Asymmetrical parkinsonism due to novel WDR45 variant with beta-propeller protein-associated neurodegeneration (BPAN).

Beta-propeller protein-associated neurodegeneration (BPAN) encompasses a group of refractory neurodegenerative diseases that are caused by excessive iron deposition in the brain, especially in the basal ganglia. We reported a case of BPAN with a novel variant of the WDR45 gene at Xp11.23. Our patient was a 31-year-old woman who has had an intellectual disability since childhood. Approximately 3 years ago, she developed asymmetric parkinsonism affecting the distal right upper and lower limbs. Consistent with her neurological findings, dopamine transporter single-photon emission computed tomography demonstrated the differences between the left and right sides. She was diagnosed as BPAN according to genetic analysis, which showed a novel heterozygous variant (c.345-3C>G) in WDR45. To the best of our knowledge, only a few previous case reports on asymmetric BPAN have described the quantitative differences in neuroimaging parameters between the left and right sides. These neuroimaging features were similar to those of Parkinson's disease, among the other neurodegenerative diseases. Our report may provide clues to elucidate the pathological mechanism of BPAN which is a refractory neurodegenerative disease.

WDR45-dependent impairment of cell cycle in fibroblasts of patients with beta propeller protein-associated neurodegeneration (BPAN).

De novo mutations in the WDR45 gene have been found in patients affected by Neurodegeneration with Brain Iron Accumulation type 5 (NBIA5 or BPAN), with Non-Transferrin Bound Iron (NTBI) accumulation in the basal ganglia and WDR45-dependent impairment of autophagy. Here we show the downregulation of TFEB and cell cycle impairment in BPAN primary fibroblasts. Noteworthy, TFEB overexpression rescued this impairment, depicting a novel WDR45-dependent cell cycle phenotype.

Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

BACKGROUND: Although WD repeat domain 45 (WDR45) mutations have been linked to ß -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system. METHODS: To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration. RESULTS: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits. CONCLUSIONS: In this study, we uncovered the molecular mechanisms underlying the contribution of WDR45 deficiency to axonal degeneration, which involves complex relationships between phospholipid metabolism, autophagy, and tubular ER. These findings greatly advance our understanding of the fundamental molecular mechanisms driving axonal degeneration and may provide a foundation for developing novel mechanistically based therapeutic interventions for BPAN and other neurodegenerative diseases.

A Rare Coincidence of Three Inherited Diseases in a Family with Cardiomyopathy and Multiple Extracardiac Abnormalities.

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband's eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband's sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype-phenotype correlations in cardiomyopathy.

Congenital syndromic Chiari-like malformation (CSCM) in Holstein cattle: towards unravelling of possible genetic causes.

BACKGROUND: Chiari malformation type II (CMII) was originally reported in humans as a rare disorder characterized by the downward herniation of the hindbrain and towering cerebellum. The congenital brain malformation is usually accompanied by spina bifida, a congenital spinal anomaly resulting from incomplete closure of the dorsal aspect of the spinal neural tube, and occasionally by other lesions. A similar disorder has been reported in several animal species, including cattle, particularly as a congenital syndrome. A cause of congenital syndromic Chiari-like malformation (CSCM) in cattle has not been reported to date. We collected a series of 14 CSCM-affected Holstein calves (13 purebred, one Red Danish Dairy F1 cross) and performed whole-genome sequencing (WGS). WGS was performed on 33 cattle, including eight cases with parents (trio-based; group 1), three cases with one parent (group 2), and three single cases (solo-based; group 3). RESULTS: Sequencing-based genome-wide association study of the 13 Holstein calves with CSCM and 166 controls revealed no significantly associated genome region. Assuming a single Holstein breed-specific recessive allele, no region of shared homozygosity was detected suggesting heterogeneity. Subsequent filtering for protein-changing variants that were only homozygous in the genomes of the individual cases allowed the identification of two missense variants affecting different genes, SHC4 in case 4 in group 1 and WDR45B in case 13 in group 3. Furthermore, these two variants were only observed in Holstein cattle when querying WGS data of > 5,100 animals. Alternatively, potential de novo mutational events were assessed in each case. Filtering for heterozygous private protein-changing variants identified one DYNC1H1 frameshift variant as a candidate causal dominant acting allele in case 12 in group 3. Finally, the presence of larger structural DNA variants and chromosomal abnormalities was investigated in all cases. Depth of coverage analysis revealed two different partial monosomies of chromosome 2 segments in cases 1 and 7 in group 1 and a trisomy of chromosome 12 in the WDR45B homozygous case 13 in group 3. CONCLUSIONS: This study presents for the first time a detailed genomic evaluation of CSCM in Holstein cattle and suggests an unexpected genetic and allelic heterogeneity considering the mode of inheritance, as well as the type of variant. For the first time, we propose candidate causal variants that may explain bovine CSCM in a certain proportion of affected calves. We present cattle as a large animal model for human CMII and propose new genes and genomic variants as possible causes for related diseases in both animals and humans.

