Dados do Trabalho

Título

CANVAN'S DISEASE CASE REPORT

Apresentação do caso

In the present work, we analyze the case of a child, daughter of consanguineous parents, without acquisition of developmental milestones and already at 4 months without cephalic control. With hypotonia in the first months of life, could sit with support, and lost this milestone at age three. There is no social interaction, severe delay language and significant dysphagia with the need for a Gastrostomy and an increase in the head circumference. At the age of four, started tonic-clonic at right and bilateral crises, usually in the presence of an infectious condition. On physical examination presented macrocephaly with a prominent forehead, ocular hypertelorism, and a low nasal bridge. Has spasticity and bilateral pyramidal release. No eye fixation, absent blink, with limited left eye abduction and upbeat nystagmus with bilaterally absent cochleopalpebral reflex. In a serial resonance examination in 2018 and 2021, there was evidence of a reduction in brain volume with the appearance of areas of diffusion restriction affecting the globus pallidus, pons and middle cerebellar peduncles, with a slight swelling effect, suggestive of disease progression and T2 signal changes in white matter and N-acetylaspartate peak in spectroscopy. Such clinical findings were sufficient for a diagnostic hypothesis of Canavan Syndrome, with molecular examination demonstrating a mutation in the ASPA gene in homozygous splice c.526+1G>C.

Discussão

Canavan disease is caused by pathogenic variants in the ASPA gene, leading to N-acetylaspartic acid toxicity in the brain and other parts of the body1. The presentation is characterized as ataxia, hypotonia, and failure to acquire normal developmental milestones, often in association with macrocephaly and late seizures2, in which most common variants are missense such as p.Tyr231Ter, p.Glu285Ala, and p.Ala305Glu with pathogenic variants in the homozygous or compound heterozygous (with each other) state are associated with neonatal/infantile disease 3. The mutation found in the patient so far has not been described in the literature, this affects a donor splice site in intron 3 of the gene. It is expected to disrupt RNA splicing, leading to a loss of protein function3

Comentários finais

This splice mutation with pathogenic potential described first in this case is compatible with the patient's symptoms described by Blay et al 2. It is necessary to provide genetic counseling and treatment for the symptoms presented, to this date, no treatment proved to be curative.

Referências (se houver)

1. Pleasure D, Guo F, Chechneva O, Bannerman P, McDonough J, Burns T, Wang Y, Hull V. Pathophysiology and Treatment of Canavan Disease. Neurochem Res. 2020 Mar;45(3):561-565. doi: 10.1007/s11064-018-2693-6. Epub 2018 Dec 8. PMID: 30535831.

2. Bley, A., Denecke, J., Kohlschütter, A. et al. The natural history of Canavan disease: 23 new cases and comparison with patients from literature. Orphanet J Rare Dis 16, 227 (2021). https://doi.org/10.1186/s13023-020-01659-3

3. Zeng, B.J., Wang, Z.H., Ribeiro, L.A., Leone, P., De Gasperi, R., Kim, S.J., Raghavan, S., Ong, E., Pastores, G.M. and Kolodny, E.H. (2002), Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. J Inherit Metab Dis, 25: 557-570. https://doi.org/10.1023/A:1022091223498

Declaração de conflito de interesses de TODOS os autores

Dr. Fernando Kok é diretor médico da Mendelic. Demais autores sem conflitos de interesse.