Dados do Trabalho

Título

TITLE: POSSIBLE INTRAFAMILIAL PHENOTYPIC VARIATION OF PEROXISOMAL BIOGENESIS DISORDER 4B, ASSOCIATED WITH THE PEX6 GENE.

Apresentação do caso único

LFSM, male, 11 yo, firstborn of a non-consanguineous couple, premature 35 weeks, APGAR 8/8, remained in NICU due to early neonatal sepsis, severe respiratory failure, requiring antibiotics, vasoactive drugs and ventilatory support. BERA showed bilateral hearing loss. Evoluted with global developmental delay, stereotypes and behavioral disorder. At 7 years, he showed loss of balance, muscle weakness, ataxia, cognitive and behavioral impairment. Brain MRI showed hyperintense signal in T2/FLAIR in splenium of corpus callosum, hyperintense foci in T1 and contrast enhancement in trigeminal nerves and internal auditory canal; electroneuromyography expose sensory-motor polyneuropathy, primarily demyelinating, with secondary axonal degeneration; CHG-array, acylcarnitine profile and very long chain fatty acid (VLCFA) were normal; exome showing pathogenic variant c. 2578 C>T;p.(Arg860Trp) heterozygous in PEX6 gene, associated with peroxisome biogenesis 4B disorder. The couple's second child, born without complications, 2 yo, has adequate neuropsychomotor development for his age. However, VLCFA was altered (hexacosaenoic acid C26:0 4.64 mmol/L, VR<1.02), with no molecular diagnosis yet.

Discussão

Peroxisome biogenesis disorder 4B includes overlapping phenotypes that represent milder manifestations of the Zellweger syndrome spectrum (ZSS), with dominant or recessive inheritance. Those individuals don`t have congenital malformations, hypotonia and developmental delay are common and with peroxisome dysfunction progression they manifest sensory loss (hearing or visual), ataxia, polyneuropathy and leukodystrophy. Our patient presented neonatal complications presumed to be secondary to prematurity, with global development delay and early deafness, evolving with neurological deterioration (demyelinating and axonal polyneuropathy, ataxia and leukodystrophy). Despite the normal isolated dosage of VLCFA, the clinical picture associated with molecular tests showing pathogenic variants in the PEX6 strongly suggests the diagnosis of ZSS. Despite his brother's lack of neurologic symptoms, the presence of elevated VLCFA may represent an even milder manifestation of ZSS, which makes follow-up and molecular research of the utmost importance.

Comentários finais

ZSS is a rare disease, with a wide phenotypic and genotypic variety and risk of intrafamilial variability, demanding to continue with diagnostic investigation with molecular genetic tests even with initial negative screening for the main hypotheses.

Referências

Steven J Steinberg, PhD, Gerald V Raymond, MD, Nancy E Braverman, MS, MD, and Ann B Moser, BA. Zellweger Spectrum Disorder.
Bose M., Yergeau C., D'Souza Y., