ERN-RND

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

BACKGROUND: Patient journey maps are increasingly used as a tool that enables healthcare providers to refine their service provision to best meet patient needs. We developed a cervical dystonia patient journey map (CDPJM) that describes the holistic patient experience from pre-diagnosis through to long-term treatment. METHODS: The CDPJM was developed in 2 stages; a patient survey (open questions and multichoice) of 15 patients with CD was conducted to inform the design of the CDPJM, which was then refined and validated by an expert-patient focus group. RESULTS: Qualitative analysis of the patient survey supported five key stages of the patient journey: symptom onset, diagnosis and therapeutic relationship with healthcare professionals, initiation of care for CD, start of CD treatment, and living with treated CD. Following symptom onset, survey respondents described having multiple visits to their family doctor who prescribed strong pain killers and muscle relaxants and referred their patient to up to 10 different specialists for diagnosis. Over half (53.3%) of respondents had received ≥ 1 misdiagnosis. Respondents reported relief at having a diagnosis but a lack of understanding of the prognosis and treatment options; 46.7% said their neurologist did not spend enough time addressing their concerns. Survey respondents reported using a variety of alternative sources of information, including the internet (86.7%), self-help groups (66.7%) and information leaflets provided by health care professionals (60.0%). While botulinum toxin (BoNT) was consistently discussed as the main treatment option, some neurologists also mentioned physiotherapy, counselling, and other complementary approaches. However, patients were often left to seek complementary services themselves. Patients reported a 'rollercoaster' of relief with BoNT treatment with symptoms (and subsequent impact on daily life) returning towards the end of an injection cycle. "When BoNT works well I can return to an almost normal life … when the injections stop working so well, I have to rest more and avoid going to work and experience life restrictions." CONCLUSIONS: We present the first patient journey map for CD that can be used to guide local service mapping and to compare current provision with what patients say they want and need.

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.

Inherited metabolic diseases or inborn errors of metabolism frequently manifest with both hyperkinetic (dystonia, chorea, myoclonus, ataxia, tremor, etc.) and hypokinetic (rigid-akinetic syndrome) movement disorders. The diagnosis of these diseases is in many cases difficult, because the same movement disorder can be caused by several diseases. Through a literature review, two hundred and thirty one inborn errors of metabolism presenting with movement disorders have been identified. Fifty-one percent of these diseases exhibits two or more movement disorders, of which ataxia and dystonia are the most frequent. Taking into account the wide range of these disorders, a methodical evaluation system needs to be stablished. This work proposes a six-step diagnostic algorithm for the identification of inborn errors of metabolism presenting with movement disorders comprising red flags, characterization of the movement disorders phenotype (type of movement disorder, age and nature of onset, distribution and temporal pattern) and other neurological and non-neurological signs, minimal biochemical investigation to diagnose treatable diseases, radiological patterns, genetic testing and ultimately, symptomatic, and disease-specific treatment. As a strong action, it is emphasized not to miss any treatable inborn error of metabolism through the algorithm.

BackgroundVariants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype–phenotype correlations of SCN8A-related ataxia.MethodsWe collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.FindingsVariants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms.InterpretationWe identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.FundingBMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

