EXOME REPORT: Novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities

Shaw, Marie; Winczewska‐Wiktor, Anna; Badura‐Stronka, Magdalena; Koirala, Soniya; Gardner, Alison; Kuszel, Łukasz; Kowal, P; Steinborn, Barbara; Starczewska, Monika; Garry, Sarah; Scheffer, Ingrid E.; Berkovic, Samuel F.; Gécz, Jozef

doi:10.1016/j.ejmg.2019.103799

Cited by 18 publications

(12 citation statements)

References 21 publications

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“…This is not unique for CDG; for example, it is a rather frequent finding in Phosphomannomutase deficiency . Interesting is the presence of proteinuria without other symptoms in some carriers.There is some phenotypic overlap with defects in other vacuolar H + ‐ATPase subunits: cutis laxa in ATP6V0A2‐CDG, ATP6V1A, ATP6V1E1 and ATP6AP2; liver disease in ATP6AP2‐CDG, CCDC115‐CDG and TMEM199‐CDG; and immunodeficiency in ATP6AP2 . In males with sensorineural deafness, hair loss and proteinuria, screening for CDG should be performed.…”

Section: Discussionmentioning

confidence: 99%

“…There is some phenotypic overlap with defects in other vacuolar H + -ATPase subunits: cutis laxa in ATP6V0A2-CDG, ATP6V1A, ATP6V1E1 and ATP6AP2; liver disease in ATP6AP2-CDG, CCDC115-CDG and F I G U R E 1 Family pedigree TMEM199-CDG; and immunodeficiency in ATP6AP2. [6][7][8][9][10][11] In males with sensorineural deafness, hair loss and proteinuria, screening for CDG should be performed.…”

Section: Discussionmentioning

confidence: 99%

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ATP6AP1‐CDG: Follow‐up and female phenotype

et al. 2020

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In 2016, 11 male patients were reported with immunodeficiency and hepatic, gastric and (in some) neurological disease due to X-linked ATP6AP1 deficiency (ATP6AP1-CDG). In 2018, three other patients were reported with additional features: connective tissue abnormalities, sensorineural hearing loss, hyperopia, glomerular and tubular dysfunction, exocrine pancreatic insufficiency and altered amino acid and lipid metabolism. We here present a followup of three reported siblings showing progression of deafness to total hearing loss, progressive loss of hair up to alopecia, chestnut skin and, at last followup, in some of them proteinuria. Three female carriers showed a normal serum transferrin isoelectrofocusing but in two of them there was a persistent proteinuria. K E Y W O R D SATP6AP1 deficiency, congenital disorder of glycosylation, proteinuria

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ATP6AP1‐CDG: Follow‐up and female phenotype

et al. 2020

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“…Seizures are hallmarks of TBC1D24-related disorders ( 17 , 18 ), and the presence of seizures was also demonstrated in patients harboring the heterozygous p.E374Q or p.L398V (a large Polish family with seven affected members) mutations in the ATP6V1B2 gene ( 8 , 9 ). In these latter autosomal dominantly inherited cases with positive EEG findings, the age of onset ranged from 3 to 16 years.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, two patients harboring a p.R485P heterozygous mutation were confirmed to have Zimmermann-Laband syndrome (7). Interestingly, ATP6V1B2 gene mutations have also been identified in some patients presenting with complete DOORS syndrome (unpublished findings), or in clinical syndromes overlapping with the three entities mentioned above in patients harboring the p.E374Q or p.L398V mutations in a heterozygous state (8,9), thus widening the clinical picture of these syndromes ( Table 1). Although it has been revealed that the p.Arg506X mutation may impair lysosome acidification in the brain (4,10), there are no detailed neuropathological reports of the clinicopathological relationships associated with this mutation.…”

Section: Introductionmentioning

confidence: 93%

Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene

et al. 2020

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DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann-Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder.

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“…Besides the recurrent ATP6V1B2:p.Arg506* nonsense variant (Beauregard‐Lacroix et al, 2021; Menendez et al, 2017; Yuan et al, 2014; Zádori et al, 2020) detected in DDOD and DOORS syndromes, four additional variants have been described (Figure 1), two of which are related to a predominantly epileptic phenotype (Inuzuka et al, 2020; Popp et al, 2017; Shaw et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A novel pathogenic ATP6V1B2 variant: Widening the genotypic spectrum of the epileptic neurodevelopmental phenotype

Veltra

Kosma

Papavasiliou

et al. 2022

American J of Med Genetics Pt A

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ATP6V1B2 pathogenic variants are linked with variable phenotypes, such as dominant deafness-onychodystrophy syndrome (DDOD), autosomal dominant Zimmermann-Laband syndrome type 2 (ZLS2), and some cases of DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [ID], and seizures). Epilepsy was first linked to ATP6V1B2, when the p.(Glu374Gln) missense variant was detected in a patient with ID and seizures, but without characteristic features of DDOD or ZLS2 syndromes. We herein report a novel pathogenic ATP6V1B2:p.Glu374Gly variant detected in an adult patient with ID and myoclonic-atonic seizures. The (re)occurrence of different variants affecting the same highly conserved hydrophilic glutamic acid on position 374 of the V-proton ATPase subunit B, indicates a potential novel pathogenic hotspot and a critical role for the specific residue in the development of epilepsy. ATP6V1B2 gene defects should be considered when analyzing patients with epilepsy, even in the absence of most cardinal features of DDOD, DOORS, or ZLS such as deafness, onychodystrophy, and osteodystrophy.

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EXOME REPORT: Novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities

Cited by 18 publications

References 21 publications

ATP6AP1‐CDG: Follow‐up and female phenotype

ATP6AP1‐CDG: Follow‐up and female phenotype

Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene

A novel pathogenic ATP6V1B2 variant: Widening the genotypic spectrum of the epileptic neurodevelopmental phenotype

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