Home visits in the Danish High Risk and Resilience Study - VIA 7: assessment of the home environment of 508 7-year-old children born to parents diagnosed with schizophrenia or bipolar disorder.

OBJECTIVE: The home environment provided by the caregivers of a child is an influential single factor for development and well-being. We aimed to compare the quality of the home environment of children at familial high risk of schizophrenia or bipolar disorder with population-based controls. METHODS: Danish nationwide registers were used to retrieve a cohort of 522 7-year-old children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) or none of these diagnoses (N = 200). The home environment was assessed using the Middle Childhood-Home Observation for Measurement of the Environment Inventory (MC-HOME Inventory). RESULTS: The proportion of children living in home environments that were evaluated not to meet the needs of a 7-year-old child was significantly larger in the two familial high-risk groups. This was true for 21% of the children with familial predisposition for schizophrenia and 7% of children with familial disposition for bipolar disorder. CONCLUSION: Children born to parents diagnosed with schizophrenia and to a lesser extent bipolar disorder are at an increased risk of growing up in a home environment with an insufficient level of stimulation and support. Identifying families with inadequate home environments is a necessary step towards specialized help and support to at-risk families.

Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.

Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.

Inhibition of protein kinase C (PKC) response of voltage-gated calcium (Cav)2.2 channels expressed in Xenopus oocytes by Cavß subunits.

Cav2.2 channels are a substrate for phosphorylation by protein kinase C (PKC) isozymes. The contribution of Cavß, an auxiliary subunit of these channels, in the PKC modulation was studied. Cav2.2 channels were expressed in Xenopus oocytes in various subunit combinations with or without Cavß subunits. Currents were recorded using a two-electrode voltage clamp with barium as the charge carrier (IBa). Acetyl-ß-methylcholine (MCh), an activator of PKCα, potentiated Cav2.2 currents expressed with Cav2.2α1 alone or Cav2.2α1α2/δ. Similarly PKC isozymes α, ßII or ɛ potentiated IBa through Cav2.2α1 subunit channels. In contrast, MCh failed to potentiate currents expressed with Cav2.2α1 and Cavß1b, ß2a, ß3 or ß4 subunits. Similarly, in the presence of Cavß1b subunits, PKC isozymes failed to potentiate these currents; contrarily, PKCs α or ßII decreased the IBa. MCh failed to potentiate Cav2.2α1 subunit currents in the serine/threonine (Ser/Thr)→alanine mutants, T422A, S1757A or S2132A of Cav2.2α1 subunits. Hence Thr-422, Ser-1757 and Ser-2132 may be PKCα isozyme target sites. The action of PKC on these sites was further substantiated by the increased basal IBa along with the loss of MCh potentiation when Ser/Thr was mutated to aspartate. The observation that MCh or PKC isozymes failed to affect Cav2.2 currents in the presence of Cavß subunits suggests that these subunits may have interfered with the interaction between PKC and Ser/Thr sites of Cav2.2α1 subunits. In addition to affecting channel expression and current kinetics, Cavß subunits may also modulate the response of these channels to neurochemicals.

The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study.

This study aimed to evaluate the response to and safety of an 8-day course of sapropterin dihydrochloride (6R-tetrahydrobiopterin or 6R-BH4) 10 mg/kg per day in patients with phenylketonuria (PKU), who have elevated blood phenylalanine (Phe) levels, and to identify a suitable cohort of patients who would respond to sapropterin dihydrochloride treatment with a reduction in blood Phe level. Eligible patients were aged > or = 8 years, had blood Phe levels > or = 450 micromol/L and were not adhering to a Phe-restricted diet. Suitable patients were identified by a > or = 30% reduction in blood Phe level from baseline to day 8 following sapropterin dihydrochloride treatment. The proportion of patients who met these criteria was calculated for the overall population and by baseline Phe level (< 600, 600 to < 900, 900 to < 1200 and > or = 1200 micromol/L). In total, 485/490 patients completed the study and 20% (96/485) were identified as patients who would respond to sapropterin dihydrochloride. A reduction in Phe level was observed in all subgroups, although response was greater in patients with lower baseline Phe levels. Wide variability in response was seen across all baseline Phe subgroups. The majority of adverse events were mild and all resolved without complications. Sapropterin dihydrochloride was well tolerated and reduced blood Phe levels across all PKU phenotypes tested. Variability in reduction of Phe indicates that the response to sapropterin dihydrochloride cannot be predicted by baseline Phe level.

Urea cycle disorders.

