Inborn errors of metabolism

Inborn errors of metabolism are caused by genetic mutations which result in enzyme defects that impair the metabolism or transport of metabolites. A complete cure is usually not possible but disease outcomes and life expectancy can be improved with supportive treatment and appropriate diets.

• Mode of inheritance: autosomal codominant
  • Mild form affects 5–10% of the population
  • Severe form affects < 0.2% of the population
• Pathophysiology
  • α1-antitrypsin is a protease inhibitor that is synthesized in the liver.
  • The underlying cause in most cases of α1-antitrypsin deficiency is a gene mutation. This gene mutation causes a conformational change in the structure of α1-antitrypsin and impairs its secretion by hepatocytes. (There is also a form of α1-antitrypsin deficiency in which no α1-antitrypsin is synthesized.)
  • Effect on the liver: impaired secretion of α1-antitrypsin by hepatocytes → intracellular accumulation of α1-antitrypsin → hepatocyte destruction → hepatitis and liver cirrhosis
    • Histological finding: PAS-positive, spherical inclusion bodies in periportal hepatocytes
  • Effect on the lungs: deficiency of α1-antitrypsin in plasma → increased protease activity in the lungs → destruction of the pulmonary architecture → panacinar emphysema
• Clinical features
  • The severe form manifests early with prolonged neonatal jaundice, hepatitis, cirrhosis, and pulmonary emphysema.
  • The mild form manifests in adolescence, primarily with pulmonary disease; hepatic symptoms may also be present.
  • Patients are at increased risk for hepatocellular carcinoma.
• Diagnostics
  • Electrophoresis (decreased alpha-1 peak), serum antitrypsin level, liver biopsy
  • Causes panlobular emphysema seen on CXR (in contrast to centrilobular emphysema in smoking-related emphysema)
• Therapy
  • Avoid active and passive exposure to smoke.
  • Symptomatic treatment: bronchodilators, pulmonary rehabilitation, preventive vaccination, nutritional support if necessary
  • Antitrypsin replacement; : used in patients with severe AAT deficiency with decreased ATT levels < 11 micromol/L or < 57 mg/dL and evidence of decreased airflow
  • Liver transplantation: donor liver corrects AAT deficiency, considered with end-stage liver disease

A diagnosis of α1-antitrypsin deficiency should be considered in all COPD patients under the age of 50!

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

General considerations

In the case of mitochondrial myopathies, the production of energy in mitochondria (by oxidative phosphorylation) is impaired. Organs with a high energy requirement (e.g., brain, skeletal muscles) are particularly affected. Clinical features include external ophthalmoplegia, ptosis, and muscle weakness; , which is exacerbated by exertion. Mitochondrial myopathies are inherited only from the mother.

Immunohistochemistry; : a characteristic picture which is described as "ragged red fibers; " (subsarcolemmal and intermyofibrillar accumulation of mitochondria in muscles; the mitochondria stains red)

Special forms

Chronic progressive external ophthalmoplegia (CPEO)

• Etiology: mitochondriopathy
• Clinical features: progressive ophthalmoplegia
• Diagnostics
  • ↑ Lactate in serum and cerebrospinal fluid
  • A muscle biopsy shows characteristic "red ragged fibers"

Kearns-Sayre syndrome

• Clinical features
  • Ophthalmoplegia and retinitis pigmentosa
  • Impaired electrical activity of the heart, especially AV block

MELAS (“Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes”)

• Clinical features: variable presentation (due to heteroplasmy)
  • Muscle weakness
  • Tonic-clonic seizures
  • Recurring strokes
  • Dementia
• Diagnostics
  • Lactic acidosis both in blood and CSF
  • Molecular genetic testing shows pathogenic variants in mtDNA, occurrence of heteroplasmy
  • Muscle biopsy shows characteristic "red ragged fibers"

MERRF (“Myoclonic Epilepsy with Ragged Red Fibers”)

• Etiology: point mutation of the 8344^th base pair of mitochondrial DNA (in 80% of cases) → destruction of important proteins involved in oxidative phosphorylation
• Clinical features: : myoclonic jerks, generalized seizures, cerebellar ataxia, dementia
• Diagnostics: : evidence of ragged red fibers on muscle biopsy

References:^{[8][9][10][11][12][13][14]}

Alkaptonuria

• Etiology: : rare, autosomal recessive disorder of tyrosine metabolism, caused by deficient activity of homogentisic acid dioxygenase
• Pathophysiology: accumulation of the metabolite homogentisic acid → organ damage
• Clinical features:
  • Cartilage, tendons, skin, sclera → ochronosis
    • Ochronosis ultimately results in arthritis and degenerative changes in the vertebral column.
  • Heart valves → calcification
  • Kidneys → nephrolithiasis
• Diagnostics:
  • Urine initially appears normal but turns dark brown or black when left standing or alkalinized.
  • Confirmed with measurement of homogentisic acid in the urine

Homocystinuria

• Definition: : a group of diseases in which the blood and urine levels of the amino acid homocysteine are elevated
• Pathophysiology: genetic defects in enzymes involved in homocysteine metabolism (e.g., cystathionine synthase deficiency)
• Clinical features: (the severity of the disease varies greatly)
  • Nonspecific features in infancy include failure to thrive and developmental delay.
  • Eyes: subluxation of the ocular lens (ectopia lentis) after age 3, myopia and glaucoma later in life
  • Progressive intellectual disability
  • Psychiatric and behavioral disorders
  • Marfanoid skeletal abnormalities: tall and thin, elongated limbs, arachnodactyly
  • Vascular system: thromboembolism, premature arteriosclerosis, and coronary heart disease
• Diagnostics: addition of sodium nitroprusside to urine → urine changes color to an intense red
• Treatment: 50% of patients respond to large doses of pyridoxine (vitamin B₆)

Hartnup disease

• Etiology: autosomal recessive mutation of Na⁺-dependent neutral amino acid transporter
• Pathophysiology: decreased absorption of tryptophan from the gut and renal tubules → inability to synthesize vitamin B3 (niacin)
• Clinical features: symptoms of vitamin B3 deficiency (pellagra) → "4 D's": dermatitis, diarrhea, dementia, da big tongue (glossitis)
• Diagnostics: neutral aminoaciduria
• Treatment
  • High-protein diet
  • Nicotinic acid (niacin) supplementation

Phenylketonuria (PKU)

• Mode of inheritance: autosomal recessive
• Pathophysiology: defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosine (tyrosine becomes nutritionally essential) → accumulation of phenylalanine (in CNS, not in the liver!) → impaired brain growth in children and excretion of the metabolites of phenylalanine in urine (phenylketonuria)
• Clinical features
  • A lag in psychomotor development after the 4^th–6^th postnatal month
  • 50% have seizures with cerebral foci
  • Light, pale hair, and blue eyes
  • Predisposition for eczema, “musty” odor
• Diagnostics
  • Direct measurement of phenylalanine levels as a part of newborn screening for metabolic disorders (The screening test is done on the 2^nd day after birth using blood obtained from a heel prick.)
    • An oral tetrahydrobiopterin loading test is done when increased phenylalanine levels are detected by a screening test.
  • Outdated: indirect measurement of phenylalanine levels on the 5^th postnatal day (Guthrie-Test
• Treatment: diet with decreased phenylalanine content and increased tyrosine content
• Differential diagnosis: tetrahydrobiopterin deficiency (THBD)
  • Pathophysiology: Due to a deficiency in dihydropteridine reductase, which normally reduces dihydrobiopterin (DHB) to tetrahydrobiopterin (THB).
    • THB constitutes an essential cofactor for phenylalanine hydroxylase, which catalyzes the conversion of phenylalanine to tyrosine.
      • Deficiency of THB leads to impaired catabolism of phenylalanine → hyperphenylalaninemia.
    • THB is also required as a cofactor for the synthesis of dopamine, norepinephrine, and serotonin.
      • Deficiency of THB leads to diminished levels of these neurotransmitters.
  • Clinical features: hyperphenylalaninemia, similar to PKU, and progressive encephalopathy
  • Diagnosis
    • Hyperphenylalaninemia
    • ↓ Dihydropteridine reductase levels in RBCs
    • ↑ Biopterin levels in urine, blood, and CSF
  • Management: a diet low in phenylalanine + supplementation of tetrahydrobiopterin, folate, and precursors of insufficient neurotransmitters (does not reverse encephalopathy)

Cystinosis

• Definition: cystine storage disorder
  • Three clinical forms (with variable age onset and severity) exist: infantile, juvenile, and ocular cystinosis.
• Mode of inheritance: autosomal recessive
• Epidemiology: The infantile form is the most common and the most severe form.
• Clinical features
  • Failure to thrive
  • Fanconi syndrome
  • Progressive renal failure
  • Polyuria and polydipsia
  • Additional organ involvement
• Diagnosis
  • Observation of cystine crystals in the cornea during slit lamp examination
  • Confirmed by measurement of increased leukocyte cystine content
• Treatment
  • Directed at correcting metabolic abnormalities associated with Fanconi syndrome or renal failure
  • Specific therapy available with cysteamine

Cystinuria

See cystinuria.

