Psychiatric symptoms and disorders in phenylketonuria.

Psychological and psychiatric problems are well documented across the lifespan of individuals with early-treated phenylketonuria (PKU). Early-treated children and adolescents tend to display attentional problems, school problems, lower achievement motivation, decreased social competence, decreased autonomy, and low-self-esteem. As they enter adulthood, early-treated individuals may carry forward low self-esteem and lack of autonomy but also tend to develop depressed mood, generalized anxiety, phobias, decreased positive emotions, social maturity deficits, and social isolation. The correlation between level of metabolic control and severity of symptoms suggests a biological basis of psychiatric dysfunction. Additionally, psychosocial factors such as the burden of living with a chronic illness may contribute to psychological and psychiatric outcomes in PKU. The lack of a PKU-specific psychiatric phenotype combined with the observation that not everyone with PKU is affected highlights the complexity of the problem. More research on psychiatric and psychological outcomes in PKU is required. Of particular importance is the routine monitoring of emotional, behavioral, and psychosocial symptoms in individuals with this metabolic disorder. Longitudinal studies are required to evaluate the impact of new and emerging therapies on psychiatric and psychosocial functioning in PKU. Unidentified or untreated emotional and behavioral symptoms may have a significant, lifelong impact on the quality of life and social status of patients.

The natural history of classic galactosemia: lessons from the GalNet registry.

BACKGROUND: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms.

The medical and neurodevelopmental characteristics of 14 children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) are described. Eight were detected as neonates by newborn screening. Three children diagnosed on the basis of clinical symptoms had normal newborn screening results while three were born in states that did not screen for SCADD. Treatment included frequent feedings and a low fat diet. All children identified by newborn screening demonstrated medical and neuropsychological development within the normative range on follow-up, although one child had a relative weakness in the motor area and another child exhibited mild speech delay. Of the three clinically identified children with newborn screening results below the cut-off value, two were healthy and performed within the normal range on cognitive and motor tests at follow-up. Four clinically identified children with SCADD experienced persistent symptoms and/or developmental delay. However, in each of these cases, there were supplementary or alternative explanations for medical and neuropsychological deficits. Results indicated no genotype-phenotype correlations. These findings suggest that SCADD might be benign and the clinical symptoms ascribed to SCADD reflective of ascertainment bias or that early identification and treatment prevented complications that may have occurred due to interaction between genetic susceptibility and other genetic factors or environmental stressors.

Unplanned pregnancies in young women with diabetes. An analysis of psychosocial factors.

OBJECTIVE: To assess psychosocial factors related to preventing birth defects in children born to diabetic women. Diabetic women are at high risk for bearing children with congenital anomalies associated with teratogenic effects early in pregnancy. This study focuses on factors related to the family planning behavior of diabetic women. RESEARCH DESIGN AND METHODS: Sixty-six diabetic women were included in a 5-yr, prospective, longitudinal study along with 69 phenylketonuric women, who also face a high risk of bearing children with birth defects, and 68 healthy women. Annual interviews and questionnaires were administered. Women who did not want a pregnancy completed measures related to contraceptive behavior and quality of life. Areas assessed were knowledge, personality, attitudes, and social support. RESULTS: Diabetic women were more likely to be sexually active than women with phenylketonuria. Use and type of birth control were comparable among the groups except that diabetic women used condoms more often. For diabetic women, social support and positive attitudes towards birth control were associated with consistent birth control use. Of the diabetic women, 23 became pregnant, and only 6 (26%) were planned pregnancies. CONCLUSIONS: Birth control use by diabetic women needs to be addressed by health professionals. Attitudes about birth control of the women and those close to them appear to be important factors in consistent birth control use. Suggestions are made for addressing these factors.

Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics.