Deficiency of any of the five enzymes in the urea cycle results in the accumulation of ammonia and leads to encephalopathy. Episodes of encephalopathy and associated symptoms are unpredictable and, if untreated, are lethal or produce devastating neurologic sequelae in long-term survivors. Although these disorders do not produce liver disease, the consequences of hyperammonemia resemble those seen in patients with hepatic failure or in a transient interference with the urea cycle, as seen in some forms of organic acidemias. Therefore, investigation for hyperammonemia in any infant or child with altered mental status (in the absence of obvious causes, such as trauma, infection, or poisoning) is essential for prompt diagnosis of urea cycle disorders and institution of treatment to avoid brain damage and death. This article addresses the function of the urea cycle and the diagnosis and management of urea cycle disorders.

Mosaic trisomy 7 in a patient with pigmentary abnormalities.

Somatic chromosomal mosaicism may present as isolated pigmentary abnormalities or multiple congenital anomalies with mental retardation. Pigmentary lesions are visually dramatic and are differentiated based on appearance when the underlying pathogenesis is not known. It is now clear that mosaicism is responsible for the pigmentary findings in hypomelanosis of Ito (HI) and linear and whorled nevoid hypermelanosis (LWH). Both hypopigmentation and hyperpigmentation have been noted in the same individual, and both LWH and HI can be caused by similar chromosomal abnormalities. Both of these conditions exhibit similar systemic involvement. We present a case of LWH associated with mosaic trisomy 7 and review the relevant literature.

Correction of ureagenesis after gene transfer in an animal model and after liver transplantation in humans with ornithine transcarbamylase deficiency.

We report effects of gene transfer and liver transplantation on urea synthesis in ornithine transcarbamylase deficiency (OTCD). We measured the formation of [15N] urea after oral administration of 15NH4Cl in two girls with partial OTCD before and after liver transplantation. Ureagenesis was less than 20% of that observed in controls before transplantation, and was normalized afterward. Studies performed on the OTCD sparse fur (spf/Y) mouse showed discordance between OTC enzyme activity and ureagenesis with modest increases in OTC enzyme activity after gene transfer resulting in significant improvement in ureagenesis. This study suggests that both liver transplantation and gene therapy may be effective in improving ureagenesis in OTCD.

Effect of long-term beta-blockade on aortic root compliance in patients with Marfan syndrome.

BACKGROUND: This study was undertaken to assess the effect of long-term beta-blockade on the aortic root stiffness index and distensibility in patients with Marfan syndrome. METHODS: Aortic root stiffness index and distensibility were calculated according to the formulas of Stefanadis and Hirai, respectively, with 2-dimensional guided M-mode echocardiogram before and after an average of 26 months of atenolol administration. RESULTS: Twenty-three asymptomatic patients were studied (11 men and 12 women, aged 31 +/- 14.2 years). The follow-up was 4 +/- 2.2 years. The dose of atenolol was individualized (mean 43.5 +/- 21.6 mg/d). Heart rate decreased from 79 +/- 9 beats/min to 64 +/- 9 beats/min (P =. 01), and systolic blood pressure decreased from 124 +/- 13 mm Hg to 114 +/- 2 mm Hg (P =.01). Distensibility increased from 1.85 +/- 0. 70 x 10(-6) cm2/dynes-1 to 2.21 +/- 0.76 x 10-6 cm2/dynes-1 (P =.02), and the stiffness index decreased from 9.68 +/- 3.78 to 8.85 +/- 3. 15 ( P =.2). Two groups of responses to treatment were identified. Compared with baseline values 15 (65%) patients who responded to treatment had increased distensibility and decreased stiffness index of the aortic root (P =.05). Eight patients (35%) who did not respond to treatment had no significant change. Body weight >91 kg and baseline end-diastolic aortic root diameter >40 mm were significantly associated with no response (P =.05). Two patients in the nonresponding group had echocardiographic progression of aortic insufficiency. CONCLUSIONS: There was a heterogeneous response in the aortic root elastic properties after long-term treatment with atenolol in asymptomatic patients with Marfan syndrome. Stiffness index and distensibility are more likely to respond when the baseline end-diastolic aortic root diameter is <40 mm.

Inborn errors of metabolism in infancy: a guide to diagnosis.

