Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

Hamed, Ahlam A.; Mohamed, Inaam N.; Elseed, Maha A.; Salih, Mustafa A.; El-Sadig, Sarah Misbah; Siddig, Hassab Elrasoul; Nasreldien, Ali; Abdullah, Mohamed Ahmed; Elzubair, Maha; Omer, Farouk Yassen; Bakhiet, Aisha Motwakil; Abubaker, Rayan; Abozar, Fatima; Adil, Rawaa; Emad, Sara; Musallam, Mhammed Alhassan; Eltazi, Isra Z M; Omer, Zulfa; Malik, Hiba; Mohamed, Mayada; Elhassan, Ali A.; Mohamed, Eman O E; Ahmed, Ahmed K M A; Ahmed, Elhami A A; Eltaraifee, Esraa; Hussein, Bidour; Allah, Amal S I Abd; Salah, Lina; Nimir, Mohammed; Elhassan, Tasneem; Elbashier, Abubakr; Alfadul, Esraa S. A.; Fadul, Moneeb; Taha, Shaimaa; Bushara, Elfatih; Amin, Mutaz; Koko, Mahmoud; Ibrahim, Muntaser E.; Ahmed, Ammar; Elsayed, Liena; Stevanin, Giovanni

doi:10.1038/s41431-023-01344-6

“…However, if the protein is synthesized, phospholipase activity will be lost due to the absence of the catalytic domains. The same variant was previously reported in French and Sudanese patients 19 , 38 and has additional entries in ClinVar. Individuals affected by DDHD2 variants have a wide range of phenotypes, including mild to moderate intellectual disability, wide upper and lower limb spasticity, impaired gait, and brisk tendon reflexes 39 .…”

Section: Discussionsupporting

confidence: 71%

Identification and analyses of exonic and copy number variants in spastic paraplegia

Shafique,

Nadeem,

Aslam

et al. 2024

Sci Rep

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Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertion‒deletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.

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“…Ashraf Yahia, Hassab Elrasoul Siddig and Mahmoud Koko. This family was part of a cohort of Sudanese families with hereditary spinocerebellar degenerations (Yahia et al 2023). At the time of examination, in 2015, patients were 33 and 24 years old, respectively.…”

Section: Methodsmentioning

confidence: 99%

Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage

Martins,

Yahia,

Costa

et al. 2023

Preprint

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Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG)n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3,211 ± 693 years ago.

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Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage

Martins,

Yahia,

Costa

et al. 2023

Hum. Genet.

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Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG)n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3211 ± 693 years ago.

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Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

Cited by 5 publications

References 40 publications

Identification and analyses of exonic and copy number variants in spastic paraplegia

Identification and analyses of exonic and copy number variants in spastic paraplegia

Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage

Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage

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