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.

Two-port totally extraperitoneal inguinal hernia repair: a 10-year experience.

PURPOSE: To evaluate the feasibility, safety, and long-term outcomes of laparoscopic two-port totally extraperitoneal (TEP) inguinal hernia repair. METHODS: A 10-year retrospective analysis from 2004 to 2013 of patients undergoing two-port TEP performed by a single surgeon at three surgical centers. RESULTS: 336 consecutive patients underwent two-port TEP repairing 478 hernias. 315 (93.8 %) patients were male and 21 (6.2 %) were female. Mean age ± SD was 47 ± 14 years and mean body mass index ± SD was 28.0 ± 4.7 kg/m(2). Indications for surgery included primary repair 303 (90.2 %), recurrence from open repair 28 (8.3 %), and incarcerated inguinal hernia 5 (1.5 %). 194 (57.7 %) cases were unilateral and 142 (42.3 %) were bilateral. Operative time ± SD was 38.7 ± 14.9 min for unilateral repair and 43.4 ± 17.6 min for bilateral repair. Two-port TEP was successful in 316 (94.0 %). 20 (6.0 %) cases required the addition of a third port. 2 (0.6 %) cases were converted to open repair. Mean follow-up time ± SD was 5.4 ± 2.7 years. Postoperative complications included urinary retention 5 (1.5 %), seroma 7 (2.1 %), hematoma 1 (0.3 %), surgical site infection 4 (1.2 %), and chronic inguinal pain 3 (0.9 %). 11 (2.3 %) hernias recurred. CONCLUSION: Two-port TEP appears to be a feasible, safe, and effective method for laparoscopic inguinal hernia repair and should be considered a viable, less invasive alternative to conventional three-port techniques.

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.

A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria.

Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced.

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.

Screening for cognitive and social-emotional problems in individuals with PKU: tools for use in the metabolic clinic.

Cognitive deficits, learning difficulties, and emotional problems occur at significantly higher rates in individuals with phenylketonuria (PKU) than in the general population. The relationship between elevated blood phenylalanine (Phe) levels and the severity of these problems often remain unrecognized. Children and adults with PKU require ongoing screening so that referrals to psychologists or psychiatrists familiar with metabolic disorders can be made when necessary for in-depth evaluation and treatment. To identify screening instruments that can be used by non-psychologists as well as psychologists, a group of 10 psychologists and a psychiatrist in the United States with expertise in neuropsychological assessment and PKU proposed a Uniform Assessment Method for PKU. Questionnaires were selected that reliably detect problems in adaptive behavior, executive function, and emotional well-being, representing the most vulnerable areas for individuals with PKU. These questionnaires are appropriate for individuals from infancy through adulthood, may be administered in less than 1h, have computerized scoring accessibility, have no practice effects, and are available in Spanish and English. In addition to assessing function at a single point in time, the screening measures may be administered at each clinic visit to assess changes in function related to metabolic status or treatment (e.g., Phe-restricted diet, food supplements). The following questionnaires comprise the Uniform Assessment Method for PKU: for 0-2 years, Adaptive Behavior Assessment System-Second Edition (ABAS-II); for 2-17 years, Behavior Rating Inventory of Executive Function (BRIEF) and Behavior Assessment System for Children-Second Edition (BASC-II); and for adults, BRIEF, Beck Anxiety Inventory (BAI), and Beck Depression Inventory-Second Edition (BDI-II). In addition to long-term monitoring of outcomes in PKU, this uniform screening approach facilitates PKU research, as data may be pooled across multiple clinics using a consistent battery of assessment measures.

20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits.