A Case of Beta-Propeller Protein-Associated Neurodegeneration With a Unique Truncating Variant in the WDR45 Gene and Uncommon Clinical and Radiologic Findings.

Beta-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation, is caused by variants in the WDR45 gene. In this paper, we describe a patient with an atypical presentation of BPAN whose whole exome sequencing revealed a previously unattested truncating variant in the WDR45 gene (c.830+3G>C/p.Leu278Ter), the pathogenicity of which was verified by RNA transcriptomics. A number of uncommon neuroanatomic and clinical findings in our patient are discussed, expanding the phenotype associated with BPAN. This unique case challenges existing genotype-phenotype correlations and highlights the role of X chromosome skewing in shaping the clinical spectrum of BPAN.

A c.726C>G (p.Tyr242Ter) nonsense mutation-associated with splicing alteration (NASA) of WDR45 gene underlies ß-propeller protein-associated neurodegeneration (BPAN).

Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous disease characterized by increased iron deposition in the basal ganglia and progressive degeneration of the nervous system in adulthood. However, in early childhood, there were no characteristic features to perform early diagnosis. In our study, a female child exhibited global developmental delay, intellectual disability, and febrile seizure without other distinct clinical phenotypes. Through whole exome sequencing (WES), a de novo nonsense mutation (c.726C > G, p. Tyr242Ter) of WDR45 gene was identified in this child. She was finally diagnosed as ß-propeller protein-associated neurodegeneration (BPAN), one of the recently identified subtypes of NBIA. This mutation could act as a premature stop codon (PSC) which rendered the mutated transcripts to be degraded by nonsense-mediated mRNA decay (NMD), leading to decreased levels of PSC-containing mRNAs. Additionally, through mini-gene splicing assays, this mutation could result in an unprecedented novel transcript with the exon 9 of WDR45 excluded by nonsense-associated splicing alteration (NASA). Transcriptome sequencing (RNA-seq) on total RNAs from PBMCs of the trio revealed three types of alternative splicing events in the patient. Further research implied that downregulation of iron transport genes (TFRC, TFR2, SCARA5) might be the underlying mechanism for the iron accumulation in patients with deficient WDR45. This is the first report about NASA happening in WDR45. It implies that nonsense mutations approximal to splicing sites could affect the disease pathogenesis through more than one molecular mechanism and should be taken into consideration when conducting genetic counseling.

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn.

BACKGROUND: ß-Propeller protein-associated neurodegeneration (BPAN) is a genetic neurodegenerative disease caused by mutations in WDR45. The impairment of autophagy caused by WDR45 deficiency contributes to the pathogenesis of BPAN; however, the pathomechanism of this disease is largely unknown. Lipid dyshomeostasis is involved in neurogenerative diseases, but whether lipid metabolism is affected by Wdr45 deficiency and whether lipid dyshomeostasis contributes to the progression of BPAN are unclear. METHODS: We generated Wdr45 knockout SN4741 cell lines using CRISPR‒Cas9-mediated genome editing, then lipid droplets (LDs) were stained using BODIPY 493/503. Chaperone-mediated autophagy was determined by RT-qPCR and western blotting. The expression of fatty acid synthase (Fasn) was detected by western blot in the presence or absence of the lysosomal inhibitor NH4Cl and the CMA activator AR7. The interaction between Fasn and HSC70 was analyzed using coimmunoprecipitation (Co-IP) assay. Cell viability was measured by a CCK-8 kit after treatment with the Fasn inhibitor C75 or the CMA activator AR7. RESULTS: Deletion of Wdr45 impaired chaperone-mediated autophagy (CMA), thus leading to lipid droplet (LD) accumulation. Moreover, Fasn can be degraded via CMA, and that defective CMA leads to elevated Fasn, which promotes LD formation. LD accumulation is toxic to cells; however, cell viability was not rescued by Fasn inhibition or CMA activation. Inhibition of Fasn with a low concentration of C75 did not affect cell viability but decreases LD density. CONCLUSIONS: These results suggested that Fasn is essential for cell survival but that excessive Fasn leads to LD accumulation in Wdr45 knockout cells.

Human WIPI ß-propeller function in autophagy and neurodegeneration.

