Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.5 and 2 per million live births. On the basis of small case series and sibling data, presymptomatic treatment with oral supplements of creatine, ornithine, and sodium benzoate, and a protein-restricted diet to reduce arginine intake, appear to substantially improve health and developmental outcomes. Without newborn screening, diagnosis typically happens after the development of significant impairment, when treatment has limited utility. GAMT deficiency newborn screening can be incorporated into the tandem-mass spectrometry screening that is already routinely used for newborn screening, with about 1 per 100 000 newborns screening positive. After a positive screen, diagnosis is established by finding an elevated guanidinoacetate concentration and low creatine concentration in the blood. Although GAMT deficiency is significantly more rare than other conditions included in newborn screening, the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023.

Implementation of Newborn Screening for Conditions in the United States First Recommended during 2010-2018.

The Recommended Uniform Screening Panel (RUSP) is the list of conditions recommended by the US Secretary of Health and Human Services for inclusion in state newborn screening (NBS). During 2010-2022, seven conditions were added to the RUSP: severe combined immunodeficiency (SCID) (2010), critical congenital heart disease (CCHD) (2011), glycogen storage disease, type II (Pompe) (2015), mucopolysaccharidosis, type I (MPS I) (2016), X-linked adrenoleukodystrophy (X-ALD) (2016), spinal muscular atrophy (SMA) (2018), and mucopolysaccharidosis, type II (MPS II) (2022). The adoption of SCID and CCHD newborn screening by programs in all 50 states and three territories (Washington, D.C.; Guam; and Puerto Rico) took 8.6 and 6.8 years, respectively. As of December 2022, 37 programs screen for Pompe, 34 for MPS I, 32 for X-ALD, and 48 for SMA. The pace of implementation based on the average additional number of NBS programs per year was most rapid for SMA (11.3), followed by CCHD (7.8), SCID (6.2), MPS I (5.4), Pompe (4.9), and X-ALD (4.7).

Evidence and recommendation for mucopolysaccharidosis type II newborn screening in the United States.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.

Health and economic outcomes of newborn screening for infantile-onset Pompe disease.

PURPOSE: To estimate health and economic outcomes associated with newborn screening (NBS) for infantile-onset Pompe disease in the United States. METHODS: A decision analytic microsimulation model simulated health and economic outcomes of a birth cohort of 4 million children in the United States. Universal NBS and treatment was compared with clinical identification and treatment of infantile-onset Pompe disease. Main outcomes were projected cases identified, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) over the life course. RESULTS: Universal NBS for Pompe disease and confirmatory testing was estimated to cost an additional $26 million annually. Additional medication costs associated with earlier treatment initiation were $181 million; however, $8 million in medical care costs for other services were averted due to delayed disease progression. Infants with screened and treated infantile-onset Pompe disease experienced an average lifetime increase of 11.66 QALYs compared with clinical detection. The ICER was $379,000/QALY from a societal perspective and $408,000/QALY from the health-care perspective. Results were sensitive to the cost of enzyme replacement therapy. CONCLUSION: Newborn screening for Pompe disease results in substantial health gains for individuals with infantile-onset Pompe disease, but with additional costs.

Cognitive outcomes and age of detection of severe mucopolysaccharidosis type 1.

The US Secretary of Health and Human Services recommended in February 2016 that mucopolysaccharidosis type 1 (MPS I) be added to the recommended uniform screening panel for state newborn screening programs. One of the key factors in this decision was the evidence suggesting that earlier treatment with hematopoietic cell transplantation (HCT) for the most severe form, Hurler syndrome (MPS IH), would lead to improved cognitive outcomes. Consistent evidence from peer-reviewed studies suggests that transplantation in the first year of life is associated with improved developmental quotient or intelligence quotient and continued cognitive growth, with earlier age of treatment associated with improved outcomes. However, available evidence suggests that cognitive functioning and attention can still lag behind unaffected age-matched children, leading to the need for special education services. Verbal and nonverbal cognitive abilities outcomes may be affected differently by HCT. With the recent addition of MPS I to the recommended uniform screening panel, future work is needed to evaluate the impact of earlier, presymptomatic detection and treatment initiation and other supportive therapies on cognitive outcomes.Genet Med advance online publication 26 January 2017.

Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation.

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.Genet Med 19 1, 121-126.

Decision-making process for conditions nominated to the recommended uniform screening panel: statement of the US Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children.

PURPOSE: The US Secretary of Health and Human Services provides guidance to state newborn screening programs about which conditions should be included in screening (i.e., the "Recommended Uniform Screening Panel"). This guidance is informed by evidence-based recommendations from the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. This report describes the Advisory Committee's revised decision-making process for considering conditions nominated to the panel. METHODS: An expert panel meeting was held in April 2012 to revise the decision matrix, which helps to guide the recommendation process. In January 2013, the Advisory Committee voted to adopt the revised decision matrix. RESULTS: The revised decision matrix clarifies the approach to rating magnitude and certainty of the net benefit of screening to the population of screened newborns for nominated conditions, and now includes the consideration of the capability of state newborn screening programs for population-wide implementation by evaluating the feasibility and readiness of states to adopt screening for nominated conditions. CONCLUSION: The revised decision matrix will bring increased quality, transparency, and consistency to the process of modifying the recommended uniform screening panel and will now allow formal evaluation of the challenges that state newborn screening programs face in adopting screening for new conditions.

The Case for Examining and Treating the Combined Effects of Parental Drug Use and Interparental Violence on Children in their Homes.

This review examines what have been, to this point, generally two divergent lines of research: (a) effects of parental drug abuse on children, and (b) effects of children's exposure to interparental violence. A small, but growing body of literature has documented the robust relationship between drug use and intimate partner violence. Despite awareness of the interrelationship, little attention has been paid to the combined effect of these deleterious parent behaviors on children in these homes. Thus, we argue for the need to examine the developmental impact of these behaviors (both individually and combined) on children in these homes and for treatment development to reflect how each of these parent behaviors may affect children of substance abusers.

Computer-assisted cognitive rehabilitation for the treatment of patients with substance use disorders: a randomized clinical trial.

The purpose of this study was to examine the comparative efficacy of cognitive rehabilitation as an intervention for substance misuse. Patients with substance use disorders entering long-term residential care (N = 160) were randomly assigned to one of two conditions: (a) standard treatment plus computer-assisted cognitive rehabilitation (CACR), which was designed to improve cognitive performance in areas such as problem solving, attention, memory, and information processing speed; and (b) an equally intensive attention control condition consisting of standard treatment plus a computer-assisted typing tutorial (CATT). Participants were assessed at baseline, during treatment, at treatment completion, and 3-, 6-, 9-, and 12-month follow-up. Intent-to-treat analyses showed that, compared with those randomized to CATT, patients who received CACR were significantly more engaged in treatment (e.g., higher ratings of positive participation by treatment staff, higher ratings of therapeutic alliance), more committed to treatment (e.g., longer stays in residence) and reported better long-term outcomes (e.g., higher percentage of days abstinent after treatment). Mediational analyses revealed the positive comparative effect of CACR on abstinence during the year after treatment was mediated by treatment engagement and length of stay in residence.

Parent training with behavioral couples therapy for fathers' alcohol abuse: effects on substance use, parental relationship, parenting, and CPS involvement.

This pilot study examined effects of Parent Skills with Behavioral Couples Therapy (PSBCT) on substance use, parenting, and relationship conflict among fathers with alcohol use disorders. Male participants (N = 30) entering outpatient alcohol treatment, their female partners, and a custodial child (8 to 12 years) were randomly assigned to (a) PSBCT; (b) Behavioral Couples Therapy (BCT); or (c) Individual-Based Treatment (IBT). Children were not actively involved in treatment. Parents completed measures of substance use, couples' dyadic adjustment, partner violence, parenting, and Child Protection Services (CPS) involvement at pretreatment, posttreatment, 6- and 12-month follow-up. PSBCT was comparable to BCT on substance use, dyadic adjustment, and partner violence; both groups showed clinically meaningful effects over IBT. Compared to BCT, PSBCT resulted in larger effect sizes on parenting and CPS involvement throughout follow-up. PSBCT for fathers may enhance parenting couple- or individual-based treatment, and warrant examination in a larger, randomized efficacy trial.

