Amino Acid Metabolism Disorders

Amino Acid  Metabolism Disorders

1.Phenylketonuria (PKU)

Phenylketonuria is a clinical syndrome of mental retardation with cognitive and behavioral abnormalities caused by elevated serum phenylalanine. The primary cause is deficient phenylalanine hydroxylase activity. Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine levels. Treatment is lifelong dietary phenylalanine restriction. Prognosis is excellent with treatment.

Phenylketonuria (PKU) is most common in all white populations and relatively less common among Ashkenazi Jews, Chinese, and blacks. Inheritance is autosomal recessive; incidence is about 1/10,000 births among whites.

Excess dietary phenylalanine (ie, that not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is an essential cofactor for this reaction. When one of several gene mutations results in deficiency or absence of phenylalanine hydroxylase, dietary phenylalanine accumulates; the brain is the main organ affected, possibly due to disturbance of myelination. Some of the excess phenylalanine is metabolized to phenylketones, which are excreted in the urine, giving rise to the term phenylketonuria. The degree of enzyme deficiency, and hence severity of hyperphenylalaninemia, varies among patients depending on the specific mutation.

 

Variant forms: Although nearly all cases (98 to 99%) of PKU result from phenylalanine hydroxylase deficiency, phenylalanine also can accumulate if BH4 is not synthesized because of deficiencies of dihydrobiopterin synthase or not regenerated because of deficiencies of dihydropteridine reductase. Additionally, because BH4 is also a cofactor for tyrosine hydroxylase, which is involved in the synthesis of dopamine Some Trade Names INTROPIN and serotonin, BH4 deficiency alters synthesis of neurotransmitters, causing neurologic symptoms independently of phenylalanine accumulation.

Symptoms and Signs

Most children are normal at birth but develop symptoms and signs slowly over several months as phenylalanine accumulates. The hallmark of untreated PKU is severe mental retardation. Children also manifest extreme hyperactivity, gait disturbance, and psychoses and often exhibit an unpleasant, mousy body odor caused by phenylacetic acid (a breakdown product of phenylalanine) in urine and sweat. Patients also tend to have a lighter skin, hair, and eye color than unaffected family members, and some may develop a rash similar to infantile eczema.

Diagnosis

In the US and many developed countries, all neonates are screened for PKU 24 to 48 h after birth with one of several blood tests; abnormal results are confirmed by directly measuring phenylalanine levels. In classic PKU, patients often have phenylalanine levels > 20 mg/dL (1.2 mM/L). Those with partial deficiencies typically have levels < 8 to 10 mg/dL while on a normal diet (levels > 6 mg/dL require treatment); distinction from classic PKU requires a liver phenylalanine hydroxylase activity assay demonstrating activity between 5% and 15% of normal or a mutation analysis identifying mild mutations in the gene. BH4 deficiency is distinguished from other forms of PKU by elevated concentrations of biopterin or neopterin in urine, blood, CSF, or all 3; recognition is important because standard PKU treatment will not prevent neurologic damage.

Children in families with a positive family history can be diagnosed prenatally by using direct mutation studies after chorionic villus sampling or amniocentesis.

Prognosis and Treatment

Adequate treatment begun in the first days of life prevents all manifestations of disease. Treatment begun after 2 to 3 yr may be effective only in controlling the extreme hyperactivity and intractable seizures. Children born to mothers with poorly controlled PKU (ie, they have high phenylalanine levels) during pregnancy are at high risk for microcephaly and developmental deficit.

Treatment is lifelong dietary phenylalanine restriction. All natural protein contains about 4% phenylalanine, therefore dietary staples include low-protein natural foods (eg, fruits, vegetables, certain cereals); protein hydrolysates treated to remove phenylalanine; and phenylalanine-free elemental amino acid mixtures. Examples of commercially available phenylalanine-free products include XPhe products (XP Analog for infants, XP Maxamaid for children 1 to 8 yr, XP Maxamum for children > 8 yr); Phenex I and II; Phenyl-Free I and II; PKU-1, -2, and -3; PhenylAde (varieties); Loflex; and Plexy10. Some phenylalanine is required for growth and metabolism; this is supplied by measured quantities of natural protein from milk or low-protein foods.

