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Objective: N‐methyl‐d‐aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1‐3b[I481V]), p.Ala666Ser (GluN1‐3b[A666S]), and p.Tyr668His (GluN1‐3b[Y668H]). Methods: Wild‐type and variant‐containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch‐clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy. Results: Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain‐of‐function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK‐801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK‐801. These variant receptors were also activated by either glutamate or glycine alone. Single‐receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild‐type GluN1/2A receptors. Significance: Our study reveals a critical functional locus of the receptor (GluN1[Y668]) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder. [ABSTRACT FROM AUTHOR]

We report four patients from two families who presented attacks of childhood‐onset episodic ataxia associated with pathogenic mutations in the FGF14 gene. Attacks were triggered by fever, lasted several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia. These cases and literature data delineate the FGF14‐mutation‐related episodic ataxia phenotype: wide range of age at onset (from childhood to adulthood), variable durations and frequencies, triggering factors including fever, and association to chronic symptoms. We propose to add FGF14‐related episodic ataxia to the list of primary episodic ataxia as Episodic Ataxia type 9. [ABSTRACT FROM AUTHOR]

The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications. [ABSTRACT FROM AUTHOR]