Maternal phenylketonuria (MPKU) is a well-recognized complication of PKU and one of the most potent teratogenic syndromes of pregnancy. Virtually all offspring from untreated pregnancies in women with classic PKU have intellectual disabilities and microcephaly. Congenital heart disease and intrauterine growth retardation occur many times more often than expected in the general population. Control of maternal blood phenylalanine during pregnancy prevents most if not all of these complications. Previous studies demonstrated the benefits of treatment in terms of birth parameters and early development. In this study, physical examinations, a medical history, and neuropsychological evaluation were obtained in 47 children from 24 mothers with PKU who received treatment during pregnancy. Mothers were interviewed and administered an abbreviated IQ test. Associations between maternal factors and offspring outcomes were also analyzed.The 21 male and 26 female offspring ranged in age from 1 month to 26 years with 21 (62%) over 6 years. Results indicated mean intercanthal distances above the 70th percentile. Microcephaly was present in 19% of offspring, with head circumference below the third percentile. None of the offspring had cardiac anomalies. Mean offspring IQ was 94 ± 19, with 12% performing in the range of intellectual disability (IQ < 70). Among children >5 years of age, 25% had learning disabilities, 31% had attention deficit hyperactivity disorder (ADHD), 22% were on ADHD medication, and 34% had a diagnosis of anxiety and/or depression. Among the 24 mothers, 12 reported following the diet for PKU. Only one woman on diet had a blood phenylalanine concentration <360 µmol/L (recommended range) and the majority had indications of poor nutritional status. Mean maternal Full Scale IQ was 94 ± 16 (range = 61-117), with 25% performing in the borderline intellectual range (IQ < 85). Verbal IQ was significantly lower than Performance IQ (p = 0.01, CI 2.7, 16.1). On the self-report Beck Depression Inventory, Second Edition, 25% received scores indicating mild to moderate depression, and on the Beck Anxiety Inventory, 46% reported mild to moderate anxiety. Offspring IQ correlated with maternal metabolic control during pregnancy (r = 0.51), maternal IQ (r = -0.62), and socioeconomic position (r = -0.48). Offspring with ADHD, learning disabilities, or emotional disturbances were more likely to have mothers with anxiety and/or depression. To ensure optimal offspring outcomes, healthcare providers need to assess maternal nutrition, blood phenylalanine concentrations, cognitive abilities, and socioeconomic position. Interventions can then be initiated that reduce psychosocial stressors and enhance adherence to diet and positive parenting, which in turn can lead to better cognitive functioning, behavior, and emotional well-being in their children.

Predictors of intelligence quotient and intelligence quotient change in persons treated for phenylketonuria early in life.

Ninety-one individuals with phenylketonuria who were treated early in life were followed for as many as 22 years. Regression analyses were used to determine the best predictors of IQ and IQ change. Among treatment-related variables, good dietary control of the blood phenylalanine level stood out as the best predictor of IQ. Diet discontinuation and the natural (off diet) blood phenylalanine level best predicted IQ loss, suggesting that diet continuation may be important for children with natural blood phenylalanine levels greater than 18 mg/dL.

High cognitive outcome in an adolescent with mut- methylmalonic acidemia.

Methylmalonic acidemia is an inborn error of metabolism known to be a cause of ketoacidosis and mental retardation. The less severe mut(-) form of the disorder, however, has been described with only mild to moderate cognitive deficits or, rarely, with normal neurodevelopment in asymptomatic cases. Nevertheless, there has been no detailed documentation of long-term neuropsychological function in the mut(-) form and relatively few IQ scores. We performed longitudinal developmental and neuropsychological assessments on a girl with symptomatic mut(-) methylmalonic acidemia whose biochemical abnormalities were in the moderately severe range and who had had recurrent episodes of ketoacidosis. At almost 12 years of age, her full scale IQ on the Wechsler Intelligence Scale, third edition, was 129 with very superior and superior scores on nonverbal and verbal skills, respectively. On the National Achievement Test she scored above the 99th percentile in the Basic Battery and is considered to be a gifted student. This outcome suggests that the spectrum of cognitive attainment in mut(-) methylmalonic acidemia is wide and that even a moderate degree of biochemical severity with ketoacidotic episodes may not result in cognitive deficit. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:192-195, 2000.

