Inborn Errors: Amino Acid and Urea Cycle Flashcards
Phenylketonuria
a. Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders including phenylketonuria (PKU), non-PKU hyperphenylalaninemia (non-PKU HPA), and variant PKU.
b. Classic PKU is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity; without dietary restriction of phenylalanine most children with PKU develop profound and irreversible intellectual disability.
c. Non-PKU HPA is associated with a much lower risk of impaired cognitive development in the absence of treatment.
d. Diagnosis-PAH deficiency can be diagnosed by newborn screening in virtually 100% of cases based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial or other assays on a blood spot
Phenylketonuria
Diagnosis and Management
a. Diagnosis/testing. PAH deficiency can be diagnosed by newborn screening in virtually 100% of cases based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial or other assays on a blood spot obtained from a heel prick.
b. Management. Treatment of manifestations: Classic PKU: a low natural protein diet through use of a Phe-free medical formula and a regular infant formual as soon as possible after birth to achieve plasma Phe concentrations of 120-360 µmol/L (2-6 mg/dL).
i. A significant proportion of patients with PKU may benefit from adjuvant therapy with 6R-BH4 stereoisomer.
ii. Non-PKU HPA: It is debated whether those with plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) require dietary treatment.
c. Other: for women with PAH deficiency: Phe-restricted diet for at least several months prior to conception in order to maintain plasma Phe concentrations between 120 and 360 µmol/L (2-6 mg/dL); after conception, continuous nutritional guidance and weekly or biweekly measurement of plasma Phe concentration to assure that target levels are met in addition to adequate energy intake with the proper proportion of protein, fat, and carbohydrates.
Large Summary on Diagnosis of Phenylketonuria
a. Plasma Phe concentration. The main route for phenylalanine metabolism is hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase (PAH).
i. The diagnosis of primary phenylalanine hydroxylase deficiency (PAH deficiency) is based on the detection of an elevated plasma phenylalanine (Phe) concentration and evidence of normal BH4 cofactor metabolism.
ii. Individuals with PAH deficiency show plasma phenylalanine (Phe) concentrations that are persistently higher than 120 µmol/L (2 mg/dL) in the untreated state [Scriver & Kaufman 2001, Donlon et al 2004].
b. Newborn screening. PAH deficiency is most commonly diagnosed upon routine screening of newborns. PAH deficiency can be detected in virtually 100% of cases by newborn screening utilizing the Guthrie card bloodspot obtained from a heel prick.
Phenylketonuria
Three methods of newborn screening are currently in use:
1) Guthrie card bacterial inhibition assay (BIA), a time-tested, inexpensive, simple, and reliable test
2) Fluorometric analysis, a reliable quantitative and automated test which produces fewer false positive test results than the BIA
3) Tandem mass spectrometry (MS/MS), which has the same benefits as fluorometric analysis, can also measure tyrosine concentration, and can be useful in interpreting Phe concentration.
i. Tandem mass spectrometry can be used to identify numerous other metabolic disorders on the same sample
Management of PKU (Phenylketonuria)
- Restriction of dietary phenylalanine. The generally accepted goal of treatment for the hyperphenylalaninemias is normalization of the concentrations of Phe and Tyr in the blood and thus prevention of the cognitive deficits that are attributable to this disorder
- Supplementation with BH4. An ever-growing body of evidence indicates that many individuals with primary phenylalanine hydroxylase deficiency are responsive to the 6R-BH4 stereoisomer in pharmacologic doses (≤20 mg/kg daily in divided oral doses)
Pregnant Women with PAH Deficiency.
a. Women with PAH deficiency who have been properly treated throughout childhood and adolescence have normal physical and intellectual development.
b. However, if the woman has high plasma Phe concentrations, her intrauterine environment will be hostile to a developing fetus as phenylalanine is a potent teratogen.
i. It is strongly recommended that women with PAH deficiency use reliable methods of contraception to prevent unplanned pregnancies
c. Women with PAH deficiency who are off diet and are planning a pregnancy should start a Phe-restricted diet prior to conception and should maintain plasma Phe concentrations between 120 and 360 µmol/L (2-6 mg/dL), ideally over several months, before attempting conception .
d. The abnormalities that result from exposure of a fetus to high maternal plasma Phe concentration are the result of ‘maternal HPA/PKU’ .