Behavioral couple therapy for gay and lesbian couples with alcohol use disorders.

Gay (n = 52) and lesbian (n = 48) patients with alcohol use disorder (AUD) and their non-substance-abusing same-sex relationship partners were randomly assigned to equally intensive interventions consisting of (a) behavioral couples therapy (BCT) plus individual-based treatment (IBT) or (b) IBT only. This study reports two separate trials, one with gay male participants and one with lesbian female participants. For both gay and lesbian patients with AUD, those who received BCT had a significantly lower percentage of days of heavy drinking during the year after treatment than patients who received IBT only. In addition, both gay and lesbian couples who received BCT reported higher levels of relationship adjustment at the end of treatment and in the year after treatment than those who received IBT only. Thus, the response of gay and lesbian couples with an alcoholic member to BCT was consistent with what has been observed with heterosexual couples.

Perceived neighborhood safety and depressive symptoms among African American crack users.

This study examined the association between perceived neighborhood safety and depressive symptoms among 443 out-of-treatment African American crack cocaine users interviewed between 2000 and 2002 in North Carolina and tested the regression of depression on perceived neighborhood safety and common predictors of depression. Perceived neighborhood safety was an important predictor of depressive symptoms in models that adjusted for other correlates of depression. The findings are limited by the cross-sectional nature of the data and the complex etiology and course of depression. Additional research is needed to clarify the relationship between perceived neighborhood safety and depression. The study was supported by the National Institute on Drug Abuse.

Gender differences in the impact of social support on crack use among African Americans.

This article examines the influence of social support on crack use in a sample of 435 African American out-of-treatment crack users recruited through street outreach in Raleigh, North Carolina, between 2000 and 2002. Multivariate regression models indicated that social support was not a strong influence on crack use. For women, no social support variables predicted crack use, whereas for men, having a non-using partner was negatively associated with crack use. Findings indicate that existing social support is not strongly linked to drug use among African Americans, but African American men may be positively influenced by non-using sexual partners. Limitations of the sample and data are discussed. Further research is needed on the influence of social support for African American drug-using populations.

Correlates of HIV-related risk behaviors in African American adolescents from substance-using families: patterns of adolescent-level factors associated with sexual experience and substance use.

PURPOSE: To examine adolescent-level correlates of HIV-related risk behaviors among urban African American adolescents whose mothers use crack cocaine. METHODS: Interviews were conducted with 208 African American adolescents (aged 12-17 years) to assess psychosocial, behavioral, and perceived environment correlates of HIV-related risk behavior. Adolescents were children of community-recruited African American women not currently in drug treatment who reported crack cocaine use (in last 6 months). Bivariate and multivariate regression models were used to evaluate associations among adolescent-level factors, sexual experience, and substance use. RESULTS: Of the adolescents, 30% reported being sexually experienced, and 23% reported alcohol or drug use in the past month. Older age and lower school satisfaction were associated with both sexual experience and substance use, but no other factors were associated with both risk behaviors. Male gender, current substance use, high HIV/AIDS knowledge, and high risk perception were associated with being sexual experienced. Sexual experience and lower expectations for future life outcomes were associated with substance use. A general pattern of protective factors related to attitudes about future goals, help-seeking behavior, and positive feelings about school emerged for substance use. CONCLUSIONS: These results suggest that the patterns of adolescent-level risk and protective factors for sexual experience and substance use may be unique in African American adolescents from substance-abusing families. Instead of an increase in problem behaviors associated with using substances, protective factors were evident, suggesting these adolescents may have resiliency for dealing with environmental stressors related to substance use. Implications for HIV prevention programs involving mentoring and goal development are discussed.

Children of African-American mothers who use crack cocaine: parenting influences on youth substance use.

