Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study.

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 < 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 < 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.

Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.

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 knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.

Comprehensive molecular testing in patients with high functioning autism spectrum disorder.

Autism spectrum disorders (ASD) include a range of complex neurodevelopmental disorders with extreme genetic heterogeneity. Exome and target sequencing studies have shown to be an effective tool for the discovery of new ASD genes. The aim of this study was to design an ASD candidate gene panel that covers 44 of the top ASD candidate genes. As a pilot study we performed comprehensive molecular diagnostic testing, including the study of the FMR1 and FMR2 repeat regions, copy number variant analysis in a collection of 50 Spanish ASD cases and mutation screening using targeted next generation sequencing-based techniques in 44 out of the total cohort. We evaluated and clinically selected our cohort, with most of the cases having high functioning ASD without facial dysmorphic features. The results of the present study allowed the detection of copy number and single nucleotide variants not yet identified. In addition, our results underscore the difficulty of the molecular diagnosis of ASD and confirm its genetic heterogeneity. The information gained from this and other genetic screenings is necessary to unravel the clinical interpretation of novel variants.

Effectiveness of antiepileptic therapy in patients with PCDH19 mutations.

PURPOSE: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. METHODS: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years). RESULTS: The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year. SIGNIFICANCE: The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.

Microdeletion 5q14.3 and anomalies of brain development.

5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable. We describe two unrelated patients with overlapping de novo interstitial deletions of 4.1 and 1.9 Mb, including MEF2C in 5q14.3, one of whom had a complex brain malformation which could be best described as microcephaly with simplified gyral pattern (MSG). Expression analysis in both patients confirmed haploinsufficiency for MEF2C, decreased MECP2 expression and increased C3ORF58 (DIA1) expression, which is a new finding. A detailed analysis of brain and white matter abnormalities reported in patients with 5q14.3 deletion syndrome to date revealed a greater number of reported abnormalities in patients with deletions not including MEF2C than those with deletions or mutations directly affecting MEF2C. Screening an additional 43 patients with malformations of cerebral cortical development (MCD) for mutations in MEF2C and/or deletions in 5q14.3q15, did not detect any additional mutations, allowing us to conclude that 5q14.3 deletion syndrome is a rare cause of microcephaly with simplified gyral pattern.

Maturation of inhibitory and excitatory motor cortex pathways in children.

OBJECTIVE: To study intracortical inhibition and facilitation with paired-pulse transcranial magnetic stimulation in children, adolescents and adults. METHODS: Paired-pulse transcranial magnetic stimulation (interstimulus intervals (ISI): 1, 3, 5, 10 and 20 ms) was applied over the primary motor cortex (M1) in 30 healthy subjects (range 6-30 years, median age 15 years and 8 months, SD 7,9) divided in three groups: adults (>or=18 years), adolescents (> 10 and < 18 years) and children (

Unilateral venous thalamic infarction in a child mimicking a thalamic tumor.

Unilateral thalamic infarction is a rare condition in adults. This is a case report of a young child presenting with left-sided hemiparesis of sudden onset due to an unilateral venous thalamic infarction. This was attributed to an asymmetric thrombosis of the cerebral internal veins, a partial thrombosis of the vein of Galen and straight sinus. Magnetic resonance imaging resulted primarily in the differential diagnosis of a cerebral tumor or an intracerebral abscess, leading to stereotactic puncture. Subsequent magnetic resonance venography facilitated the correct diagnosis. Heparin-induced thrombocytopenia necessitated anticoagulation treatment with hirudin and later, warfarin. The patient made a complete recovery. We conclude that unclear unilateral thalamic lesions might be symptomatic of a cerebral deep venous thrombosis and might mimic a thalamic tumor. In uncertain cases, we suggest rapid performance of magnetic resonance angiography.

Altered cortical inhibitory function in children with spastic diplegia: a TMS study.

Periventricular leukomalacia (PVL) is the most frequent cause of spastic diplegia. The movement disorder is attributed to damage to the corticospinal tract, but there is increasing evidence of additional cortical dysfunction associated with PVL. Aim of the present study was to evaluate the integrity of the corticospinal tract and cortical inhibitory function using transcranial magnetic stimulation. Fifteen children with bilateral PVL and spastic diplegia and twenty-two healthy children underwent single-pulse stimulations to the right tibial anterior muscle. We compared central motor conduction time and amplitudes of motor evoked potentials as markers for corticospinal integrity and the postexcitatory silent period (SP), representing cortical inhibitory interneurons. The patients' parameters of corticospinal tract function did not differ significantly from those in the control children. In contrast, the SP was significantly shortened in children with PVL (mean 25.6 +/- 6.9 ms; controls: mean 47.6 +/- 23.2 ms, P = 0.018). This suggests cortical involvement with reduced cortical inhibitory function in PVL. This could be due to impaired functioning of the cortical interneurons themselves, or to decreased input from activating fibres, e.g. thalamocortical or cortico-cortical connections.

Validation of the Gross Motor Function Measure for use in children and adolescents with traumatic brain injuries.

OBJECTIVES: Motor function recovery is a key goal during rehabilitation of children and adolescents with traumatic brain injury. To evaluate how well treatment strategies improve motor function, we need validated outcome measures that are responsive to change in pediatric patients with traumatic brain injury. The Gross Motor Function Measure has demonstrated excellent psychometric properties in children with cerebral palsy and Down syndrome, yet its responsiveness in patients with pediatric traumatic brain injury has not been proven irrefutably. Our aim was to validate the Gross Motor Function Measure for this patient group. METHODS: Seventy-three patients (mean age: 11.4 years; range: 0.8-18.9 years) with moderate-to-severe traumatic brain injury were recruited in 12 rehabilitation centers and assessed twice with the Gross Motor Function Measure-88 over 4 to 6 weeks. As an external standard, we used judgements of change made independently by parents, physiotherapists, and 2 video assessors who were not familiar with the patients. We formulated and statistically investigated a priori hypotheses of how Gross Motor Function Measure change scores would correlate with those judgements of change. Both Gross Motor Function Measure versions, the original Gross Motor Function Measure-88 and the more recently developed Gross Motor Function Measure-66, were evaluated. RESULTS: Both Gross Motor Function Measure change scores correlated significantly with all of the clinical judgements of change. The degree of correlation that we postulated, that the Gross Motor Function Measure change score would correlate highest with the video rating followed by physiotherapists and parents, was fully confirmed by the Gross Motor Function Measure-88 and largely confirmed by the Gross Motor Function Measure-66. Both Gross Motor Function Measure versions revealed convincing discriminative capability. Test-retest reliability was excellent. CONCLUSIONS: We demonstrate convincing evidence of responsiveness and validity to support the use of both Gross Motor Function Measure versions as evaluative measures of gross motor function in children and adolescents with traumatic brain injury.