Relation of severity of maternal hypothyroidism to cognitive development of offspring.

BACKGROUND: An association between maternal subclinical hypothyroidism and low intelligence quotient (IQ) in the offspring has recently been shown. OBJECTIVE: To provide evidence for the causality of the association by testing the hypothesis that severity of maternal hypothyroidism correlates inversely with IQ of the offspring. METHODS: IQ scores were compared among 8 year old offspring of 124 control mothers whose thyroid stimulating hormone (TSH) concentrations were < 98th percentile of a cohort of 25,000 mothers at 17 weeks gestation, of 28 untreated hypothyroid women whose TSH was between the 98th and 99.85th percentiles, and of 20 untreated women whose TSH concentration was > or = 99.85th percentile. RESULTS: Mean (SD) IQs for each group of children (in ascending order of maternal TSH concentration) were 107 (13), 102 (15), and 97 (14). The difference between the extremes was significant (p = 0.003). The percentage of children with IQs > 1 SD below the control mean was 15, 21, and 50 respectively (p = 0.003). The odds ratio of having an IQ > 1 SD below the control mean, after controlling for socioeconomic status, was 4.7 (p = 0.006) for the third group compared with the controls. CONCLUSIONS: The inverse correlation between severity of maternal hypothyroidism and IQ of the offspring supports a causal relation and makes the need to screen for and treat pregnant women for hypothyroidism even more compelling.

PKU in adolescents: rationale and psychosocial factors in diet continuation.

Follow-up of early-treated children with PKU has shown that diet discontinuation in childhood presents risks of cognitive and emotional dysfunction in a substantial number of adolescents and young adults. This dysfunction includes IQ loss, mental processing abnormalities, learning difficulties, anxiety and personality disorders. In addition, neurologic deterioration has been reported in several such individuals. As a consequence of this current understanding of PKU, diet continuation, at least through adolescence and in the young adult years, is now recommended. Many centers are extending this to a policy of "diet for life". This represents a major challenge to adolescents and their families. Metabolic control using the criteria applied during childhood is virtually impossible to achieve past 12 years of age. Time constraints, social pressures, financial limitations and growing independence from the family combine to interfere with dietary control. Added to these difficulties are the biological changes during teenage years which reduce phenylalanine tolerance. To meet these challenges, we have identified a number of psychosocial factors that interfere with adherence to medical recommendations. The factors most highly related to metabolic control were social support for the diet and positive perceptions of treatment. This information has led to the development of support programs for adolescents and young adults with PKU.(ABSTRACT TRUNCATED AT 250 WORDS)

Review of neuropsychological functioning in treated phenylketonuria: an information processing approach.

Phenylketonuria is no longer associated with mental retardation and other devastating neurological effects. Nonetheless, learning disabilities and IQ loss are common, even in early-treated individuals. Until recently, IQ was used as the sole measure of mental functioning in this population. As specific academic deficits were recognized and as a greater variety of tests became available, evaluation of children with phenylketonuria has included neuropsychological testing. A review of the 21 published reports highlights the areas of consensus and the need for additional well designed studies in the future. Problem solving, particularly abstract reasoning and executive functions, appears to be impaired in children with phenylketonuria. Reaction time, or speed of mental processing, appears to be the other important area affected in PKU. An information processing model is presented as a paradigm for further research and development of remedial strategies for children with phenylketonuria.

A review of the psychosocial effects of false-positive results on parents and current communication practices in newborn screening.

As more states adopt expanded newborn screening for metabolic disorders, the overall number of false positives increases. False-positive screening results have been associated with increased anxiety and stress in parents of infants who require follow-up testing, even after the infant's good health is confirmed. This article reviews the literature on the negative impact of false-positive newborn screening results on parents, along with a review of current communication practices for follow-up screening. The results of this review suggest that parental stress and anxiety can be reduced with improved education and communication to parents, specifically at the time of follow-up screening. Communication strategies with sample materials are proposed.

The knowledge gap in expanded newborn screening: survey results from paediatricians in Massachusetts.