Recent advances in the diagnosis and treatment of inborn errors of metabolism have improved substantially the prognosis for many of these conditions. This makes it essential that the practicing pediatrician be familiar with the clinical presentation of these disorders. A practical clinical approach to the recognition of inborn errors of metabolism in the young infant is presented in this review. Indications for specific laboratory studies are discussed. Guidelines are provided for the stabilization and emergency treatment of critically ill infants. This approach will identify those infants who will benefit from additional evaluation and specific treatment. Many of the inborn errors of metabolism, including urea cycle defects, organic acidemias, and certain disorders of amino acid metabolism, present in the young infant with symptoms of an acute or chronic metabolic encephalopathy. Typical symptoms include lethargy, poor feeding, apnea or tachypnea, and recurrent vomiting. Metabolic acidosis and/or hyperammonemia are observed in many of these conditions, but there are notable exceptions, including nonketotic hyperglycinemia and molybdenum co-factor deficiency. Therefore, appropriate laboratory testing for metabolic disorders should be performed in any infant who exhibits these findings. Although sepsis may be the initial consideration in a neonate with these symptoms, inborn errors of metabolism should always be in the differential diagnosis, particularly in a full-term infant with no specific risk factors. Hypoglycemia may be the predominant finding in a number of inborn errors of metabolism, including glycogen storage disorders, defects in gluconeogenesis, and fatty acid oxidation defects. The latter disorders, among the most common encountered, exhibit marked clinical variability and also may present as a sudden death, a Reye's-like episode, or a cardiomyopathy. Jaundice or other evidence of hepatic dysfunction is the mode of presentation of another important group of inborn errors of metabolism including galactosemia, hereditary tyrosinemia, neonatal hemochromatosis, and a number of other conditions. A subset of lysosomal storage disorders may present very early with coarse facial features, organomegaly, or even hydrops fetalis. Specific patterns of dysmorphic features and congenital anomalies characterize yet another group of inherited metabolic disorders, such as Zellweger syndrome and the Smith-Lemli-Opitz syndrome. Each of these symptom complexes, and the appropriate evaluation of the affected infants, is discussed in more detail in this review.

Altered newborn gender distribution in patients with low mid-trimester maternal serum human chorionic gonadotropin (MShCG).

OBJECTIVE: to determine if the sex ratio (male/female) is altered in infants born to patients with low mid-trimester maternal serum human chorionic gonadotropin (MShCG). STUDY DESIGN: Between 2/1/90 and 1/3/91, 3,116 patients underwent prenatal screening using second-trimester maternal serum alpha-fetoprotein (MSAFP), MShCG, and maternal serum unconjugated estriol (MSuE3). Among these, there were 132 patients with low second-trimester MShCG (< 0.4 MoM), normal MSAFP and MSuE3. The gender distribution of these term, normal newborns was compared to that of 237 controls, matched for race, maternal age, and referral source and delivered at term to mothers with normal mid-trimester MSAFP, MSuE3, and MShCG. The gender distribution of these two groups of newborns was also compared to that of 78 term newborns from the same obstetrical population delivered to mothers with second-trimester MShCG > 2.5 MoM and normal MSAFP and MSuE3. All patients had a complete obstetrical history. RESULTS: Forty-nine percent of the controls were male vs. 62% of the group with slow second-trimester MShCG (P < .01). Within the group with low MShCG, 59% of infants were male when the MShCG was between 0.19 and 0.4 MoM (A) and 80% when the MShCG was < 0.2 MoM (B) (control vs. A vs. B P < .005). The sex ratio in the high-MShCG group was similar to control. CONCLUSION: The data suggest that gender distribution is different from normal in patients with low mid-trimester MShCG.

Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy.

We report the occurrence of severe ventricular arrhythmias in a patient with isovaleric acidemia during general anesthesia for suction lipectomy. The timing of events and character of the ECG changes are most consistent with bupivacaine toxicity after subcutaneous injection of tumescence solution containing this local anesthetic. The patient had previously documented carnitine deficiency, a condition which, we speculate, may lower the threshold for bupivacaine induced cardiotoxicity. We review clinical considerations in isovaleric acidemia and conclude that the use of bupivacaine in these patients probably should be avoided.

Pregnancy outcome in women with low midtrimester maternal serum unconjugated estriol.

