FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3196635183> ?p ?o ?g. }

• W3196635183 abstract "GLB1 encodes beta-galactosidase-1, a lysosomal hydrolase that cleaves the terminal beta-galactose from ganglioside substrates. Biallelic variants in GLB1 cause beta-galactosidase deficiency leading to GM1 gangliosidosis.1 Type III GM1 gangliosidosis shows extreme clinical variability and is less severe than GM1-gangliosidosis types I and II.2 Here we describe a new family with GM1-gangliosidosis type III extending the geographic range of reported cases to Transcaucasia and expanding the disease phenotype. The index case (II-5) is a 20-year-old female born full-term after uneventful pregnancy and delivery to neurologically healthy parents of Azerbaijani origin. No consanguinity was reported in the family but the parents are from the same village. The proband had a similarly affected older brother and three unaffected adult siblings (Fig. 1A). She had normal early development and was healthy until the age of 12 years. At this age, the gradual onset of muscular stiffness and slowness of movements were noticed. This progressed to speech and swallowing impairment, walking difficulties, cognitive deterioration, and urinary frequency. Her past medical history was remarkable for nocturnal hypoventilation and the family history was positive for parkinsonism and unspecified movement disorders in the paternal relatives. Upon examination, she was cognitively impaired and anarthric with risus sardonicus, orolingual dystonia, and impaired saccades with a reduced range of vertical eye movements. Her body movements were slow and rigid, and her gait was stiff and shuffling with postural instability. There were axial dystonia leading to stooped posture and the lateral flexion of the body, bilateral asymmetric parkinsonism, limb dystonia and spasticity, and brisk tendon reflexes (Video 1). The proband's affected older brother (II-2), currently aged 31 years old, presented with a similar but significantly milder phenotype. He manifested at age 12 years old and displayed minimal upper limb dystonia upon walking but asymmetric parkinsonism (Video 1). Both affected siblings were short-statured with kyphoscoliosis and had no organomegaly, cerebellar ataxia, corneal opacity, or Kayser-Fleischer ring. Serum ceruloplasmin and 24-hour urinary copper levels were unremarkable. Brain MRI in both affected siblings revealed well-defined symmetrical high signal intensities in the posterior part of the putamina on T2-weighted images (Fig. 1G). Neither susceptibility-weighted MRI images, nor DATscan, nor leukocyte beta-galactosidase activity levels were available. Bone radiography excluded skeletal dysplasia. To identify the genetic cause of the disease in the affected individuals, exome sequencing (ES) on DNA extracted from probands' leucocytes and variant filtering were performed as previously described.3 An ultra-rare homozygous missense variant in exon 3 of GLB1 c.319 T > C, p.(Phe107Leu) (NM_000404.4) residing within a 9.9 Mb region of homozygosity was identified. This variant resides in a highly conserved region of the catalytic TIM-barrel domain of beta-galactosidase1 (Fig. 1B,C) and destabilizes the neighboring residues that flank the active ligand-binding site4 (Fig. 1E). The variant has one allele count in a heterozygous state in gnomAD and is predicted to be deleterious/damaging by various in-silico prediction tools (Fig. 1D). Sanger sequencing confirmed the homozygous and the heterozygous carrier status for p. (Phe107Leu) in the affected siblings and their parents respectively (Fig. 1A). ES data was negative for all other disease-causing genes. Half of the reported families with GM1-gangliosidosis type III come from Japan with almost all harboring a homozygous pathogenic founder p. (Ile51Thr) variant.2 The majority of non-Japanese cases harbor compound heterozygous GLB1 variants;2 therefore, the present family with the homozygous GLB1 variant expands the genotypic spectrum of the non-Japanese cases and extends their geographic range to Transcaucasia. Over 90% of GM1-gangliosidosis type III cases present with progressive dystonia, which is usually moderate-to-severe and generalized.2, 5 In our report, the affected brother (II-2) presented with minimal dystonia if any but parkinsonism over the disease course of 19 years. No impaired saccades and limited vertical gaze, seen in our cases, have previously been reported in GM1-gangliosidosis type III.2, 4 The presented MRI finding is typical of GM1-gangliosidosis type III and Glutaric aciduria type 1.6 The discussed features seem to expand the clinico-genetic phenotype of the disease. We would like to thank the family involved in this study. We are grateful to Queen Square genomics at the Institute of Neurology University College London for bioinformatics support. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. R.K.: 1A, 1B, 1C, 3A U.G.: 1C, 3B S.G: 1C, 3B K.S.: 1C, 3B A.M.: 1C, 3B P.A.: 1C, 3B M.P.F.: 1C, 3B H.H.: 1A, 1B, 3B Written informed consent for genetic testing and photo/video materials were obtained from the parents. The study was conducted in accordance with the Declaration of Helsinki and approved by the relevant institutional review boards.We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. This study was funded by the Medical research council (MRC) (MR/S01165X/1, MR/S005021/1, G0601943). The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report." @default.
