GALACTOSEMIA AND PHENYLKETONURIA

GALACTOSEMIA AND PHENYLKETONURIA

Introduction

            Cell metabolism is a complex progression of chemical  changes that determines the final use of  nutrients in the body. Cell metabolism  has two phases catabolism and anabolism. Basal body metabolism  refers to the energy that the resting  body needs to  maintain life. To maintain  an activity  level, a person  needs energy above and beyond the basal metabolic rate. Some  metabolic anomalies are inherited and some are acquired  many can be treated with dietary changes

Inborn errors of metabolism

             It  comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases.

·         Disorders of carbohydrate metabolism

o    E.g., glycogen storage disease , galactosemia

·         Disorders of amino acid metabolism

o    E.g., phenylketonuria , maple syrup urine disease, glutaric acidemia type 1

·         Disorders of organic acid metabolism (organic acidurias)

o    E.g., alcaptonuria

·         Disorders of fatty acid oxidation and mitochondrial metabolism

o    E.g., medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)

·         Disorders of porphyrin metabolism

o    E.g., acute intermittent porphyria

·         Disorders of purine or pyrimidine metabolism

o    E.g., Lesch-Nyhan syndrome

·         Disorders of steroid metabolism

o    E.g., congenital adrenal hyperplasia

·         Disorders of mitochondrial function

o    E.g., Kearns-Sayre syndrome

·         Disorders of peroxisomal function

o    E.g., Zellweger syndrome

·         Lysosomal storage disorders

o    E.g., Gaucher's disease

o    E.g., Niemann Pick disease

Galactosemia

            Galactosemia is caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive deficits, cataracts, and premature ovarian failure. Diagnosis is by enzyme analysis of RBCs. Treatment is dietary elimination of galactose. Physical prognosis is good with treatment, but cognitive and performance parameters are often subnormal.

Galactose is found in dairy products, fruits, and vegetables; autosomal recessive enzyme deficiencies cause 3 clinical syndromes.

Galactose-1-phosphate uridyl transferase deficiency:

            This deficiency causes classic galactosemia. Incidence is 1/62,000 births; carrier frequency is 1/125. Infants become anorectic and jaundiced within a few days or weeks of consuming breast milk or lactose-containing formula. Vomiting, hepatomegaly, poor growth, lethargy, diarrhea, and septicemia (usually Escherichia coli) develop, as does renal dysfunction (eg, proteinuria, aminoaciduria, Fanconi syndrome), leading to metabolic acidosis and edema. Hemolytic anemia may also occur. Without treatment, children remain short and develop cognitive, speech, gait, and balance deficits in their teenage years; many also have cataracts, osteomalacia (caused by hypercalciuria), and premature ovarian failure. Patients with the Duarte variant have a much milder phenotype.

Galactokinase deficiency:

            Patients develop cataracts from production of galactitol, which osmotically damages lens fibers; idiopathic intracranial hypertension (pseudotumor cerebri) is rare. Incidence is 1/40,000 births.

Uridine diphosphate galactose 4-epimerase deficiency:

             There are benign and severe phenotypes. Incidence of the benign form is 1/23,000 births in Japan; no incidence data are available for the more severe form. The benign form is restricted to RBCs and WBCs and causes no clinical abnormalities. The severe form causes a syndrome indistinguishable from classic galactosemia, although sometimes with hearing loss.

Diagnosis

Diagnosis is suggested clinically and supported by elevated galactose levels and the presence of reducing substances other than glucose (eg, galactose, galactose 1-phosphate) in the urine; it is confirmed by enzyme analysis of RBCs, hepatic tissue, or both. Most states require that neonates be screened for galactose-1-phosphate uridyl transferase deficiency.

Treatment

Treatment is elimination of all sources of galactose in the diet, most notably lactose, which is a source of galactose present in all dairy products, including milk-based infant formulas and a sweetener used in many foods. A lactose-free diet prevents acute toxicity and reverses some manifestations (eg, cataracts) but may not prevent neurocognitive deficits. Many patients require supplemental Ca and vitamins. For patients with epimerase deficiency, some galactose intake is critical to ensure a supply of uridine-5′-diphosphate-galactose (UDP-galactose) for various metabolic processes.

PHENYLKETONURIA

            Phenylketonuria (PKU is an inborn error in amino acid metabolism. It result in high serum levels of phenylalanine increased urine concentrations of phenylalanine and its by products, cerebral damage, and mental retardation. It is also called phenylalaninemia and phenyalpyruvic  oligophrenia.

Causes

            PKU is transmitted through an autosomal recessive  gene. Patietns with classic PKU, the most common and clinically important of the hyperphenylalaninemias, have almost totally deficient activity of phenylalanine hydroxylase, an enzyme that acts as a catalyst  in the conversion of phenylalanine to tyrosine. As a result phenylalanine accumulates in the blood and  urine and reduced  tyrosine formation results.

Pathophysiology

            The most serious genetic disorder involving  phenylalamine metabolism is phenylketonuria.

In Classic PKU absence of phenylalamine hydroxylase from liver cells prevents the conversion of phenylalanine to tyrosine . Phenylalanine accumulates in the blood and some is converted to phenylpyruvic acid, phenyllactic acid, or phenylacetic acid. These compounds  are excreted in the urine giving it a characteristic musty odor. The excess of phenylalamine and its by products in the  blood results in various metabolic disturbances, especially alterations in nervous system development including delayed psychomotor development, seizures hyperactivity and mental retardation. In addition excess phenylalanine in the blood inhibits the activity of tyrosinase. Because this enzyme is necessary for the synthesis of melanin an catecholamine.

The most commonly used test  the Guthrie bacterial inhibition assay which indicates phenylalanine level in the blood is not positive until the infant has consumed enough protein to allow phenylalanine build up.

Signs and symptoms

ü  Mental retardation

ü  Seizures

ü  Decrease in IQ in the first year of life

ü  Blue eyes

ü  Macrocephaly

ü  Eczematous skin lesions

ü  Rough skin

ü  Hyper active and irritable

ü  Shows purposeless

ü  Repetitive motions

ü  Awakward  gait

ü  Must odor from the skin

ü  Urinary exretion.

Diagnostic tests

The Guthrie on a capillary blood sample is used to reliably detect the disorder.

Treatment

                  To prevent or minimize  brain damage phenylalanine  blood levels are kept between 3 and 9 mg/dl by restricting dietary intake of the amino acid phenylalanine. During the first month of life, a special low phenylalanine, amino acid mixture is substituted for most of the protein in the diet, supplemented with a small amount of natural foods. An enzymatic hydrolysate of case in, such as lofenalac powder or progestimil powder is substituted for milk in the diets of affected infants. Dietary restrictions will probably continue throughout life.