IEM

• Phenylketonuria (PKU)


  Defect in amino acid metabolism
• Tyrosinemia type 1


  Defect in amino acid metabolism
• Maple syrup urine disease


  Defect in amino acid metabolism
• Characteristics of phenylketonuria (PKU), tyrosinemia type 1, and maple syrup urine disease are summarized in Table 5-5
• Homocystinuria


  Autosomal recessive disorder caused by cystathionine β-synthase deficiency, resulting in increased levels of homocysteine and methionine
• Homocystinuria


  • Marfanoid body habitus (tall, slender), scoliosis, and pes planus
  • Myopia. High risk for lens dislocation. Note that in Marfan syndrome, the lens more often dislocates superiorly, whereas in homocystinuria, the lens more often dislocates inferiorly
  • Developmental delay, with variable intellectual disability
  • Thromboembolism can occur in any vessel, increasing the risk of stroke and systemic thrombosis, as well as developmental delay
• If a patient is developmentally delayed and has a marfanoid habitus, perform screening tests for homocystinuria. Homocystinuria screening should also be performed in patients who test negative for Marfan syndrome.
• Management of Homocystinuria


  1. Special diet (methionine restricted, cystine enhanced)

  2. Betaine therapy (lowers homocysteine levels and reduces risk for thromboembolism)

  3. Some patients are responsive to treatment with vitamin B6
• Urea cycle disorders (UCDs)


  Result from deficiencies in one of the enzymes involved in the urea cycle. The urea cycle is responsible for the metabolism of excess nitrogen into urea. Defects in the urea cycle result in accumulation of ammonia, which is toxic, especially to the nervous system.
• Ornithine transcarbamylase (OTC) deficiency

  Most common of the UCDs, with X-linked recessive inheritance
• OTC deficiency


  • Male infants become symptomatic in first 48 hours of life with poor feeding, hypotonia, and hyperventilation, which can rapidly progress to lethargy, coma, and seizures
• Management of OTC deficiency

  Includes a low-protein diet and modalities to decrease ammonia levels. Medications can "scavenge" ammonia (e.g., sodium benzoate binds with ammonia and provides an alternative pathway to excrete nitrogen). For severe episodes of hyperammonemia, hemodialysis and/or liver transplant may be indicated.
• Prognosis of OTC deficiency is variable, depending on the severity of hyperammonemic episodes. In most cases, at least some degree of developmental delay and intellectual disability will be present.
• Transient hyperammonemia of the newborn

  A self-limited disease that may present in premature infants within the initial 24–48 hours of life. Symptoms are nonspecific and can be similar to those of a UCD. Aggressive treatment of hyperammonemia is required to prevent neurologic sequelae.
• Organic acidemias


  The most common organic acidemias are caused by abnormal amino acid catabolism of branched-chain amino acids, and are characterized by urinary excretion of nonamino organic acids.
• Propionic aciduria (PA) and methylmalonic aciduria (MMA)

  Typically present after the first few days of life with vomiting, poor feeding, hypotonia, and other neurologic symptoms, which will progress if left untreated. Laboratory studies show metabolic acidosis, hyperammonemia, and ketotic hypoglycemia. Hyperammonemia results from inhibition of one of the urea cycle enzymes, and measurement of urine organic acids will diagnose the disorders.
• Isovaleric acidemia


  Presentation is similar to PA and MMA. Patient may also have an odor of sweaty feet.
• Glutaric acidemia type I

  This diagnosis should be considered in any infant with macrocephaly, basal ganglia changes on magnetic resonance imaging (MRI), and a movement disorder exacerbated by intercurrent illness.