Inborn errors of metabolism

Inborn errors of metabolism are a group of inherited genetic 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.

See also “Inborn errors of carbohydrate metabolism” and “Lysosomal storage diseases”.

General considerations ^[1]

• Definition: : A group of disorders characterized by an impaired energy production that mainly affects organs with a high energy requirement (e.g., brain).
• Epidemiology
  • Rare disease
  • Prevalence: 13:100,000
• Etiology: caused by defects in mitochondrial DNA, which are maternally inherited
  • Children of an affected mother will likewise be affected.
  • Genetic expression is variable due to heteroplasmy.
• General pathophysiology
  • Impaired oxidative phosphorylation → decreased production of energy in mitochondria (lack of ATP) → up-regulation of glycolysis → overproduction of pyruvate → accumulation of lactate and alanine
  • Organs with a high energy requirement (e.g., retina, brain, inner ear, skeletal, cardiac muscles) are particularly affected.
• Clinical features
  • Commonly external ophthalmoplegia, ptosis, and/or exertional muscle weakness.
  • 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 defective mitochondria in muscles (mitochondria stain red).
  • Laboratory studies
    • Normal CK
    • Elevated lactate and alanine in serum, urine and/or CSF
  • Electron microscopy: shows crystalline inclusions within the mitochondria
• Treatment: mainly supportive

Mitochondrial myopathies are maternally inherited and manifest with ragged red fibers, lactic acidosis, myopathy, and neurological symptoms.

Subtypes of mitochondrial myopathies ^[1][2][3]

• MELAS: characterized by mitochondrial encephalomyopathy, lactic acidosis, recurring stroke-like episodes ^[4][5]
  • Other findings include
    • Muscle weakness
    • Tonic-clonic seizures
• MERRF: characterized by myoclonic epilepsy with ragged red fibers ^[6]
  • Cause: Point mutation of the 8344^thbase pair of mitochondrial DNA (in 80% of cases) → destruction of important proteins involved in oxidative phosphorylation
  • Other findings include
    • Generalized seizures
    • Cerebellar ataxia
    • Dementia
• CPEO: characterized by chronic progressive external ophthalmoplegia (with bilateral ptosis) ^[7]
• Kearns-Sayre syndrome: ^[8]
  • Epidemiology: most commonly occurs in individuals < 20 years of age
  • Etiology: hereditary deletion in mitochondrial DNA → disruption of mitochondrial energy production
  • Clinical features
    • Impaired electrical activity of the heart, especially AV block
    • Ophthalmoplegia and retinitis pigmentosa
    • Unsteady posture and gait due to cerebellar ataxia
• LHON (Leber hereditary optic neuropathy)
  • Epidemiology
    • Most commonly occurs in teenagers and young adults
    • ♂ > ♀ (3:1) ^[9]
  • Etiology: point mutation in mtDNA that leads to dysfunction of complex I in the electron transport chain
  • Pathophysiology: cellular death in optic nerve neurons
  • Clinical features: painless acute or subacute bilateral vision loss which is usually irreversible
• Leigh syndrome ^[10]
  • 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
  • Clinical features
    • Vomiting, diarrhea, dysphagia
    • Growth faltering
    • Hypotonia, dystonia, ataxia
    • Rapidly progressive psychomotor regression
    • Ophthalmoparesis, nystagmus, optic atrophy
    • Peripheral neuropathy
    • Hypertrophic cardiomyopathy

All amino acid metabolism disorders are autosomal recessive disorders.

