• Information
  1. Tests Recommended by ACMG Task Force
  2. Hypothyroidism
  3. Phenylketonuria
  4. Galactosemia
  5. Hemoglobinopathies
  6. Maple Syrup Urine Disease
  7. Homocystinuria
  8. Other Genetic Disorders
• Resources

A. Tests Recommended by ACMG Task Force [1]

1. Disorders of Organic-Acid Metabolism
   1. Isovaleric acidemia
   2. Glutaric aciduria type I
   3. 3-Hydroxy-3-methylglutaric aciduria
   4. Multiple carboxylase deficiency
   5. Methylmalonic acidemia, mutase deficiency form
   6. 3-Methylcrotonyl-CoA carboxylase deficiency
   7. Methylmalonic acidemia, Cbl A and Cbl B forms
   8. Propionic acidemia
   9. beta-ketohiolase deficiency
2. Disorders of Fatty Acid Metabolism
   1. Medium chain acyl-CoA dehydrogenase deficiency
   2. Very long-chain acyl-CoA dehydrogenase deficiency
   3. Long-chain L-3-hydroxy acyl-CoA dehydrogenase deficiency
   4. Trifunctional protein deficiency
   5. Carnitine uptake defect
3. Disorders of Amino Acid Metabolism
   1. Phenylketonuria (PKU)
   2. Maple Syrup Urine Disease
   3. Homocystinuria
   4. Citrullinemia
   5. Arginosuccinic acidemia
   6. Tyrosinemia type I
4. Hemoglobinopathies
   1. Sickle cell anemia
   2. Hemoglobin S-ß-thalassemia
   3. Hemoglobin SC disease
5. Other Disorders
   1. Congenital Hypothyroidism
   2. Biotinidase Deficiency
   3. Galactosemia
   4. Hearing Deficiency
   5. Cystic Fibrosis
   6. Congenital Adrenal Hyperplasia
6. Genomic applications will likely increase genetic testing considerably [2]

B. Hypothyroidism

1. ~1:5000 live births
2. Diagnosis made with TSH and T4 levels
3. Failure to treat: irreversible mental retardation, growth failure, neurologic, cretinism

C. Phenylketonuria (PKU) [6]

1. Autosomal recessive trait occurs in ~1:10,000 live births in North America
2. Cannot metabolize phenylalanine
3. About 50% of patients have mild phenotypes
   1. Normal Phe blood levels 1.3-2.0mg/dL (80-120µmol/L)
   2. Mild hyperphenylalaninemia Phe blood levels 3-10mg/dL
   3. Atypical / mild PKU: 10-20mg/dL
   4. Classical PKU: >20mg/dL
4. Failure to treat: irreversible mental retardation
5. Treatment
   1. Low Phe containing diet
   2. Vegan-vegetarian fare: no meat, milk, cheese, eggs, nuts or bread AND
   3. Synthetic Phe-free formula with fats, essential amino acids, vitamins, minerals
   4. Risk of general and specific nutritional deficiencies and these should be monitored
   5. Frequent measurements of blood Phe levels recommended
   6. Treated patients are living >40 years with fairly normal lives
6. Maternal PKU [3]
   1. Untreated maternal PKU increases risk for developmental problems in offspring
   2. This is particularly a problem during the first trimester
   3. Treatment during pregnancy may reduce developmental problems
   4. Women should maintain Phe blood levels <10mg/dL during pregnancy

D. Galactosemia

1. Cannot metabolize galactose (galactase deficiency)
2. ~1:60,000 live births
3. Failure to treat: irreversible mental retardation, liver disease, vomiting, cataracts

E. Hemoglobinopathies

1. Abnormalities in hemoglobulin sequences (quality) and/or gene expression (quantity)
2. Mutations in hemoglobin gene expression lead to thalassemia diseases
3. Mutations in actual protein sequence of hemoglobin lead to abnormal red blood cells

F. Maple Syrup Urine Disease

1. Autosomal recessive, 1:200,000 live births
2. Disorder of branched chain amino acid metabolism
3. Accumulation of amino and oxoacids
4. Failure to treat: metabolic acidosis, hypoglycemia, death

G. Homocystinuria [4]

1. Autosomal recessive disease, 1:180,000
2. Absence of or severe decrease in cystathionine ß-synthase
3. Therefore, patients cannot convert homocysteine to cysteine
   1. High serum levels of homocysteine lead to disease pathology
   2. Pyridoxine (vitamin B6) is cofactor for cystathionine ß-synthase
   3. Vitamin B12 (cobalamin) and folic acid are cofactors for one recycling pathway
   4. betaine, a choline derivative, is cofactor for the other homocysteine recycling pathway
4. Signs and Symptoms of Untreated Homocystinuria
   1. Marfenoid appearance with stiff enlarged joints
   2. Thrombotic events
   3. Premature Atherosclerosis
   4. Osteoporosis
   5. Lens dislocation
   6. Psychosis
5. ~20% of patients will have a thromboembolic event by age 20
6. Management
   1. High intake of pyridoxine, folic acid and vitamin B12 intake - ~50% patients respond
   2. Add betaine (Cystadane®) 3gm (or higher) po bid [5]
   3. betaine substantially decreases plasma homocysteine levels and is well tolerated [5]
   4. A low methionine or decreased protein diet may also be beneficial

H. Other Genetic Disorders

1. Testing required in some states include:
2. Biotinase deficiency
3. Congenital Adrenal Hyperplasia
4. Tyrosinemia
5. Cystic Fibrosis - abnormal chloride channel
6. Congenital Toxoplasmosis

Resources

Apgar Score

References

1. Natowicz M. 2005. NEJM. 353(9):867
2. Collins FS. 1999. NEJM. 341(1):28
3. Waisbren SE, Hanley W, Levy HL, et al. 2000. JAMA. 283(6):756
4. Robinson K, Mayer E, Jacobsen DW. 1994. Clev Clin J Med. 61(6):438
5. betaine. 1997. Med Let. 39(993):12
6. Hanley WB. 2004. Am J Med. 117(8):591