochondria in muscles (mitochondria stain red).
  • Laboratory studies
    • Normal CK
    • Elevated lactate and alanine in serum, urine and/or CSF ^[10]
• Treatment: mainly supportive

Subtypes of mitochondrial myopathies ^[10]

• MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)
  • Lactic acidosis
  • Muscle weakness
  • Tonic-clonic seizures
  • Recurring strokes
  • Encephalopathy
• MERRF (myoclonic epilepsy with ragged red fibers)
  • Point mutation of the 8344^th base pair of mitochondrial DNA (in 80% of cases); → destruction of important proteins involved in oxidative phosphorylation ^[11]
  • Myoclonic jerks
  • Generalized seizures
  • Cerebellar ataxia
  • Dementia
• CPEO (chronic progressive external ophthalmoplegia): progressive extraocular ophthalmoplegia with bilateral ptosis
• Kearns-Sayre syndrome
  • Ophthalmoplegia and retinitis pigmentosa
  • Impaired electrical activity of the heart, especially AV block
• LHON (Leber hereditary optic neuropathy):
  • Cellular death in optic nerve neurons
  • Painless acute or subacute bilateral vision loss. Usually irreversible
  • Vision loss most commonly occurs in teenagers and young adults, predominantly in males
• Leigh syndrome ^[12]
  • Etiology: in 80% of cases, caused by a mutation in nuclear DNA (e.g., SURF1); in 20% of cases, caused by a mutation in mitochondrial DNA (e.g., MT-ATP6) → most common cause is disruption of complex I
  • Vomiting, diarrhea, dysphagia
  • Failure to thrive
  • Hypotonia, dystonia, ataxia
  • Rapidly progressive psychomotor regression
  • Ophthalmoparesis, nystagmus, optic atrophy
  • Peripheral neuropathy
  • Hypertrophic cardiomyopathy

References:^{[13][14][15][16][17][11][18][10][12][19]}

Alkaptonuria ^[20][21]

• Definition: : congenital disorder of impairement to degrade tyrosine to fumarate
• Etiology: mutation in HGD gene
• Inheritance: autosomal recessive
• Pathophysiology
  • Deficient activity of homogentisic acid dioxygenase → impaired conversion of homogentisate to 4-maleylacetoacetate
  • Accumulation of homogentisic acid → tissue discoloration and organ damage
• Clinical features
  • Usually a benign condition
  • Ochronosis ;: bluish-black discoloration of connective tissues
    • Affects cartilage (i.e., ears), tendons, skin, and/or sclera
    • Body fluids that are exposed to air turn black (e.g., perspiration, urine)
  • Calcifications
    • Cartilage → arthritis (ochronotic osteoarthropathy);
      • May present with disabling pain in joints (arthralgias).
      • Degenerative changes in the vertebral column
    • Kidneys → nephrolithiasis
    • Heart valves → mitral valve stenosis
    • Coronary arteries → coronary artery disease
• Diagnostics
  • Urine turns black when left standing for prolonged time or when alkalinized.
  • ↑ Homogentisic acid in urine and serum; normal tyrosine levels
• Treatment: diet low in tyrosine and phenylalanine → reduced formation of homogentisic acid

Homocystinuria ^[22]