• Definition: inherited genetic disorder characterized by the accumulation of phenylalanine ^[11][12][13]
• Epidemiology: incidence is up to 1:15,000 ^[14]
• Etiology: mutation in the PAH gene
• Inheritance: autosomal recessive
• Pathophysiology
  • Accumulation of phenylalanine
    • Most commonly due to a defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosine → tyrosine becomes nutritionally essential (classical PKU)
    • Less commonly
      • Tetrahydrobiopterin deficiency (malignant PKU) due to impaired tetrahydrobiopterin biosynthesis or recycling, resulting in:
        • Hyperphenylalaninemia due to ↓ conversion of phenylalanine to tyrosine → ↓ synthesis of catecholamines (BH₄ is a cofactor for phenylalanine hydroxylase and tyrosine hydroxylase)
        • ↓ Synthesis of serotonin (BH₄ is a cofactor for tryptophan hydroxylase) → deficiencies of neurotransmitters
        • Symptom severity varies between affected individuals.
      • Phenylalanine embryopathy (maternal PKU): For more information, see "Teratogenesis."
  • Excess of phenylalanine is transformed into phenylketone metabolites (e.g., phenylpyruvate, phenylacetate, and phenyllactate) that are excreted 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.
  • Growth restriction
  • Psychomotor delay (starting as early as 4–6 months of age)
  • Seizures ^[15]
  • Blue eyes, light skin, pale hair
  • Eczema
  • Musty odor (due to an increase in aromatic amino acids)
  • Infants with maternal PKU may show
    • Microcephaly, growth restriction
    • Facial dysmorphisms
    • Congenital heart defects
    • Intellectual disability
• Diagnostics ^[16]
  • Newborn screening: direct measurement of serum phenylalanine levels on 2^nd–3^rd day after birth (phenylalanine levels are normal at birth because of circulating maternal PAH)
  • If the screening test is positive:
    • Quantitative plasma amino acid analysis to confirm elevated phenylalanine levels
    • Oral tetrahydrobiopterin loading test to differentiate between PKU and BH₄ deficiency
      • If phenylalanine levels remain unchanged: PAH deficiency
      • If phenylalanine levels are decreased: BH₄ deficiency
  • ↑ Phenylketones in urine
• Pathology: shows abnormal myelination in affected individuals ^[17]
  • Pallor in regions that undergo postnatal myelination (e.g., axonal connections to the prefrontal cortex, cortico-hippocampal relay circuits)
  • Animal models reveal synaptic and dendritic changes (e.g., malformed dendritic trees, reduced neocortical synaptic density)
• Treatment
  • Low phenylalanine and high tyrosine diet
  • BH₄ deficiency: supplementation of BH₄ and possibly levodopa and 5-hydroxytryptophan
• Prognosis: Untreated individuals with BH₄ deficiency usually die within the first years of life.

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

• Definition: a group of inherited genetic disorders characterized by impaired homocysteine metabolism
• Epidemiology: affects 1:200,000–335,000 people worldwide ^[18]
• Etiology: mutations in CBS, MTHFR, MTR, MTRR, and MMADHC genes
  • Cause deficiencies in one or more of the following enzymes
    • Cystathionine synthase: an enzyme that catalyzes the conversion of homocysteine and serine to cystathionine, using vitamin B6 as a cofactor.
    • Methionine synthase
    • Methylenetetrahydrofolate reductase (MTHFR): an enzyme involved in folate metabolism that reduces N5,10-methylenetetrahydrofolate to methyltetrahydrofolate.
  • Impaired affinity of cystathionine synthase for pyridoxal phosphate
• Inheritance: : all enzyme deficiencies that cause homocystinuria are autosomal recessive
• 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 the accumulation of homocysteine.
• Clinical features: Disease severity varies greatly. ^[19]
  • Nonspecific features in infancy: growth faltering, developmental delay
  • Eyes
    • Downward and inward subluxation of the ocular lens; (ectopia lentis) after 3 years of age (in Marfan syndrome, the lens usually luxates upwards and outwards)
    • Myopia and glaucoma later in life
  • Progressive intellectual disability
  • Psychiatric and behavioral disorders
  • Light skin
  • Marfanoid features
    • Tall, thin
    • Pectus deformities (e.g., pectus excavatum)
    • Scoliosis
    • Elongated limbs (↑ arm:height ratio; ↓ upper:lower body segment ratio), arachnodactyly
    • Hyperlaxity of joints and hyperelasticity of the skin
  • Osteoporosis
  • Cardiovascular complications like thromboembolism, premature arteriosclerosis, and coronary heart disease increase the risk of myocardial infarction and stroke
• Diagnostics
  • ↑ Homocysteine in urine and serum
  • Urine sodium nitroprusside test: Urine changes color to an intense red in the presence of homocysteine. ^[20]
  • Serum methionine levels
    • Increased in cystathionine synthase deficiency
    • Decreased in methionine synthase deficiency and methylenetetrahydrofolate reductase deficiency
• Treatment
  • Some patients respond to large doses of pyridoxine (vitamin B₆). ^[21]
  • Methionine synthase deficiency: high-methionine diet
  • Cystathionine synthase deficiency
    • Low-methionine, high-cysteine diet
    • Supplementation of vitamin B₁₂ and folate
  • Impaired affinity of cystathionine synthase for pyridoxal phosphate: high-cysteine diet
  • MTHFR deficiency
    • Supplementation of folate
    • Betaine ^[22]

