Summary
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.
Alpha-1 antitrypsin deficiency (AAT deficiency)
- Definition: inherited genetic 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.
-
The severity of disease depends on the specific genotypic expression, which correlates with the amount of α1-antitrypsin protein synthesis [2][3]
- PiMM: 100% expression of normal protein and therefore normal serum levels of AAT
- PiMS: 80% of normal serum levels of AAT
- PiSS, PiMZ, PiSZ: 40–60% of normal serum levels of AAT
- PiZZ: 10–15% of normal serum levels of AAT (severe AAT deficiency) [4]
- 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 → dysfunctional (or absent) AAT
- Effect on the liver: accumulation of AAT in hepatocellular endoplasmic reticulum → hepatocyte destruction → hepatitis and liver cirrhosis
- Effect on the lungs: deficient AAT → uninhibited neutrophil elastase activity → destruction of the pulmonary parenchyma → panacinar emphysema
-
Clinical features: The age of onset and the severity of the symptoms depend on the type of mutation (see “Etiology” above).
-
Pulmonary manifestations
- Cough, wheezing
- Dyspnea
- Diminished breath sounds
- Barrel chest
-
Hepatic manifestations
- Prolonged neonatal jaundice
- Hepatitis
- Cirrhosis
- Increased risk of hepatocellular carcinoma (HCC)
-
Pulmonary manifestations
-
Diagnostics
- Serum: decreased antitrypsin protein levels
- Electrophoresis: decreased alpha-1 peak [5]
-
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 [6]
- Panacinar emphysema (in contrast to centriacinar emphysema in smoking-related emphysema)
- Bronchiectasis
- Bullae
-
Liver biopsy
- PAS-positive, spherical inclusion bodies in periportal hepatocytes
- Signs of cirrhosis [7]
-
Treatment
- General measures
- Avoid active and passive exposure to cigarette smoke.
- Preventive vaccination (e.g., influenza vaccine, pneumococcus vaccine)
-
Symptomatic treatment
- Bronchodilators
- Pulmonary rehabilitation
- Nutritional support if necessary
- Antitrypsin replacement: in patients with severe AAT deficiency (e.g., ATT < 57 mg/dL ) and evidence of decreased airflow [8]
-
Liver transplantation
- Results in correction of AAT deficiency
- Considered for end-stage liver disease [9]
- General measures
The diagnosis of AAT deficiency should be considered in all patients with emphysema under the age of 50 years.
Mitochondrial myopathies
General considerations [10]
- 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
- Treatment: mainly supportive
Subtypes of mitochondrial myopathies [10][11][12]
-
MELAS: characterized by mitochondrial encephalomyopathy, lactic acidosis, recurring stroke-like episodes [13][14]
- Other findings include
- Muscle weakness
- Tonic-clonic seizures
- Other findings include
-
MERRF: characterized by myoclonic epilepsy with ragged red fibers [15]
- Cause: Point mutation of the 8344thbase pair of mitochondrial DNA (in 80% of cases) → destruction of important proteins involved in oxidative phosphorylation
- Other findings include
- CPEO: characterized by chronic progressive external ophthalmoplegia (with bilateral ptosis) [16]
-
Kearns-Sayre syndrome: characterized by [17]
- Ophthalmoplegia and retinitis pigmentosa
- Impaired electrical activity of the heart, especially AV block
-
LHON (Leber hereditary optic neuropathy)
- Epidemiology
- Cause: cellular death in optic nerve neurons
- Clinical features: painless acute or subacute bilateral vision loss which is usually irreversible
-
Leigh syndrome [19]
- 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
- Failure to thrive
- Hypotonia, dystonia, ataxia
- Rapidly progressive psychomotor regression
- Ophthalmoparesis, nystagmus, optic atrophy
- Peripheral neuropathy
- Hypertrophic cardiomyopathy
- Etiology
Disorders of amino acid metabolism
This section gives an overview of disorders affecting the metabolism of amino acids.