• Definition: a group of congenital disorders characterized by impaired homocysteine metabolism
• Etiology: mutations in CBS, MTHFR, MTR, MTRR, and MMADHC genes
  • Methionine synthase deficiency
  • Cystathione synthase deficiency
  • Impaired affinity of cystathionine synthase for pyridoxal phosphate
  • Methylenetetrahydrofolate reductase (MTHFR) deficiency
• Inheritance: autosomal recessive (all enzyme deficiencies that cause homocystinuria are AR)
• Pathophysiology
  • Methionine synthase (homocysteine methyltransferase) deficiency → impaired conversion of homocysteine into methionine
  • Cystathionine synthase deficiency → impaired conversion of homocysteine into cystathionine
  • All forms result in accumulation of homocysteine.
• Clinical features: Disease severity varies greatly.
  • Nonspecific features in infancy: failure to thrive, developmental delay
  • Eyes: downward subluxation of the ocular lens (ectopia lentis) after age 3 ; myopia and glaucoma later in life ^[23]
  • Progressive intellectual disability
  • Psychiatric and behavioral disorders
  • Fair complexion
  • Marfanoid habitus: tall, thin, elongated limbs, arachnodactyly ^[23]
  • Osteoporosis, kyphosis
  • Vascular system: thromboembolism, premature arteriosclerosis, coronary heart disease
• Diagnostics
  • ↑ Homocysteine in urine and serum
  • Urine sodium nitroprusside test: Urine changes color to an intense red in the presence of homocysteine. ^[24]
• Treatment
  • Some patients respond to large doses of pyridoxine (vitamin B₆). ^[25]
  • Methionine synthase deficiency
    • ↑ methionine diet
  • Cystathionine synthase deficiency
    • Diet with↓ methionine and ↑ cysteine diet; ↑ vitamin B₆, ↑ vitamin B₁₂, and folate supplementation
  • Impaired affinity of cystathionine synthase for pyridoxal phosphate
    • Diet with ↑ cysteine, ↑↑ vitamin B₆
  • MTHFR deficiency
    • Folate supplementation

Marfan syndrome and homocystinuria both present with marfanoid habitus. Distinguishing features include intellectual disability, which is only seen in homocystinuria, and the direction of lens dislocation (downwards in homocystinuria; upwards in Marfan syndrome).

Remember HOMOCYstinuria: Homocystinuria, Osteoporosis, Marfanoid habitus, Ocular changes (lens subluxation), Cardiovascular (thromboembolism, accelerated atherosclerosis), kYphosis.

Hartnup disease ^[22][26]

• Definition: : congenital disorder characterized by a defect in the renal and intestinal transport of neutral amino acids (e.g., tryptophan)
• Etiology: mutation in the SLC6A19 gene
• Inheritance: autosomal recessive
• Pathophysiology:
  • Impaired Na⁺-dependent neutral amino acid transporter → decreased absorption of tryptophan from the gut and renal proximal tubules → inability to synthesize vitamin B₃ (niacin)
• Clinical features: symptoms of vitamin B₃ deficiency
  • Pellagra: dermatitis, diarrhea, dementia, glossitis
  • Cerebellar ataxia
• Diagnostics: ↑ amino acids in urine (neutral aminoaciduria)
• Treatment
  • High-protein diet
  • Niacin supplementation

Phenylketonuria (PKU) ^{[27][28][29][30]}

• Definition: : congenital disorder characterized by accumulation of phenylalanine
• Epidemiology: incidence ∼ 1:10,000
• Etiology: mutations in the PAH gene
• Inheritance: autosomal recessive
• Pathophysiology
  • Accumulation of phenylalanine due to impaired conversion to tyrosine
    • Defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosine → tyrosine becomes nutritionally essential (classical PKU)
    • Deficiency in tetrahydrobiopterin (BH₄), a cofactor of phenylalanine metabolism (e.g., PAH) → decreased conversion of phenylalanine to tyrosine (malignant PKU)
      • Often due to a deficiency in dihydropteridine reductase: normally reduces dihydrobiopterin (DHB) to tetrahydrobiopterin (THB)
  • Excess of phenylalanine → transformed into phenylketone metabolites; (e.g., phenylpyruvate, phenylacetate, and phenyllactate) → excretion of metabolites in the urine
  • Tyrosine deficiency → decreased neurotransmitter, melanin, and thyroxine synthesis (see amino acid derivatives)
• Clinical features
  • Symptoms may manifest within the first few months of life.
  • Psychomotor delay (starting as early as 4–6 months of age)
  • Seizures ^[31]
  • Blue eyes; light, pale hair
  • Eczema
  • Musty odor
  • Maternal PKU; : in pregnant women with PKU who do not follow proper diet during pregnancy; infant is at risk of microcephaly, growth restriction, facial dysmorphisms, congenital heart defects, intellectual disability
• Diagnostics
  • Newborn screening: direct measurement of serum phenylalanine levels on the 2^nd–3^rd day after birth
  • If screening test is positive: oral tetrahydrobiopterin loading test
    • Performed to differentiate between PKU and tetrahydrobiopterin deficiency ^[28][29][30]
    • In the case of BH₄ deficiency, phenylalanine levels decrease; in the case of PAH deficiency, they remain unchanged. ^[32]
  • ↑ Phenylketones in urine: phenylacetate, phenyllactate, phenylpyruvate
• Treatment
  • Low phenylalanine and high tyrosine diet
  • BH₄ deficiency: supplementation of tetrahydrobiopterin

Patients with PKU should be advised to avoid aspartame, an artificial sweetener that contains phenylalanine!