The lipid molecule ceramide is transported from the endoplasmic reticulum to the Golgi apparatus for sphingomyelin production via the ceramide transport protein (CERT), encoded by CERT1. Hyperphosphorylation of CERT’s serine-repeat motif (SRM) decreases its functionality. Some forms of inherited intellectual disability (ID) have been associated with a serine-to-leucine substitution in the SRM (S132L mutation) and a glycine-to-arginine substitution outside the SRM (G243R mutation) in CERT; however, it is unclear if mutations outside the SRM disrupt the control of CERT functionality. In the current investigation, we identified a new CERT1 variant (dupAA) in a patient with mild ID that resulted from a frameshift at the C-terminus of CERT1. However, familial analysis revealed that the dupAA variant was not associated with ID, allowing us to utilize it as a disease-matched negative control for CERT1 variants that are associated with ID. Biochemical analysis showed that G243R and S132L, but not dupAA, impair SRM hyperphosphorylation and render the CERT variants excessively active. Additionally, both S132L and G243R mutations but not dupAA caused the proteins to be distributed in a punctate subcellular manner. On the basis of these findings, we infer that the majority of ID-associated CERT variants may impair SRM phosphorylation-dependent repression, resulting in an increase in sphingomyelin production concurrent with CERT subcellular redistribution. The lipid molecule ceramide is transported from the endoplasmic reticulum to the Golgi apparatus for sphingomyelin production via the ceramide transport protein (CERT), encoded by CERT1. Hyperphosphorylation of CERT’s serine-repeat motif (SRM) decreases its functionality. Some forms of inherited intellectual disability (ID) have been associated with a serine-to-leucine substitution in the SRM (S132L mutation) and a glycine-to-arginine substitution outside the SRM (G243R mutation) in CERT; however, it is unclear if mutations outside the SRM disrupt the control of CERT functionality. In the current investigation, we identified a new CERT1 variant (dupAA) in a patient with mild ID that resulted from a frameshift at the C-terminus of CERT1. However, familial analysis revealed that the dupAA variant was not associated with ID, allowing us to utilize it as a disease-matched negative control for CERT1 variants that are associated with ID. Biochemical analysis showed that G243R and S132L, but not dupAA, impair SRM hyperphosphorylation and render the CERT variants excessively active. Additionally, both S132L and G243R mutations but not dupAA caused the proteins to be distributed in a punctate subcellular manner. On the basis of these findings, we infer that the majority of ID-associated CERT variants may impair SRM phosphorylation-dependent repression, resulting in an increase in sphingomyelin production concurrent with CERT subcellular redistribution. Intellectual disability (ID) is a developmental disorder that includes intellectual and adaptive functioning deficits in conceptual, social, and practical domains (1American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders.5th Ed. American Psychiatric Association Publishing, Washington, DC2013Crossref Google Scholar). ID has an overall general prevalence in the population of approximately 1%, which varies by age (1American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders.5th Ed. American Psychiatric Association Publishing, Washington, DC2013Crossref Google Scholar). Although the origins of ID are complex and diverse, specifying the origin of ID is crucial for developing rational intervention methods to ameliorate disorders. By using whole-exon sequencing analysis, several independent studies recently showed that de novo mutations in CERT1 are associated with ID (Fig. 1A) (2de Ligt J. Willemsen M.H. van Bon B.W. Kleefstra T. Yntema H.G. Kroes T. Vulto-van Silfhout A.T. Koolen D.A. de Vries P. Gilissen C. del Rosario M. Hoischen A. Scheffer H. de Vries B.B. Brunner H.G. et al.Diagnostic exome sequencing in persons with severe intellectual disability.N. Engl. J. Med. 2012; 367: 1921-1929Crossref PubMed Scopus (1085) Google Scholar, 3Hamdan F.F. Srour M. Capo-Chichi J.M. Daoud H. Nassif C. Patry L. Massicotte C. Ambalavanan A. Spiegelman D. Diallo O. Henrion E. Dionne-Laporte A. Fougerat A. Pshezhetsky A.V. Venkateswaran S. et al.De novo mutations in moderate or severe intellectual disability.PLoS Genet. 2014; 10e1004772Crossref PubMed Scopus (270) Google Scholar, 4The Deciphering Developmental Disorders StudyLarge-scale discovery of novel genetic causes of developmental disorders.Nature. 