Phenylketonuria
- Definition: : inherited genetic disorder characterized by the accumulation of phenylalanine [20][21][22]
- Epidemiology: incidence is up to 1:15,000 [23]
- 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
-
Malignant PKU: due to tetrahydrobiopterin deficiency (a cofactor of phenylalanine metabolism), caused by a deficiency in dihydropteridine reductase (normally reduces dihydrobiopterin to BH4), 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
- Maternal PKU: the developmental malformations in a newborn resulting from PKU during pregnancy.
-
Malignant PKU: due to tetrahydrobiopterin deficiency (a cofactor of phenylalanine metabolism), caused by a deficiency in dihydropteridine reductase (normally reduces dihydrobiopterin to BH4), resulting in:
- 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”)
-
Accumulation of phenylalanine
-
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 [24]
- Blue eyes, light, pale hair (fair complexion)
- 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
- Newborn screening: direct measurement of serum phenylalanine levels on 2nd–3rd day after birth (phenylalanine levels are normal at birth because of circulating maternal PAH)
- If screening test is positive: oral tetrahydrobiopterin loading test
- Performed to differentiate between PKU and tetrahydrobiopterin deficiency
- If phenylalanine levels are decreased: BH4 deficiency
- If phenylalanine levels remain unchanged: PAH deficiency [25]
- Performed to differentiate between PKU and tetrahydrobiopterin deficiency
- ↑ Phenylketones in urine
- Hyperphenylalaninemia
-
Treatment
- Low phenylalanine and high tyrosine diet
- BH4 deficiency: supplementation of BH4 and possibly levodopa and 5-hydroxytryptophan
Patients with PKU should be advised to avoid aspartame, an artificial sweetener that contains phenylalanine!
Homocystinuria
- Definition: a group of inherited genetic disorders characterized by impaired homocysteine metabolism
- Epidemiology: affects 1:200,000–335,000 people worldwide [26]
-
Etiology: mutations in CBS, MTHFR, MTR, MTRR, and MMADHC genes
- Cause deficiencies in one or more of the following enzymes
- Methionine synthase
- Cystathionine synthase: an enzyme that catalyzes the conversion of homocysteine and serine to cystathionine, using vitamin B6 as a cofactor.
- Methylenetetrahydrofolate reductase (MTHFR): an enzyme involved in folate metabolism that reduces N5,10-methylenetetrahydrofolate to methyltetrahydrofolate.
- Impaired affinity of cystathionine synthase for pyridoxal phosphate
- Cause deficiencies in one or more of the following enzymes
- 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. [27]
- Nonspecific features in infancy: failure to thrive, 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
- Fair complexion
-
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. [28]
-
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). [29]
- 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
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.”
Hartnup disease
- Definition: : inherited genetic disorder characterized by a defect in the renal and intestinal transport of neutral amino acids (e.g., tryptophan) [30]
- Epidemiology: incidence is 1:30,000 [31]
- 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
Alkaptonuria
- Definition: inherited genetic disorder characterized by a mutation in the HGD gene and subsequent homogentisic acid dioxygenase deficiency and impaired tyrosine catabolism [32][33]
- Epidemiology: affects 1:250,000–1,000,000 people worldwide [34]
- Etiology: mutation in the HGD gene
- Inheritance: autosomal recessive
-
Pathophysiology
- Lack of functional homogentisic acid dioxygenase → impaired conversion of homogentisate to 4-maleylacetoacetate
- Accumulation of homogentisate → tissue discoloration and organ damage
-
Clinical features
- Usually, a benign condition
- Ochronosis: bluish-black discoloration of connective tissues
-
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
-
Cartilage: arthritis (ochronotic osteoarthropathy)
-
Diagnostics
- Urine turns black when left standing for a prolonged time or when alkalinized.
- ↑ Homogentisate in urine and serum
- Normal tyrosine levels
- Treatment: diet low in tyrosine and phenylalanine to reduce the formation of homogentisic acid
Maple syrup urine disease
- Definition: : inherited genetic disorder characterized by the impaired break down of branched-chain amino acids (BCAA) [35][36][37]
- Epidemiology: incidence is 1:185,000 (worldwide) [38]
- 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
-
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
- Ultima ratio: 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.
Cystinuria
-
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. [39]
- 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.”
