Case of Infantile Onset Spinocerebellar Ataxia Type 5

Jacob, Francois-Dominique; Ho, Eugenia; Martinez-Ojeda, Mayra; Darras, Basil T.; Khwaja, Omar

doi:10.1177/0883073812454331

Cited by 34 publications

(41 citation statements)

References 18 publications

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“…SPTBN2 encodes a b3-spectrin with high expression in Purkinje cells that is involved in excitatory glutamate signaling through stabilization of the glutamate transporter EAAT4 at the membrane's surface. Heterozygous in-frame SPTBN2 mutations cause SCA5, a rare SCA subtype with only five mutations reported, [4][5][6] with the mean age of onset at 33 years and mostly normal lifespan.…”

Section: Discussionmentioning

confidence: 99%

“…8 A single SCA5 patient has been reported with a heterozygous missense SPTBN2 mutation and an infantile onset, resembling the phenotype in our family. 6 Her mutation affects a highly conserved protein residue (p.Arg480Trp). Arg480 may represent a residue of particular importance for SPTBN2 function, with an unusually severe phenotype when mutated.…”

Section: Discussionmentioning

confidence: 99%

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Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

et al. 2013

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Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

et al. 2013

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“…However, a novel heterozygous mutation (R480W) has also been reported in a patient exhibiting infantile onset and global developmental delay (Jacob et al . ). It may be that in this case there is an undetected mutation in trans or an environmental modifier resulting in a much earlier and more severe phenotype than other β‐III spectrin heterozygous mutations.…”

Section: Introductionmentioning

confidence: 97%

“…B , location of mutations associated with infantile cerebellar ataxia: heterozygous R480W mutation identified in two cases of infantile ataxia with global developmental delay (Jacob et al . ; Parolin Schnekenberg et al . ); homozygous stop codon (C627X) within third spectrin repeat, UK family (Lise et al .…”

Section: Introductionmentioning

confidence: 99%

Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

Perkins

Šuminaite

Jackson

2016

The Journal of Physiology

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Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β‐III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin‐R, cell adhesion molecules, metabotropic glutamate receptor‐1 (mGluR1), voltage‐gated sodium channels (Nav) and glutamate transporters. This scaffold of interactions connects β‐III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β‐III spectrin (SPTBN2) underlie SCA type‐5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type‐1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss‐of β‐III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss‐of‐function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing.

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“…Homozygous loss of function mutations of SPTBN2 have been identified in four families with early-onset cerebellar ataxia associated with cognitive impairment, eye movements abnormalities and variable additional neurological signs, defined as autosomal recessive spinocerebellar ataxia 14 (SCAR14; MIM#615386). [12][13][14][15] We used targeted next-generation sequencing (NGS) in 100 unrelated patients with non-progressive congenital or early onset ataxia associated with cerebellar atrophy. [7][8][9][10][11] The identification of three unrelated Francesco Nicita and Marta Nardella have contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

et al. 2019

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Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

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Case of Infantile Onset Spinocerebellar Ataxia Type 5

Cited by 34 publications

References 18 publications

Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

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