• W3196635183 created "2021-09-13" @default.
• W3196635183 creator A5001574766 @default.
• W3196635183 creator A5016656760 @default.
• W3196635183 creator A5018506306 @default.
• W3196635183 creator A5024430094 @default.
• W3196635183 creator A5043426250 @default.
• W3196635183 creator A5053408641 @default.
• W3196635183 creator A5082436384 @default.
• W3196635183 creator A5089988446 @default.
• W3196635183 date "2021-08-01" @default.
• W3196635183 modified "2023-10-18" @default.
• W3196635183 title "<scp>GM1</scp> ‐Gangliosidosis Type <scp>III</scp> Associated Parkinsonism" @default.
• W3196635183 cites W1976750661 @default.
• W3196635183 cites W2036233971 @default.
• W3196635183 cites W2090666699 @default.
• W3196635183 cites W2792984064 @default.
• W3196635183 cites W3046956275 @default.
• W3196635183 doi "https://doi.org/10.1002/mdc3.13289" @default.
• W3196635183 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8414511" @default.
• W3196635183 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34514040" @default.
• W3196635183 hasPublicationYear "2021" @default.
• W3196635183 type Work @default.
• W3196635183 sameAs 3196635183 @default.
• W3196635183 citedByCount "1" @default.
• W3196635183 countsByYear W31966351832023 @default.
• W3196635183 crossrefType "journal-article" @default.
• W3196635183 hasAuthorship W3196635183A5001574766 @default.
• W3196635183 hasAuthorship W3196635183A5016656760 @default.
• W3196635183 hasAuthorship W3196635183A5018506306 @default.
• W3196635183 hasAuthorship W3196635183A5024430094 @default.
• W3196635183 hasAuthorship W3196635183A5043426250 @default.
• W3196635183 hasAuthorship W3196635183A5053408641 @default.
• W3196635183 hasAuthorship W3196635183A5082436384 @default.
• W3196635183 hasAuthorship W3196635183A5089988446 @default.
• W3196635183 hasBestOaLocation W31966351831 @default.
• W3196635183 hasConcept C118552586 @default.
• W3196635183 hasConcept C126322002 @default.
• W3196635183 hasConcept C15744967 @default.
• W3196635183 hasConcept C187212893 @default.
• W3196635183 hasConcept C2776525014 @default.
• W3196635183 hasConcept C2778261627 @default.
• W3196635183 hasConcept C2778559928 @default.
• W3196635183 hasConcept C2779012798 @default.
• W3196635183 hasConcept C2779134260 @default.
• W3196635183 hasConcept C2779734285 @default.
• W3196635183 hasConcept C2780405171 @default.
• W3196635183 hasConcept C71924100 @default.
• W3196635183 hasConcept C99508421 @default.
• W3196635183 hasConceptScore W3196635183C118552586 @default.
• W3196635183 hasConceptScore W3196635183C126322002 @default.
• W3196635183 hasConceptScore W3196635183C15744967 @default.
• W3196635183 hasConceptScore W3196635183C187212893 @default.
• W3196635183 hasConceptScore W3196635183C2776525014 @default.
• W3196635183 hasConceptScore W3196635183C2778261627 @default.
• W3196635183 hasConceptScore W3196635183C2778559928 @default.
• W3196635183 hasConceptScore W3196635183C2779012798 @default.
• W3196635183 hasConceptScore W3196635183C2779134260 @default.
• W3196635183 hasConceptScore W3196635183C2779734285 @default.
• W3196635183 hasConceptScore W3196635183C2780405171 @default.
• W3196635183 hasConceptScore W3196635183C71924100 @default.
• W3196635183 hasConceptScore W3196635183C99508421 @default.
• W3196635183 hasIssue "S1" @default.
• W3196635183 hasLocation W31966351831 @default.
• W3196635183 hasLocation W31966351832 @default.
• W3196635183 hasLocation W31966351833 @default.
• W3196635183 hasOpenAccess W3196635183 @default.
• W3196635183 hasPrimaryLocation W31966351831 @default.
• W3196635183 hasRelatedWork W1523112753 @default.
• W3196635183 hasRelatedWork W157595835 @default.
• W3196635183 hasRelatedWork W2025538995 @default.
• W3196635183 hasRelatedWork W2139883696 @default.
• W3196635183 hasRelatedWork W2167537858 @default.
• W3196635183 hasRelatedWork W2316794111 @default.
• W3196635183 hasRelatedWork W2357576458 @default.
• W3196635183 hasRelatedWork W3201145921 @default.
• W3196635183 hasRelatedWork W4248058291 @default.
• W3196635183 hasRelatedWork W4281792295 @default.
• W3196635183 hasVolume "8" @default.
• W3196635183 isParatext "false" @default.
• W3196635183 isRetracted "false" @default.
• W3196635183 magId "3196635183" @default.
• W3196635183 workType "article" @default.