Organic acidemias
- Definition: inherited genetic disorders characterized by impaired metabolism of fats and proteins [40][41][42]
- Epidemiology: incidence of propionic acidemia is ∼ 1:100,000
-
Etiology
- Propionic acidemia: PCCA and PCCB gene mutations
-
Methylmalonic acidemia
- MMUT, MMA, MMAB, MMADHC, or MCEE 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
-
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
- Failure to thrive
- Lethargy
- Seizures
- Hypotonia
- Intellectual disability, developmental delay
- Hepatomegaly
- Death may occur without appropriate treatment
-
Diagnostics
- ↑ Propionic acid or ↑ methylmalonic acid in urine and serum
- High anion gap metabolic acidosis
- Hyperammonemia
-
Treatment: to avoid further build-up 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.
Cystinosis
- Definition: inherited genetic disorder characterized by impaired cystine storage [43][44]
- 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 (The infantile form is the most severe form.)
- Defective transport of cystine out of lysosomes → accumulation of cystine within lysosomes
-
Clinical features
- Failure to thrive
- 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
Histidinemia
- Definition: a rare, benign inherited genetic disorder characterized by an impaired histidine metabolism which leads to an elevation in histidine. [45][46]
- 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
- Treatment: usually not required
Pyruvate dehydrogenase complex deficiency
- 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
- Clinical features
-
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) [47]
Disorders of fatty acid metabolism
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) [48][49][50]
- 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
-
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 [48]
-
Complications
- Encephalopathy
- Fatty liver disease and impaired hepatic function
- Sudden death
Primary carnitine deficiency [50]
- 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 (long-chain fatty acids) in the cytosol of the liver and cardiac and skeletal muscle cells → toxicity
-
Clinical features
- Onset: early childhood
- Failure to thrive
- 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) [51][52][53]
- 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 [52]
-
Clinical features
- Symptoms may occur as early as the neonatal period.
- Presentation is variable
- Failure to thrive
- 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, ↑ acylcarnitine
- 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
Purine salvage deficiencies
Lesch-Nyhan syndrome [54][55]
- 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 [56]
- 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
- Failure to thrive
- See “Severe combined immunodeficiency.”
- Treatment: supportive care, IVIG, bone marrow transplantation
Urea cycle disorders
Ornithine transcarbamylase deficiency (OTC deficiency) [57][58][59]
- 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
- Enzyme analysis of OTC activity
- Treatment
OTC deficiency is the only urea cycle disorder that is X-linked recessive. All other urea cycle disorders are autosomal recessive.
Arginase deficiency [57][60]
- 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
-
Acute: episodic hyperammonemia
-
Diagnostics
- ↑ Serum arginine
- Hyperammonemia
- ↓ 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
-
Reduce serum ammonia
Carbamoyl phosphate synthetase 1 (CPS1) deficiency [61]
- Definition: rare, inherited genetic disorder characterized CPS1 gene mutations and subsequent hyperammonemia
- Epidemiology: incidence between 1:50,000 and 1:300,000 [62]
- 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
-
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)
- Acute management
- Prognosis: fatal if left untreated
N-acetylglutamate synthase deficiency [63]
- Definition: rare, inherited genetic disorder characterized by NAGS gene mutations and subsequent hyperammonemia due to N-acetylglutamate synthetase (NAGS) deficiency
- Epidemiology: rarest urea cycle disorder; incidence between 1:3,500,000 and 1:7,000,000 [64]
- 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.
- Acute management
- Prognosis: fatal if left untreated
Orotic aciduria
- 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 [65]
-
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
- Failure to thrive
- Delayed physical and mental development
- Megaloblastic anemia, which does not respond to folate and vitamin B12 supplementation
- Orotic acid crystalluria
-
Diagnostics [65]
-
Serum
- ↓ Hemoglobin
- ↑ Mean corpuscular volume
- ↑ Orotic acid
- Normal ammonia levels and BUN
- Urine: ↑ orotic acid
-
Serum
-
Treatment [65]
- Uridine monophosphate substitution
- Uridine triacetate substitution
Orotic aciduria can be distinguished from ornithine transcarbamylase deficiency by the presence of megaloblastic anemia and the absence of hyperammonemia.