e. The likelihood that the fetus will have congenital heart disease, intrauterine and postnatal growth retardation, microcephaly, and intellectual disability depends upon the severity of the maternal HPA and the effectiveness of the mother’s dietary management
PKU
Phenylketonuria
a. Due to phenylalanine hydroxylase deficiency
b. Incidence of about 1 in 15,000 births (4 new patients per year in CO)
c. Autosomal recessive inheritance
d. 1% of cases result from disorders of tetrahydrobiopterin (cofactor) metabolism
e. Pathophysiology is incompletely understood, but likely aspects of both Phe toxicity and deficiency of downstream products
Untreated PKU (Phenylketonuria)
1) Intellectual disability
2) Hypopigmentation
3) Eczema
4) Hypomyelination on brain MR
Dietary Treatment of Phenylketonuria (PKU)
a. Restrict dietary protein (a moving target with age)
b. Supplement all non-Phe amino acids
c. Monitor closely to ensure that there is not iatrogenic protein malnutrition
d. Ultimate IQ is directly related to the age of initiation of therapy and the Phe levels achieved in childhood
e. Previous practice was to discontinue dietary therapy at age 6 years; current recommendation is for life-long treatment
The paradigm of inborn errors of metabolism
- All of these diseases are autosomal recessive
- The substrate before the missing enzyme will be too high, and the product below the missing/mutated enzyme will be too low
Sapropterin
PKU Treatment
Sapropterin is the Cofactor that can be given for PKU Treatment
a. Some patients have residual enzyme activity that can be further increased with supplementation of the BH4 cofactor
b. Specific genotypes are known to respond or not
Maternal Phenylketonuria (PKU)
a. With successful treatment of PKU came women with PKU having children
b. It is now known that exposure to elevated phenylalanine in utero is teratogenic
c. Infants born to mothers with uncontrolled PKU have growth restriction, microcephaly, intellectual disability and heart malformations
Maple Syrup Urine Disease
Disease characteristics
Branched-chain alpha-keto acid dehydrogenase mutation
a. Maple syrup urine disease (MSUD) in untreated neonates is characterized by maple syrup odor in cerumen (ear wax) at 12-24 hours after birth;
i. elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine
ii. as well as a generalized disturbance of plasma amino acid concentration ratios, by 12-24 hours of age
b. Other findings: ketonuria, irritability, and poor feeding by age 2-3 days; deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as “fencing” and “bicycling” by age 4-5 days; and coma and central respiratory failure that may occur by age 7-10 days.
c. The phenotype is classified as classic or intermediate. Rarely, affected individuals have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; individuals with intermediate or intermittent forms of MSUD can experience severe metabolic intoxication and encephalopathy under sufficient catabolic stress.
Maple Syrup Urine Disease
Diagnostic and Management
a. Diagnosis/testing. MSUD is diagnosed by the presence of clinical features and by decreased levels of BCKAD enzyme activity causing accumulation of BCAAs, allo-isoleucine, and branched-chain ketoacids (BCKAs) in tissues and plasma.
i. The three genes associated with MSUD are BCKDHA (E1a subunit gene, MSUD type 1A), BCKDHB (E1b subunit gene, MSUD type 1B), and DBT (E2 subunit gene, MSUD type 2).
ii. Molecular genetic testing of all three genes is available on a clinical basis.
b. Management. Treatment of manifestations: Treatment includes dietary leucine restriction, high-calorie BCAA-free formulas, judicial supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring.
i. Metabolic decompensation is corrected by treating the precipitating stress while delivering sufficient calories, insulin, free amino acids, isoleucine, and valine to achieve sustained net protein synthesis in tissues.
ii. Some centers use hemodialysis/hemofiltration to remove BCAAs from the extracellular compartment, but this alone does not establish net protein accretion.
c. Brain edema, a common complication of metabolic decompensation, requires immediate therapy in an intensive care setting.
d. Adolescents and adults with MSUD are at increased risk for ADHD, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressent medications.
i. Orthotopic liver transplantation is an effective therapy for classic MSUD
Maple syrup urine disease
Wiki
a. Maple syrup urine disease (MSUD), also called branched-chain ketoaciduria, is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia.
i. The condition gets its name from the distinctive sweet odor of affected infants’ urine, particularly prior to diagnosis, and during times of acute illness
b. Signs- The disease is named for the presence of sweet-smelling urine, an odor similar to that of maple syrup, when the person goes into metabolic crisis.
i. The smell is also present and sometimes stronger in the ear wax of an affected individual at these times. In populations to whom maple syrup is unfamiliar, the aroma can be likened to fenugreek, and fenugreek ingestion may impart the aroma to urine
ii. Between 0 and 5 months[edit]
Infants with this disease seem healthy at birth but quickly deteriorate, often with severe brain damage, which may be permanent.
After 5 months
More commonly the symptoms present between 5 months and 2 years of age. Untreated in older individuals, and during times of metabolic crisis, symptoms of the condition include anorexia, weight loss[6], anemia,[7] diarrhea[7], vomiting, dehydration, lethargy[4], oscillating hypertonia and hypotonia[6], ataxia[5], seizures[8], hypoglycaemia, ketoacidosis[9], opisthotonus, osteopenia[10] and osteoporosis[7], pancreatitis[
Mechanism of Maple syrup urine disease
a. MSUD is a metabolic disorder caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine.
b. The enzyme complex consists of four subunits designated E1α, E1β, E2, and E3. The E3 subunit is also a component of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex.
i. MSUD can result from mutations in any of the genes that code for the enzyme subunits.