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 and upwards in Marfan syndrome).

The most important features of homocystinuria are Marfanoid habitus, skeletal abnormalities (e.g., osteoporosis, kyphosis), accelerated atherosclerosis, and downward lens subluxation: “Tall grown, brittle bone, vessels of stone, lens in downward zone.”

• Definition: : inherited genetic disorder characterized by a defect in the renal and intestinal transport of neutral amino acids (e.g., tryptophan) ^[23]
• Epidemiology: incidence is 1:30,000 ^[24]
• Etiology: mutation in the SLC6A19 gene
• Inheritance: : autosomal recessive
• Pathophysiology: impaired Na⁺-dependent neutral amino acid transporter on enterocytes and proximal renal tubular cells → decreased renal and intestinal absorption of tryptophan → inability to synthesize vitamin B₃ (niacin)
• Clinical features: symptoms of vitamin B₃ deficiency
  • Pellagra: dermatitis, glossitis, diarrhea, dementia
  • Cerebellar ataxia
• Diagnostics: ↑ neutral amino acids in urine (neutral aminoaciduria)
• Treatment
  • High-protein diet
  • Niacin supplementation

• Definition: inherited genetic disorder characterized by a mutation in the HGD gene and subsequent homogentisic acid dioxygenase deficiency and impaired tyrosine catabolism ^[25][26]
• Epidemiology: affects 1:250,000–1,000,000 people worldwide ^[27]
• Etiology: mutation in the HGD gene
• Inheritance: autosomal recessive
• Pathophysiology
  • Lack of functional homogentisic acid dioxygenase → impaired conversion of homogentisic acid 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 (e.g., ears), tendons, skin, and/or sclera
    • Body fluids (e.g., urine, sweat) often turn black when exposed to air
    • Calcifications of the following
      • Cartilage: arthritis (ochronotic osteoarthropathy)
        • May manifest with arthralgias due to accumulation of homogentisic acid, which attacks cartilage, in the joints
        • 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 a prolonged time or when alkalinized.
  • ↑ Homogentisic acid in urine and serum
  • Normal tyrosine levels
• Treatment: diet low in tyrosine and phenylalanine to reduce the formation of homogentisic acid

• Definition: : inherited genetic disorder characterized by the impaired break down of branched-chain amino acids (BCAA) ^[28][29][30]
• Epidemiology: incidence is 1:185,000 (worldwide) ^[31]
• Etiology: mutations in BCKDHA, BCKDHB, and DBT genes
• Inheritance: : autosomal recessive
• Pathophysiology: absent or deficient branched-chain alpha-ketoacid dehydrogenase → impaired degradation of BCAA (valine, leucine, isoleucine) → elevated α-ketoacid formation
• Clinical features
  • Symptom onset: early neonatal period
  • Vomiting, lethargy, poor feeding
  • Sweet-smelling urine (maple syrup or burnt sugar odor)
  • Intellectual disability
  • Dystonia
  • Damage to the CNS can be severe (elevated leucine level leads to brain injury)
  • Death may occur without appropriate treatment
• Diagnostics
  • Part of newborn screening
  • Serum
    • Increased levels of alpha-ketoacids (especially leucine alpha-ketoacids)
    • Increased levels of leucine, isoleucine, and valine
    • Hypoglycemia
  • Urine: presence of abnormal branched-chain hydroxy acids and ketoacids
• Treatment
  • Avoid foods containing BCAA
  • Supplementation of thiamine, a cofactor of branched-chain alpha-ketoacid dehydrogenase
  • Treatment of last resort: liver transplantation