Histidinemia

• Rare autosomal recessive disorder
• Histidase deficiency → histidine breakdown impaired → histidine accumulation
• May cause intellectual disability

Maple syrup urine disease

• Mode of inheritance: autosomal recessive
• Pathophysiology: absent or deficient branched-chain α-ketoacid dehydrogenase enzyme → impaired degradation of branched-chain amino acids (valine, leucine, isoleucine)
• Clinical features
  • Onset: early neonatal period
  • Vomiting, lethargy, poor feeding
  • Dystonia
  • Hypoglycemia
  • Sweet-smelling urine (maple syrup odor)
• Diagnosis: ↑ alpha-ketoacids of branched-chain amino acids in serum
• Treatment
  • Avoidance of branched-chain amino acids in the diet
  • Thiamine supplementation

Pyruvate dehydrogenase complex deficiency

• Mode of inheritance: X-linked
• 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)
• Clinical features
  • Neonates: poor feeding, lethargy; , tachypnea, developmental delays, progressive neurological symptoms, severe lactic acidosis
• Diagnosis
  • ↑ Serum lactate and pyruvate
  • ↑ Serum and urine alanine
• Treatment
  • Acute: correction of acidosis
  • Long-term: ketogenic diet (high-fat, low-carbohydrate, and including glucogenic amino acids, e.g. valine), cofactor supplementation with thiamine, carnitine, and lipoic acid

Propionic aciduria

• Mode of inheritance: autosomal recessive
• Pathophysiology: defective alpha (13q32) or beta (3q13) subunit of propionyl-CoA carboxylase (most common defect) → impaired conversion of propionyl-CoA to methylmalonyl-CoA → buildup of propionyl-CoA and conversion into propionic acid in the circulation
  • Propionyl-CoA is produced during the catabolism of certain amino acids (isoleucine, valine, threonine, methionine), odd-chain fatty acids, pyrimidines (thymine, uracil), and cholesterol
• Clinical features
  • Typically presents in the neonatal period, with organic acidosis, vomiting, failure to thrive, generalized hypotonia; , lethargy, and seizures.
• Diagnosis
  • ↑ Urine and serum propionic acid
• Treatment
  • Low protein diet, with an amino acid supplement that is completely devoid of methionine, threonine, isoleucine, and valine

References:^{[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]}

Lesch-Nyhan syndrome

• Etiology
  • X-linked recessive inheritance
  • Defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
• Clinical features
  • Usually asymptomatic for the first 6 months of life
  • Developmental delay and cognitive impairment
  • Pyramidal and extrapyramidal signs (dystonic movements, spasticity)
  • Gouty arthritis, urate nephropathy
  • Self-injurious behavior
• Diagnostics
  • Analysis of HGPRT enzyme demonstrating decreased enzyme activity
  • Hyperuricemia (hyperuricemia is a result of impaired purine metabolism)
  • Megaloblastic anemia
• Treatment
  • Allopurinol, febuxostat; (treating hyperuricemia, the underlying enzyme defect is not possible to treat)
  • Diet deficient in purines
• Prognosis: : The disease is associated with a high mortality if the infant is not treated within the first year after birth; (hyperuricemia-induced; organ damage → renal failure).

References:^[18][30]

Medium chain Acyl-CoA dehydrogenase deficiency (MCAD deficiency)

• Pathophysiology
  • Defect in the breakdown of medium-chain fatty acids → disorder of fatty acid oxidation
  • Fat cannot function as an alternate energy source in the case of carbohydrate deficiency.
  • Symptoms usually triggered by:
    • Prolonged fasting (during weaning or off night-time feeds)
    • State of increased metabolic demand (e.g., infection, exercise)
• Clinical features
  • Vomiting and lethargy
  • Can progress to coma, seizures, or cardiopulmonary collapse.
• Complications
  • Encephalopathy
  • Fatty liver disease and decreased hepatic function
  • Sudden death
• Diagnostics
  • Newborn screening
  • Laboratory findings: hypoglycemia, ↓ ketones in blood and urine, hyperuricemia, metabolic acidosis, ↑ AST and ALT, ↑ serum ammonia, prolonged PT and aPTT
  • Genetic testing for the common A985G mutation
• Treatment
  • IV administration of 10% dextrose during acute decompensation
  • Avoid fasting states

References:^[16]