Massachusetts currently offers an optional expanded newborn screening programme that tests for 20 biochemical genetic disorders in addition to the mandated newborn screening tests, including phenylketonuria (PKU) and nine other biochemical genetic disorders. We conducted a mail survey of 550 paediatricians listed in the 2000 Massachusetts Healthcare Directory to determine paediatricians' preparedness in discussing expanded newborn screening and its results with families, and to determine in what specific format physicians in Massachusetts would prefer to receive educational materials and updates. Of surveys mailed, 35% (190/550) were returned within the allotted 3 weeks: 25 paediatricians (14%) were unaware of expanded newborn screening; 78 respondents (42%) indicated feeling less than prepared talking about test results with families; 100 paediatricians (54%) indicated a lack of information about metabolic disorders; 134 (73%) preferred information sent in postal mailings, 62 (34%) preferred grand rounds, 60 (33%) preferred educational seminars, and 58 (32%) preferred websites. Other formats receiving preferences of less than 30% included e-mail (27%), phone calls (8%), video (6%), and distance learning (1%). Paediatricians are ill-prepared for expanded newborn screening for biochemical genetic disorders. To address this problem, paediatricians in Massachusetts indicated a preference for unsolicited periodic mailings including short reviews and brochures.

Parents' reactions after the birth of a developmentally disabled child.

Thirty families with a developmentally disabled child less than 1.5 years old were compared to 30 families with a nonhandicapped child. One-half of the families lived in California, and half lived in Denmark. Findings indicated that parents with a very young developmentally disabled child see themselves more negatively after the baby's birth, and they express more negative feelings about their child. Regarding Danish--American differences, the supportive services in Denmark did not have a significantly greater impact on the parents' adjustment than did the supports in the United States. Furthermore, the use of supportive services correlated with positive adjustment in some areas and negative adjustment in others.

Agoraphobia in phenylketonuria.

We describe agoraphobia as a complication of phenylketonuria (PKU) in young adults. The five patients have classic PKU and received phenylalanine-restricted diet only in childhood. Only one has normal intelligence. All but one were also depressed. All were anxious. Three of the five had initiated the phenylalanine-restricted diet after 3 months of age. Two returned to the phenylalanine-restricted diet with dramatic reduction of symptoms. The frequency of manifestations of agoraphobia was also examined in 50 young women with PKU enrolled in a longitudinal study of psychosocial factors in maternal PKU, 47 of their acquaintances and 49 women with diabetes. All were administered a test of agoraphobic-avoidant behaviour. The women with PKU appeared to be more prone to social withdrawal and fear of leaving home. Twenty per cent were within the agoraphobia range of the Mobility Inventory. Those still on diet and those with non-PKU hyperphenylalaninaemia reported less avoidant behaviour than those who had terminated the diet in childhood. These results suggest that young adults with PKU are at risk for agoraphobia but that return to the phenylalanine-restricted diet may be an effective treatment.

Personality disorder in young women with treated phenylketonuria.

Twenty-eight young women with phenylketonuria (PKU) attending a Maternal PKU Summer Camp were interviewed and administered a personality inventory, the Minnesota Multiphasic Personality Inventory (MMPI). The 12 young women who were either late-treated (treatment initiated after 90 days) or who had terminated the diet for a period of at least 5 years (the extended exposure group) were compared to the 16 women who were early-treated and had remained continuously on diet (the continuously treated group). Although the mean blood phenylalanine and tyrosine concentrations at the camp for the two groups were comparable (973 +/- 344 and 1033 +/- 284 mumol/L for phenylalanine and 43 +/- 16 and 40 +/- 25 mumol/L for tyrosine), the women in the extended exposure group evidenced significantly greater psychopathology as measured by the MMPI and self-report; thought disorder and mood disturbances were associated with diet termination in PKU.

Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus.

