أسئلة الثانية أطفال الجديدة - Inborn Errors of Metabolism (IEM)

• Inborn Errors of Metabolism (IEM) involve deficient activity of a single enzyme in a metabolic pathway.
• This results in accumulation of substrate behind the block or deficiency of the product.
• IEMs are individually rare, but collectively common, with an overall incidence greater than 1:1000.
• Majority of IEMs are inherited in an autosomal recessive manner.
• Clinical signs that indicate IEM include positive consanguinity, neonatal death or multiple abortions, and history of child with neurologic deterioration.
• Physical findings include poor oral intake, lethargy, seizures, mental retardation, failure to thrive, jaundice and skin rash.
• Ocular findings such as cataract, lens dislocation, and retinitis pigmentosa can indicate IEM.
• Laboratory investigations for IEMs can include tests for metabolic acidosis, hyperammonemia, hypoglycemia and ketosis.
• Impaired liver functions, Neutropenia and Thrombocytopenia may also be present.
• Newborn screening programs are applied in many countries for early identification of IEMs to improve long term health or survival.
• Early detection, diagnosis, and intervention can prevent death or disability that could result from IEMs.
• Blood tests include blood glucose, arterial blood gas, liver and renal function tests, and complete blood picture.
• Tests also include blood ammonia, Lactate, and Extended metabolic screen.
• Urine tests look for color, odor, pH, glucose, ketones, reducing substances, and amino acids.
• IEM management includes treatment specific to each disorder, hydration, nutrition, acid-base management, and elimination of toxic metabolites.
• Classification of IEMs includes disorders of carbohydrate metabolism, amino acid metabolism & transport, and lipid metabolism.
• Glycogen storage diseases and Galactosemia are disorders of carbohydrate metabolism.
• Phenylketonuria, Tyrosinemia, and Urea cycle disorders are disorders of amino acid metabolism & transport.
• Hypercholesterolemia and Hypertriglyceridemia are disorders of lipid metabolism.

Phenylketonuria (PKU)

• PKU is a metabolic disease characterized by decreased activity of phenylalanine hydroxylase (PAH).
• It is an autosomal recessive disorder with > 850 mutations in the PAH locus described.
• Incidence is around 1:7000 live births.
• The national neonatal screening program in Egypt started November 2015.
• PKU is mostly identified by NBS (3-5 days) by the presence of elevated Phenylalanine
• Tandem mass spectrometry can test
• Prenatal diagnosis and family counseling includes PAH gene DNA analysis on CVS or amniocentesis.
• Clinical manifestations may not be evident at birth, with onset at 3-4 months.
• General signs include light sensitivity, hair loss, and an increased risk of pyogenic infection.
• Skin symptoms include fair skin and hair due to impaired melanin synthesis, and eczema.
• CNS symptoms include microcephaly, with epilepsy incidence 25%, tremor 30%, and EEG abnormalities 80%. Behavioral problems and Parkinsonian signs can also be present.

Galactosemia

• Galactosemia is an inherited defect of galactose metabolism due to enzyme deficiency which prevents proper metabolism of galactose.
• The galactose-1-phosphate uridyl transferase (GALT) enzyme is affected.
• Main dietary source of galactose is lactose, found in all forms of milk.
• Infants with galactosemia may appear normal at birth, but develop symptoms within a few days post milk feedings. Symptoms can become very severe if left untreated
• Symptoms include poor growth, jaundice, bleeding, liver issues, cataracts, lethargy, hypotonia, and sepsis caused by E. coli and brain edema,
• Newborn screening is designed to detect classical galactosemia due to deficient galactose-1-phosphate uridyl transferase (GALT) enzyme
• Initial testing determines the level of galactose in the blood specimen, when an elevated level is detected
• Another test is performed to measure erythrocyte GALT enzyme activity.
• Prenatal Diagnosis is preformed by assay of GALT activity in cultured amniotic fluid cells or Genetic testing on CVS or amniotic fluid sample.

Maple Syrup Urine Disease (MSUD)

• MSUD is known as branched-chain ketoaciduria due to a deficiency of branched-chain alpha-keto acid dehydrogenase (BCKD).
• This enzyme defect affects the catabolic pathway of leucine, isoleucine, and valine.
• Infants appear normal at birth, with symptoms developing in neonates around 3-7 days old.
• Breastfeeding may delay symptoms until the second week of life.
• Symptoms include lethargy, decreased nursing, emesis, and a characteristic maple syrup smell in the urine.
• Other symptoms may include fussiness, hypotonia/hypertonia, high-pitched cry and seizures.
• Non-classic MSUD presents with intermediate intermittent maple syrup urine disease.
• Symptoms more mild, and harder to notice early.
• A burnt maple sugar smell may be noticeable in diaper after it has dried.
• Plasma amino acids testing should be performed to see elevated levels of branched-chain amino acids (BCAAs).
• This test also can detect l-alloisoleucine derived from l-isoleucine.
• Urine organic acids can also be tested to detect abnormalities.
• BCKD enzyme activity can be measured in lymphocytes or cultured fibroblasts.
• Molecular testing should be pursued in all diagnosed with maple syrup urine disease to confirm.
• Prenatal diagnosis involves measuring BCKD enzyme activity in cultured amniocytes or chorionic villus cells through mutation analysis.
• Molecular analysis is the most reliable and preferred method for prenatal diagnosis of MSUD.
• For most IEMs, the prognosis for survival or normal neurological outcome is guarded.
• Outcomes will likely improve with pre-symptomatic diagnosis (prenatal or expanded neonatal screening).