Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes

Hady-Cohen, Ronen; Ben-Pazi, Hila; Adir, Vardit; Yosovich, Keren; Blumkin, Luba; Lerman‐Sagie, Tally; Lev, Dorit

doi:10.1016/j.ejpn.2018.07.003

Cited by 22 publications

(23 citation statements)

References 19 publications

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“…The generally static nature of the patient's condition suggests that these findings may reflect primary developmental abnormalities of the brain. On the other hand, it is possible that her findings could be due to a progressive process, as described in patients with VPS53 mutations 23,25 . Our patient's normal early brain MRI scan followed by the discovery of multiple abnormalities on subsequent imaging would support the latter possibility.…”

Section: Discussionmentioning

confidence: 88%

“…These mutations are predicted to affect the C-terminal region of VPS53 23 , although the effects of these mutations on the properties of the protein were not experimentally addressed. Phenotypic overlap between PCCA2 and an autosomal recessive condition known as progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) 24 has also been described, as two siblings with a PEHO-like syndrome were recently found to have compound heterozygous mutations in VPS53 25 . This disorder was primarily characterized by severe developmental delay, postnatal microcephaly, progressive cerebellar and cerebral atrophy, seizures, ophthalmologic abnormalities, facial/limb edema, and dysmorphic features 25 .…”

Section: Introductionmentioning

confidence: 99%

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A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

Gershlick

Ishida

Jones

et al. 2018

Preprint

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GARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a six-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino-acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully-assembled GARP and EARP complexes. Likely because of this deficiency, the patient's fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient's fibroblasts exhibit swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

Gershlick

Ishida

Jones

et al. 2018

Preprint

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“…Among the five subunits of the GARP/EARP complexes, VPS53 was the first to be associated with a human disease. Loss-of-function mutations in VPS53 have been associated with two forms of degenerative NDDs, autosomal recessive pontocerebellar hypoplasia type 2E (PCH2E, MIM #615851), characterized by a severe early-onset neurodegeneration with profound intellectual disability (ID), progressive microcephaly, spasticity, and early-onset epilepsy (Feinstein et al, 2014), and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) characterized by a severe developmental delay, limb and facial edema, intractable epilepsy, optic atrophy and dysmorphic features (Hady-Cohen et al, 2018). Recently, a 6-year-old patient with severe global developmental delay, pontocerebellar abnormalities, microcephaly, hypotonia, epilepsy and several systemic and peripheral dysfunctions has been reported (Gershlick et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Uwineza

Caberg

Hitayezu

et al. 2019

European Journal of Medical Genetics

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Genome-wide linkage analysis and whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sortingassociated protein, one the four subunits of the GARP and EARP complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.

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“…Ma to ma sme ge nø þie vës at ro fi ja -ga lu tinë se li gos sta di jo se at ro fuo ja si tiek pil ko ji, tiek bal to ji sme ge nø me dþia ga, pa na ðûs po ky èiai vyks ta ir sme ge nëlë se. Kai ku riems pa cien tams ste bi ma vë luo jan ti mie li niza ci ja [27][28][29].…”

Section: Diferencinë Diagnostikaunclassified

“…MRT ste bi ma sme ge në liø kir mi no hi pop la zi ja ir sme ge në liø pus ru tu liø apa ti nës da lies su maþë ji mas, ðie po þy miai ryð kiai pro gre suo ja. Taip pat ga li bûti ste bi ma ne þy mi su pra ten to ri në at ro fi ja, hi pop las tið kas cor pus cal lo sum, neu ro nø mig ra ci jos su tri ki mai ir su tri kusi mie li ni za ci ja [29,35,36].…”

Section: Diferencinë Diagnostikaunclassified

Pontocerebellar hypoplasia: clinical case and literature review

Anužis¹,

Buivydas²,

Petrova³

et al. 2019

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Pontocerebeliarinė hipoplazija (PCH) – tai grupė retų autosominiu recesyviniu būdu paveldimų neurodegeracinių sutrikimų, prasidedančių intrauteriniu periodu ir pasireiškiančių smegenėlių hipoplazija ar atrofija, mikrocefalija, ventralinės tilto dalies hipoplazija bei įvairiais klinikiniais simptomais. Šiai patologijai būdingi pirmieji klinikiniai simptomai pasireiškia jau neonataliniu arba kūdikystės periodu. Stebima progresuojanti mikrocefalija, rijimo ir čiulpimo refleksų sutrikimai, naujagimio neramumas, generalizuotas klonusas, nepakankamas valingų judesių ir kognityvinių funkcijų vystymasis, distonija. Magnetinio rezonanso tomografijos tyrimas (MRT), kartu su klinikiniais požymiais, yra labai reikšmingas įtariant ir diagnozuojant PCH. Būdingiausi PCH2 tipo MRT požymiai: koronariniuose pjūviuose stebima smegenėlių „laumžirgio“ konfigūracija, nestebimas tilto iškyšulys arba matomas ryškus jo sumažėjimas, įvairaus laipsnio smegenų žievės atrofija, vėluojanti mielinizacija. Pontocerebeliarinės hipoplazijos 2A subtipo diagnozei patvirtinti reikalingi genetiniai tyrimai – nustatytas homozigotinis aminorūgštį keičiantis pokytis TSEN54 gene. Šiame straipsnyje pristatomas paciento, sergančio PCH2A subtipu, klinikinis atvejis, kai diagnozė buvo įtarta, remiantis klinikiniais bei MRT požymiais, ir patvirtinta nustačius homozigotinį aminorūgštį keičiantį pokytį TSEN54 gene.

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Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes

Cited by 22 publications

References 19 publications

A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Pontocerebellar hypoplasia: clinical case and literature review

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