The four human WIPI ß-propellers, WIPI1 through WIPI4, belong to the ancient PROPPIN family and fulfill scaffold functions in the control of autophagy. In this context, WIPI ß-propellers function as PI3P effectors during autophagosome formation and loss of WIPI function negatively impacts autophagy and contributes to neurodegeneration. Of particular interest are mutations in WDR45, the human gene that encodes WIPI4. Sporadic WDR45 mutations are the cause of a rare human neurodegenerative disease called BPAN, hallmarked by high brain iron accumulation. Here, we discuss the current understanding of the functions of human WIPI ß-propellers and address unanswered questions with a particular focus on the role of WIPI4 in autophagy and BPAN.

Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, ß-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.

Pathological characteristics of axons and proteome patterns in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

Background: Although WD repeats domain 45 (WDR45) mutations have been linked to ß-propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the effects of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. By examining pathological and molecular alterations, we hope to better understand the disease process. Methods: To investigate the effects of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in mouse behavior using open field, rotarod, Y-maze, and 3-chamber social approach tests. To examine the pathological changes in DAergic neuron soma and axons, we utilized a combination of immunofluorescence staining and transmission electron microscopy. Additionally, we performed proteomic analyses of the striatum to identify the molecules and processes involved in striatal pathology. Results: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound loss of midbrain DAergic neurons. Prior to neuronal loss, we observed massive axonal enlargements in both the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Additionally, we found that WDR45cKO mice exhibited disrupted autophagic flux. Proteomic analysis of the striatum in these mice showed that many differentially expressed proteins (DEPs) were enriched in amino acid, lipid, and tricarboxylic acid metabolisms. Of note, we observed significant alterations in the expression of genes encoding DEPs that regulate phospholipids catabolic and biosynthetic processes, such as lysophosphatidylcholine acyltransferase 1, ethanolamine-phosphate phospho-lyase, and abhydrolase domain containing 4, N-acyl phospholipase B. These findings suggest a possible link between phospholipid metabolism and striatal axon degeneration. Conclusions: In this study, we have uncovered the molecular mechanisms underlying the contribution of WDR45-deficiency to axonal degeneration, revealing intricate relationships between tubular ER dysfunction, phospholipid metabolism, BPAN and other neurodegenerative diseases. These findings significantly advance our understanding of the fundamental molecular mechanisms driving neurodegeneration and may provide a foundation for developing novel, mechanistically-based therapeutic interventions.

Targeted resequencing reveals high-level mosaicism for a novel frameshift variant in WDR45 associated with beta-propeller protein-associated neurodegeneration.

OBJECTIVES: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant neurodegenerative disease, which is characterized by iron accumulation in the basal ganglia. BPAN is associated with pathogenic variation in WDR45, which has been reported almost exclusively in females most probably due to male lethality in the hemizygous state. METHODS: Whole exome sequencing (WES) and targeted deep sequencing were performed for a male with a clinical diagnosis of BPAN at the age of 37. RESULTS: The novel frameshift variant in WDR45 detected by WES was further analyzed with targeted resequencing to detect a mosaic variant with a level of 85.5% in the blood sample of the proband. DISCUSSION: Although the main role of WDR45 remains elusive, recent studies show that WDR45 may contribute to neurodegeneration through defects in autophagy, iron storage and ferritin metabolism, mitochondria organization, and endoplasmic reticulum homeostasis. The extend of spatiotemporal haploinsufficiency of WDR45 frameshifting variants caused by mosaicism in males may lead to variable clinical severity, which may be hard to elaborate clinically. Promising genetic analysis strategies using targeted deep sequencing may help determine the clinical outcome of somatic mosaicism in neurological disorders including BPAN. Additionally, we suggest that deep sequencing should be conducted in cerebrospinal fluid samples to provide more reliable results in terms of reflecting the mosaicism level in the brain for future studies.

Autophagy-Related Gene WD Repeat Domain 45B Promotes Tumor Proliferation and Migration of Hepatocellular Carcinoma through the Akt/mTOR Signaling Pathway.

