Dados do Trabalho

Título

P.ARG499HIS MUTATION IN SPAST ASSOCIATED WITH INFANTILE-ONSET COMPLICATED SPASTIC PARAPLEGIA IN A CHILD WITH BILATERAL RETINOBLASTOMA: ASSOCIATION OR COINCIDENCE?

Apresentação do caso

Patient was the first child of non-consanguineous parents whose father was healthy, but mother had mild intellectual deficiency and spastic paraparethic gait that had been attributed to cerebral palsy. At birth he presented congenital talipes equinovarus. He began to crawl at 1yo but was never able to walk independently despite orthopedic feet correction. At 1yo, leukocoria in the left eye was noticed. Bilateral retinoblastoma was diagnosed by the age of 2y 9m. He was submitted to primary bilateral enucleation that confirmed extra-ocular bilateral undifferentiated retinoblastoma. At 3yo it was noticed prominent forehead, underdeveloped supraorbital ridges, low set ears, triangular shaped face, tongue protrusion, long hand and feet fingers, axial hypotonia, upper limb hypotonia, lower limb hypertonia, oral hypotonia and tendon reflexes were 4+ globally, with unsustained knee clonus and bilateral extension of hallux. He emitted guttural sounds and only partially obey commands. His MRI showed post-surgical manipulation status in both orbits and bilateral hippocampal rotation. A genetic panel revealed a heterozygous pathogenic missense variant, c.1496G>A (p.Arg499His), confirming the autosomal dominant hereditary spastic paraplegia 4 (SPG4) diagnostic.

Discussão

Hereditary Spastic Paraplegia (HSP) is a group of neurodegenerative disorders with wide range of different genetics and phenotypes. SPG4, caused by a pathogenic variant in gene SPAST, is the most frequent type and in most cases is considered a pure HSP, rarely associated with additional neurological signs. Exceptionally, patients with p.Arg499His mutations are associated with complicated phenotypes and also suffered from a more severe type of spastic paraplegia with onset within 2 year of life. Retinoblastoma cells contain a mutation or deletion of the retinoblastoma gene (RB1 gene), a tumor-suppressor gene, located on chromosome 13q. In literature, cases of SPG and retinoblastoma has not been described.

Comentários finais

We have not found sufficient evidence to support a causal association between the presence of bilateral retinoblastoma and SPG4. SPG 4 usually presents in motor pure HSP. This rare report case aims to describe a infantile-onset complicated spastic paraplegia due to p.Arg499His mutation in SPAST, presenting with language and cognitive delay in a child with bilateral
retinoblastoma. This rare association represents a challenging case and aims to raise awareness for cerebral palsy mimics.

Referências (se houver)

1 Blackstone C, O’Kane CJ, Reid E. Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci 2011; 12(01):31–42
2 de Souza PV, Bortholin T, Naylor FG, de Rezende PintoWB, Oliveira AS. Infantile-onset ascending spastic paraplegia phenotype associated with SPAST mutation. J Neurol Sci 2016;371:34–35
3. Nan, H., Shiraku, H., Mizuno, T. et al. A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature. BMC Neurol 21, 439 (2021).
4 Balmer, A., Zografos, L., Munier, F. Diagnosis and current management of retinoblastoma. Oncogene 25: 5341-5349, 2006.
5 Smith, S. M., Sorsby, A. Retinoblastoma: some genetic aspects. Ann. Hum. Genet. 23: 50-58, 1958.

Fonte de Fomento (se houver)

Declaração de conflito de interesses de TODOS os autores

The authors declare that they have no competing interests.

Área

Neurogenética