GM3 synthase deficiency due to <i>ST3GAL5</i> variants in two Korean female siblings: Masquerading as Rett syndrome‐like phenotype

Lee, Jin Sook; Yoo, Yongjin; Lim, Byung Chan; Kim, Ki Joong; Song, Junghan; Choi, Murim; Chae, Jong Hee

doi:10.1002/ajmg.a.37773

Cited by 54 publications

(44 citation statements)

References 23 publications

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“…In another study of 22 patients with RTT, who had prior negative clinical testing for mutations in MECP2 , CDKL5 , and FOXG1 , WES revealed likely pathogenic variants in the majority of cases, including in IQSEC2 , TCF4 , and WDR45 [10], three of the genes identified in our cohort. In addition to these cohort studies, there have been numerous WES-based case reports implicating a variety of genes in RTT-like phenotypes, such as SATB2 [11], ST3GAL5 [12], and TBL1XR1 [13]. …”

Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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Background. Rett syndrome (RTT) is caused by mutations in methyl-CpG binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. Methods. We performed a retrospective chart review on n=319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results (3) ultimately arrived at a diagnosis other than RTT with WES. Results. n=7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These 7 patients collectively possessed pathogenic variants in 6 different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n=2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT associated features included the following: loss of hand or language skills (n=3; IQSEC2, KCNB1 × 2); disrupted sleep (n=4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n=5; FOXG1, KNCB1 × 2, MEIS2, TCF4); bruxism (n=3; KCNB1 × 2; TCF4); and hypotonia (n=7). Conclusion. Clinically-based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

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Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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“…Whether changes in GSL composition are a result of or a requirement for differentiation processes has been a longstanding question in the fields of glycobiology and developmental biology. GM3S) cause a neurological syndrome (Simpson et al, 2004) where its manifestations include untreatable epilepsy, brain atrophy, severe cognitive impairment, and autism-like manifestations (Simpson et al, 2004;Fragaki et al, 2013;Boccuto et al, 2014;Lee et al, 2016). During neural differentiation, stem cells that produce mainly globo-series GSLs differentiate into neural cells that are rich in ganglio-series GSLs (Liang et al, 2010(Liang et al, , 2011.…”

Section: Discussionmentioning

confidence: 99%

“…Defects in GSL remodelling due to loss-of-function mutations in the first and rate-limiting enzyme involved in ganglio-series GSL production (i.e. GM3S) cause a neurological syndrome (Simpson et al, 2004) where its manifestations include untreatable epilepsy, brain atrophy, severe cognitive impairment, and autism-like manifestations (Simpson et al, 2004;Fragaki et al, 2013;Boccuto et al, 2014;Lee et al, 2016). Thus, understanding how the GSL remodelling is accomplished and how it influences neural differentiation are fundamental questions for both cell and neurodevelopmental biologists.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, mutations in GM3S resulting in the absence of ganglio-series GSLs (and metabolic redirection towards globo-series GSL production) cause a severe disease in humans (i.e. GM3S deficiency syndrome, OMIM: #609056) characterised by epilepsy, brain atrophy and impaired psychomotor development (Simpson et al, 2004;Fragaki et al, 2013;Lee et al, 2016). Moreover, genetic manipulations in animal models have highlighted a fundamental role for GSLs in brain function (Jennemann et al, 2005;Yamashita et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Glycosphingolipid metabolic reprogramming drives neural differentiation

et al. 2017

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Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo- to ganglio-series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self-contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo-series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate-limiting ganglioside-producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology.

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“…Variants of all the other genes listed in Figure , except for WDR45 , have been observed in only 1 or 2 patients, and these genes are described in more detail in Appendix S1 (Supporting information).…”

Section: Clinical or Genetic Diagnosis?mentioning

confidence: 99%

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

et al. 2018

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The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

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GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome‐like phenotype

Cited by 54 publications

References 23 publications

Monogenic disorders that mimic the phenotype of Rett syndrome

Monogenic disorders that mimic the phenotype of Rett syndrome

Glycosphingolipid metabolic reprogramming drives neural differentiation

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

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