Dados do Trabalho

Título

MITOCHONDRIAL DISORDER RELATED TO THE AFG3L2 GENE IN A BOY WITH NEURODEVELOPMENTAL DELAY, ATAXIA AND REFRACTORY EPILEPSY

Apresentação do caso

J.A.R, 2 years old, only child of a couple with no history of neurological diseases, born at term, pregnancy and delivery without complications, normal development in the first trimester of life.
At 4 months, delayed neuromotor development was noticed, without cephalic support, did not follow objects or search for faces, presented tongue fasciculation, hypotonia and hyporeflexia. At 5 months he had strabismus and nystagmus; and at 10, he was diagnosed with West syndrome, started using vigabatrin but due to evolution with magnetic resonance imaging (MRI) uptake, it was suspended, he used other anticonvulsants without achieving optimal seizure control.
Currently, he has refractory epilepsy, 12-hour VEEG showed moderately disorganized background activity, frequent polymorphic discharges either generalized or multifocal and generalized myoclonic seizures; significant delay in neuropsychomotor development, ataxia, dystonia, choreathetosis and gastroesophageal reflux.
In the exome, the mutation p.L772F:C>T in the AFG3L2 gene was identified in heterozygosity; changes in this gene are associated with autosomal dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome.

Discussão

The AFG3L2 gene encodes an ATP-dependent proteolytic complex of the mitochondrial membrane and is involved in several crucial pathways for mitochondrial function, including mitochondrial protein quality control and homeostasis.

The impairment of this gene can lead to dysfunctions in mitochondrial protein synthesis, respiration, mitochondrial integrity and networking. Mutations in AFG3L2 have been associated with both autosomal dominant spinocerebellar ataxia type 28 (SCA28) and autosomal recessive spastic ataxia‐neuropathy syndrome (SPAX5)

Comentários finais

Different forms of the disease, with different levels of severity and neuropathological correlations, were found in different mutations of the AFG3L2 gene in mice, indicating that these variants differently alter the structure and activity of the m-AAA protease. Possibly justifying the reason for the patient, who, although he has a heterozygous mutation, has a clinic more similar to the cases of homozygosity, with more severe symptoms and early onset.

Referências (se houver)

Di Bella D, Lazzaro F, Brusco A, Plumari M, Battaglia G, Pastore A, Finardi A, Cagnoli C, Tempia F, Frontali M, Veneziano L, Sacco T, Boda E, Brussino A, Bonn F, Castellotti B, Baratta S, Mariotti C, Gellera C, Fracasso V, Magri S, Langer T, Plevani P, Di Donato S, Muzi-Falconi M, Taroni F. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet. 2010 Apr;42(4):313-21. doi: 10.1038/ng.544. Epub 2010 Mar 7. PMID: 20208537.

Zühlke C, Mikat B, Timmann D, Wieczorek D, Gillessen-Kaesbach G, Bürk K. Spinocerebellar ataxia 28: a novel AFG3L2 mutation in a German family with young onset, slow progression and saccadic slowing. Cerebellum Ataxias. 2015 Dec 16;2:19. doi: 10.1186/s40673-015-0038-7. PMID: 26677414; PMCID: PMC4681123.

Dosi C, Galatolo D, Rubegni A, Doccini S, Pasquariello R, Nesti C, Sicca F, Barghigiani M, Battini R, Tessa A, Santorelli FM. Expanding the clinical and genetic heterogeneity of SPAX5. Ann Clin Transl Neurol. 2020 Apr;7(4):595-601. doi: 10.1002/acn3.51024. Epub 2020 Apr 1. PMID: 32237276; PMCID: PMC7187698.

Fonte de Fomento (se houver)

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Área

Neurogenética