OBJECTIVE: To examine relationships between parenting behaviors, parent-child relationship, and moderating effects of age on youth substance use among a community sample of African-American mothers who use crack cocaine and their children (12-17 years). METHODS: Maternal-child dyads (n = 208) were recruited through street outreach and snowball sampling and completed interviews about substance use and parenting. RESULTS: Regression analyses found significant main effects of youth age, family conflict, warmth, and disapproval of youth substance use on children's substance use. Age x Parenting interactions were significant for conflict and disapproval. Higher family conflict increased older youths' risk, while higher perceived maternal disapproval protected against substance use for older youth. CONCLUSIONS: Family influences may offer risk and protective effects for adolescent children of maternal drug users. Outreach and family-focused interventions that address family conflict and communication of disapproval of substance use may help reduce intergenerational risk transmission. However, longitudinal research with comprehensive parenting assessments is needed.

African-American crack abusers and drug treatment initiation: barriers and effects of a pretreatment intervention.

BACKGROUND: Individual and sociocultural factors may pose significant barriers for drug abusers seeking treatment, particularly for African-American crack cocaine abusers. However, there is evidence that pretreatment interventions may reduce treatment initiation barriers. This study examined the effects of a pretreatment intervention designed to enhance treatment motivation, decrease crack use, and prepare crack abusers for treatment entry. METHODS: Using street outreach, 443 African-American crack users were recruited in North Carolina and randomly assigned to either the pretreatment intervention or control group. RESULTS: At 3-month follow-up, both groups significantly reduced their crack use but the intervention group participants were more likely to have initiated treatment. CONCLUSION: The intervention helped motivate change but structural barriers to treatment remained keeping actual admissions low. Policy makers may be interested in these pretreatment sites as an alternative to treatment for short term outcomes.

Substance use, sexual risk, and violence: HIV prevention intervention with sex workers in Pretoria.

This paper describes an HIV prevention intervention designed in the US that was adapted and implemented in South Africa. Using an experimental design, 93 women who reported recent substance use and sex trading were randomly assigned to a modified Standard HIV intervention or to a Woman-Focused HIV prevention intervention. Eighty women completed the one-month follow-up interview. Participants reported high rates of sexual risk and violence at baseline. At follow-up, findings showed decreases in the proportion of women reporting unprotected sex and the daily use of alcohol and cocaine. Daily alcohol and cocaine use decreased more for women receiving the Woman-Focused intervention. Although violence continued to be a problem, at follow-up Woman-Focused participants reported being victimized less often than women receiving the Standard intervention. This study demonstrates the feasibility of implementing cross-cultural behavioral HIV prevention interventions, and supports the need for future studies of women's contextual issues and the effectiveness of targeted interventions.

African-American women who use crack cocaine: a comparison of mothers who live with and have been separated from their children.

OBJECTIVE: This study examined factors that influenced caregiver status for African-American mothers who use crack cocaine but are not receiving drug treatment and participated in an HIV prevention study in North Carolina. METHOD: Caregiver mothers who were living with at least one of their children at intake (n = 257) were compared with non-Caregivers who were separated from all of their children (n = 378). Bivariate analyses and logistic regression were used to compare these mothers at intake on current drug use, risky sex practices, psychological symptoms, victimization, and aggression. RESULTS: Compared with Caregiver mothers, non-Caregivers reported higher frequencies of drug use, risky sex practices, psychological distress, and victimization experiences. Caregiver mothers were more likely than non-Caregiver mothers to have health insurance, but were less likely to have received drug treatment. Logistic regression found that non-Caregiver mothers were significantly more likely than Caregiver mothers to be older, to have been physically abused as children, to trade sex more frequently, to be homeless, and to have no health insurance. Recent crack use, psychological symptoms, and victimization were not significantly related to caregiver status. CONCLUSIONS: Findings that socio-environmental factors were more strongly associated with caregiver status than crack use underscore the importance of contextual issues such as housing, victimization history, and resources in serving maternal crack users. Community outreach and interventions that engage mothers who use drugs and live with their children may be more effective strategies than formal office-based services to link mothers who use crack and their children to needed drug treatment and family and child services.