The Genetic Landscape and Epidemiology of Phenylketonuria.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

Parental Burden and its Correlates in Families of Children with Autism Spectrum Disorder: A Multicentre Study with Two Comparison Groups.

BACKGROUND: The effects of having a child with Autism Spectrum Disorder (ASD) on parents are multifaceted and pervasive. While ample evidence has been provided that these families are under severe stress, there are still several knowledge gaps and unresolved questions. OBJECTIVE: This study aimed at quantifying the subjective and objective burden of ASD in mothers and fathers, and at improving the understanding of the interplay between parental burden, child's characteristics, and parents' coping resources and strategies. METHODS: The parents of 359 children/adolescents with ASD were compared to parents of age-matched patients with Down syndrome (N=145) and Type 1 diabetes mellitus (N=155). Child's clinical characteristics and parents' caregiving burden, psychological distress, coping resources and strategies were assessed. RESULTS: The parents of children with ASD reported higher objective and subjective burden, more frequent psychological distress, lower social support. Mothers reported greater subjective burden than fathers. Structural equation modeling showed that the most consistent positive and negative predictors of objective and subjective burden were ASD symptom severity and social support, respectively. Other positive predictors were engagement, distraction and disengagement coping, intellectual disability, and adaptive functioning. Other negative predictors were spiritual wellbeing and hardiness. Some effects were indirect through social support and coping strategies. CONCLUSION: This study confirmed that parents of children with ASD carry a huge caregiving burden, and added to our understanding of the factors associated with burden. The findings may help inform the design of effective interventions aimed at reducing burden among the parents of children with ASD.

Living with phenylketonuria in adulthood: The PKU ATTITUDE study.

Dietary treatment is the cornerstone of therapy for phenylketonuria (PKU), but adherence to low- phenylalanine diet progressively decreases after adolescence. We designed a survey to characterize the dietary habits of Italian adult PKU patients and to identify psychological factors influencing disease perception and adherence to diet. Participants to the survey (n = 111; response rate 94%) were asked to complete a structured questionnaire. Patients appeared to have an altered perception and awareness of the disease. About 40% of them did not consider PKU a disease and, despite declaring regular monitoring of phenylalanine levels (85%), nearly half of them reported a high plasma value over the last 6 months (>600 µmol/L, 48%) or were unable to specify it (31%). Adherence to PKU diet was unsatisfactory, with increased consumption of natural protein sources and reduced daily use of amino-acid supplements (<4-5 times/day in 82% patients). In addition to the intrinsic characteristics of AA formula (palatability, ease of use), the most important factor influencing their consumption was the increased social pressure associated with their use (55%). Plasma phenylalanine periodical measurements (61%) and examinations at metabolic centers (49%) were considered relevant for compliance to diet. In Italian adult PKU patients dietary management was found to be inadequate, likely due to inappropriate perception and knowledge of the disease, and lack of awareness of the negative impact of poor metabolic control in adult life. Clinicians should consider implementing more intense and tailored educational measures, as well as structured transitional care processes.

Acute psychosis in an adolescent with undiagnosed homocystinuria.

Homocystinuria due to cystathionine-ß-synthase deficiency (CBS deficiency) usually presents with ectopia lentis, myopia, intellectual disability, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Whereas neurodevelopment impairments have been often described in untreated homocystinuria adult patients, acute psychosis has rarely been reported as a presenting symptom of the disease. Here, we describe a 17-year-old girl affected by CBS deficiency presenting acute onset of visual hallucinations, behavioral perseverance, psychomotor hyperactivity, and affective inappropriateness. Ectopia lentis, diagnosed several years before, didn't have been considered as possible sign of a metabolic disorder. Psychotic symptoms were unresponsive to the conventional antipsychotic drugs and relieved after pyridoxine and folic acid treatment. CONCLUSION: A diagnosis of homocystinuria due to CBS deficiency should be considered in patients presenting, as target signs, ectopia lentis with or without learning difficulties, and should also be taken into account as a potentially treatable cause of acute psychosis in childhood and adolescence. WHAT IS KNOWN: • Homocystinuria frequently present with ectopia lentis, myopia, cognitive impairment, Marfan-like phenotype, osteoporosis, cerebrovascular, or cardiac thrombosis. • Acute psychosis has rarely been reported as a presenting symptom of the disease. WHAT IS NEW: • The complete psychotic symptoms' remission with pharmacological doses of pyridoxine and folic acid, without antipsychotic drugs.

Geographical epidemiology of neonatal transitory hypothyroidism. Trend evidence in central Italian region.