Cystinosis

• Definition: A congenital disorder characterized by impaired cystine storage.
• Etiology: autosomal recessive inheritance
• Epidemiology: Incidence of the most common form (infantile cystinosis): 1:100,000-200,000
• Pathology:
  • Defective transport of cystine out of lysosomes → accumulation of cystine within lysosomes
    • Formation of cystine crystals and cellular dysfunction (particularly, renal proximal tubular cells)
    • Toni-Debré-Fanconi syndrome: tubular disorder with increased excretion of sodium, potassium, phosphate, bicarbonate, glucose, amino acids, uric acid, and water
  • Three clinical forms with variable age onset and severity → infantile form is the most severe form (infantile > juvenile > ocular (adult) cystinosis)
• Clinical features
  • Failure to thrive
  • Vomiting, weakness, dehydration
  • Polyuria and polydipsia
  • Progressive renal failure
  • Photophobia due to corneal crystal formation
  • Additional organ involvement (e.g., hepatomegaly)
• Diagnosis
  • Observation of cystine crystals in the cornea during slit lamp examination
  • Progressive ↓GFR
  • Hypokalemia, hyponatremia, metabolic acidosis
  • Confirmed by ↑cystine content in leukocytes
• Treatment
  • Correction of metabolic abnormalities associated with Fanconi syndrome or renal failure
  • Specific therapy available with cysteamine
  • Renal transplantation ^[33][34]

Cystinuria ^[35]

• Definition: : congenital disorder characterized by hereditary defect in the amino acid transporter in the proximal convoluted tubule of the kidneys and in the intestines
• Epidemiology: incidence ∼ 1:7,000
• Inheritance: autosomal recessive
• Pathophysiology: impaired renal resorption of dibasic amino acids (COAL – cystine, ornithine, arginine, lysine) → accumulation of cystine in the urine → precipitation of hexagonal cystine stones
• Clinical features: recurrent nephrolithiasis, starting as early as childhood (see also cystine stones)
• Diagnostics: urine microscopy shows hexagonal cystine stones; urinary cyanide nitroprusside test positive
• Treatment:
  • Adequate hydration
  • Urinary alkalinization: acetazolamide, potassium citrate
  • Chelating agents: penicillamine

Histidinemia

• Definition: A rare, benign congenital disorder characterized by an impaired histidine metabolism which leads to an elevation in histidine.
• Epidemiology: 1:11,500 ^[36]
• Etiology: autosomal recessive inheritance
• Pathology: histidase deficiency → impaired histidine breakdown → histidine accumulates
• Clinical symptoms
  • Mostly asymptomatic
  • Complications during or after birth (e.g., temporary lack of oxygen) → possible risk factor for the development of intellectual disability
• Diagnostics
  • ↑ Histidine in serum
  • ↑ Histidine and imidazole metabolites in urine
• Treatment: not required ^[36][37]

Maple syrup urine disease ^{[22][38][39][40]}

• Definition: : congenital disorder characterized by the impaired break down of branched-chain amino acids
• Etiology: mutations in BCKDHA, BCKDHB, and DBT genes
• Inheritance: autosomal recessive
• Pathophysiology: absent or deficient branched-chain alpha-ketoacid dehydrogenase → impaired degradation of branched-chain amino acids (valine, leucine, isoleucine) → elevated α-ketoacid formation
• Clinical features
  • Symptom onset: early neonatal period
  • Dystonia
  • Vomiting, lethargy, poor feeding
  • Intellectual disability
  • Sweet-smelling urine (maple syrup or burnt sugar odor)
  • Death may occur without appropriate treatment.
• Diagnostics
  • Part of newborn screening
  • Serum: increased alpha-ketoacids (especially leucine alpha-ketoacids); increased blood levels of leucine, isoleucine, and valine
  • Urine: presence of abnormal branched-chain hydroxy acids and ketoacids
  • Hypoglycemia
• Treatment
  • Avoidance of foods containing branched-chain amino acids
  • Thiamine supplementation
  • Liver transplantation