BACKGROUND: Wolff-Parkinson-White syndrome (WPW) is a bypass re-entrant tachycardia that results from an abnormal connection between the atria and ventricles. Mutations in PRKAG2 have been described in patients with familial WPW syndrome and hypertrophic cardiomyopathy. Based on the role of bone morphogenetic protein (BMP) signalling in the development of annulus fibrosus in mice, it has been proposed that BMP signalling through the type 1a receptor and other downstream components may play a role in pre-excitation. METHODS AND RESULTS: Using the array comparative genomic hybridisation (CGH), we identified five individuals with non-recurrent deletions of 20p12.3. Four of these individuals had WPW syndrome with variable dysmorphisms and neurocognitive delay. With the exception of one maternally inherited deletion, all occurred de novo, and the smallest of these harboured a single gene, BMP2. In two individuals with additional features of Alagille syndrome, deletion of both JAG1 and BMP2 were identified. Deletion of this region has not been described as a copy number variant in the Database of Genomic Variants and has not been identified in 13 321 individuals from other cohort examined by array CGH in our laboratory. CONCLUSIONS: Our findings demonstrate a novel genomic disorder characterised by deletion of BMP2 with variable cognitive deficits and dysmorphic features and show that individuals bearing microdeletions in 20p12.3 often present with WPW syndrome.

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.

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.

Maternal Phenylketonuria Collaborative Study (MPKUCS)--the 'outliers'.

Analysis of outcome data from 305 of the 414 offspring from the Maternal Phenylketonuria Collaborative Study (MPKUCS), plus 70 control offspring, revealed significant deficits in the IQ (intelligence quotient), as measured by the Wechsler Intelligence Scale for Children--Revised (WISC-R), when maternal metabolic control during pregnancy was delayed and/or inadequate. There were, however, 23 'outliers' (7.5% of the 305) in which the offspring's intellectual IQ was worse (n =10) or better (n =13) than expected. The aim of this study was to determine whether collection parameters were incomplete or whether these subjects were true biological variants influenced by other undetected factors or, perhaps, by modifier genes. Among the 10 offspring whose intellectual functioning was worse than expected, additional complications were uncovered that could explain the poor outcome. Four of the 13 offspring with higher than expected IQ had mothers with mild variants of PKU in which the insult to the fetus would not be expected to be as profound. For the other nine offspring whose intellectual performance was better than expected, there was no explanation, based on the parameters studied. We hypothesize that modifier genes will, at times, protect the fetus despite high maternal concentrations of phenylalanine. Not all offspring from the same (untreated) PKU mother may be similarly affected. Finding the source of these modifiers might effect the treatment of MPKU.

The Resource Mothers Study of Maternal Phenylketonuria: preliminary findings.

Women with phenylketonuria (PKU) must follow a strict low-phenylalanine diet during pregnancy in order to protect the fetus from the deleterious effects of high maternal blood phenylalanine. The Resource Mothers Study of Maternal PKU was undertaken to determine whether a home visitation programme was effective in helping women with PKU attain blood phenylalanine control earlier during pregnancy. Resource Mothers were trained to provide social support and practical assistance to women with PKU during pregnancy. Eight metabolic clinics in the United States participated in the study. Women with PKU who were planning pregnancy or already pregnant were enrolled in the study and were treated with a low-phenylalanine diet aimed at controlling blood phenylalanine to 120-360 micromol/L. They were randomly assigned to receive the services of a Resource Mother (RM group) or to a control group. Fifty women were enrolled, and accounted for 44 pregnancies which resulted in 28 live births, and 6 spontaneous abortions. Ten women are currently pregnant and another 6 have not become pregnant. Fifty-six percent of enrolled women began the diet prior to becoming pregnant. Fifty-three percent of women in the Resource Mother group were in metabolic control by 10 weeks gestation as compared to 39% in the control group. In addition, women who began diet after pregnancy and had a Resource Mother attained metabolic control earlier (mean gestational age of 22.4 weeks in the RM group vs 29.8 weeks in the control group). There was no difference in birth measurement z -scores of offspring born to women in the RM group compared to controls. All but 4 women rated themselves as feeling worse about the diet at the end of pregnancy than at the beginning, and few women in either group remained on diet after delivery.

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.