AIM: To study the geographical distribution of high thyroid-stimulating hormone (TSH) level in the Marche region (central Italy). METHODS: Data were drawn from the Register of Neonatal Screening for Congenital Hypothyroidism (CH) of the Marche region (Italy), located at the Child Neuropsychiatry Department of Civil Hospital in Fano (Marche, Italy). Data were analyzed by Ohno's method. RESULTS: The findings of this study show a nonuniform distribution of high TSH levels in the Marche region, with an evident gradient from North to South. CONCLUSIONS: It is not possible to provide a definitive interpretation of these findings, although the specialized literature suggests that a high level of TSH in neonates should be interpreted as a marker of insufficient iodine uptake. Other factors affecting TSH level are also taken into consideration.

Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis.

CONTEXT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000-4000 at birth. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2-5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease. OBJECTIVE: In the present work we investigated the possible involvement of NKX2-5 mutations in TD. RESULTS: Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis and that NKX2-5 mutations contribute to TD. NKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2-5. CONCLUSION: Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.

Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003).

OBJECTIVE: To identify risk factors for permanent and transient congenital hypothyroidism (CH). DESIGN: A population-based case-control study was carried out by using the network created in Italy for the National Register of Infants with CH. METHODS: Four controls were enrolled for each new CH infant; 173 cases and 690 controls were enrolled in 4 years. In order to distinguish among risk factors for permanent and transient CH, diagnosis was re-evaluated 3 years after enrollment when there was a suspicion of transient CH being present. Familial, maternal, neonatal and environmental influences were investigated. RESULTS: An increased risk for permanent CH was detected in twins by a multivariate analysis (odds ratio (OR) = 12.2, 95% confidence interval (CI): 2.4-62.3). A statistically significant association with additional birth defects, female gender and gestational age >40 weeks was also confirmed. Although not significant, an increased risk of CH was observed among infants with a family history of thyroid diseases among parents (OR = 1.9, 95% CI: 0.7-5.2). Maternal diabetes was also found to be slightly associated with permanent CH (OR = 15.7, 95% CI: 0.9-523) in infants who were large for gestational age. With regard to transient CH, intrauterine growth retardation and preterm delivery were independent risk factors for this form of CH. CONCLUSION: This study showed that many risk factors contribute to the aetiology of CH. In particular, our results suggested a multifactorial origin of CH in which genetic and environmental factors play a role in the development of the disease.

In congenital hypothyroidism bone maturation at birth may be a predictive factor of psychomotor development during the first Year of life irrespective of other variables related to treatment.

OBJECTIVE: To evaluate in a cohort of infants with congenital hypothyroidism (CH): (a) the frequency of bone maturation (BM) retardation at birth and (b) whether BM delay at birth may be considered as a tool to make a prognosis of psychomotor status at the age of 1 Year, irrespective of other variables related to treatment. DESIGN: BM at birth, CH severity and developmental quotient (DQ) at the age of 1 Year were retrospectively evaluated in 192 CH infants selected by the following inclusion criteria: (a) gestation age ranging between 38 and 42 weeks; (b) onset of therapy within the first Month of life; (c) initial thyroxine (l-T(4)) dosage ranging from 10 to 12 microg/kg/day; (d) normalization of serum thyrotropin (TSH) levels before the age of 3 Months; (e) Monthly adjustments of l-T(4) dose during the first Year of life with serum TSH levels ranging from 0.5 to 4 mIU/l; (f) no major diseases and/or physical handicaps associated with CH; (g) availability of both thyroid scanning and knee X-rays at the time of treatment initiation; (h) availability of DQ assessment at an average age of 12 Months. METHODS: BM was considered normal if the distal femur bony nucleus diameter exceeded 3 mm (group A) or retarded if either this nucleus was absent (subgroup B1) or its diameter was <3 mm (subgroup B2). DQ was evaluated with the Brunet-Lezine test. RESULTS: In 44.3% of cases BM was either delayed (23.5%) or severely delayed (20.8%). The risk of BM retardation was higher in the patients with athyreosis than in the remaining patients (41/57 vs 44/135, chi(2)=25.13, P<0.005). BM-retarded infants showed a more severe biochemical picture of CH at birth and a lower DQ at the age of one Year compared with the group A patients. If compared with infants of subgroup B2 those of subgroup B1 exhibited significantly lower T(4) levels at birth and a more frequent association with athyreosis (70.0 vs 30.0%; chi(2)=7.49, P<0.01), whereas DQ was superimposable in both subgroups. CONCLUSIONS: (a) BM at birth is delayed in almost half of CH patients and (b) CH severity per se can affect DQ at the age of 1 Year irrespective of other variables related to therapy.