High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism

Nishioka, Kenya; Oyama, Genko; Yoshino, Hideaki; Li, Yuanzhe; Mizutani, Takashi; Takeuchi, Chisen; Mochizuki, Yoko; Mori‐Yoshimura, Madoka; Murata, Miho; Yamasita, Chikara; Nakamura, Nobuhiro; Konishi, Y.; Ohi, Kazuki; Ichikawa, Kazuhisa; Terada, Tatsuhiro; Obi, Tomokazu; Funayama, Manabu; Saiki, Sachio; Hattori, Nobutaka

doi:10.1016/j.neurobiolaging.2015.01.020

Cited by 37 publications

(50 citation statements)

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“…The meaning of XCI skewing favoring the mutated allele, as seen in the proband's sister, or biallelic expression of both wild-type and mutant alleles as has been previously reported, remains unclear. 12,16 In 2013, Hayflick et al 10 recommended that because gonadal or germline mosaicism was a theoretical possibility, parental testing for variants in WDR45 should be considered. In agreement with this early suggestion and despite its rarity, the demonstration that maternal gonadal and germline mosaicism is possible supports this argument.…”

Section: Discussionmentioning

confidence: 99%

Lessons from a pair of siblings with BPAN

Zárate

Jones

et al. 2015

Eur J Hum Genet

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Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered. European Journal of Human Genetics (2016) 24, 1080-1083; doi:10.1038/ejhg.2015.242; published online 18 November 2015 INTRODUCTIONNeurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited, progressive neurological diseases characterized by cognitive impairment and prominent dystonia and/or parkinsonism. 1-6 Beta-propeller protein-associated neurodegeneration (BPAN, NBIA5, OMIM: 300894) has been estimated to account for~7% of all cases of NBIA. 7 Besides being the only type of NBIA with an X-linked dominant pattern of inheritance, BPAN has distinctive clinical and brain imaging findings. Its clinical course is described as biphasic with an initial presentation during childhood, as spastic quadriplegia or static encephalopathy with early developmental delay with or without seizures, followed by dementia in adulthood and the development of parkinsonism and dystonia. 1,4,[7][8][9][10][11] Heterozygous variants in the WD repeat-containing protein 45 gene (WDR45, OMIM: 300526) located in Xp11.23 lead to decreased autophagic activity and the BPAN phenotype. 12 All well-described cases of BPAN in the literature have been sporadic with a clear female predominance supporting an X-linked dominant pattern of inheritance with proposed lethality in males with germline variants. We present only the fourth case of a hemizygous male and the first welldescribed brother-sister patient duo with a novel WDR45 in-frame deletion. The same variant was also detected in a mosaic state in their unaffected mother.

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Section: Discussionmentioning

confidence: 99%

Lessons from a pair of siblings with BPAN

Zárate

Jones

et al. 2015

Eur J Hum Genet

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“…Interestingly, a recent screening study for WDR45 mutations in patients with young-onset parkinsonism with childhood intellectual disability (onset before age 40) suggested that this is a relevant disease cause (responsible for one quarter of cases), at least in the Japanese population. [9] The associated protein, WIPI-4, plays a role in autophagy, cell cycle control, signal and transduction.…”

Section: Introductionmentioning

confidence: 99%

Neurodegenerations with Brain Iron Accumulation

Schneider

2016

Parkinsonism & Related Disorders

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“…1,3,4,7 We report herein a novel frameshifting mutation (c.597_598delGT, p.Leu201Lysfs*21) resulting in a premature truncation. Our patient's clinical course is somewhat unusual in that she did not have any features of parkinsonism, and the onset of her neurodegenerative symptoms was later than most previously described cases of BPAN.…”

Section: Discussionmentioning

confidence: 92%

“…Our patient's clinical course is somewhat unusual in that she did not have any features of parkinsonism, and the onset of her neurodegenerative symptoms was later than most previously described cases of BPAN. 7 Her brain MRI results were, however, classical for BPAN. This single case adds to the existing literature on a very rare neurodegenerative disease.…”

Section: Discussionmentioning

confidence: 97%

“…1 Subsequent publications include a small number of single case reports as well as small case series describing 5 or 7 mutations. 4,6,7 The phenotype is characterized by a static, global encephalopathy in early childhood with later development of progressive cognitive decline in adolescence and early adulthood. Onset of neurodegeneration is usually heralded by parkinsonism, but dystonia, sleep abnormalities, Rett-like syndrome, and epileptic encephalopathies have also been described.…”

Section: Discussionmentioning

confidence: 99%

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