The goal of newborn screening (NBS) is to detect potentially fatal or disabling conditions in newborns, thereby providing a window of opportunity for early treatment, often while the child is still asymptomatic. Such early detection and treatment can have a profound impact on the clinical severity of the condition in the affected child. If left undiagnosed and untreated, the consequences of the targeted disorders can be dire, many causing irreversible neurological damage, intellectual, developmental and physical disabilities, and even death. In 2006, the American College of Medical Genetics (ACMG) developed newborn screening guidelines that recommend that all newborn infants be screened for 29 "core conditions" and that 26 secondary conditions identified during the core evaluations be reported as part of the Recommended Uniform Screening Panel (RUSP). These recommendations have been accepted by the HHS Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) (authorized by the Children's Health Act of 2000), and by the Secretary of HHS. Since acceptance of the core conditions, 6 additional conditions have been added. Most states now use this or very similar panels for newborn screening. Currently, there are thousands of rare disorders that have been identified and hundreds that could potentially benefit from newborn screening. Classic homocystinuria (often abbreviated as HCU) is the most common genetic disorder of sulfur metabolism and is inherited in an autosomal recessive manner. This disorder is caused by deficiency of the cystathionine beta-synthase enzyme and is characterized by visual changes, skeletal problems, vascular changes, and problems in the central nervous system. Its metabolic hallmark is an increased excretion of homocysteine in the urine and elevated levels of homocysteine (HCY) in the plasma and other tissues. Treatment includes the dietary protein/methionine restriction, and supplementation with B vitamins and/or betaine. Early intervention appears to make a significant difference in reducing complications and improving outcomes. There is a milder and later-onset form, associated with less severe mutations in the causative gene, characterized as pyridoxine-responsive. Although known to be rare, the prevalence of HCU ranges from 1/20,000-1/344,000; however, due to a founder effect and high rates of consanguinity in Qatar, the prevalence rate is 1/1800 in that country, and the disease is a classic severe form. HCU is a primary condition that was adopted at the inception of the RUSP. Each state in the United States screens for classic homocystinuria in newborns, typically by measuring elevated methionine (Met) using tandem mass spectrometry (TMS) on dried blood spots. However, Met is a surrogate metabolite for HCY, and may not be elevated in the immediate postnatal period depending on the age and nutritional status of the infant; if a baby has had minimal di...