Mnemonic for amino acids involved in maple syrup urine disease: I Love Vermont maple syrup from maple trees (with branches) → I = Isoleucine, Love = Leucine, Vermont = Valine, branches = branched-chain amino-acids

Pyruvate dehydrogenase complex deficiency ^[22][41]

• Definition: : congenital disorder characterized by impaired pyruvate metabolism
• Inheritance: X-linked recessive
• Pathophysiology:
  • Absent pyruvate dehydrogenase complex (PDC) → impaired conversion of pyruvate to acetyl-CoA → reduced production of citrate → impaired citric acid cycle leads to energy deficit (especially in the CNS) and neurological dysfunction.
• Clinical features
  • Onset: early neonatal period
  • Poor feeding, lethargy, tachypnea
  • Developmental delay
  • Progressive neurological symptoms
• Diagnostics
  • ↑ Lactate and pyruvate in serum
  • ↑ Alanine in serum and urine
• Treatment
  • Acute: correction of acidosis
  • Long-term: ketogenic diet (high-fat, low-carbohydrate, high in ketogenic amino acids); , avoidance of glucogenic acids (e.g., valine)
  • Supplementation of thiamine, carnitine, and lipoic acid (cofactors of PDC)

Propionic acidemia ^[42][43]

• Definition: : congenital disorder characterized by impaired metabolism of fats and proteins
• Epidemiology: incidence ∼ 1:100,000
• Etiology: mutations in the PCCA and PCCB genes
• Inheritance: autosomal recessive
• Pathophysiology:
  • Propionyl-CoA carboxylase deficiency → impaired conversion of propionyl-CoA to methylmalonyl-CoA → ↑ propionyl-CoA and ↓ methylmalonic acid → conversion into propionic acid, which accumulates in serum and urine
    • Propionyl-CoA is produced during the catabolism of certain amino acids (isoleucine, valine, threonine, and methionine), odd-chain fatty acids, pyrimidines (thymine, uracil), and cholesterol.
• Clinical features
  • Manifests in the neonatal period
  • Vomiting, poor feeding
  • Failure to thrive
  • Intellectual disability, developmental delay
  • Generalized hypotonia, lethargy, seizures
  • Anion gap metabolic acidosis
  • Hepatomegaly
  • Death may occur without appropriate treatment.
• Diagnostics: ↑ propionic acid in urine and serum (organic acidosis)
• Treatment
  • Low protein diet (e.g., avoidance of methionine, threonine, isoleucine, or valine)
  • Amino acid supplementation

References: ^{[21][25][23][24][26][34][37][38][40][41][42][43]}

Lesch-Nyhan syndrome ^[44][22][45]

• Definition: : a congenital disorder characterized by impaired purine salvage pathway, resulting in an overproduction of uric acid
• Inheritance: : X-linked recessive
• Pathophysiology: defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) → impaired conversion of hypoxanthine to IMP and guanine to GMP → excess uric acid and ↑ de novo purine synthesis
• Clinical features
  • Usually asymptomatic for the first 6 months of life
  • Orange sand-like sodium urate crystals; can be found in the diapers of infants with hyperuricemia.
  • Developmental delay and cognitive impairment
  • Pyramidal and extrapyramidal signs (dystonia, spasticity)
  • Gouty arthritis, urate nephropathy
  • Aggression, self-injurious behavior
  • Renal failure
• Diagnostics
  • Hyperuricemia
  • Megaloblastic anemia may occur.
  • Analysis of HGPRT: ↓ enzyme activity
• Treatment
  • There is no treatment for the underlying enzyme defect.
  • Reduce uric acid levels:
    • Allopurinol (first-line)
    • Febuxostat (second-line)
  • Low-purine diet
• Prognosis: high mortality if the infant is not treated within the first year of life

To remember the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which is involved in Lesch-Nyhan syndrome: He's Got Purine Recovery Troubles OR Hyperuricemia, Gout, Pissed off (aggression, self-mutilation), Retardation (ID), DysTonia!