OBJECTIVE: To determine if unexplained low second-trimester maternal serum unconjugated estriol (MSuE3) is a useful predictor of complications of pregnancy. STUDY DESIGN: Between February 1, 1990, and January 3, 1993, 10,492 patients underwent prenatal screening using second-trimester maternal serum alpha-fetoprotein (MSAFP), maternal serum human chorionic gonadotropin (MShCG) and MSuE3. One hundred ninety-five patients with complete obstetric history/delivery records and with < 0.4 multiples of the median (MoM) second-trimester MSuE3 values were matched with 261 controls with complete obstetric history/delivery records and normal second-trimester MSAFP, MSuE3 and MShCG. RESULTS: The relative risk of pregnancy loss, as compared to that in controls, was 3.7 (1.4-9.1 confidence interval [CI], P < .0001) in patients with 0.2-0.4 MoM MSuE3 and 19.3 (6.1-60.5 CI, P < .0001) in patients with < 0.2 MoM MSuE3. After exclusion of patients with low and high MSAFP and MShCG, the relative risk of pregnancy loss for the remaining patients with low MSuE3 was 3.3 (1.3-8.5 CI, P < .008). CONCLUSION: The data suggest that patients with unexplained low second-trimester MSuE3 have an increased risk of pregnancy loss that may not be associated with a high or low MSAFP, MShCG or higher incidence of pregnancy-induced hypertension, gestational diabetes, premature rupture of membranes or premature onset of labor.

Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2.

Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome. However, subsequent reports of families in which the BBB and G syndrome segregated within a single kindred suggested that they were a single clinical entity. Although the original pedigrees were consistent with X-linked and autosomal dominant inheritance, male-to-male transmission in subsequent reports suggested that OS was inherited as an autosomal dominant trait. Here we report that OS is a heterogeneous disorder, with an X-linked and an autosomal locus. Three families were linked to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. Five families were linked to D22S345 from chromosome 22q11.2, with a lod score of 3.53 at zero recombination. This represents the first classic multiple congenital anomaly syndrome with an X-linked and an autosomal form.

An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS).

The incidence of haemangiomas was ascertained by questionnaire in infants born to 578 consecutive CVS patients and 445 consecutive mid-trimester amniocentesis patients seen at a single institution between 1 January 1989 and 31 May 1991. The incidence of 7.4 per cent reported in the amniocentesis group was comparable to previous estimates of the incidence of haemangiomas in the general population. In contrast, a 21.1 per cent incidence, three-fold higher than that observed in the amniocentesis group, was observed among CVS-exposed infants (P < 0.001). This increased incidence was largely confined to patients undergoing a transcervical procedure. No correlation was observed between the incidence of haemangiomas and gestational age at sampling, sample size, number of sampling attempts, or a history of bleeding following the procedure.

Microcephaly, lymphedema, and chorioretinal dysplasia: report of two additional cases.

In recent years, several patients with microcephaly, lymphedema and chorioretinal dysplasia have been described. We have studied two additional patients with similar findings. The question of whether microcephaly with lymphedema and microcephaly with chorioretinal dysplasia and lymphedema are distinct entities remains unanswered. Identification of other patients in the future may provide additional information.

Clinical significance of low levels of second-trimester maternal serum human chorionic gonadotropin.

OBJECTIVE: To determine if unexplained low second-trimester maternal serum human chorionic gonadotropin (MShCG) is a useful predictor of complications of pregnancy. STUDY DESIGN: Between 2/1/90 and 1/3/91, 3,116 patients underwent prenatal screening using second-trimester maternal serum alpha-fetoprotein (MSAFP), MShCG and maternal serum unconjugated estriol (MSuE3). Among these, there were 160 patients with complete obstetrical history who had second-trimester MShCG < 0.4 multiples of the median (MoM). These were compared to 261 controls with complete obstetrical history and a normal second-trimester MSAFP, MSuE3 and MShCG. RESULTS: No differences were found in gestational age at delivery, neonatal weight, premature rupture of membranes or pregnancy loss. The relative risk of pregnancy-induced hypertension in the study group was 0.29 (p < 0.01) and that of gestational diabetes was 0.3 (p < 0.05). Only when low MShCG was associated with a high or low MSAFP or low MSuE3 was there a significantly increased loss of pregnancy (relative risk 11.7; p < 0.0001). CONCLUSION: The data suggest that second-trimester MShCG < 0.4 MoM by itself has no influence on the outcome of pregnancy.

Oromandibular-limb hypogenesis syndrome following chorionic villus sampling.

A female infant with hypoglossia-hypodactyly syndrome is presented. Her mother underwent chorionic villus sampling (CVS) at 9 weeks gestation. This is the seventh reported case of oromandibular-limb hypogenesis syndrome associated with maternal CVS, the first from the United States. These seven CVS-related cases represent a significant increase over this syndrome's 'natural' incidence of 1 per 175,000 live births. An excess of limb reduction deformities has also been seen following CVS. These seven cases are reviewed, and the possible etiology of this rare condition is discussed.