Carnitine transporter deficiency

• Pathophysiology
  • Inherited disease caused by a mutation in the carnitine transporter gene expressed in the heart, kidneys, lymphoblasts, and fibroblasts
  • Impaired entry of long-chain fatty acids into mitochondria via the carnitine-dependent shuttle → impaired fatty acid metabolism via β-oxidation → decreased production of ketone bodies + decreased energy production from fatty acids (↓ gluconeogenesis) → hypoketotic hypoglycemia + accumulation of fat in the liver and cardiac and skeletal muscle
• Clinical features
  • Liver dysfunction (↑ liver enzymes) and hyperammonemia
  • Cardiomyopathy
  • Low muscle tone (hypotonia)
• Diagnostics
  • Newborn screening
  • ↓ Blood glucose and ↓ urine ketones (hypoketotic hypoglycemia)
  • Very low plasma carnitine level
• Treatment
  • Oral carnitine supplementation
  • Acute hypoketotic hypoglycemic encephalopathy: administer IV carnitine and 10% dextrose in water
• Complications
  • Encephalopathy
  • Congestive heart failure
  • Rhabdomyolysis → renal failure
  • Failure to thrive

Carnitine palmitoyltransferase II deficiency (CPT II deficiency)

• Pathophysiology
  • Autosomal recessive mutation in the carnitine palmitoyltransferase II gene
  • Long-chain fatty acids enter mitochondria attached to carnitine → Inside the mitochondria, CPT II normally removes carnitine.
  • If CPT II is defective, carnitine cannot be removed → fatty acid oxidation is not possible → no substrate for gluconeogenesis and ketogenesis → hypoketotic hypoglycemia
    • also, fatty acids and long-chain acylcarnitines build up in cells → damage liver, heart, and muscles
• Clinical features
  • Signs of hypoglycemia
  • Myalgia, weakness
  • Hepatomegaly, liver dysfunction (↑ liver enzymes), hyperammonemia
  • Cardiomyopathy
  • Low muscle tone (hypotonia)
• Diagnostics
  • Expanded newborn screening
  • Blood glucose and urine ketones → hypoketotic hypoglycemia → check plasma carnitine levels (low total and free carnitine levels, high acylcarnitine)
  • Serum and/or urine screen positive for myoglobin and serum creatine kinase
  • Elevated transaminase levels
• Treatment
  • Avoiding prolonged strenuous activity, fasting, and long-chain triglyceride intake
  • Medium-chain fatty acid supplementation
  • Increased carbohydrate intake
• Complications
  • Encephalopathy
  • Congestive heart failure
  • Rhabdomyolysis → renal failure
  • Failure to thrive
  • Liver failure

References:^{[31][32][33][34][35]}

Ornithine transcarbamylase deficiency (OTC deficiency)

• Etiology
  • X-linked recessive inheritance
  • Defect in the enzyme ornithine transcarbamylase
  • Most common urea cycle defect
• Clinical features
  • Nausea, vomiting, irritability
  • Delayed growth and cognitive impairment
  • In severe cases, metabolic encephalopathy with coma and death
• Diagnostics
  • Hyperammonemia (usually > 100 μmol/L)
  • Increased urine orotic acid
  • Enzyme analysis of OTC activity
• Treatment
  • Strict low-protein diet
  • Sodium benzoate (nitrogen-scavenging)
  • Arginine supplement

Arginase deficiency

• Pathophysiology
  • Autosomal recessive inheritance
  • Absent or nonfunctional arginase enzyme → impaired conversion of arginine to ornithine → episodic accumulation of ammonia in the serum
• Clinical features
  • Episodic hyperammonemia
    • Often asymptomatic
    • Rarely severe (typically triggered by metabolic stress, e.g. infections, trauma, surgery)
  • In untreated cases
    • Diminishing linear growth by three years
    • Gradually progressive spasticity (especially of lower extremities), dystonia, ataxia, poor cognitive development, and loss of developmental milestones by school age
    • Seizures
    • By young adulthood: severe spasticity, inability to ambulate, complete loss of bowel and bladder control, and severe intellectual disability
    • Treatment typically renders the condition asymptomatic
• Diagnostics
  • Elevated serum arginine
  • No or only mild hyperammonemia
  • Orotic aciduria (not considered diagnostic)
  • Decreased serum urea nitrogen
  • Gene sequencing of arginase gene
• Treatment
  • Promptly reduce serum ammonia via:
    • Dialysis (severe cases)
    • Nitrogen scavengers such as sodium phenylacetate and sodium benzoate
    • Fluid management
  • Avoid heavily nitrogenous diets (proteins)
  • Seizure treatment

References:^[36][37][38]