Adenosine deaminase deficiency ^[46]

• Definition: : a congenital disorder characterized by the impaired metabolism of deoxyadenosine during DNA breakdown
• Etiology: mutations in ADA gene
• Inheritance: autosomal recessive
• Pathophysiology:
  • Deficiency in adenosine deaminase → ↓ breakdown of adenosine and deoxyadenosine → ↑ deoxyadenosine accumulation → lymphocyte toxicity → immunodeficiency
  • See purines and pyrimidines.
• Clinical features
  • SCID (see severe combined immunodeficiency)
  • Severe, recurrent infections
• Treatment: supportive care, IVIG, bone marrow transplantation

References:^[22][44][45]

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) ^[47][48]

• Inheritance: autosomal recessive
• Pathophysiology
  • Deficiency of medium-chain acyl-CoA dehydrogenase → defective breakdown of medium-chain fatty acids into acetyl-CoA → accumulation of fatty acyl-CoA in the blood → hypoketotic hypoglycemia
  • Symptoms usually triggered by
    • Prolonged fasting
    • States of increased metabolic demand (e.g., infection, exercise)
• Clinical features
  • Onset: within the first years of life
  • Dehydration, poor feeding
  • Hypotonia
  • Vomiting and lethargy
  • Coma, seizures, cardiopulmonary collapse
  • Sudden death in infants and children
• Diagnostics
  • Part of newborn screening
  • Laboratory findings: hypoglycemia, ↓ ketones in blood and urine, hyperuricemia, metabolic acidosis, ↑ AST and ALT, hyperammonemia, prolonged PT and aPTT
  • Plasma acylcarnitine profile
  • Genetic testing for the common A985G mutation
• Treatment
  • IV administration of 10% dextrose during acute decompensation
  • Avoid fasting states
  • Diet high in carbohydrates and low in fat ^[49]
• Complications
  • Encephalopathy
  • Fatty liver disease and impaired hepatic function
  • Sudden death

References:^{[49] [48]}

Primary carnitine deficiency ^[48][22]

• Definition: : a condition characterized by a defect of the carnitine transporter, which transfers fatty acids across the mitochondrial membrane
• Inheritance: autosomal recessive
• Pathophysiology
  • Defective carnitine transporter → impaired entry of long-chain fatty acids into mitochondria via carnitine-dependent shuttle → impaired fatty acid metabolism via beta-oxidation
  • ↓ Energy production from fatty acids (↓ gluconeogenesis) and ↓ production of ketones → hypoketotic hypoglycemia
  • Accumulation of fat in the liver and cardiac and skeletal muscle
• Clinical features
  • Onset: early childhood
  • Failure to thrive
  • Liver dysfunction
  • Cardiomyopathy → congestive heart failure
  • Hypotonia
  • Encephalopathy, lethargy
  • Rhabdomyolysis → renal failure
• Diagnostics
  • Part of newborn screening
  • ↓ Glucose and ↓ ketones in serum (hypoketotic hypoglycemia); , hyperammonemia, ↑ ALT, ↑ AST
  • Very low plasma carnitine levels
• Treatment
  • Acute hypoketotic hypoglycemic encephalopathy: administer IV carnitine and 10% dextrose in water
  • Oral carnitine supplementation
  • Avoid fasting states

Carnitine palmitoyltransferase II deficiency (CPT II deficiency) ^[50][51][52]

• Definition: : a disorder characterized by impaired long-chain fatty acid oxidation in the mitochondria
• Inheritance: autosomal recessive
• Pathophysiology
  • CPT II normally removes carnitine from long-chain fatty acids in the mitochondria, which is necessary for fatty acid oxidation to occur
  • Defective carnitine palmitoyltransferase II (CPT II) → carnitine cannot be removed from long-chain fatty acids→ no fatty acid oxidation → no substrate for gluconeogenesis and ketogenesis → hypoketotic hypoglycemia
  • Accumulation of fatty acids and long-chain acylcarnitines → damage to liver, heart, and muscles ^[51]
• Clinical features
  • Symptoms may occur as early as the neonatal period.
  • Presentation is variable.
  • Myalgia, hypotonia, failure to thrive
  • Hepatomegaly, liver dysfunction → liver failure
  • Cardiomyopathy → congestive heart failure
  • Encephalopathy, seizures
  • Rhabdomyolysis → renal failure
  • Sudden death
• Diagnostics
  • Part of the expanded newborn screening
  • Hypoglycemia, ↓ serum ketones
  • ↓ Total and free carnitine levels, ↑ acylcarnitine
  • Myoglobinuria and ↑ serum creatine kinase
  • ↑ ALT, ↑ AST, hyperammonemia
• Treatment
  • Avoid prolonged strenuous activity and fasting
  • Diet low in long-chain triglyceride, high in medium-chain fatty acids, and high in carbohydrates