Grab the Maple BRANCH if you want to LIVe! In Maple syrup urine disease, the breakdown of BRANCHED amino acids (Leucine, Isoleucine, and Valine) is impaired.

• Definition: : an inherited genetic disorder characterized by the accumulation of cystine in the kidneys and bladder due to a disruption of amino acid transporter function in the proximal convoluted tubule and intestine. ^[32]
• Epidemiology: incidence is ∼ 1:7,000
• Inheritance: autosomal recessive
• Pathophysiology: impaired renal reabsorption of dibasic amino acids (cystine, ornithine, arginine, lysine) → accumulation of cystine in the urine → frequent formation of hexagonal cystine stones
• Clinical features: recurrent nephrolithiasis, starting as early as childhood (see also “Cystine stones”)
• Diagnostics
  • Urine microscopy: hexagonal cystine stones
  • Urinary cyanide nitroprusside test: positive
• Treatment: increase cystine solubility to counter the formation of renal stones
  • Adequate hydration
  • Urinary alkalinization: acetazolamide, potassium citrate
  • Chelating agents: penicillamine

To remember the four dibasic amino acids that cannot be absorbed by the kidney in cystinuria, think of “Dibasic COAL: Cystine, Ornithine, Arginine, Lysine.”

• Definition: inherited genetic disorders characterized by impaired metabolism of fats and proteins ^[33][34][35]
• Epidemiology ^[35]
  • Incidence of propionic acidemia is ∼ 1:100,000
  • Incidence of methylmalonic acidemia is ∼ 1:50,000
• Etiology
  • Propionic acidemia: PCCA and PCCB gene mutations
  • Methylmalonic acidemia
    • MMUT, MMA, MMAB, or MMADHC gene mutations (methylmalonyl-CoA mutase deficiency)
    • MCEE gene mutation (methylmalonyl-CoA epimerase deficiency)
• Inheritance: autosomal recessive
• Pathophysiology
  • Propionic acidemia: propionyl-CoA carboxylase deficiency → impaired conversion of propionyl-CoA to methylmalonyl-CoA → ↑ propionyl-CoA and ↓ methylmalonate → conversion into propionic acid, which accumulates in serum and urine
  • Methylmalonic acidemia: methylmalonyl-CoA mutase deficiency or vitamin B₁₂ deficiency → accumulation of methylmalonic acid
    • Methylmalonyl-CoA is transformed into succinyl-CoA by the enzyme methylmalonyl-CoA mutase, which requires adenosylcobalamin, the active form of vitamin B₁₂, as a cofactor.
  • Accumulation of organic acids leads to
    • Urea cycle inhibition → hyperammonemia
    • Gluconeogenesis inhibition → hypoglycemia during fasting periods and increased risk of ketoacidosis (high anion gap metabolic acidosis)
• Clinical features
  • Manifests in the neonatal period
  • Vomiting, poor feeding
  • Growth faltering
    Lethargy
  • Seizures
  • Hypotonia
  • Intellectual disability, developmental delay
  • Hepatomegaly
  • Coma
  • Death may occur without appropriate treatment
• Diagnostics
  • ↑ Propionic acid or ↑ methylmalonic acid in urine and serum
  • High anion gap metabolic acidosis
  • Hyperammonemia
  • Ketonuria
• Treatment: to avoid further production of propionyl-CoA, follow a diet that is low in
  • Protein, especially low in amino acids isoleucine, valine, threonine, and methionine
  • Pyrimidines (thymine and uracil)
  • Odd-chain fatty acids, cholesterol

Infants PRObably VOMIT when affected by organic acidemia: in PROpionic acidemia, Valine, Odd-chain fatty acids, Methionine, Isoleucine, and Threonine should be avoided.

