BackgroundPhenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients.MethodsTo this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers.ResultsIn total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms.ConclusionsBased on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0890-7) contains supplementary material, which is available to authorized users.

Aims/hypothesis Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B 1 ) in a cohort of individuals with TRMA-related diabetes. Methods We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.Results We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months . At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Followup data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and A list of the members of the International Neonatal Diabetes Consortium is included in the electronic supplementary material (ESM).Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4554-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient's clinical diagnosis was then confirmed with molecular Int.

Background: Parents of children with phenylketonuria are at risk of reduced quality of life. Aims: This study determined the quality of life of parents of children with phenylketonuria in Tehran Province. Methods: The study was conducted in 2015 and included parents of children with phenylketonuria referred to three government children's hospitals in Tehran Province that provide phenylketonuria services. Data were collected using the Farsi version of the World Health Organization Quality of Life-Bref questionnaire. Analysis of variance, t-test, Pearson correlation coefficient and multiple linear regression were used to assess the relationship between quality of life domains and sociodemographic characteristics of the parent and child. Results: The study included 240 parents; 55% were mothers. Quality of life of parents in psychological, social relationships and environment domains was low. Significant relationships were found between: physical domain and age of child at phenylketonuria diagnosis (P = 0.044); psychological domain and parent's age (P = 0.019), child's age (P = 0.007) and parent's education (P = 0.015); social relationships domain and parent's age (P = 0.003), and education (P = 0.002), household income (P = 0.025) and child's age (P = 0.004; and environmental domain and residence (P = 0.034), parent's education (P = 0.007), household income (P = 0.002) and child's age (P = 0.049). In the multivariable analysis, parent's age and education, child's age, and household income were significantly associated with parent's quality of life. Conclusion: Given the low levels of quality of life in the parents, education and more financial support are recommended.

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