@article {806, title = {Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 10}, pages = {2272-2283}, abstract = {

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

}, keywords = {Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Male, Muscle Hypotonia, Muscle Weakness, Mutation, Missense, Myasthenic Syndromes, Congenital, Pedigree, Phenotype, Synaptic Transmission, Synaptotagmin II}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61765}, author = {Donkervoort, Sandra and Mohassel, Payam and Laugwitz, Lucia and Zaki, MAH S and Kamsteeg, Erik-Jan and Maroofian, Reza and Chao, Katherine R and Verschuuren-Bemelmans, Corien C and Horber, Veronka and Fock, Annemarie J M and McCarty, Riley M and Jain, Minal S and Biancavilla, Victoria and McMacken, Grace and Nalls, Matthew and Voermans, Nicol C and Elbendary, Hasnaa M and Snyder, Molly and Cai, Chunyu and Lehky, Tanya J and Stanley, Valentina and Iannaccone, Susan T and Foley, A Reghan and Lochm{\"u}ller, Hanns and Gleeson, Joseph and Houlden, Henry and Haack, Tobias B and Horvath, Rita and B{\"o}nnemann, Carsten G} } @article {866, title = {Genetics of schizophrenia in the South African Xhosa.}, journal = {Science}, volume = {367}, year = {2020}, month = {2020 01 31}, pages = {569-573}, abstract = {

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

}, keywords = {Age Factors, Autistic Disorder, Bipolar Disorder, Dopamine, Female, gamma-Aminobutyric Acid, Genetic Variation, Glutamine, Humans, Male, Mutation, Neural Pathways, Schizophrenia, Sex Factors, South Africa, Synapses, Synaptic Transmission}, issn = {1095-9203}, doi = {10.1126/science.aay8833}, author = {Gulsuner, S and Stein, D J and Susser, E S and Sibeko, G and Pretorius, A and Walsh, T and Majara, L and Mndini, M M and Mqulwana, S G and Ntola, O A and Casadei, S and Ngqengelele, L L and Korchina, V and van der Merwe, C and Malan, M and Fader, K M and Feng, M and Willoughby, E and Muzny, D and Baldinger, A and Andrews, H F and Gur, R C and Gibbs, R A and Zingela, Z and Nagdee, M and Ramesar, R S and King, M-C and McClellan, J M} } @article {544, title = {A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5.}, journal = {Ann N Y Acad Sci}, volume = {1413}, year = {2018}, month = {2018 02}, pages = {119-125}, abstract = {

We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50\% decrement of compound muscle action potential amplitudes but 250\% facilitation immediately after exercise, similar to that seen in Lambert-Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α-laminins.

}, keywords = {Adult, Female, Humans, Lambert-Eaton Myasthenic Syndrome, Laminin, Motor Endplate, Myasthenic Syndromes, Congenital, Synaptic Transmission}, issn = {1749-6632}, doi = {10.1111/nyas.13585}, author = {Maselli, Ricardo A and Arredondo, Juan and V{\'a}zquez, Jessica and Chong, Jessica X and Bamshad, Michael J and Nickerson, Deborah A and Lara, Marian and Ng, Fiona and Lo, Victoria Lee and Pytel, Peter and McDonald, Craig M} } @article {51, title = {Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1249-1255}, abstract = {

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Brain Diseases, Electrophysiology, Epilepsy, Female, Humans, Hyperkinesis, Infant, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree, Synaptic Transmission}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.008}, author = {Madeo, Marianna and Stewart, Michelle and Sun, Yuyang and Sahir, Nadia and Wiethoff, Sarah and Chandrasekar, Indra and Yarrow, Anna and Rosenfeld, Jill A and Yang, Yaping and Cordeiro, Dawn and McCormick, Elizabeth M and Muraresku, Colleen C and Jepperson, Tyler N and McBeth, Lauren J and Seidahmed, Mohammed Zain and El Khashab, Heba Y and Hamad, Muddathir and Azzedine, Hamid and Clark, Karl and Corrochano, Silvia and Wells, Sara and Elting, Mariet W and Weiss, Marjan M and Burn, Sabrina and Myers, Angela and Landsverk, Megan and Crotwell, Patricia L and Waisfisz, Quinten and Wolf, Nicole I and Nolan, Patrick M and Padilla-Lopez, Sergio and Houlden, Henry and Lifton, Richard and Mane, Shrikant and Singh, Brij B and Falk, Marni J and Mercimek-Mahmutoglu, Saadet and Bilguvar, Kaya and Salih, Mustafa A and Acevedo-Arozena, Abraham and Kruer, Michael C} }