Source: Phenotypic and Imaging Spectrum Associated With WDR45
Adang LA, Pizzino A, Malhotra A, Dubbs H, Williams C, Sherbini O, Anttonen AK, Lesca G, Linnankivi T, Laurencin C, Milh M, Perrine C, Schaaf CP, Poulat AL, Ville D, Hagelstrom T, Perry DL, Taft RJ, Goldstein A, Vossough A, Helbig I, Vanderver A. Phenotypic and Imaging Spectrum Associated With WDR45. Pediatr Neurol. 2020 Aug;109:56-62.
doi: 10.1016/j.pediatrneurol.2020.03.005. Epub 2020 Mar 11. PMID: 32387008; PMCID: PMC7387198.
Findings from the largest series of WDR45 cases to date
A recent of publication in Pediatric Neurology, "Phenotypic and Imaging Spectrum Associated With WDR45" describes 123 individuals with WDR45 variants, outlining a spectrum of clinical and radiographic findings. The 123 individuals were identified through natural history studies and a review of the medical literature, which included 19 males, with pathogenic or likely pathogenic WDR45 variants. All affected individuals carried de novo variants except for five affected males who inherited variants from their reportedly asymptomatic mothers.
KEY FINDINGS
87.5% of individuals with WDR45-related disease had seizures (70 of 81 females and 14 of 15 males)
Seizure onset in the majority of patients occurred before the age of 4-1/2 years
92.9% of males had refractory epilepsy (a number of different terms may be used to describe these including: “uncontrolled,” “intractable,” “refractory,” or “drug resistant.”)
50% of females had refractory epilepsy
Seizures ranged in severity from fever-provoked seizures (febrile seizures) to subclinical seizures (seizures that occur due to abnormal electrical activity within the brain, but the symptoms are not noticeable, even to the patient) to infantile spasms. The spectrum of seizures included febrile, tonic-clonic, atonic, focal, myoclonic, absence seizures and epileptic and infantile spasms
A mix of generalized and focal discharges was common on EEG's
Several types of seizures have been reported in BPAN even within the same individual. Seizures reported included:
Febrile Seizures: caused by high fever are often the first type of seizures individuals with BPAN may experience.
Tonic-Clonic Seizures: affects the entire body, causing muscle stiffness and loss of consciousness; previously called "grand mal".
Atonic Seizures: suddenly loses muscle tone so their head or body may go limp. In some children, only their head drops suddenly. Also known as drop attacks.
Focal Seizures: person remains alert or partially aware and may be able to interact
Myoclonic Seizures: brief shock-like jerks of a muscle or group of muscles
Absence Seizures: marked by lapses in awareness, sometimes with staring; may begin and end abruptly, lasting only a few seconds
Epileptic and Infantile Spasms: spasms consist of brief (1-3 second) events of arm, leg and head flexion (arms and legs pull into the body) or extension. Spasms will have several clusters per day. Most commonly in children less than 2 years of age. Spasms are most commonly seen in infants with serious epilepsies such as West syndrome or Ohtahara syndrome, and may also be seen in Lennox-Gastaut syndrome.
Across the cohort, there was early developmental delay, frequently accompanied by seizures. Imaging revealed early myelination delay, followed by evidence of iron deposition.
Some people with BPAN syndrome develop seizure patterns similar to those seen in epileptic syndromes such as West Syndrome or Lennox-Gastaut Syndrome.
Limitations of the Study: Although this report represents the largest series of WDR45 cases to date, availability of medical reports and information from case reports placed some limitations to the report findings. Also, individuals with mild or normal phenotypes may not have been captured in this study as this was a cohort collected by enrollment and published cases, therefore there may be a bias toward the inclusion of individuals with a stronger phenotype.
As more and more BPAN patients are identified globally, seemingly daily, this report further elucidates the wide spectrum of variable clinical features observed in individuals affected by WDR45 variants with other genetic conditions. For this cohort, there was an average delay of 15.7 years from presentation to diagnosis of BPAN. Utilizing WGS (whole genome sequencing) or WES (whole exome sequencing) as a first-tier diagnostic test may shorten the diagnostic odyssey and expedite appropriate clinical care and counseling for BPAN patients.
ADDITIONAL BPAN RELATED RESEARCH:
Single-center experience with Beta-propeller protein-associated neurodegeneration (BPAN); expanding the phenotypic spectrum
Chard M, Appendino JP, Bello-Espinosa LE, Curtis C, Rho JM, Wei XC, Al-Hertani W. Single-center experience with Beta-propeller protein-associated neurodegeneration (BPAN); expanding the phenotypic spectrum. Mol Genet Metab Rep. 2019 Jun 19;20:100483. doi: 10.1016/j.ymgmr.2019.100483. PMID: 31293896; PMCID: PMC6595096.
Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45
Carvill GL, Liu A, Mandelstam S, Schneider A, Lacroix A, Zemel M, McMahon JM, Bello-Espinosa L, Mackay M, Wallace G, Waak M, Zhang J, Yang X, Malone S, Zhang YH, Mefford HC, Scheffer IE. Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45. Epilepsia. 2018 Jan;59(1):e5-e13. doi: 10.1111/epi.13957. Epub 2017 Nov 24. PMID: 29171013; PMCID: PMC5760358.
Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants
Chen H, Qian Y, Yu S, Xiao D, Guo X, Wang Q, Hao L, Yan K, Lu Y, Dong X, Zhou W, Wu B, Zhou S, Wang H. Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants. Eur J Med Genet. 2019 Feb;62(2):149-160. doi: 10.1016/j.ejmg.2018.07.002. Epub 2018 Jul 6. PMID: 29981852.
West syndrome: a comprehensive review
Pavone P, Polizzi A, Marino SD, Corsello G, Falsaperla R, Marino S, Ruggieri M. West syndrome: a comprehensive review. Neurol Sci. 2020 Aug 22. doi: 10.1007/s10072-020-04600-5. Epub ahead of print. PMID: 32827285.
Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration
Belohlavkova A, Sterbova K, Betzler C, Burkhard S, Panzer A, Wolff M, Lassuthova P, Vlckova M, Kyncl M, Benova B, Jahodova A, Kudr M, Goerg M, Dusek P, Seeman P, Kluger G, Krsek P. Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration. Eur J Paediatr Neurol. 2020 Aug 4:S1090-3798(20)30154-9. doi: 10.1016/j.ejpn.2020.07.010. Epub ahead of print. PMID: 32811771.
De novo variants in WDR45 underlie beta‐propeller protein‐associated neurodegeneration in five independent families
Tang X, Lan X, Song X, Xu W, Zhang Y, Zhang H, Wu S. De novo variants in WDR45 underlie beta-propeller protein-associated neurodegeneration in five independent families. Mol Genet Genomic Med. 2020 Oct 10:e1499. doi: 10.1002/mgg3.1499. Epub ahead of print. PMID: 33037762.