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor. It has been found that autophagy plays a role both as a tumor promoter and inhibitor in HCC carcinogenesis. However, the mechanism behind is still unveiled. This study aims to explore the functions and mechanism of the key autophagy-related proteins, to shed light on novel clinical diagnoses and treatment targets of HCC. Bioinformation analyses were performed by using data from public databases including TCGA, ICGC, and UCSC Xena. The upregulated autophagy-related gene WDR45B was identified and validated in human liver cell line LO2, human HCC cell line HepG2 and Huh-7. Immunohistochemical assay (IHC) was also performed on formalin-fixed paraffin-embedded (FFPE) tissues of 56 HCC patients from our pathology archives. By using qRT-PCR and Western blots we found that high expression of WDR45B influenced the Akt/mTOR signaling pathway. Autophagy marker LC3- II/LC3-I was downregulated, and p62/SQSTM1 was upregulated after knockdown of WDR45B. The effects of WDR45B knockdown on autophagy and Akt/mTOR signaling pathways can be reversed by the autophagy inducer rapamycin. Moreover, proliferation and migration of HCC can be inhibited after the knockdown of WDR45B through the CCK8 assay, wound-healing assay and Transwell cell migration and invasion assay. Therefore, WDR45B may become a novel biomarker for HCC prognosis assessment and potential target for molecular therapy.

WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism.

Ferritin is the main iron storage protein that plays a pivotal role in the regulation of iron homeostasis. Mutations in the autophagy protein WD repeat domain 45 (WDR45) that lead to iron overload is associated with the human ß-propeller protein-associated neurodegeneration (BPAN). Previous studies have demonstrated that ferritin was decreased in WDR45 deficient cells, but the mechanism remains unclear. In this study, we have demonstrated that the ferritin heavy chain (FTH) could be degraded via chaperone-mediated autophagy (CMA) in ER stress/p38-dependent pathway. In HeLa cells, inducing the ER stress activated CMA, therefore facilitated the degradation of FTH, and increased the content of Fe2+. However, the increased CMA activity and Fe2+ as well as the decreased FTH by ER stress inducer were restored by pre-treatment with p38 inhibitor. Overexpression of a mutant WDR45 activated CMA thus promoted the degradation of FTH. Furthermore, inhibition of ER stress/p38 pathway resulted in reduced activity of CMA, which consequently elevated the protein level of FTH but reduced the Fe2+ level. Our results revealed that WDR45 mutation dysregulates iron homeostasis by activating CMA, and promotes FTH degradation through ER stress/p38 signaling pathway.

Time course of serum neuron-specific enolase levels from infancy to early adulthood in a female patient with beta-propeller protein-associated neurodegeneration.

Beta-propeller protein-associated neurodegeneration (BPAN), a subgroup of neurodegeneration with brain iron accumulation, is typically characterized by non-progressive global developmental delay and seizures in childhood, followed by progressive neurological decline with parkinsonism and dementia in adolescence or early adulthood. It is difficult to clinically identify a patient with BPAN in childhood. Recent studies reported that serum levels of neuron-specific enolase (NSE) were elevated in children with BPAN. We reviewed the time course of serum NSE levels in a 21-year-old female patient genetically diagnosed (a de novo WDR45 variant c.268A > T) with BPAN, which was suspected based on prolonged elevation of serum NSE. There was an overall tendency for serum NSE levels to decrease in a stepwise fashion. The peak serum NSE level was observed during the first 2 years of age and then decreased rapidly in 1 year. High serum NSE levels persisted between 3 and 11 years of age. Subsequently, serum NSE levels decreased and plateaued after 13 years of age. There were tendencies for both blood AST and LDH levels to decrease over time in parallel with serum NSE levels. Serum NSE levels may be a diagnostic biomarker of BPAN in children but becomes of less value in identifying a patient with BPAN after childhood.

Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in ß-Propeller Protein-Associated Neurodegeneration.

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient's fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients' cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients' cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.

A homozygous variant of WDR45B results in global developmental delay: Additional case and literature review.

BACKGROUND: Global developmental delay (GDD) has a heterogeneous clinical profile among patients, accounting for approximately 1%-3% of cases in children. An increasing number of gene defects have been demonstrated to be associated with GDD; up to now, only limited studies have reported developmental disorders driven by WDR45B. METHODS: Trio-whole exome sequencing (Trio-WES) was performed for the patient and her family. All variants with a minor allele frequency <0.01 were selected for further interpretation according to the ACMG guidelines. Candidate pathogenic variants were validated by Sanger sequencing in her family. RESULTS: A homozygous nonsynonymous variant in WDR45B [NM_019613.4: c.677G>C (p. Arg226Thr)] was identified from the proband. The variant was absent in published databases such as gnomAD and Exome Aggregation Consortium (ExAC). The variant was predicted to be damaging for proteins and classified as VUS according to the ACMG guidelines. We reviewed the literature, and the development delay level in our case was less severe than the other reported cases. CONCLUSION: We reported another case with a novel homozygous variant of WDR45B and showed the heterogeneity of clinical features.

Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN).

BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.