2015; 519: 223-228Crossref PubMed Scopus (663) Google Scholar, 5Deciphering Developmental Disorders StudyPrevalence and architecture of de novo mutations in developmental disorders.Nature. 2017; 542: 433-438Crossref PubMed Scopus (699) Google Scholar, 6Lelieveld S.H. Wiel L. Venselaar H. Pfundt R. Vriend G. Veltman J.A. Brunner H.G. Vissers L. Gilissen C. Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes.Am. J. Hum. Genet. 2017; 101: 478-484Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7Murakami H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). CERT1 encodes the ceramide transport protein CERT, which mediates interorganelle trafficking of ceramide from the endoplasmic reticulum (ER) to the trans-Golgi regions for the synthesis of sphingomyelin (SM) in mammalian cells (8Hanada K. Kumagai K. Yasuda S. Miura Y. Kawano M. Fukasawa M. Nishijima M. Molecular machinery for non-vesicular trafficking of ceramide.Nature. 2003; 426: 803-809Crossref PubMed Scopus (807) Google Scholar, 9Hanada K. Co-evolution of sphingomyelin and the ceramide transport protein CERT.Biochim. Biophys. Acta. 2014; 1841: 704-719Crossref PubMed Scopus (30) Google Scholar, 10Goto A. Mizuike A. Hanada K. Sphingolipid metabolism occurring at the ER-Golgi contact zone and its impact on membrane trafficking.Contact. 2020; 3: 1-13Crossref PubMed Google Scholar). When a serine-repeat motif (SRM) of CERT undergoes multiple phosphorylations, the function of CERT is repressed (11Kumagai K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. Interorganelle trafficking of ceramide is by phosphorylation-dependent the and domains of Full Text Full Text PDF PubMed Scopus Google Scholar, T. D. Kumagai K. C. T. K. Hanada K. H. by the in ceramide protein is by hyperphosphorylation of an serine-repeat Full Text Full Text PDF PubMed Scopus Google Scholar, K. Hanada K. and of CERT, a protein for the of ceramide at the ER-Golgi membrane contact PubMed Scopus Google Scholar). variants in but not variants are to the the SRM (2de Ligt J. Willemsen M.H. van Bon B.W. Kleefstra T. Yntema H.G. Kroes T. Vulto-van Silfhout A.T. Koolen D.A. de Vries P. Gilissen C. del Rosario M. Hoischen A. Scheffer H. de Vries B.B. Brunner H.G. et al.Diagnostic exome sequencing in persons with severe intellectual disability.N. Engl. J. Med. 2012; 367: 1921-1929Crossref PubMed Scopus (1085) Google Scholar, 3Hamdan F.F. Srour M. Capo-Chichi J.M. Daoud H. Nassif C. Patry L. Massicotte C. Ambalavanan A. Spiegelman D. Diallo O. Henrion E. Dionne-Laporte A. Fougerat A. Pshezhetsky A.V. Venkateswaran S. et al.De novo mutations in moderate or severe intellectual disability.PLoS Genet. 2014; 10e1004772Crossref PubMed Scopus (270) Google Scholar, 4The Deciphering Developmental Disorders StudyLarge-scale discovery of novel genetic causes of developmental disorders.Nature. 2015; 519: 223-228Crossref PubMed Scopus (663) Google Scholar, 5Deciphering Developmental Disorders StudyPrevalence and architecture of de novo mutations in developmental disorders.Nature. 2017; 542: 433-438Crossref PubMed Scopus (699) Google Scholar, 6Lelieveld S.H. Wiel L. Venselaar H. Pfundt R. Vriend G. Veltman J.A. Brunner H.G. Vissers L. Gilissen C. Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes.Am. J. Hum. Genet. 2017; 101: 478-484Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7Murakami H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). ID-associated variants in the CERT SRM have been to impair the SRM phosphorylation-dependent H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). However, ID-associated variants at regions the function of CERT In we a in CERT1 in a patient with ID. using of and CERT that CERT variants with ID-associated mutations impair SRM phosphorylation-dependent repression, resulting in an increase in synthesis concurrent with CERT subcellular redistribution. The is a was to a was for of ID to the de with developmental at that and with with a of and a disorder that from to and as to In and contact was at by an and was was for with developmental On at the was not and and The patient was with was to in a with showed with The of and and was was and not of was to and and using and with and from and or identified and and to to The for showed a of which was with a mild ID However, not for of and and function analysis, and the However, and the showed a in the at of analysis, analysis for ID, and analysis an approximately of and an approximately of not to the The a variant variants of that not to the ID The of the the of the from to CERT1 in Additionally, in the of CERT1 encodes a ceramide