Ornithine transcarbamylase deficiency (OTC deficiency) ^[53][54][55]

• Definition: congenital disorder characterized by the inability to excrete ammonia
• Epidemiology: most common urea cycle defect
• Inheritance: X-linked recessive
• Pathophysiology:
  • Defect in the enzyme ornithine transcarbamylase → impaired conversion of carbamoyl phosphate and ornithine to citrulline (and phosphate) → ammonia cannot be eliminated and accumulates
  • Accumulation of carbamoyl phosphate → conversion to orotic acid
• Clinical features
  • 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
  • In severe cases, metabolic encephalopathy with coma and death
  • Does not cause megaloblastic anemia (as opposed to orotic aciduria)
• Diagnostics
  • Hyperammonemia (usually > 100 μmol/L)
  • ↑ Orotic acid in urine and blood, ↓ BUN
  • ↑ Carbamoyl phosphate and ↓ citrulline in the serum
  • Enzyme analysis of OTC activity
• Treatment
  • Strict low-protein diet
  • Reduce serum ammonia
    • Nitrogen scavengers such as sodium benzoate
    • Fluid management
    • Dialysis (in severe cases)
  • Arginine supplementation → promotes urea formation

OTC deficiency is the only urea cycle disorder that is X-linked recesssive. All of the other urea cycle disorders are autosomal recessive.

Arginase deficiency ^[53][56]

• Definition: congenital disorder characterized by impaired arginase activity, resulting in the accumulation of nitrogen (in the form of ammonia)
• Inheritance: autosomal recessive
• Pathophysiology: absent or nonfunctional arginase enzyme → impaired conversion of arginine to ornithine → accumulation of ammonia and arginine in the serum
• Clinical features
  • Acute: episodic hyperammonemia
    • Often asymptomatic
    • Triggered by metabolic stress (e.g., infections, trauma, surgery)
  • Chronic
    • Delayed growth (usually present by three years of age)
    • Progressive spasticity (especially of lower extremities), dystonia, ataxia, poor cognitive development, and missed developmental milestones
    • Seizures
    • By young adulthood: severe spasticity, inability to ambulate, complete loss of bowel and bladder control, severe intellectual disability
• Diagnostics
  • ↑ Serum arginine
  • Hyperammonemia
  • ↓ BUN
  • Genetic testing, arginase activity analysis
• Treatment
  • Reduce serum ammonia
    • Dialysis (severe cases)
    • Nitrogen scavengers such as sodium phenylacetate and sodium benzoate
    • Fluid management
  • Low-protein diet

References:^{[57][54][56] [53]}

• Definition: a rare, hereditary condition that is characterized by an elevation of orotic acid in the serum and urine due to defective UMP synthase
• Inheritance: autosomal recessive ^[58]
• Pathophysiology
  • UMP synthase normally converts orotic acid into uridine monophosphate.
  • Deficiency of UMP synthase → accumulation of orotic acid in serum and urine
  • Defect de novo synthesis of pyrimidine nucleotides.
• Clinical features
  • Manifests in early childhood
  • Failure to thrive
  • Delayed physical and mental development
  • Megaloblastic anemia, which does not respond to folate and vitamin B12 supplementation
  • Orotic acid crystalluria
• Diagnostics ^[58]
  • Serum: ↓ hemoglobin, ↑ mean corpuscular volume, ↑ orotic acid, normal ammonia levels, normal BUN
  • Urine: ↑ orotic acid
• Treatment: uridine monophosphate substitution ^[58]

Orotic aciduria can be distinguished from ornithine transcarbamylase deficiency by the presence of megaloblastic anemia and absence of hyperammonemia!