Severe brain involvement in 5q spinal muscular atrophy type 0

Mendonça, Rodrigo Holanda; Rocha, Antônio José da; Lozano-Arango, Andrés; Diaz, Astry B.; Castiglioni, Claudia; Silva, André Macedo Serafim; Reed, Umbertina Conti; Kulikowski, Leslie Domenici; Paramonov, Ida; Cuscò, Ivon; Tizzano, Eduardo F.; Zanoteli, Edmar

doi:10.1002/ana.25549

Annals of Neurology

2019

DOI: 10.1002/ana.25549

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Severe brain involvement in 5q spinal muscular atrophy type 0

Rodrigo Holanda Mendonça

Antônio José da Rocha²,

Andrés Lozano-Arango

et al.

Abstract: View this article online at wileyonlinelibrary.com.

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Cited by 31 publications

(47 citation statements)

References 21 publications

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“…1 These cases support the hypothesis that survival motor neuron (SMN), the causative gene for SMA, was expressed widely throughout the central nervous system (CNS), including cerebral cortex and cerebellum. 1 These cases support the hypothesis that survival motor neuron (SMN), the causative gene for SMA, was expressed widely throughout the central nervous system (CNS), including cerebral cortex and cerebellum.…”

supporting

confidence: 56%

“…1 Our case demonstrated a more severe phenotype, with brainstem and cerebellum atrophy accompanied by epilepsy. 1 Our case demonstrated a more severe phenotype, with brainstem and cerebellum atrophy accompanied by epilepsy.…”

mentioning

confidence: 59%

“…The report by Mendonça et al showed sparring of the cerebellum. 1 Our case demonstrated a more severe phenotype, with brainstem and cerebellum atrophy accompanied by epilepsy.…”

mentioning

confidence: 59%

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Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0

Maeda

Chong

Yamashita

et al. 2019

Annals of Neurology

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Mendonça et al reported 3 spinal muscular atrophy (SMA) type 0 cases that demonstrated progressive supratentorial brain atrophy. 1 These cases support the hypothesis that survival motor neuron (SMN), the causative gene for SMA, was expressed widely throughout the central nervous system (CNS), including cerebral cortex and cerebellum. 2 Herein, we describe 1 SMA type 0 case with severe diffuse CNS atrophy involving the supra-and infratentorial brain and the spinal cord.A 2-year-old girl was born at term with no fetal movements detected from the 3rd trimester onwards. The Apgar scores at 1 and 5 minutes after birth were 1 and 6, respectively. Absence of spontaneous breathing required immediate tracheal intubation. She had marked muscle weakness, generalized hypotonia, absent deep tendon reflexes, and tongue fasciculations. Polymerase chain reaction revealed homozygous deletion of SMN1 and neuronal apoptosis inhibitory protein (NAIP) genes. A multiplex ligation-dependent probe amplification assay detected 1 copy of SMN2; thus, she was diagnosed with SMA type 0. At 4 months of age, she developed distal necrosis (Fig). Intermittent bradycardia appeared during infancy. Eye and limb movements were absent since early infancy, but pupillary reflex was preserved. Before 2 years of age, clonic seizures with minimal limb and eyelid movement and tachycardia appeared. Seizures lasted a few minutes, and no convulsive status epilepticus was observed. Interictal electroencephalography revealed a suppression burst pattern unobserved in the neonatal period. Head magnetic resonance imaging (MRI) findings suggesting hypoxic ischemic encephalopathy were undocumented in the neonatal period. Serial MRI presented progressive atrophy of the cerebral cortex, subcortical white matter, thalamus, and basal ganglia. Although volumes of cervical cord, brainstem, and cerebellum were relatively spared at 7 months, these volumes were reduced at 2 years.The report by Mendonça et al showed sparring of the cerebellum. 1 Our case demonstrated a more severe phenotype, with brainstem and cerebellum atrophy accompanied by epilepsy.As previously reported in some severe cases, our patient had distal necrosis, probably due to autonomic dysfunction and perfusion impairment. 3 A recent study showed that concurrent homozygous deletion of SMN1 and NAIP was associated with a severe phenotype. 4 NAIP is adjacent to SMN and is known as the modifying gene of the SMA phenotype, although its direct role has not been fully investigated. The genotype in our case may explain the phenotypic severity and demonstrate SMA pathology extending to the entire CNS.