transport CERT, of H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). we the of CERT for the CERT1 (Fig. The frameshift dupAA variant the in CERT to (Fig. Although the variant was by sequencing (Fig. and we that it was of ID it was from ID in familial to the has the has ID (Fig. By a of the patient not have the variant was with ID. The not have the variant not the of the dupAA on the function of CERT, we dupAA (Fig. In with the analysis, and not in CERT function in studies (Fig. we that the dupAA was not in patient with ID. the dupAA was not associated with ID, we that CERT variant as an negative control to ID-associated CERT of multiple of the CERT SRM the of CERT (11Kumagai K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. Interorganelle trafficking of ceramide is by phosphorylation-dependent the and domains of Full Text Full Text PDF PubMed Scopus Google Scholar, K. Hanada K. and of CERT, a protein for the of ceramide at the ER-Golgi membrane contact PubMed Scopus Google Scholar). substitution at the in CERT was to render the protein (11Kumagai K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. Interorganelle trafficking of ceramide is by phosphorylation-dependent the and domains of Full Text Full Text PDF PubMed Scopus Google the variant has not been in to However, whole-exon sequencing studies have recently of missense mutations S132L, and that in the SRM of CERT and are associated with inherited ID (2de Ligt J. Willemsen M.H. van Bon B.W. Kleefstra T. Yntema H.G. Kroes T. Vulto-van Silfhout A.T. Koolen D.A. de Vries P. Gilissen C. del Rosario M. Hoischen A. Scheffer H. de Vries B.B. Brunner H.G. et al.Diagnostic exome sequencing in persons with severe intellectual disability.N. Engl. J. Med. 2012; 367: 1921-1929Crossref PubMed Scopus (1085) Google Scholar, 3Hamdan F.F. Srour M. Capo-Chichi J.M. Daoud H. Nassif C. Patry L. Massicotte C. Ambalavanan A. Spiegelman D. Diallo O. Henrion E. Dionne-Laporte A. Fougerat A. Pshezhetsky A.V. Venkateswaran S. et al.De novo mutations in moderate or severe intellectual disability.PLoS Genet. 2014; 10e1004772Crossref PubMed Scopus (270) Google Scholar, 4The Deciphering Developmental Disorders StudyLarge-scale discovery of novel genetic causes of developmental disorders.Nature. 2015; 519: 223-228Crossref PubMed Scopus (663) Google Scholar, 5Deciphering Developmental Disorders StudyPrevalence and architecture of de novo mutations in developmental disorders.Nature. 2017; 542: 433-438Crossref PubMed Scopus (699) Google Scholar, 6Lelieveld S.H. Wiel L. Venselaar H. Pfundt R. Vriend G. Veltman J.A. Brunner H.G. Vissers L. Gilissen C. Spatial clustering of de novo missense mutations identifies candidate neurodevelopmental disorder-associated genes.Am. J. Hum. Genet. 2017; 101: 478-484Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7Murakami H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). that are by the ID-associated CERT1 variants are in (Fig. In to in the SRM of CERT, for the ID-associated G243R which is in a is for in (Fig. However, ID-associated variants in regions in CERT the of the the of CERT, subcellular we to and of S132L was to impair SRM and we CERT and a but CERT CERT in the of CERT, we a CERT1 in which both of CERT1 in CERT with or in the CERT1 cells and to the CERT in the or CERT showed a the or CERT S132L forms and are in with on CERT (11Kumagai K. Kawano M. Shinkai-Ouchi F. 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Nishijima M. to a and for complex of the protein with the protein for Full Text Full Text PDF PubMed Scopus Google Scholar). that the CERT S132L and G243R but not the dupAA showed with CERT cells and (Fig. that the CERT S132L and G243R but not the dupAA showed and G243R variants the function of and CERT1 cells that by and CERT1 cells that with for that on a and was not and CERT1 cells that with of for was with a not variant CERT1 we analysis of the When with the not the of ceramide but that of in CERT1 cells (Fig. to to the in the of in with a T. Hanada K. of in using One. 2014; PubMed Scopus Google Scholar). by CERT in CERT1 cells (Fig. However, the ID-associated variants S132L and G243R in CERT1 was in in the cells with the cells (Fig. the of the not CERT variants recently showed that ID-associated and in CERT caused these proteins to and a punctate subcellular H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). When CERT variants in CERT1 CERT was the with in the which are to a protein (Fig. The CERT S132L and G243R showed a punctate and of the was with the membrane protein (Fig. By CERT dupAA showed punctate and showed a that was to that of