• Definition: inherited genetic disorder characterized by impaired cystine storage ^[36][37]
• Epidemiology: incidence of the most common form (infantile cystinosis) is up to 1:200,000
• Inheritance: autosomal recessive
• Pathophysiology
  • Defective transport of cystine out of lysosomes → accumulation of cystine within lysosomes
    • Formation of cystine crystals and cellular dysfunction (particularly, renal proximal tubular cells)
    • Fanconi syndrome: a tubular disorder with increased excretion of sodium, potassium, phosphate, bicarbonate, glucose, amino acids, uric acid, and water
  • Three clinical forms in order of severity: infantile > juvenile > ocular (adult) cystinosis
• Clinical features
  • Growth faltering
  • Vomiting, weakness, dehydration
  • Polyuria, 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 decrease of GFR
  • Hypokalemia, hyponatremia, metabolic acidosis
  • Confirmed by elevated cystine content in leukocytes
• Treatment
  • Correction of metabolic abnormalities associated with Fanconi syndrome or renal failure
  • Specific therapy: cysteamine
  • Renal transplantation

• Definition: a rare, benign inherited genetic disorder characterized by an impaired histidine metabolism which leads to an elevation in histidine. ^[38][39]
• Epidemiology: 1:11,500
• Inheritance: autosomal recessive
• Pathophysiology: histidase deficiency → impaired histidine breakdown → histidine accumulates
• Clinical features
  • Mostly asymptomatic
  • Complications during or after birth (e.g., temporary lack of oxygen)
  • Possible intellectual disability
• Diagnostics
  • ↑ Histidine in serum
  • ↑ Histidine and imidazole metabolites in urine
• Treatment: usually not required

• Definition: : inherited genetic disorder characterized by impaired pyruvate metabolism
• Inheritance: X-linked recessive or autosomal recessive
• Pathophysiology
  • Absent pyruvate dehydrogenase complex (PDC) → impaired conversion of pyruvate to acetyl-CoA → reduced production of citrate → impaired citric acid cycle → energy deficit (especially in the CNS) → neurological dysfunction
  • Excess pyruvate is further metabolized in the Cahill cycle to the following
    • Lactate via lactate dehydrogenase
    • Alanine via alanine aminotransferase
• Clinical features
  • Onset: early neonatal period
  • Poor feeding, lethargy
  • Tachypnea
  • Developmental delay
  • Progressive neurological symptoms (e.g., seizures)
• Diagnostics
  • ↑ Lactate (lactic acidosis) and pyruvate in serum
  • ↑ Alanine in serum and urine
• Treatment
  • Acute: correction of acidosis
  • Long-term: ketogenic diet
    • High in fat, low in carbohydrates
    • High in ketogenic amino acids (lysine and leucine)
    • Avoidance of glucogenic acids (e.g., valine)
  • Supplementation of cofactors of PDC (thiamine, carnitine, and lipoic acid) ^[40]

The main features of PDCD are X-linked recessive inheritance, neurological symptoms, and increased lactate and alanine in serum. A ketogenic diet helps to control lactic acidosis.

Overview

• Autosomal recessive disorders caused by disruptions in mitochondrial beta-oxidation or in carnitine transport and fatty acid oxidation
• Cause an inability to break down fatty acids, which then accumulate in the liver, cardiac, and skeletal muscles
• Although clinical presentation varies, most fatty acid metabolism disorders manifest with hypoketotic hypoglycemia, encephalopathy, skeletal myopathy, cardiomyopathy, and liver dysfunction.

