Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1•5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. Findings: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24•0 months (IQR 12•0-60•0, range 0•0-744•0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35•0 years (95% CI 8•3-61•7). Individuals who did not attain head control by age 1•5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3•46, 95% CI 1•76-8•34; log-rank test p=0•0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4•71, 95% CI 1•26-17•58, p=0•021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. Interpretation: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides ...

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

Context Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Objective Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. Methods In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. Results From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P &lt; 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P &lt; 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. Conclusions Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Introduction: The risk of obesity in children with Down syndrome is high. Undoubtedly, proper nutrition plays an important role in the prevention of excess body weight and is associated with a reduction of metabolic complications. The aim of the study was to assess the problem of disturbances in the nutritional status and eating habits of children with DS. Methods: A total of 39 patients were included in the study. The nutritional status was assessed by anthropometric tests and Dual X-ray Absorptiometry. Eating habits were assessed using the Child Eating Behavior Questionnaire and the Food Frequency Questionnaire. Blood samples were taken to determine the oxidative stress and lipid parameters. Results: Obesity was recognized in 15% of subjects and 23% were overweight. Children that were overweight were characterized by higher levels of triglycerides, atherogenic index of plasma, and apoA2 and apoE levels. Fat mass, fat mass/height2 index, and visceral fat mass correlated with thiobarbituric acid reactive substances and advanced oxidative protein product level. The analysis of the Child Eating Behavior Questionnaire showed that children struggling with being overweight were more interested in food compared to those with normal body weight. A positive correlation was identified between waist circumference and food interest categories. Insufficient consumption of dairy products, vegetables, whole grain products, as well as fruits, seeds, nuts, and fatty fish was noted. Patients were less likely to consume products that are a good source of mono- and polyunsaturated fatty acids. Conclusions: In children with Down syndrome and obesity, disturbances in lipid and oxidative stress parameters are observed. Abnormal eating habits in all children with Down syndrome regardless of their nutritional status were noted. Proper nutritional education, nutritional control, and management of metabolic problems are essential in this group of patients.

Background: The relationship between intelligence quotient (IQ) and somatic development, especially growth, has been demonstrated in various groups of children. Down syndrome (DS) is characterized by short stature, overweight, and cognitive impairment. The objective of our work was to assess whether anthropometric measurements [weight, height, body mass index (BMI)] of children with DS correlate with their IQ. The results of the study may be valuable for this population in the light of increasing access to growth hormone therapy (GHT) in various genetic syndromes with short stature. Based on previous studies on children, we hypothesized that a link exists between IQ and somatic development, particularly growth.Methods: This cross-sectional study included 40 children with DS, who were aged 9-18 years. The studied population was selected from the registry of the Genetic Clinic at the University Clinical Center in Gdańsk (Poland). Anthropometric measurements (weight and height) were taken for all the children, and their BMI was determined using these data. The obtained results were plotted on charts for children with DS. The IQ of the children was assessed using the Stanford Binet Intelligence Scale, Fifth Edition. The correlations between IQ and anthropometric data were analyzed using univariate correlation and multiple regression analyses. Results:The results showed that full-scale, verbal, and nonverbal IQ correlated with height percentile (P=0.03, P=0.02, and P=0.04, respectively), but not with weight (P=0. 26, P=0.19, and P=0.61, respectively) or BMI (P=0.6, P=0.5, and P=0.72, respectively). In multiple linear regression analysis, height percentile remained as an independent determinant of the IQ results after adjusting for birth weight, hypothyroidism with L-thyroxine replacement therapy, and congenital cardiac defect (β=0.48, P=0.018). Conclusions:The results of our study suggest an association between growth and IQ in children with DS. The presented findings may be valuable for improving access to GHT for populations with genetic syndromes characterized by short stature. However, these should be confirmed by further research with a longitudinal sample of children with DS.