CERT (Fig. with studies of CERT and which showed a punctate H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar, K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. Interorganelle trafficking of ceramide is by phosphorylation-dependent the and domains of Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. Hanada K. of the ceramide transport protein CERT at in the with protein for trafficking of ceramide in mammalian 2014; Full Text Full Text PDF PubMed Scopus Google us to that CERT a subcellular punctate that the punctate of CERT may be as a to CERT is by CERT1 genetic sequencing is to with neurodevelopmental ID. and of the of sequencing sequencing showed a of for ID A. Y. C. E. E. D. sequencing in and intellectual and PubMed Scopus Google Scholar). of from to K. S. G. M. R. M. L. E. J. et of analysis and sequencing in with 2015; PubMed Scopus Google Scholar, H. Y. Y. Y. H. H. L. Y. of and sequencing in with intellectual J. Med. Genet. A. PubMed Scopus Google Scholar). In the of of the genetic that to us a the of ID The dupAA variant was analysis of patient with ID using a sequencing regions of the However, the was to be to ID in familial analysis and showed in analysis (Fig. showed that ID-associated missense mutations at the for in CERT1 SRM phosphorylation-dependent of CERT H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). In the we that the G243R which is an ID-associated that outside of the SRM F.F. Srour M. Capo-Chichi J.M. Daoud H. Nassif C. Patry L. Massicotte C. Ambalavanan A. Spiegelman D. Diallo O. Henrion E. Dionne-Laporte A. Fougerat A. Pshezhetsky A.V. Venkateswaran S. et al.De novo mutations in moderate or severe intellectual disability.PLoS Genet. 2014; 10e1004772Crossref PubMed Scopus (270) Google Scholar, 7Murakami H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google was in hyperphosphorylation of the resulted in of CERT (Fig. and punctate subcellular was (Fig. to the ID-associated CERT SRM variants S132L and H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar). CERT dupAA, which is a but CERT variant with to the synthesis of was to a SRM and to not a punctate to the CERT and On the basis of these with a H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. 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Interorganelle trafficking of ceramide is by phosphorylation-dependent the and domains of Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. Hanada K. of the ceramide transport protein CERT at in the with protein for trafficking of ceramide in mammalian 2014; Full Text Full Text PDF PubMed Scopus Google CERT are distributed to not Golgi with the but to punctate punctate to CERT are with but not with Additionally, of CERT to punctate the of the CERT H. Tamura N. Enomoto Y. Shimasaki K. Kurosawa K. Hanada K. Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT.PLoS One. 2020; 15e0243980Crossref PubMed Scopus (7) Google Scholar, K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. Interorganelle trafficking of ceramide is by phosphorylation-dependent the and domains of Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. Hanada K. of the ceramide transport protein CERT at in the with protein for trafficking of ceramide in mammalian 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). Although the of the punctate is at the may membrane contact and trans-Golgi CERT ceramide transport from the to the the punctate and ceramide to and synthesis in the Golgi complex CERT is a has that of proteins in the of membrane in the van M. de J. van J. analysis and as membrane contact proteins with 2020; Full Text Full Text PDF PubMed Scopus Google it is that clustering of in the in the of membrane be to the punctate ID-associated the G243R variant in hyperphosphorylation of the SRM is In the of CERT is to be a F. F. R. A. E. R. E. N. D. J. J. A. A. E. et of in the PubMed Scopus Google Scholar). Hyperphosphorylation of the SRM an that in CERT to the and lipid domains (11Kumagai K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. 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Background GNAO1 -related disorders ( GNAO1 -RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1 -RD. Objectives This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies. Methods A Delphi consensus process was conducted involving international experts in GNAO1 -RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise. Results Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis. Conclusion This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1 -RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1 -RD research.

