RSS-Feed abonnieren
DOI: 10.1055/s-0041-1727174
WDR45 Gene and Its Role in Pediatric Epilepsies
![](https://www.thieme-connect.de/media/10.1055-s-00029030/202401/lookinside/thumbnails/10-1055-s-0041-1727174_2100034-1.jpg)
Abstract
WD repeat domain 45 (WDR45) gene has been increasingly found in patients with developmental delay (DD) and epilepsy. Previously, WDR45 de novo mutations were reported in sporadic adult and pediatric patients presenting iron accumulation, while heterozygous mutations were associated with β-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation disorders, characterized by extrapyramidal movement disorders and abnormal accumulation of iron in the basal ganglia. Overall, people harboring WDR45 mutations have moderate to severe DD and different types of seizures. The phenotype of adult patients is characterized by extrapyramidal movement, dystonia, parkinsonism, language impairment, and involvement of the substantia nigra and in the globus pallidus at brain magnetic resonance imaging. Importantly, there are no findings of brain iron accumulation in brain in BPAN patients in the first decade of life, thus suggesting a progressive course of the disease. Comparatively, the main phenotype of pediatric patients is epilepsy with early onset, most of which present infantile spasms and arrest or regression of psychomotor development. The phenotype of patients with WDR45 mutations is variable, being different if caused by somatic mosaicism or germline mutations, and presenting with a different spectrum of manifestations in males and females. The treatment of affected individuals is symptomatic. Regarding the seizures, specific, gene-based approaches with specific antiepileptic drugs are not currently available. The early diagnosis of BPAN could be useful in some aspects, such as providing families a supportive treatment to their affected children.
Keywords
WDR45 - epilepsy - intellectual disability - β-propeller protein-associated neurodegeneration - ironPublikationsverlauf
Eingereicht: 21. Februar 2021
Angenommen: 22. Februar 2021
Artikel online veröffentlicht:
13. April 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Ortega-Moreno L, Giráldez BG, Soto-Insuga V. et al; Grupo Español de Genética de las Epilepsias de la Infancia (GEGEI). Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes. PLoS One 2017; 12 (11) e0188978
- 2 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
- 3 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
- 4 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
- 5 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
- 6 Saitsu H, Nishimura T, Muramatsu K. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 2013; 45 (04) 445-449 , e1
- 7 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
- 8 Hayflick SJ, Kruer MC, Gregory A. et al. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 2013; 136 (Pt 6): 1708-1717
- 9 Allen AS, Berkovic SF, Cossette P. et al; Epi4K Consortium, Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 2013; 501 (7466): 217-221
- 10 Takano K, Shiba N, Wakui K. et al. Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: additional case report and review of the literature. Am J Med Genet A 2016; 170A (02) 322-328
- 11 Nishioka K, Oyama G, Yoshino H. et al. High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. Neurobiol Aging 2015; 36 (05) 2004.e9-2004.e15
- 12 Salpietro V, Polizzi A, Di Rosa G. et al. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014: 282489
- 13 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
- 14 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
- 15 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
- 16 Zarate YA, Jones JR, Jones MA. et al. Lessons from a pair of siblings with BPAN. Eur J Hum Genet 2016; 24 (07) 1080-1083
- 17 Xixis KI, Mikati MA. Epileptic spasms: a previously unreported manifestation of WDR45 gene mutation. Epileptic Disord 2015; 17 (04) 467-472
- 18 Salpietro V, Mankad K, Kinali M. et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
- 19 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
- 20 Chen H, Qian Y, Yu S. et al. Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants. Eur J Med Genet 2019; 62 (02) 149-160
- 21 Haack TB, Hogarth P, Kruer MC. et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 2012; 91 (06) 1144-1149
- 22 Kruer MC, Boddaert N, Schneider SA. et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am J Neuroradiol 2012; 33 (03) 407-414
- 23 Doorn JM, Kruer MC. Newly characterized forms of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep 2013; 13 (12) 413
- 24 Kruer MC, Boddaert N. Neurodegeneration with brain iron accumulation: a diagnostic algorithm. Semin Pediatr Neurol 2012; 19 (02) 67-74
- 25 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
- 26 Hogarth P. Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord 2015; 8 (01) 1-13
- 27 Liu W-T, Chen Q, Gao Z-J, Ji XN, Xu KM, Cao YY. A novel WDR45 mutation in a 9-month-old male infant with epileptic spasms. Chin Med J (Engl) 2018; 131 (24) 2991-2992
- 28 Abidi A, Mignon-Ravix C, Cacciagli P, Girard N, Milh M, Villard L. Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient. Eur J Hum Genet 2016; 24 (04) 615-618
- 29 Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009; 46 (02) 73-80
- 30 Kulikovskaja L, Sarajlija A, Savic-Pavicevic D, Dobricic V, Klein C, Westenberger A. WDR45 mutations may cause a MECP2 mutation-negative Rett syndrome phenotype. Neurol Genet 2018; 4 (02) e227
- 31 Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C. Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015; 7 (07) 5532-5539
- 32 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
- 33 Carvill GL, Liu A, Mandelstam S. et al. Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45 . Epilepsia 2018; 59 (01) e5-e13
- 34 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
- 35 Osborne JP, Lux AL, Edwards SW. et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia 2010; 51 (10) 2168-2174
- 36 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
- 37 Morikawa M, Takano K, Motobayashi M. et al. Clinical features of a female with WDR45 mutation complicated by infantile spasms: a case report and literature review. Brain Dev 2017; 39 (09) 804-807
- 38 Falsaperla R, D'Angelo G, Praticò AD. et al. Ketogenic diet for infants with epilepsy: a literature review. Epilepsy Behav 2020; 112: 107361
- 39 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
- 40 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
- 41 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
- 42 Redon S, Benech C, Schutz S. et al. Intragenic deletion of the WDR45 gene in a male with encephalopathy, severe psychomotor disability, and epilepsy. Am J Med Genet A 2017; 173 (05) 1444-1446