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supporting

confidence: 56%

mentioning

confidence: 59%

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Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0

Maeda

Chong

Yamashita

et al. 2019

Annals of Neurology

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“…1 We would like to reply to some of the comments in their letter. 1 We would like to reply to some of the comments in their letter.…”

mentioning

confidence: 98%

“…1 Maeda et al ascribe the extreme severity of their patient to the presence of 1 SMN2 copy and the absence of the NAIP gene. This case represents another example of evolutionary brain atrophy that becomes worse with time in patients with type 0 spinal muscular atrophy (SMA), who survive longer through artificial invasive ventilation.…”

mentioning

confidence: 99%

Reply to “Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0”

Mendonça

Rocha²,

Lozano-Arango

et al. 2019

Annals of Neurology

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We thank Dr Maeda et al for their careful review and for their contribution of an additional case related to our previous report, "Severe Brain Involvement in 5q Spinal Muscular Atrophy Type 0." 1 We would like to reply to some of the comments in their letter.The case they reported showed severe diffuse atrophy, compromising the supra-and infratentorial central nervous system with seizures. This case represents another example of evolutionary brain atrophy that becomes worse with time in patients with type 0 spinal muscular atrophy (SMA), who survive longer through artificial invasive ventilation. Although the 3 cases that we reported did not show evident cerebellar compromise or seizures, there are previous reports of type 0 SMA with cerebellar involvement and seizures 2 that we commented on in our paper. 1 Maeda et al ascribe the extreme severity of their patient to the presence of 1 SMN2 copy and the absence of the NAIP gene.In addition to the SMN1 gene, 2 other genes located in the 5q13.2 region, NAIP (neuronal apoptosis inhibitory protein, currently BIRC1) and SERF1A (small EDRK-rich factor 1A), have been postulated as possible modifier genes because they are deleted in approximately one-half the patients with severe SMA. 3 However, the roles of these genes have not been unequivocally established, and there is a consensus that the association of these genes with the phenotype may be the result of large-scale rearrangements causing deletion of multiple genes (including the SMNs and other adjacent genes), as previously described by other groups. 4 Thus, true deletions of SMN1 or null alleles are usually associated with the deletion of surrounding genes. NAIP mutations were not specifically studied in our patients. However, 1 of them, who also developed distal necrosis (Patient 3), had 1 allele with the presence of SMN1 and a point pathogenic variant in exon 6, suggesting the presence of surrounding genes, including NAIP. Bernal et al 5 reported that 8 patients with 2 SMN2 copies (usually expected to develop severe type I disease) showed better phenotypes because of the presence of the c.859G>C variant in exon 7 of the SMN2 gene (type II sitter or type III walker). These patients also showed homozygous deletion of NAIP, further supporting the hypothesis that the absence of NAIP is not primarily involved in worsening of the SMA phenotype. References1. Mendonça RH, Rocha AJ, Lozano-Arango A, et al. Severe brain involvement in 5q spinal muscular atrophy type 0. Ann Neurol 2019; 86:458-462. 2. Rudnik-Schöneborn S, Forkert R, Hahnen E, et al. Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropediatrics 1996;27:8-15. 3. Medrano S, Monges S, Gravina LP, et al. Genotype-phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina. Eur J Paediatr Neurol 2016;20:910-917. 4. Wang CH, Carter TA, Das K, et al. Extensive DNA deletion associated with severe disease alleles on spinal muscular atroph...

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Cerebellar degeneration in adult spinal muscular atrophy patients

2020

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Severe brain involvement in 5q spinal muscular atrophy type 0

Abstract: View this article online at wileyonlinelibrary.com.

Cited by 31 publications

References 21 publications

Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0

Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0

Reply to “Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0”

Cerebellar degeneration in adult spinal muscular atrophy patients

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