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) ^[42][43][44]

• Definition: : a condition characterized by a defect in the breakdown of medium-chain fatty acids, which renders fatty acids an unusable alternative energy source in case of carbohydrate deficiency.
• Inheritance: autosomal recessive
• Pathophysiology
  • Deficiency of 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
  • Symptoms are usually triggered by the following:
    • Prolonged fasting
    • States of increased metabolic demand (e.g., infection, exercise)
• Clinical features
  • Onset: within the first years of life
  • Dehydration, poor feeding
  • Vomiting
  • CNS
    • Lethargy
    • Seizures
    • Coma
    • Hypotonia
  • Cardiopulmonary collapse
• Diagnostics
  • Part of newborn screening
  • Laboratory findings
    • Hypoglycemia
    • ↓ Ketones in blood and urine
    • Hyperammonemia, hyperuricemia
    • Metabolic acidosis
    • ↑ AST and ALT
    • 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 ^[42]
• Complications
  • Encephalopathy
  • Fatty liver disease and impaired hepatic function
  • Sudden death

Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD deficiency) ^[45][46]

• Definition: a condition in which a deficiency in long-chain fatty acid oxidation causes a buildup of toxic fatty acid intermediates
• Inheritance: autosomal recessive
• Pathophysiology ^[47]
  • Long-chain hydroxyacyl-CoA dehydrogenase deficiency → defective breakdown of long-chain fatty acids → buildup of toxic fatty acid intermediates → hypoketotic hypoglycemia
  • Symptoms are usually triggered by the following:
    • Prolonged fasting
    • States of increased metabolic demand (e.g., infection, exercise)
• Clinical features
  • Onset: within the first few years of life
  • Poor feeding
  • Growth faltering
  • Irritability, lethargy
  • Hypoglycemia
  • Skeletal myopathy (hypotonia, myalgia)
  • Rhabdomyolysis
  • Hepatomegaly, liver dysfunction
  • Cardiomyopathy
• Diagnostics
  • Newborn screening
  • Laboratory findings
    • Hypoglycemia
    • ↓ Ketones in blood and urine
    • Hyperammonemia
    • Metabolic acidosis
    • ↑ 3-hydroxydicarboxylic acids in urine
    • ↑ Lactic acid in urine
    • ↑ AST and ALT
    • ↑ Creatine kinase
  • Genetic testing for HADHA gene variant
  • Enzymatic assay in skin fibroblasts or lymphocytes
• Treatment ^[45]
  • IV administration of 10% dextrose during acute decompensation
  • Frequent feeding intervals
  • Diet low in fat and high in carbohydrates ^[45]
  • Dietary supplementation with medium-chain fatty acids (e.g., Triheptanoin)
  • Avoid prolonged fasting.
• Complications
  • Encephalopathy
  • Retinopathy

Peripheral neuropathy

• Pregnancy-associated disorders (e.g., preeclampsia, HELLP syndrome, acute fatty liver of pregnancy) ^[46]

Primary carnitine deficiency ^[48]

• Definition: : a congenital condition characterized by a defective plasma-membrane carnitine transporter that leads to renal loss, systemic carnitine deficiency, and impaired fatty acid oxidation of the carnitine transporter
• 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 (long-chain fatty acids) in the cytosol of the liver and cardiac and skeletal muscle cells → toxicity
• Clinical features
  • Onset: early childhood
  • Growth faltering
  • Weakness, lethargy
  • Liver dysfunction
  • Dilated cardiomyopathy, congestive heart failure
  • Hypotonia
  • Encephalopathy
  • Rhabdomyolysis (can cause renal failure)
• Diagnostics
  • Part of newborn screening
  • ↓ Glucose and ↓ ketones in serum (hypoketotic hypoglycemia), hyperammonemia, ↑ ALT, ↑ AST
  • Very low plasma carnitine levels
• Treatment
  • Avoid fasting states
  • Oral carnitine supplementation
  • Acute hypoketotic hypoglycemic encephalopathy: administer IV carnitine and 10% dextrose in water

Carnitine palmitoyltransferase II deficiency (CPT II deficiency) ^[49][50][51]

