Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

Santos, Mariana; Damásio, Joana; Kun‐Rodrigues, Célia; Barbot, Clara; Sequeiros, Jorge; Brás, José; Alonso, Isabel; Guerreiro, Rita

doi:10.3390/jcm9041212

Cited by 4 publications

(3 citation statements)

References 41 publications

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“…Mutation of C19ORF12 induces spasticity and weakness confined to lower extremities, with skin peeling and declining intellect [101]. MAG proteins expressed by myelination cells and are designated as Siglec-4a (sialic acid-binding immunoglobulin type lectin) necessary for axon attachment with glial cells, axon regenerating, neurites outgrowth inhibition, and neuron protection from axonal damage and any missense variations lead to oculomotor apraxia, neuropathy ataxia [102].…”

Section: Chromosome 19mentioning

confidence: 99%

Hereditary Spastic Paraplegia: An Update

Meyyazhagan

Orlacchio

2022

IJMS

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Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disorder with the predominant clinical manifestation of spasticity in the lower extremities. HSP is categorised based on inheritance, the phenotypic characters, and the mode of molecular pathophysiology, with frequent degeneration in the axon of cervical and thoracic spinal cord’s lateral region, comprising the corticospinal routes. The prevalence ranges from 0.1 to 9.6 subjects per 100,000 reported around the globe. Though modern medical interventions help recognize and manage the disorder, the symptomatic measures remain below satisfaction. The present review assimilates the available data on HSP and lists down the chromosomes involved in its pathophysiology and the mutations observed in the respective genes on the chromosomes. It also sheds light on the treatment available along with the oral/intrathecal medications, physical therapies, and surgical interventions. Finally, we have discussed the related diagnostic techniques as well as the linked pharmacogenomics studies under future perspectives.

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Section: Chromosome 19mentioning

confidence: 99%

Hereditary Spastic Paraplegia: An Update

Meyyazhagan

Orlacchio

2022

IJMS

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“…These families had been identified during our national population survey in Portugal [10], but remained for many years without a molecular diagnosis, after testing the most common genes. More recently, new causal-genes were identified in undiagnosed families, including PNKP in eight families with AOA4 [11], MAG in one family with AOA and neuropathy [12], and DAB1 in three AD families with SCA37 [34].…”

Section: Discussionmentioning

confidence: 99%

“…Targeted genetic testing was conducted ab initium, according to the main clinical phenotype; 61 families (83 patients), however, remained without a genetic diagnosis [10]. Pathogenic variants in PNKP [11] were later identified in eight families (11 patients), and in MAG [12] in one family (3 patients), all with AOA. More recently, expansion of an intronic repeat in RFC1 [13] was excluded in all families with genomic DNA available who persisted without diagnosis.…”

Section: Genetic Analysismentioning

confidence: 99%

Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia

Santos

Damásio

Carmona

et al. 2022

Cells

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Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.

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Convergent gene expression highlights shared vocal motor microcircuitry in songbirds and humans

Gedman

Biegler

Haase

et al. 2022

Preprint

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Vocal learning is a skilled motor behavior observed in several mammalian and avian species and is critical for human speech. While convergent gene expression patterns have highlighted similar primary motor and striatal pathways for vocal imitation in songbirds and humans, the extent of molecular and circuit convergence remains unresolved. Here we profiled the four principal song nuclei of the zebra finch (HVC, LMAN, RA, Area X) and their surrounding brain regions using RNA-Seq and compared them with specialized markers we identified for human speech brain regions. Expanding previous work, both songbird RA and HVC exhibited convergent specialized gene expression of ~350 genes with human laryngeal sensorimotor cortex. The songbird HVCRA intratelencephalic (IT) neurons were the predominant cell type that was convergent with human, specifically layer 2/3 IT neurons, while the songbird RA extratelencephalic (ET) projection neurons exhibited convergent expression with human layer 5 ET projection neurons. The molecular specializations of both songbird LMAN and human Brocas area were more unique to each species. These findings demonstrate the extent of convergent molecular specializations in distantly related species for vocal imitation and emphasize important evolutionary constraints for this complex trait.

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Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

Cited by 4 publications

References 41 publications

Hereditary Spastic Paraplegia: An Update

Hereditary Spastic Paraplegia: An Update

Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia

Convergent gene expression highlights shared vocal motor microcircuitry in songbirds and humans

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