GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description

Alrohaif, Hadil; Pogoryelova, Oksana; Al-Ajmi, Abdullah; Al‐Jeryan, L.; Alrashidi, Nuwayer H; Alefasi, Sara A; Urtizberea, Andoni; Lochmüller, Hanns; Bastaki, Lailá

doi:10.1002/mus.26337

Cited by 7 publications

(4 citation statements)

References 23 publications

(58 reference statements)

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“…Especially for a high frequency variant, this inheritance model could be considered. Pseudo‐dominant inheritance pattern has been described in the GNE myopathy (Alrohaif et al, 2018; Chamova et al, 2015) and in the LGMD R8 TRIM32‐related, in the Hutterite population (Frosk et al, 2005). In those cases, the pseudodominance was caused either by high consanguinity or the high disease‐causing allele frequency in the isolated population.…”

Section: Figurementioning

confidence: 99%

CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related

et al. 2022

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The investigated intronic CAPN3 variant NM_000070.3:c.1746‐20C>G occurs in the Central and Eastern Europe with a frequency of >1% and there are conflicting interpretations on its pathogenicity. We collected data on 14 patients carrying the CAPN3 c.1746‐20C>G variant in trans position with another CAPN3 pathogenic/likely pathogenic variant. The patients compound heterozygous for the CAPN3 c.1746‐20C>G variant presented a phenotype consistent with calpainopathy of mild/medium severity. This variant is most frequent in the North/West regions of Russia and may originate from that area. Molecular studies revealed that different splicing isoforms are produced in the muscle. We hypothesize that c.1746‐20C>G is a hypomorphic variant with a reduction of RNA and protein expression and only individuals having a higher ratio of abnormal isoforms are affected. Reclassification of the CAPN3 variant c.1746‐20C>G from variant with a conflicting interpretation of pathogenicity to hypomorphic variant explains many unidentified cases of limb girdle muscular dystrophy R1 calpain 3‐related in Eastern and Central Europe.

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Section: Figurementioning

confidence: 99%

CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related

et al. 2022

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“…It is known that patients carrying at least one allele with the c.620A>T (p.(Asp207Val)) variant have a later onset and a milder phenotype [ 12 , 32 ]. At the same time, there is a rather pronounced intra- and inter-familial phenotype heterogeneity even in cohorts of patients with the identical homozygous variant [ 8 , 36 ]. Unfortunately, our data were insufficient for genotype–phenotype analysis due to limited patient number.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Clinical Spectrum of GNE Myopathy in Russia

Муртазина

Никитин

Rudenskaya

et al. 2022

Genes

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GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients with GNEM from Russia and analyzed their mutational spectrum and clinical data. In our cohort, 10 novel variants were found, including 2 frameshift variants and 2 large deletions. One novel missense variant c.169_170delGCinsTT (p.(Ala57Phe)) was detected in 4 families in a homozygous state and in 3 unrelated patients in a compound heterozygous state. It was the second most frequent variant in our cohort. All families with this novel frequent variant were non-consanguineous and originated from the 3 neighboring areas in the European part of Russia. The clinical picture of the patients carrying this novel variant was typical, but the severity of clinical manifestation differed significantly. In our study, we reported two atypical cases expanding the phenotypic spectrum of GNEM. One female patient had severe quadriceps atrophy, hand joint contractures, keloid scars, and non-classical pattern on leg muscle magnetic resonance imaging, which was more similar to atypical collagenopathy rather than GNEM. Another patient initially had been observed with spinal muscular atrophy due to asymmetric atrophy of hand muscles and results of electromyography. The peculiar pattern of muscle involvement on magnetic resonance imaging consisted of pronounced changes in the posterior thigh muscle group with relatively spared muscles of the lower legs, apart from the soleus muscles. Different variants in the GNE gene were found in both atypical cases. Thus, our data expand the mutational and clinical spectrum of GNEM.

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“…The human GNE gene (NM_001128227.2), localized on chromosome 9p13.3, consists of 14 exons and encodes 724 amino acids [3,5,6,11] The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), which is a precursor of sialic acid [12] .…”

Section: Discussionmentioning

confidence: 99%

“…UDP-N-acetyl-glucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), a key enzyme of sialic acid biosynthesis, initiates and regulates the biosynthesis of Nacetylneuraminic acid [3] Mutations in GNE have been identified in both hereditary inclusion body myopathy and Nonaka myopathy, which is also termed as distal myopathy with rimmed vacuoles (DMRV; MIM#605820) [2,4] In recent years, the relationship between GNE mutations and congenital thrombocytopenia has been reported [3,[5][6][7][8] Here, we report a case of twin sisters who were shown to have novel combined heterozygous GNE mutations and diagnosed with refractory thrombocytopenia.…”

Section: Introductionmentioning

confidence: 99%

Congenital thrombocytopenia associated with GNE mutations in twin sisters: a case report and literature review

Liu

Lei

et al. 2020

BMC Med Genet

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Background Neonatal thrombocytopenia is common in preterm and term neonates admitted to neonatal intensive care units. The etiology behind neonatal thrombocytopenia is complex. Inherited thrombocytopenia is rare and usually results from genetic mutations. Case presentation Here we report a case of twins with severe inherited thrombocytopenia presented in the neonatal period who were shown to be compound heterozygotes for 2 UDP-N-acetylglucosamine 2-epimerase (GNE) gene mutations, c.1351C > T and c.1330G > T, of which c.1330G > T is a novel mutation. Conclusion These two GNE mutations may help in the diagnosis and management of thrombocytopenia diagnosed in neonates.

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GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description

Abstract: The scope of the p.M743T mutation now includes the Arabian Peninsula. Variations in age of onset, disease progression, and distribution in patients harboring the same mutation suggest the role of other genetic- and environment-modifying factors. Muscle Nerve 58: 700-707, 2018.

Cited by 7 publications

References 23 publications

CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related

CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related

Genetic and Clinical Spectrum of GNE Myopathy in Russia

Congenital thrombocytopenia associated with GNE mutations in twin sisters: a case report and literature review

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