Abstract
Homocystinuria, caused by cystathionine β-synthase deficiency, is a rare inherited disorder involving metabolism of methionine. Impaired synthesis of cystathionine leads to accumulation of homocysteine that affects several organ systems leading to abnormalities in the skeletal, cardiovascular, ophthalmic and central nervous systems. We report a 14-month-old and a 7-year-old boy who presented with neurologic dysfunction and were found to have cerebral venous sinus thromboses on brain magnetic resonance imaging (MRI)/magnetic resonance venogram (MRV) and metabolic and hypercoagulable work-up were consistent with classic homocystinuria. The 14-month-old boy had normal newborn screening. The 7-year-old boy initially had an abnormal newborn screen for homocystinuria but second tier test that consisted of total homocysteine was normal, so his newborn screen was reported as normal. With the advent of expanded newborn screening many treatable metabolic disorders are detected before affected infants and children become symptomatic. Methionine is the primary target in newborn screening for homocystinuria and total homocysteine is a secondary target. Screening is usually performed after 24–48 h of life in most states in the US and some states perform a second screen as a policy on all tested newborns or based on when the initial newborn screen was performed. This is done in hopes of detecting infants who may have been missed on their first screen. In the United Kingdom, NBS using dried blood spot is performed at 5 to 8 days after birth. It is universally known that methionine is a poor target and newborn screening laboratories have used different cutoffs for a positive screen. Reducing the methionine cutoff increases the sensitivity but not necessarily the specificity of the test and increasing the cutoff will miss babies who may have HCU whose levels may not be high enough to be detected at their age of ascertainment. It is not clear whether adjusting methionine level to decrease the false negative rates combined with total homocysteine as a second-tier test can be used effectively and feasibly to detect newborns with HCU. Between December 2005 and December 2020, 827,083 newborns were screened in Kentucky by MS/MS. Kentucky NBS program uses the postanalytical tools offered by the Collaborative Laboratory Integrated Reports (CLIR) project which considers gestational age and birthweight. One case of classical homocystinuria was detected and two were missed on first and second tier tests respectively. The newborn that had confirmed classical homocystinuria was one of twenty-three newborns that were referred for second tier test because of elevated methionine (cutoff is >60 µmol/L) and/or Met/Phe ratio (cutoff is >1.0); all 23 dried blood spots had elevated total homocysteine. One of the subjects of this case report had a normal methionine on initial screen and the other had a normal second-tier total homocysteine level. The performance of methionine and total homocysteine as screening analytes for homocystinuria suggest that it may be time for newborn screening programs to consider adopting next generation sequencing (NGS) platforms as alternate modality of metabolic newborn screening. Because of cost considerations, newborn screening programs may not want to adopt NGS, but the downstream healthcare cost incurred due to missed cases and the associated morbidity of affected persons far exceed costs to newborn screen programs. Since NGS is becoming more widely available and inexpensive, it may be feasible to change testing algorithms to use Newborn Metabolic NGS as the primary mode of testing on dry blood specimens with confirmation with biochemical testing. Some commercial laboratories have Newborn Screening Metabolic gene panel that includes all metabolic disorders on the most comprehensive newborn screening panel in addition to many other conditions that are not on the panel. A more targeted NGS panel can be designed that may not cost much and eventually help avoid the pitfalls associated with delayed diagnosis and cost of screening.
Highlights
The homocystinurias are a heterogeneous group of metabolic disorders due to defects in the methionine metabolic cycle [1]
Classical homocystinuria due to cystathionine β-synthase deficiency affects an estimated 1 in 200,000 newborns in the US, but the true prevalence may be much higher since current newborn screening protocols that utilize methionine and, in many screening programs, total homocysteine as a second-tier test, may fail to identify all newborns affected by the disorder [6,7]
It is estimated that about 50% of CBS patients respond to vitamin B6 supplementation but almost all infants identified by newborn screening (NBS) are B6 non-responsive, so it is likely that many pyridoxine (B6 ) responsive patients who are more severely affected are either undiagnosed or have been clinically diagnosed but late treated
Summary
The homocystinurias are a heterogeneous group of metabolic disorders due to defects in the methionine metabolic cycle [1]. Classical homocystinuria due to cystathionine β-synthase deficiency affects an estimated 1 in 200,000 newborns in the US, but the true prevalence may be much higher since current newborn screening protocols that utilize methionine and, in many screening programs, total homocysteine as a second-tier test, may fail to identify all newborns affected by the disorder [6,7]. Methionine is the primary screening target but because of missed cases often due to high cutoffs, a few states have lowered the cutoff for methionine and use total homocysteine as a second-tier test in newborns whose methionine was borderline or above the cutoff level on primary screening [9] Even with these adjustments of methionine levels, some infants may be missed, and testing protocols should be considered to identify these individuals who are missed because of problems associated with reference ranges or who may not have sufficiently elevated. We discuss some of the known pitfalls associated with biochemical targets that current newborn screening programs utilize, including postanalytical tools to detect newborns with classical homocystinuria, and provide suggestions for adoption of other modalities of testing to minimize morbidity to patients and health care cost
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