• 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 ^[50]
• Clinical features
  • Symptoms may occur as early as the neonatal period.
  • Presentation is variable
  • Growth faltering
  • Myalgia, hypotonia
  • Hepatomegaly, liver dysfunction, liver failure
  • Cardiomyopathy, congestive heart failure
  • Encephalopathy
  • Seizures
  • Rhabdomyolysis (can cause renal failure)
  • Sudden death
• Diagnostics
  • Part of the expanded newborn screening
  • Hypoglycemia, ↓ serum ketones
  • ↓ Total and free carnitine levels, ↑ acylcarnitines
  • Myoglobinuria and ↑ serum creatine kinase
  • ↑ ALT, ↑ AST, hyperammonemia
• Treatment
  • Diet low in long-chain triglyceride, high in medium-chain fatty acids, and high in carbohydrates
  • Avoid prolonged strenuous activity and fasting

General

Lesch-Nyhan syndrome ^[52][53]

• Definition: : inherited genetic 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 symptoms (e.g., dystonia, spasticity)
  • Gouty arthritis, urate nephropathy
  • Aggression, self-injurious behavior
  • Renal failure
• Diagnostics
  • Hyperuricemia
  • ↓ HGPRT activity
  • Macrocytosis (megaloblastic anemia may occur)
• 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, Poor intellect, Rage/aggression, abnormal muscle Tone.

Adenosine deaminase deficiency ^[54]

• Definition: : inherited genetic disorder characterized by the impaired metabolism of deoxyadenosine during DNA breakdown
• Etiology: mutations in the ADA gene
• Inheritance: autosomal recessive
• Pathophysiology
  • Deficiency in adenosine deaminase → ↓ breakdown of adenosine and deoxyadenosine → ↑ deoxyadenosine (dATP) accumulation → ↓ enzyme activity of ribonucleotide reductase → lymphocyte toxicity → immunodeficiency
  • See “Purines and pyrimidines.”
• Clinical features
  • Severe, recurrent infections
  • Growth faltering
  • See “Severe combined immunodeficiency.”
• Treatment: supportive care, IVIG, bone marrow transplantation

Overview

Ornithine transcarbamylase deficiency (OTC deficiency) ^[55][56]

• Definition: : inherited genetic disorder characterized by the inability to excrete ammonia
• Epidemiology: most common urea cycle defect
• Inheritance: X-linked recessive (in contrast to the rest of urea cycle enzyme deficiencies which are all autosomal 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
  • Conversion of excess carbamoyl phosphate to orotic acid occurs as part of the pyrimidine synthesis pathway
• 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
  • Normal ketone and glucose levels
  • 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: to promote urea formation

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

Arginase deficiency ^[55][57]

• Definition: inherited genetic 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 3 years of age)
    • Poor cognitive development, missed developmental milestones
    • Progressive spasticity (especially of lower extremities)
    • Dystonia
    • Ataxia
    • Seizures
• Diagnostics
  • ↑ Serum arginine
  • Plasma ammonia: normal or mildly elevated
  • ↑ Orotic acid in urine and blood
  • ↓ BUN
  • Genetic testing
  • Arginase activity analysis
• Treatment
  • Reduce serum ammonia
    • Nitrogen scavengers such as sodium phenylacetate and sodium benzoate
    • Fluid management
    • Dialysis (in severe cases)
  • Low-protein diet

Carbamoyl phosphate synthetase 1 (CPS1) deficiency ^[58]

• Definition: rare, inherited genetic disorder characterized CPS1 gene mutations and subsequent hyperammonemia
• Epidemiology: incidence between 1:50,000 and 1:300,000 ^[59]
• Inheritance: autosomal recessive
• Etiopathogenesis: CPS1 gene mutations → disruptions in urea cycle → ↓ conversion of ammonia to carbamoyl phosphate → hyperammonemia
• Clinical features: See clinical features in “Hyperammonemia.”
• Diagnostics
  • Blood test as part of newborn screening showing low levels of citrulline and arginine, but high levels of glutamine, indicating hyperammonemia
  • Confirmation via molecular genetic testing for mutated CPS1 gene
  • Orotic acid levels are not increased.
• Treatment
  • Acute management
    • Lowering of serum ammonia level (e.g., lactulose, rifamixin/neomycin, phenylbutyrate)
    • Dialysis (in severe cases)
    • Fluid management
  • Long-term management
    • Dietary modifications: reduction of protein intake, amino acid supplementation (e.g., essential amino acids)
    • Tailored treatment based on symptoms (e.g., antiseizure medications, liver transplantation)
• Prognosis: fatal if left untreated