Iodine sufficiency and measurements of thyroid function in maternal hypothyroidism.

OBJECTIVES: To test the hypothesis that thyroglobulin (Tg) and free T4 (FT4) concentrations more than 2SD from the control mean are not increased in pregnancy in an iodine replete area in the absence of elevated TSH concentrations. The second hypothesis to be tested was that if such abnormalities in FT4 and Tg in the absence of elevated TSH concentrations were to exist they would not be associated with lowered IQs in the progeny. DESIGN: Cross-sectional study in New England comparing TSH, Tg, antibodies to Tg and FT4 in volunteer nonpregnant women 20-40 years old with those in hypothyroid mothers and matched euthyroid control mothers. The results are contrasted with those from similar studies reported from iodine deficient areas. SUBJECTS: Sera obtained at 17 weeks gestation and stored at -20 degrees C for 8 years were retrieved and analysed from 62 mothers with subclinical hypothyroidism and 124 matched euthyroid mothers. The diagnosis of hypothyroidism was made by finding a TSH concentration > 97.7 percentiile for 25 000 consecutive pregnant women. Sera were also analysed from 53 healthy nonpregnant volunteer women aged 20-40 years. MEASUREMENTS: TSH, Tg and Tg antibodies were measured in the sera of the nonpregnant volunteers, and Tg and Tg antibodies in the sera of the pregnant women who had previously been analysed for TSH and FT4. The incidence of FT4 concentrations below the 2.3 percentile of nonpregnant laboratory controls was compared for the euthyroid and hypothyroid mothers and the laboratory normal controls. RESULTS: Thirty-one per cent of the 62 hypothyroid mothers had FT4 concentrations below the 2.3 percentile compared with only one (0.8%) of the euthyroid mothers. Mean Tg concentrations did not differ between the nonpregnant controls and the euthyroid pregnant women, 14 +/- 10 vs. 16 +/- 10 micro g/l. Tg concentration in the hypothyroid mothers was 44 +/- 61, significantly greater than for either of the euthyroid control groups, P < 0.005. Positive antibodies to Tg were found in 9% and 10% of the control groups and 57% of the hypothyroid mothers, P < 0.0005. When TSH is included as an independent variable in multiple linear and logistic regressions, FT4 and Tg no longer correlate significantly with IQs. CONCLUSIONS: The incidences of FT4 concentrations more than 2SD below the control mean and of Tg > 2SD above the control mean are significantly increased in hypothyroid mothers in iodlne-sufficient New England. However, in the absence of elevated TSH concentrations, the incidences of such abnormalities in FT4 and TG are negligible. Indeed, concentrations for FT4, Tg and Tg antibodies for nonpregnant and pregnant controls in our iodine-replete area do not differ significantly from each other or from previously reported normative concentrations with the methods used. Thus, pregnancy in New England neither increases Tg nor lowers FT4 concentrations.

Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency.

Early diagnosis and improved treatment are leading to the potential for increased reproductive capability in homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency, but information about reproductive outcome and risk of thromboembolism in pregnancy is limited. To provide further information, clinical and biochemical information was obtained on women with maternal homocystinuria, on their pregnancies and on the offspring. This information included blood sulphur amino acids and total homocysteine, CbetaS gene mutations and developmental and cognitive scores in the offspring. The study involved 15 pregnancies in 11 women, of whom 5 were pyridoxine-nonresponsive and 6 were pyridoxine-responsive. Complications of pregnancy included pre-eclampsia at term in two pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and two pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced live-born infants with normal or above-normal birth measurements. One offspring has multiple congenital anomalies that include colobomas of the iris and choroid, neural tube defect and undescended testes. He is also mentally retarded and autistic. A second offspring has Beckwith-Wiedemann syndrome. The remaining 10 offspring were normal at birth and have remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities and maternal thromboembolic events in this series suggest that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, a cautious approach would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation.

Newborn screening compared to clinical identification of biochemical genetic disorders.

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their child's needs.