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NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup.

ABSTRACT: Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases. Thin Corpus Callosum (TCC) associated HSP is a distinguished subgroup of complex forms. Purines and pyrimidine, the basic DNA and RNA components, are regulating the cell metabolism, having roles in signal transduction, energy preservation and cellular repair. Genetic defects in nucleotide metabolism related genes have been only recently implicated in brain and neurodegenerative diseases' pathogenesis.We present a consanguineous Qatari family with two brothers, 9 and 3 years, who displayed a characteristic phenotype of early onset and markedly-severe spasticity with tiptoe walking, delayed dysarthric speech, persistent truncal hypotonia, and multiple variable-sized areas of brownish skin discoloration appearing at different places on the body. A clinical diagnosis suggestive of complex hereditary spastic paraplegia (HSP) was set after the family had the second affected child. Whole genome sequencing identified a novel homozygous NT5C2 splice site mutation (NM_012229.4/NM_001134373.2: c.1159?+?1G?>?T) that recessively segregated in family members. Brain MRI revealed dysgenic and thin corpus callosum (TCC) with peri-trigonal white matter cystic changes in both affected boys, whereas a well-developed corpus callosum with normal white matter was shown in their apparently normal brother, who found to be a carrier for the mutant variant. This mutation led to skipping of exon 14 with removal of 58 amino acid residues at the C-terminal half. The aberrantly spliced NT5C2 showed substantial reduction in expression level in the in-vitro study, indicating marked instability of the mutant NT5C2 protein.The present report expands the phenotypic spectrum of SPG45 and confirms NT5C2-SPG45 as a member of the rare TCC SPG-subtypes. Homozygous alteration in NT5C2 seems essential to produce central white matter developmental defects. The study highlights the importance of cytosolic II 5'-nucleotidase (NT5C2) in maintaining the normal balance of purines' pool in the brain, which seems to play a pivotal role in the normal development of central white matter structures.

SUBMITTER: Elsaid MF

PROVIDER: S-EPMC5359868 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup.

Elsaid Mahmoud F MF Ibrahim Khalid K Chalhoub Nader N Elsotouhy Ahmed A El Mudehki Noora N Abdel Aleem Alice A

BMC medical genetics 20170321 1

<h4>Background</h4>Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases. Thin Corpus Callosum (TCC) associated HSP is a distinguished subgroup of complex forms. Purines and pyrimidine, the basic DNA and RNA components, are regulating the cell metabolism, having roles in signal transduction, energy preservation and cellular repair. Genetic defects in nucleotide metabolism related genes have been only recently implicated in brain and neurodegenerat ...[more]

PMID: 28327087

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Project description:BackgroundThe detailed neuropathological features of patients with autosomal recessive hereditary spastic paraplegia with a thin corpus callosum (TCC) and SPG11 mutations are poorly understood, as only a few autopsies have been reported. Herein, we describe the clinicopathological findings of a patient with this disease who received long-term care at our medical facility.Case presentationA Japanese man exhibited a mild developmental delay in early childhood and intellectual disability, followed by the appearance of a spastic gait by age 13. At the age of 25 years, he became bedridden and needed a ventilator. Genetic analysis revealed a homozygous splice site variant in the SPG11 gene (c. 4162-2A > G) after the provision of genetic counselling and acquisition of informed consent from his parents. He died of pneumonia at the age of 44. His brain weighed 967 g and was characterized by a TCC, and his spinal cord was flattened. Microscopically, degeneration was observed in the posterior spinocerebellar tract, the gracile fasciculus, and the posterior column in addition to the corticospinal tract. Marked neuronal loss and gliosis were observed in the anterior horn, Clarke's column, and hypoglossal and facial nuclei. Various types of neurons, in addition to motor neurons, showed coarse eosinophilic granules that were immunoreactive for p62. The loss of pigmented neurons with gliosis was apparent in both the substantia nigra and locus coeruleus. Lateral geniculate body degeneration was a characteristic feature of this patient. Furthermore, peripheral Lewy body-related α-synucleinopathy and scattered α-synuclein-immunoreactive neurites in the locus coeruleus and reticular formation of the brainstem were observed.ConclusionsIn patients with hereditary spastic paraplegia with SPG11 mutations, a variety of clinical phenotypes develop due to widespread lesions containing p62-immunoreactive neuronal cytoplasmic inclusions. We herein report the lateral geniculate body as another degenerative site related to SPG11-related pathologies that should be studied in future investigations.

Project description:Spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) are linked to SLC1A4 genetic variants since the first reported case in 2015. SLC1A4 encodes for the neutral amino acid transporter ASCT1 which is involved in the transportation of serine between astrocytes and neurons. Although most of the reported cases are of Ashkenazi Jewish ancestry, SPATCCM has also been reported in Irish, Italian, Czech, Palestinian, and Pakistani ethnicities. Herein, we report two Pakistani male siblings from a non-consanguineous marriage presented with global developmental delay associated with spastic quadriplegia, microcephaly, and infantile spasm. Since infancy, both siblings suffered from microcephaly with brain MRI demonstrating generalized atrophy of the frontal, temporal, and parietal lobes with a prominence of the subarachnoid spaces, widening of the Sylvian fissures, and enlargement of the ventricular system not compatible with the chronological age of both patients associated with thinning of the corpus callosum. Whole-exome sequencing of both affected brothers revealed novel compound heterozygous variants in the SLC1A4 gene (NM_003038) segregating from their parents. The maternal c.971delA (p.N324Tfs*29) deletion variant disturbs the transcript reading frame leading to the generation of a premature stop codon and its subsequent degradation by nonsense-mediated mRNA decay as detected through expression analysis. The paternal c.542C > T (p.S181F) missense variant was predicted deleterious via multiple in silico prediction tools as the amino acid substitution is speculated to affect the overall ASCT1 structural confirmation due to the loss of an H-bond at the core of the protein at this position which might affect its function as concluded from the simulation analysis. The presented cases expand the genetic and clinical spectrum of ASCT1 deficiency and support the importance of including SLC1A4 gene screening in infants with unexplained global neurodevelopmental delay regardless of ethnicity.

Dataset Information

NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup.

Publications

NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup.

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