Comprehensive clinical, biochemical and genetic screening reveals four distinct GBA genotypes as underlying variable manifestation of Gaucher disease in a single family

Cullufi, Paskal; Tabaku, Mirela; Beetz, Christian; Tomori, Sonila; Velmishi, Virtut; Gjikopulli, Agim; Bauer, Péter; Wirth, Stéfan; Rolfs, Arndt

doi:10.1016/j.ymgmr.2019.100532

Cited by 10 publications

(18 citation statements)

References 15 publications

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“…As mentioned above, the genotype of one index patient (patient 14, Table S2) contained three changes, however, the p.Arg368His alteration could not be phased, and thus it remains unclear whether it comprises an allele with p.Asn409Ser or p.Leu483Pro. Of note, the marriage of two of our index patients (patients 31 and 32, Table S2) resulted in three affected offspring (patients 33‐35) with novel genotypes emerging from the combination of their parental alleles, as previously reported 14 . Thus, overall, our patients harbored 15 different genotypes (Table S2).…”

Section: Resultssupporting

confidence: 69%

“…Among these 36 individuals, 28 were unrelated index patients (4 familial and 24 sporadic; Table S2) and 8 were affected family members. Notably, two unrelated index patients formed one of the families through marriage 14 . The three remaining families consisted of sibling pairs.…”

Section: Resultsmentioning

confidence: 99%

“…Two more alleles consisting of two variants each (recombinant Rec Nci I: p.[Leu483Pro;Ala495Pro] and likely recombinant: p.[Leu422Profs*4;Asp448His] 14 ) were identified one time each.…”

Section: Discussionmentioning

confidence: 99%

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Genetic characterization of the Albanian Gaucher disease patient population

et al. 2020

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Gaucher disease (GD) is a recessive metabolic disorder caused by a deficiency of the GBA gene-encoded enzyme β-glucocerebrosidase. We characterized a cohort of 36 Albanian GD patients, 31 with GD type 1 and 5 affected by GD types 2, 3, and an intermediate GD phenotype between type 2 and type 3. Of the 12 different GBA alleles that we detected, the most frequently observed was p.Asn409Ser, followed by p.[Asp448His;His294Gln]. The prevalence of the p.Leu483Pro allele was approximately 10-fold lower than reported in other populations. We identified a novel pathogenic missense variant (c.1129G>A; p.Ala377Thr). All five of our non-type 1 patients had genotypes consisting of the p.[Asp448His;His294Gln] allele in combination with another severe GBA allele. The median Lyso-Gb1 level of treated patients carrying the p.[Asp448His;His294Gln] and no p.Asn409Ser allele was significantly higher than that of treated individuals homozygous or compound heterozygous for the p.Asn409Ser allele. In conclusion, the most important distinguishing features of the Albanian GD patient population are the underrepresentation of the p.Leu483Pro allele and an unusually high number of p.[Asp448His;His294-Gln] alleles originating from a common Balkan founder event. The presence of at least one p.Asn409Ser allele is associated with mild disease and low Lyso-Gb1 biomarker levels, while compound heterozygosity involving p.[Asp448His;His294Gln] and no p.Asn409Ser entails severe phenotypes and high Lyso-Gb1 levels.

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

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Genetic characterization of the Albanian Gaucher disease patient population

et al. 2020

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“…Another three studies providing information on plasma lyso-Gb1 as a prognostic biomarker were identified. Firstly, in a family in which all members over two generations presented with splenomegaly owing to four distinct GBA genotypes, a plasma lyso-Gb1 level spanning more than one order of magnitude correlated well with the presumed pathogenicity of the genotypes and with hepatosplenomegaly, thrombocytopenia, and bone pain [ 123 ]. Secondly, moderate-to-strong correlations between plasma lyso-Gb1 and spleen volume, liver volume, and Hb but not platelet count at baseline were detected in eliglustat clinical trials of treatment-naïve adults with type 1 GD [ 124 ].…”

Section: Discussionmentioning

confidence: 99%

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Revel‐Vilk

Fuller

Zimran

2020

IJMS

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The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.

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“…The clinical features are diverse according to the type of GD [6,8,9]. In type 1, the accumulation of substrate results in the enlargement of the liver and spleen, fatigue, growth retardation, delayed puberty, bleeding disorders, pancytopenia, and painful bone crisis related to vascular diseases or mechanic effects [6,8,10].…”

Section: Introductionmentioning

confidence: 99%

Difficulties in the Diagnosis of Gaucher Disease in a Low-Income Country: A Case Report from Mozambique

Pinto

Nassone

Ismail

et al. 2021

J. inborn errors metab. screen.

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Introduction: Gaucher disease (GD) is one of the common lysosomal storage disorder (LSD) with an estimated frequency of one in 40,000 newborns globally. GD is an autosomal recessive condition, which results from mutations in the GBA1 gene, causing partial or complete deficiency of β-glucocerebrosidase enzyme activity, which leads to the widespread accumulation of the substrate glucosylceramide. Aims: This report presents different challenges of clinical management and communication between medical specialties to reach diagnose of any rare disease in Mozambique, a low-income country, which health system has limited infrastructure, trained personnel, and budget for diagnosis and to provide treatment for rare genetic disorders such as GD. Case Presentation: The patient was a 15-year old black female patient of Mozambican nationality born from non-consanguineous parents. Three of the four patient's siblings were healthy; one sister had died of a disease with a similar clinical features. Our patient presented with abdominal distention and hepatosplenomegaly. Blood tests revealed pancytopenia and a high level of ferritin. Liver biopsy and histologic examination revealed infiltration of the splenic parenchyma and portal area of the liver as well as enlarged histiocytic cells with granular cytoplasm. Magnetic resonance imaging showed liver enlargement, changes in the femoral heads without osteonecrosis, a pathological fracture of the third thoracic vertebrae (T3), with absence of brain and spinal cord neurological abnormalities. The biochemical investigation disclosed low levels of β-glucocerebrosidase (0.223 nmol/h/ml; normal: above 0.98) and increased levels of lyso-Gb1 (0.43 µg/ml; normal: up to 0.003). Genotyping of the GBA1 gene indicated the presence of the pathogenic variant p.Arg87Trp (R48W) in homozygosis. Discussion and Conclusion: To the best of our knowledge, this report describes the first case of GD type 1 confirmed via biochemical and molecular genetic testing in Mozambique. As awareness of the GD and rare genetic diseases among Mozambican health professionals is very limited, and resources for diagnosis are scarce in the national health system, it is possible that other cases remain undiagnosed in this low-income country.

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Comprehensive clinical, biochemical and genetic screening reveals four distinct GBA genotypes as underlying variable manifestation of Gaucher disease in a single family

Cited by 10 publications

References 15 publications

Genetic characterization of the Albanian Gaucher disease patient population

Genetic characterization of the Albanian Gaucher disease patient population

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Difficulties in the Diagnosis of Gaucher Disease in a Low-Income Country: A Case Report from Mozambique

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