@article {916, title = {Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 03}, pages = {524-533}, abstract = {

PURPOSE: Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown.

METHODS: We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD.

RESULTS: We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways.

CONCLUSION: The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

}, keywords = {4-Hydroxyphenylpyruvate Dioxygenase, Animals, Dioxygenases, Exons, Mice, Mice, Knockout, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01010-y}, author = {Ghosh, Shereen G and Lee, Sangmoon and Fabunan, Rudy and Chai, Guoliang and Zaki, MAH S and Abdel-Salam, Ghada and Sultan, Tipu and Ben-Omran, Tawfeg and Alvi, Javeria Raza and McEvoy-Venneri, Jennifer and Stanley, Valentina and Patel, Aakash and Ross, Danica and Ding, Jeffrey and Jain, Mohit and Pan, Daqiang and L{\"u}bbert, Philipp and Kammerer, Bernd and Wiedemann, Nils and Verhoeven-Duif, Nanda M and Jans, Judith J and Murphy, David and Toosi, Mehran Beiraghi and Ashrafzadeh, Farah and Imannezhad, Shima and Karimiani, Ehsan Ghayoor and Ibrahim, Khalid and Waters, Elizabeth R and Maroofian, Reza and Gleeson, Joseph G} } @article {790, title = {Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 05 01}, pages = {1447-1461}, abstract = {

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

}, keywords = {Abnormalities, Multiple, Epileptic Syndromes, Female, Glutamate Decarboxylase, Humans, Infant, Newborn, Male, Mutation, Pedigree}, issn = {1460-2156}, doi = {10.1093/brain/awaa085}, author = {Chatron, Nicolas and Becker, Felicitas and Morsy, Heba and Schmidts, Miriam and Hardies, Katia and Tuysuz, Beyhan and Roselli, Sandra and Najafi, Maryam and Alkaya, Dilek Uludag and Ashrafzadeh, Farah and Nabil, Amira and Omar, Tarek and Maroofian, Reza and Karimiani, Ehsan Ghayoor and Hussien, Haytham and Kok, Fernando and Ramos, Luiza and Gunes, Nilay and Bilguvar, Kaya and Labalme, Audrey and Alix, Eudeline and Sanlaville, Damien and de Bellescize, Julitta and Poulat, Anne-Lise and Moslemi, Ali-Reza and Lerche, Holger and May, Patrick and Lesca, Gaetan and Weckhuysen, Sarah and Tajsharghi, Homa} } @article {355, title = {PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.}, journal = {Brain}, volume = {140}, year = {2017}, month = {2017 Apr 01}, pages = {940-952}, abstract = {

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

}, keywords = {Adolescent, Brain, Carrier Proteins, Cell Differentiation, Cell Movement, Cerebral Cortex, Child, Child, Preschool, Cytoskeleton, Developmental Disabilities, Female, Genes, Recessive, Heredodegenerative Disorders, Nervous System, Humans, Infant, Male, Microcephaly, Microtubules, Mutation, Pedigree, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awx014}, author = {Zollo, Massimo and Ahmed, Mustafa and Ferrucci, Veronica and Salpietro, Vincenzo and Asadzadeh, Fatemeh and Carotenuto, Marianeve and Maroofian, Reza and Al-Amri, Ahmed and Singh, Royana and Scognamiglio, Iolanda and Mojarrad, Majid and Musella, Luca and Duilio, Angela and Di Somma, Angela and Karaca, Ender and Rajab, Anna and Al-Khayat, Aisha and Mohan Mohapatra, Tribhuvan and Eslahi, Atieh and Ashrafzadeh, Farah and Rawlins, Lettie E and Prasad, Rajniti and Gupta, Rashmi and Kumari, Preeti and Srivastava, Mona and Cozzolino, Flora and Kumar Rai, Sunil and Monti, Maria and Harlalka, Gaurav V and Simpson, Michael A and Rich, Philip and Al-Salmi, Fatema and Patton, Michael A and Chioza, Barry A and Efthymiou, Stephanie and Granata, Francesca and Di Rosa, Gabriella and Wiethoff, Sarah and Borgione, Eugenia and Scuderi, Carmela and Mankad, Kshitij and Hanna, Michael G and Pucci, Piero and Houlden, Henry and Lupski, James R and Crosby, Andrew H and Baple, Emma L} }