N-acetylglutamate synthase deficiency ^[60]

• Definition: rare, inherited genetic disorder characterized by NAGS gene mutations and subsequent hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency
• Epidemiology: rarest urea cycle disorder; incidence between 1:3,500,000 and 1:7,000,000 ^[61]
• Inheritance: autosomal recessive
• Etiopathogenesis: NAGS gene mutations → ↓ function or complete loss of enzyme → disruptions in urea cycle → hyperammonemia
• Clinical features: See clinical features in “Hyperammonemia.”
• Diagnostics: usually a clinical diagnosis; confirmation via molecular genetic testing for mutated NAGS gene
• Treatment
  • Acute management
    • Lowering of serum ammonia level (especially carbamylglutamate; see “Acute management” of CPS1 deficiency above)
    • Fluid management
    • Dialysis (in severe cases)
  • Long-term management: See “Long-term management” of CPS1 deficiency above.
• Prognosis: fatal if left untreated

High levels of ammonia and ornithine in combination with normal levels of urea cycle enzymes raise suspicion for N-acetylglutamate deficiency.

• Definition: : a rare inherited genetic disorder that is characterized by an elevation of orotic acid in the serum and urine due to defective UMP synthase
• Inheritance: : autosomal recessive ^[62]
• Pathophysiology
  • UMP synthase normally converts orotic acid into uridine monophosphate.
  • Deficiency of UMP synthase → accumulation of orotic acid in serum and urine
  • Defective de novo synthesis of pyrimidine nucleotides
• Clinical features
  • Manifests in early childhood
  • Growth faltering
  • Delayed physical and mental development
  • Megaloblastic anemia, which does not respond to folate and vitamin B12 supplementation
  • Orotic acid crystalluria
• Diagnostics ^[62]
  • Serum
    • ↓ Hemoglobin
    • ↑ Mean corpuscular volume
    • ↑ Orotic acid
    • Normal ammonia levels and BUN
  • Urine: ↑ orotic acid
• Treatment ^[62]
  • Uridine monophosphate substitution
  • Uridine triacetate substitution

Increased serum orotic acid is seen in ornithine transcarbamylase deficiency (urea cycle disorder) and in orotic aciduria. However, in orotic aciduria, the urea cycle is intact, so BUN and ammonia levels are normal. Patients with orotic aciduria also have an increased MCV and megaloblastic anemia due to impaired pyrimidine synthesis.

• Definition: inherited metabolic disorder characterized by impaired breakdown of the amino acid tyrosine
• Epidemiology: incidence is approximately 1:100,000 (worldwide)
• Etiology: mutation in the FAH (fumarylacetoacetate hydrolase) gene
• Inheritance: autosomal recessive
• Pathophysiology: deficiency of fumarylacetoacetate hydrolase → accumulation of toxic tyrosine metabolites (e.g., succinylacetone) → progressive damage to the liver, kidneys, and nervous system
• Clinical features
  • Symptom onset: usually within the first months of life
  • Hepatic manifestations
    • Acute hepatic crisis
    • Hepatomegaly, jaundice, risk of hepatocellular carcinoma
  • Renal symptoms: Fanconi-like renal tubulopathy (e.g., phosphate wasting, aminoaciduria)
  • Neurologic symptoms: episodes of peripheral neuropathy and pain crises, developmental delay
• Diagnostics
  • Urine: elevated levels of succinylacetone (diagnostic marker)
  • Serum: elevated tyrosine and methionine, signs of liver dysfunction (↑ transaminases, coagulopathy)
  • Part of expanded newborn screening
• Treatment
  • Diet: low-tyrosine and low-phenylalanine diet
  • Medication: nitisinone (NTBC)
  • Liver transplantation