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [18F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer’s disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [18F]PI-2620 uptake and symptomatology in 4-repeat tauopathies. 72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson’s syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [18F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20–40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored. Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected. Our data reveal [18F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [18F]PI-2620 in 4-repeat tauopathies and whether [18F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [18F]PI-2620 PET results.

Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.

Video S1 A. Mild dystonic postures are observed in both hands, B. and the left foot. C. Gait is normal. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

by clinical sites of to the RD-Connect Genome-Phenome Analysis Platform. Genomic data were processed and filtered as detailed The Solve-RD SNV/Indel working group reported back 74,456 variants in Members of the Solve-RD-DITF-RND and The Solve-RD Consortium are listed in below Acknowledgements.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

AIMS: -adrenoreceptor antagonist with recently identified vesicular monoamine transporter type 2 inhibitory properties, as a repositioned treatment to reduce chorea in Huntington's disease (HD). METHODS: A randomized, placebo-controlled proof-of-concept study was performed in 32 HD patients allocated to 2 arms of 4 sequential 6-week periods each. Patients received placebo and SOM3355 at 100 and 200 mg twice daily in a crossover design. The primary endpoint was improvement by at least 2 points in the total maximal chorea score in any active drug period compared with the placebo period. RESULTS: The primary endpoint was met in 57.1% of the patients. Improvements ≥3, ≥4, ≥5 and ≥6 points vs. placebo treatment were observed in 28.6, 25.0, 17.9 and 10.7% of the patients, respectively. A mixed-model analysis found a significant improvement in the total maximal chorea score of -1.14 (95% confidence interval, -2.11 to -0.16; P = .0224) with 200 mg twice daily SOM3355 treatment compared with placebo treatment. These results were paralleled by Clinical and Patient Global Impression of Change ratings (secondary endpoints). An elevation in plasma prolactin levels by 1.7-1.9-fold was recorded (P < .005), probably reflecting the effect on the dopamine pathway, consistent with vesicular monoamine transporter type 2 inhibition. The most frequent adverse events during SOM3355 administration were mild to moderate. CONCLUSION: Within the limits of this study, the results suggest that SOM3355 reduces chorea in patients with HD and is well-tolerated. Larger studies are necessary to confirm its therapeutic utility as an antichoreic drug. EudraCT number: 2018-000203-16 and ClinicalTrials.gov Identifier: NCT03575676.

One percent of patients with a Huntington's disease (HD) phenotype do not have the Huntington (HTT) gene mutation. These are known as HD phenocopies. Their diagnosis is still a challenge. Our objective is to provide a diagnostic approach to HD phenocopies based on medical expertise and a review of the literature. We employed two complementary approaches sequentially: a review of the literature and two surveys analyzing the daily clinical practice of physicians who are experts in movement disorders. The review of the literature was conducted from 1993 to 2020, by extracting articles about chorea or HD-like disorders from the database Pubmed, yielding 51 articles, and analyzing 20 articles in depth to establish the surveys. Twenty-eight physicians responded to the first survey exploring the red flags suggestive of specific disease entities. Thirty-three physicians completed the second survey which asked for the classification of paraclinical tests according to their diagnostic significance. The analysis of the results of the second survey used four different clustering algorithms and the density-based clustering algorithm DBSCAN to classify the paraclinical tests into 1st, 2nd, and 3rd-line recommendations. In addition, we included suggestions from members of the European Reference Network-Rare Neurological Diseases (ERN-RND Chorea & Huntington disease group). Finally, we propose guidance that integrate the detection of clinical red flags with a classification of paraclinical testing options to improve the diagnosis of HD phenocopies.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

