SFEBES2014 Poster Presentations Thyroid (51 abstracts)
Neurocognitive and CNS abnormalities in humans with defective thyroid receptor α
Carla Moran 1 , Edward Visser 1 , Nadia Schoenmakers 1 , Francesco Muntoni 2 , Chris Clark 3 , David Gadian 3 , Kling Chong 4 , Adam Kuczynski 5 , Mehul Dattani 6 , Faraneh Vargha-Khadem 5 & Krishna Chatterjee 1
1Wellcome-MRC Insitute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK; 3Imaging and Biophysics, UCL Institute of Child Health, London, UK; 4Department of Radiology, Great Ormond
St Children’s Hospital, London, UK; 5Department of Neuropsychology, Great Ormond St Children’s Hospital, London, UK; 6Department of Endocrinlogy, Great Ormond St Children’s Hospital, London, UK.
Background: The severe neurodevelopmental phenotype of untreated congenital hypothyroidism exemplifies the critical role of thyroid hormones (TH) in CNS development, acting via thyroid hormone receptor α1 (TRα1) on cortical neurogenesis, cerebellar development and oligodendrocyte differentiation. We have identified the first humans with defective TRα1 and investigated neurocognitive phenotype and CNS abnormalities in this disorder.
Methods: Four affected individuals (P1: female 8 years; P2: female 13 years; P3: father of P2 53 years; P4: female 43 years) were studied. Neurological investigation, cognitive testing, and brain magnetic resonance imaging and spectroscopy (MRI/S) were undertaken.
Findings: All subjects exhibited developmental delay; P4 also has severe learning disability and epilepsy. Neurological abnormalities common to all cases include gross and fine motor incoordination, with ataxic gait, dysdiadochokinesis and slow speech, associated with reduced cerebellar volume on MRI. IQ is variably reduced (P1 84, P2 90, P3 85, P4 52) and adult cases exhibit marked microencephaly; reduced N-acetylaspartate (NAA) levels (expressed as NAA:creatine ratio) measured by magnetic resonance spectroscopy (frontal white matter: P3 1.77, P4 1.54, controls 2.2+/−0.2); thalamic: P3 2.05, P4 1.9, controls 2.09–2.25) suggests neuronal loss or dysfunction. Diffusion tensor imaging (P1, P2) indicates reduced axonal density/myelination and tract organisation; impaired verbal longterm memory (P1) correlates with significant reduction (20%) in hippocampal volume. Known neural target genes (hairless, KLF-9) in patient derived mononuclear cells are TH refractory.
Interpretation: Observed neurocognitive deficits (motor incoordination, reduced IQ, impaired longterm memory) and structural abnormalities (microcephaly, reduced cerebellar and hippocampal volume, diminished white matter density) accord with known developmental actions of thyroid hormone and substantiate the critical CNS role of TRα1. Studies of neural cell types generated from their inducible pluripotent stem cells may elucidate TH-dependent brain pathways.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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