We studied the effects of maternal phenylketonuria and hyperphenylalaninemia on 53 offspring from untreated pregnancies in 22 mothers who were identified by routine screening of umbilical-cord blood. The IQ of the offspring was significantly correlated with both maternal IQ (r = 0.83, P less than 0.001) and maternal blood phenylalanine level (r = 0.82, P less than 0.001), but with one exception, mental retardation in offspring was present only when the maternal blood phenylalanine level exceeded 1100 mumol per liter (18 mg per deciliter). Microcephaly in offspring was consistently present only when the maternal blood phenylalanine level exceeded 1200 mumol per liter (20 mg per deciliter). Congenital heart disease and other congenital anomalies were rare among offspring. The data suggest that severe atypical or classic phenylketonuria (blood phenylalanine level, greater than 1100 mumol per liter) in the mother has a substantial cognitive effect on her offspring but that the effect of mild hyperphenylalaninemia may have been overstated in the past.

Personality profiles of mothers of children with mitochondrial disorders.

Mothers of children with mitochondrial disorders, inherited neurodegenerative diseases, are faced with a frightening diagnosis and numerous demands associated with caring for these children. The psychological profile of mothers whose children carry a mitochondrial disorder is unknown. Forty-two mothers of children with mitochondrial disorders were interviewed and administered the Minnesota Multiphasic Personality Inventory--Second Edition (MMPI-2). Fifty-six per cent of the mothers had scores in the pathological range on three or more scales, most notably on Hypochondriasis, Hysteria and Paranoia scales. The MMPI-2 profile is associated with situational anxiety and stress or may be associated with carrier status characteristics. Whatever the cause, future studies need to determine whether supportive services can reduce the level of anxiety and stress in mothers of children with these disorders.

Diet termination in children with phenylketonuria: a review of psychological assessments used to determine outcome.

This paper reviews the 19 published studies that have utilized psychological assessments in determining the outcome of children with phenylketonuria who have discontinued a phenylalanine-restricted diet. About half the studies showed that, after diet termination, the intellectual performance of children decreased, while the other studies indicated that the intellectual performance of the children did not change. Difficulties in the use of intelligence tests to answer questions about diet termination are outlined. Due to the methodological difficulties and the varying results reported, the issue concerning the safety of diet discontinuation remains unresolved. The conclusion is that the task now is to differentiate those children who should remain on the diet from those who may safely terminate.

A psychosocial model of a medical problem: Maternal phenylketonuria.

Treatment of maternal phenylketonuria (PKU) consists of a low phenylalanine diet, begun before conception, which is believed to prevent mental retardation, microcephaly, and congenital heart disease in offspring of women with PKU. Experiences in treating these women indicate that their cooperation with medical recommendations is generally poor. We present a psychosocial model on adjustment and coping in maternal PKU. The proposed model defines four stages in the reproductive years of women with PKU, each of which has specific behavioral goals. The four stages are: (1) prevention of unplanned pregnancies; (2) reproductive decision-making; (3) diet initiation; and (4) diet continuation through pregnancy. Review of the literature on the different behaviors expected at the different stages enabled indentification of psychosocial factors that may explain success or failure in achieving the goals at each stage. Based on this theoretical framework, practical implications for treating women with PKU have been suggested.

Maternal histidinaemia: pregnancies and offspring outcomes.

Untreated pregnancies and their outcomes were studied in 10 women with histidinaemia and their 26 pregnancies. The mean maternal assigned histidine level was 727+/-186 micromol/L (range 484-1,053). Six women had classic histidinaemia (assigned level >700 micromol/L) and the remaining four had mild (atypical) histidinaemia. The pregnancies were uneventful, with only one spontaneous loss and 25 live births. Birth measurements were normal and no congenital anomalies were observed. Growth and development were normal in all offspring. IQ among the 23 offspring tested was 103+/-12 (range 79-122). Four offspring required special education for brief periods and one for several years, but this frequency, as well as that of 12% for attention deficit hyperactive disorder, was not significantly different from expected in the general population. It would appear that maternal histidinaemia, unlike maternal phenylketonuria, can be added to the list of maternal inborn errors of metabolism that are nonteratogenic.