AIM: To investigate the natural progression of SGCE-associated myoclonus dystonia from symptom onset in childhood to early adulthood. METHOD: Myoclonus and dystonia were monitored using rating scales in two cohorts of participants from Spain and the Netherlands. Individual annualized rates of change were calculated and longitudinal trends were assessed using Bayesian mixed models. Psychiatric features were evaluated cross-sectionally in the Spanish cohort. RESULTS: Thirty-eight patients (21 males, 17 females) were evaluated at a mean age (SD) of 10 years (4 years 7 months; range 2-21 years) and 14 years 2 months (4 years 8 months; range 4-25 years). We observed a significant worsening of action myoclonus, global dystonia, and dystonia during writing (mean annual increases of 1.356, 0.226, and 0.518 in the Unified Myoclonus, Burke-Fahn-Marsden, and Writer's Cramp Rating Scales respectively). Accordingly, participants perceived a significant worsening in their speech, writing, and walking abilities. Twenty-six of 32 participants suffered from anxiety (n = 13), obsessive-compulsive disorder (n = 9), and attention-deficit/hyperactivity disorder (n = 8). INTERPRETATION: This study demonstrates that, unlike in the adult population, myoclonus dystonia syndrome in childhood and adolescence follows a progressive course that can be debilitating in the early stages of life. These findings, along with a high prevalence of psychiatric symptoms, highlight the need for early therapeutic interventions to prevent long-term motor and psychological sequelae.

BACKGROUND: GNAO1-related disorders (GNAO1-RD) encompass developmental delay, epilepsy and movement disorders, including dyskinetic crises. OBJECTIVES: To explore the characteristics of dyskinetic crises in GNAO1-RD, their impact and the challenges parents face. METHODS: A cross-sectional EU survey of 26 parents of children with GNAO1-RD collected demographic, clinical, and management-related data. RESULTS: Dyskinetic crises were experienced by 80% of children. They began at a mean age of 4.17 ± 2.61 years and varied widely in frequency and duration, with triggers including infections and emotions. Dyskinetic crises significantly impacted quality of life (QoL), motor function, and emotional well-being. Medications were variably effective, and 10 children underwent deep brain stimulation with mixed outcomes. Parents reported challenges in managing crises and accessing support services, with financial burdens. CONCLUSIONS: Dyskinetic crises in GNAO1-RD significantly impact QoL and present complex management challenges. Variability in outcomes underscores the need for optimized treatment protocols, better coordination, and accessible resources for affected families.

BACKGROUND: NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated. OBJECTIVES: The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD. METHODS: This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers. RESULTS: Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging. CONCLUSION: This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.

