Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role that anti-mGluR5-antibodies play. We investigated lymphoma tissue from patients with Ophelia syndrome and with isolated classical Hodgkin lymphoma by quantitative immunocytochemistry for mGluR5-expression. Further, we studied the L-1236, L-428, L-540, SUP-HD1, KM-H2, and HDLM-2 classical Hodgkin lymphoma cell lines by FACS and Western blot for mGluR5-expression, and by transcriptome analysis. mGluR5 surface expression differed significantly in terms of receptor density, distribution pattern, and percentage of positive cells. Highest expression levels were found in the L-1236 line. RNA-sequencing revealed more than 800 genes that were higher expressed in the L-1236 line in comparison to the other classical Hodgkin lymphoma cell lines. High mGluR5-expression was associated with upregulation of PI3K/AKT and MAPK pathways and of downstream targets (e.g. EGR1) known to be involved in classical Hodgkin lymphoma progression. Finally, mGluR5 expression was increased in the classical Hodgkin lymphoma-tissue of our Ophelia syndrome patient in contrast to five classical Hodgkin lymphoma-patients without autoimmune encephalitis. Given the association of encephalitis and classical Hodgkin lymphoma in Ophelia syndrome, it is possible that mGluR5-expression on classical Hodgkin lymphoma cells not only drives tumor progression but also triggers anti-mGluR5 encephalitis even before classical Hodgkin lymphoma becomes manifest.

Primary congenital hypothyroidism is readily diagnosed based on elevated plasma TSH levels. In contrast, in the rare disorders of thyroid hormone resistance, TSH and often also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and has the same severe consequences for childhood development as congenital hypothyroidism. A total of 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free T3 to free T4 (fT3/fT4 ratio). The aim was to determine whether cases with genetically confirmed thyroid hormone resistance (MCT8, THRα, and SECSIBP2 defects) had an abnormal fT3/fT4 ratio. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend the use of the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be plotted on centile charts using our free online tool at http://www.thyroid-hormone-ratio.org that accepts various SI and non-SI units.

Background: Patients with mutations in the monocarboxylate transporter 8 (MCT8) suffer from Allan-Herndon-Dudley syndrome (AHDS), characterized by developmental delay and a highly disabling movement disorder. Despite the potential of thyroid hormone derivatives to overcome the transporter defect, current trials did not achieve patient-oriented therapeutic goals. Objectives: Since most neurological symptoms are related to the dopaminergic system, we investigated the role of dopamine and its metabolites in MCT8 deficiency with regard to pathophysiology and potential therapeutic strategies in an observational cohort study. Methods: We present longitudinal data from the DEEPTYPE registry of ten patients with video-documentation, standardized phenotyping, cerebrospinal fluid analysis, treatment response to levodopa/carbidopa supplementation, and neuroimaging data. To establish a cell-based model for pathophysiological studies, we differentiated healthy human induced pluripotent stem cells (hiPSCs) into dopaminergic neurons. Results: Children presented with signs of parkinsonism in childhood, including hypokinesia, hypomimia, inability to sit or stand, rigidity, dystonia, and autonomic dysfunction along the classification of Leuzzi and colleagues. Cerebrospinal fluid homovanillic acid concentrations were decreased (n=11), suggesting isolated dopamine pathway impairment. Six out of seven patients responded favorably to levodopa/carbidopa supplementation and we did not see any adverse drug reactions. Our cell-based studies showed that hiPSC-derived dopaminergic neurons expressed MCT8 and produced quantifiable levels of biogenic amines. Conclusions: Parkinsonism is part of AHDS's clinical presentation and may be amenable to treatment. The precise impact of MCT8 deficiency on the dopamine metabolism needs to be further elucidated, e.g. by using patient iPSC-derived dopaminergic neurons in future studies.