Progressive myoclonus epilepsies—Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Courage, Carolina; Oliver, Karen; Park, Eon Joo; Cameron, Jillian; Grabińska, Kariona A.; Muona, Mikko; Canafoglia, Laura; Gambardella, Antonio; Said, Edith; Afawi, Zaid; Baykan, Betül; Brandt, Christian; Bonaventura, Carlo Di; Chew, Hui Bein; Criscuolo, Chiara; Dibbens, Leanne M.; Castellotti, Barbara; Riguzzi, P.; Labate, Angelo; Filla, Alessandro; Giallonardo, Anna Teresa; Berecki, Géza; Jackson, Christopher B.; Joensuu, Tarja; Damiano, John A.; Kivity, Sara; Korczyn, Amos D.; Palotie, Aarno; Striano, Pasquale; Uccellini, Davide; Giuliano, Loretta; Andermann, Eva; Scheffer, Ingrid E.; Michelucci, Roberto; Bahlo, Melanie; Franceschetti, Silvana; Sessa, William C.; Berkovic, Samuel F.; Lehesjoki, Anna‐Elina

doi:10.1016/j.ajhg.2021.03.013

Cited by 55 publications

(77 citation statements)

References 64 publications

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“… 2 All previously reported, pathogenic variants were located in the last exon and presumably did not undergo nonsense‐mediated mRNA decay and are associated with PME. 2 , 3 In general, myoclonus is often difficult to treat and can be the most disabling clinical sign in patients with PME. 4 …”

Section: Introductionmentioning

confidence: 99%

Zonisamide‐responsive myoclonus in SEMA6B‐associated progressive myoclonic epilepsy

Herzog

Hellenbroich

Brüggemann

et al. 2021

Ann Clin Transl Neurol

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We present a female patient in her early twenties with global development delay, progressive ataxia, epilepsy, and myoclonus caused by a stop mutation in the SEMA6B gene. Truncating DNA variants located in the last exon of SEMA6B have recently been identified as a cause of autosomal dominant progressive myoclonus epilepsy. In many cases, myoclonus in the context of progressive myoclonic epilepsy is refractory to medical treatment. In the present case, treatment with zonisamide caused clinical improvement, particularly of positive and negative truncal myoclonus, considerably improving patient's gait and thus mobility.

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Section: Introductionmentioning

confidence: 99%

Zonisamide‐responsive myoclonus in SEMA6B‐associated progressive myoclonic epilepsy

Herzog

Hellenbroich

Brüggemann

et al. 2021

Ann Clin Transl Neurol

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“…In 4 families with 2 or 3 affected siblings, WES was performed on all patients. 5 In 1 family with 4 affected siblings, homozygosity mapping was followed by targeted NGS. 2 …”

Section: Methodsmentioning

confidence: 99%

“…and S.F.B.). Taking into account the clinical classification applied by Courage et al, 5 patients were categorized as (1) “Unverricht-Lundborg disease-like (ULD-like) PME” in case of late childhood/adolescent onset of cortical myoclonus and minimal cognitive impairment similar to EPM1, (2) “late-onset PME” in case of clinical presentation similar to EPM1, but onset after 20 years of age, (3) “PME plus developmental delay” when progressive cortical myoclonus appeared after other symptoms suggesting a developmental encephalopathy (early psychomotor delay, ataxia or seizures), and (4) “PME plus dementia” when patients showed a severe and progressive cognitive impairment as part of the phenotype.…”

Section: Methodsmentioning

confidence: 99%

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Progressive Myoclonus Epilepsies

et al. 2021

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Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

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“…14 This heteromeric enzyme is composed of two types of subunits: a catalytic subunit termed dehydrodolichyl diphosphate synthase (DHDDS) and an auxiliary quiescent subunit termed Nogo B-receptor (NgBR) (Figure 1A). 15 In line with its important biological roles, mutations in both subunits of hcis-PT were identified as causing several human diseases with ocular 16,17 and neurological [18][19][20][21] manifestations, among others. 22,23 Physiologically, hcis-PT is localized to the endoplasmic reticulum (ER) membrane via an N-terminal transmembrane domain of NgBR, where it synthesizes the precursor for dolichol-phosphate (Dol-P) by consecutive condensations of IPP onto the allylic diphosphate primer farnesyl diphosphate (FPP, C 15 ) (Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for long-chain isoprenoids synthesis by cis-prenyltransferases

Giladi

Bar-El

Vaňková

et al. 2021

Preprint

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Isoprenoids are the largest group of natural products, found in all living organisms and play an essential role in numerous cellular processes. These compounds are synthesized by prenyltransferases, catalyzing the condensation reaction between an allylic diphosphate primer and a variable number of isopentenyl diphosphate (C5) units. This superfamily of enzymes can be subdivided into trans- or cis-prenyltransferases according to the stereoisomerism of the product. The cis branch can be further classified according to product length. While the active site volume was suggested to determine the final length in enzymes synthesizing short- and medium-chain products (up to C60), long-chain enzymes (up to C120) and rubber synthases (>C10,000) fail to conform to this paradigm. Here, to resolve the structural basis for long-chain isoprenoid synthesis, we focused on the human cis-prenyltransferase complex (hcis-PT). This enzyme, peripheral to the endoplasmic reticulum membrane, produces the precursor for dolichol phosphate, a membrane residing glycosyl carrier. In line with its crucial role in the cellular protein glycosylation machinery, disease-causing mutations in hcis-PT were shown to result in a wide spectrum of clinical phenotypes. The crystallographic structures of hcis-PT in four different substrate/product-bound conformations revealed an outlet enabling product elongation into the bulk solvent. Moreover, hydrogen-deuterium exchange mass spectrometry analysis in solution showed that the hydrophobic active site core is flanked by dynamic regions consistent with separate inlet and outlet orifices. Finally, using a fluorescent substrate analog and a fluorescently-labeled lipid nanodiscs, we show that product elongation and membrane association are closely correlated. Together, our results support directional product synthesis in long-chain enzymes and rubber synthases, with a distinct substrate inlet and product outlet, allowing direct membrane insertion of the elongating isoprenoid during catalysis. This mechanism uncouples active site volume from product length and circumvents the need to expulse hydrophobic product into a polar environment prior to membrane insertion.

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Progressive myoclonus epilepsies—Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Cited by 55 publications

References 64 publications

Zonisamide‐responsive myoclonus in SEMA6B‐associated progressive myoclonic epilepsy

Zonisamide‐responsive myoclonus in SEMA6B‐associated progressive myoclonic epilepsy

Progressive Myoclonus Epilepsies

Structural basis for long-chain isoprenoids synthesis by cis-prenyltransferases

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