Glucose transporter type 1 deficiency syndrome (Glut1DS) is a treatable genetic neurometabolic disorder because of a variant in the Glut1 transporter, encoded by the SLC2A1 gene (OMIM*138140), resulting in impaired glucose transport across the blood–brain barrier. Glut1DS was initially reported in infants with progressive encephalopathy, acquired microcephaly, and drug-resistant epilepsy and can be treated with the ketogenic diet.1 With increased awareness and progress in diagnosis, the phenotype has expanded to include milder presentations of epilepsy, movement disorders, and cognitive impairment.2 Glut1DS is estimated to affect 1 in every 24,000 live births.3 A 5-year-old Spanish girl presented with paroxysmal movement disorder, characterized by abnormal leg posture, unsteady gait, and frequent falls by 2 years and 8 months of age. Five months later, she had an episode that lasted 4 hours. Subsequently, frequent episodes were reported to occur on a weekly basis. One of those episodes included dysarthria without loss of consciousness (Video 1). Given her age, her family has been unable to identify a specific trigger for these episodes. She was born to term after a normal pregnancy to healthy non-consanguineous Caucasian parents with a positive family history of epilepsy (maternal grandmother). Her early neurodevelopment was described as normal, with a slight delay in independent gait acquisition at 18 months. A neurological examination at 5 years and 7 months of age showed microcephaly (cranial circumference of 48 cm, 2nd percentile); although no other neurological signs were observed. During hospitalization, a brain MRI was performed with normal results. Video electroencephalogram (EEG) showed electroclinical myoclonic seizures. These epileptic myoclonus occurred infrequently and were not identified by the family as seizures. She had no other types of seizures. Extensive biochemical and metabolic tests showed normal results. Lumbar puncture showed hypoglycorrhachia of 32 mg/dL and a cerebrospinal fluid (CSF)/serum glucose ratio of 0.5 (reference value >0.60) and flow cytometric analysis of the surface expression of Glut1 in circulating erythrocytes was reduced to 36% compared to the general population according to the METAglut1 test (Fig. 1). Both tests were helpful in confirming the diagnostic suspicion of Glut1DS. Following that, whole exome sequencing revealed a previously reported heterozygous de novo variant on the SLC2A1 gene, p.Arg333Gln/c.998G>A. A ketogenic diet with a fat-to-protein plus carbohydrate ratio of 4:1 was started with good tolerance. In clinical follow-up after 24 months of ketogenic diet treatment, no further episodes of paroxysmal movement disorder or myoclonic seizures were reported. The video EEG did not report any epileptic abnormalities or seizures. Her neuropsychological evaluation is described in Appendix S1. The legal guardians gave their consent for publication and the study was approved by the Ethics Committee (ART-07-21). Glut1DS is a well-known clinical entity comprising a classical (90%) and a non-classical (10%) phenotype. Non-epileptic paroxysmal events, such as those presented by our patient, have been detected in 28% of a series of 57 patients with Glut1DS.4 Although paroxysmal exercise-induced dyskinesia is the most common type of paroxysmal dyskinesia in Glut1DS, other non-kinesigenic dyskinesia, episodic ataxia, or a combination of subtypes can also be present (Video 1).5 The diagnosis of Glut1DS is established with a CSF glucose concentration of <60 mg/dL in combination with a normal blood glucose concentration and with the identification of a heterozygous pathogenic variant in the SLC2A1 gene by molecular genetic testing. However, the decrease of more than 20% in Glut1 expression on the surface of the erythrocytes detected by the METAglut1 test compared to the general population is also highly suggestive.6 Gras et al,6 first introduced the METAglut1 as a simple diagnostic blood test for Glut1DS using flow cytometry, with a detection rate of 78% in patients with proven Glut1DS. An EDTA tube is used to obtain whole blood for the METAglut1 test. The patient does not need to fast before the blood draw. The sample is sent to the central lab at 4°C and results are available in 48 hours. The assay takes approximately 1 hour to run and analyze 1 to 18 samples. Glut1 expression is measured directly on erythrocytes using a simple flow cytometer.6 Currently, the test is only available in France but it is expected to be implemented soon in a number of European countries with the CE mark (Spain, Italy, and Germany). The fact that METAglut1 can be performed using blood analysis rather than a lumbar puncture and that it takes only a short time to perform compared to months for a genetic study in a hospital setting, clearly demonstrates its use in screening for Glut1DS. The latest international Glut1DS study group review concluded that the METAglut1 test is not yet a standard diagnostic tool for Glut1DS,7 whereas ongoing studies should provide actionable results soon (NCT 03722212). In conclusion, our report describes a case of non-kinesigenic paroxysmal dyskinesias associated with Glut1DS and highlights METAglut1 test use for rapid disease diagnosis. The authors thank the patient and her family. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. L.S.: 3A, 3B L.M.: 1C, 3B D.Y.: 1C, 3B C.V.: 1C, 3B V.P.: 1C, 2A, 3B J.D.O.E.: 1A, 1B, 1C, 3B The legal guardians gave their written consent to the recording of the patient for publication, and the study received ethical approval by the Ethics Committee (ART-07-21). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. V.P. is the cofounder and CEO of Metafora Biosystems. The authors declare that there are no other conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report. Appendix S1. Neuropsychological evaluation. (A) Kaufman K-BIT Brief Intelligence Test. The global composite IQ score is 94, placing the intellectual capabilities of the patient at a medium level rather than the expected level for her age. (B) Vineland-II Interview. The patient achieves appropriate sociability scores, but deviates from normal communication, daily skills, and psychomotor development. (C) Navarra oral language test (PLON). The PLON results suggest that the linguistic content and use are within normal limits. The findings of the language form section demonstrate that certain features of morphology and syntax do not develop with age. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.