Frequent monitoring of plasma phenylalanine levels is required; recommended targets are between 2 mg/dL and 4 mg/dL (120 to 240 μmol/L) for children < 12 yr and between 2 mg/dL and 10 mg/dL (120 to 600 μmol/L) for children > 12 yr. Dietary planning and management need to be initiated in women of childbearing age before pregnancy to ensure a good outcome for the child.

For those with BH4 deficiency, treatment also includes tetrahydrobiopterin 1 to 5 mg/kg po tid; levodopa, carbidopa, and 5-OH tryptophan; and folinic acid 10 to 20 mg po once/day in cases of dihydropteridine reductase deficiency. However, treatment goals and approach are the same as those for PKU.

2.Disorders of Tyrosine Metabolism

Tyrosine is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved in its metabolism lead to a variety of syndromes.

Transient tyrosinemia of the newborn: Transient immaturity of metabolic enzymes, particularly 4-hydroxyphenylpyruvic acid dioxygenase, sometimes leads to elevated plasma tyrosine levels (usually in premature infants, particularly those receiving high-protein diets); metabolites may show up on routine neonatal screening for PKU. Most patients are asymptomatic, but some demonstrate lethargy and poor feeding. Tyrosinemia is distinguished from PKU by elevated plasma tyrosine levels.

Most resolves spontaneously. Symptomatic patients should have dietary tyrosine restriction (2 g/kg/day) and vitamin C 200 to 400 mg po once/day.

2.1 Tyrosinemia type I: This disorder is an autosomal recessive trait caused by deficiency of fumarylacetoacetate hydroxylase(FAH), an enzyme important for tyrosine metabolism. Disease may manifest as fulminant liver failure in the neonatal period or as indolent subclinical hepatitis, painful peripheral neuropathy, and renal tubular disorders (eg, normal anion gap metabolic acidosis, hypophosphatemia, vitamin D–resistant rickets) in older infants and children. Long-term survivors have an increased risk of liver cancer.

 

Diagnosis is suggested by elevated plasma levels of tyrosine; it is confirmed by a high level of succinylacetone in plasma or urine and by low fumarylacetoacetate hydroxylase activity in blood cells or liver biopsy specimens. Treatment with 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclo-hexanedione (NTBC) is effective in acute episodes and slows progression. A diet low in phenylalanine and tyrosine is recommended. Liver transplantation is effective.

2.2 Tyrosinemia type II: This is a rare autosomal recessive disorder caused by tyrosine transaminase deficiency. Accumulation of tyrosine causes cutaneous and corneal ulcers. Secondary elevation of phenylalanine, though mild, may cause neuropsychiatric abnormalities if not treated. Diagnosis is by elevation of tyrosine in plasma, absence of succinylacetone in plasma or urine, and by measurement of decreased enzyme activity in liver biopsy. This disease is easily treated with mild to moderate restriction of dietary phenylalanine and tyrosine.

2.3 Alkaptonuria: This is a rare autosomal recessive disorder caused by homogentisic acid oxidase deficiency; homogentisic acid oxidation products accumulate in and darken skin, and crystals precipitate in joints. The condition is usually diagnosed in adults and causes dark skin pigmentation (ochronosis) and arthritis. Urine turns dark when exposed to air because of oxidation products of homogentisic acid. Diagnosis is by finding elevated urinary levels of homogentisic acid (> 4 to 8 g/24 h). There is no effective treatment, but ascorbic acid 1 g po once/day may diminish pigment deposition by increasing renal excretion of homogentisic acid.

2.4 Oculocutaneous albinism: Tyrosinase deficiency results in absence of skin and retinal pigmentation, causing a much increased risk for skin cancer and considerable visual loss. Nystagmus is often present, and photophobia is common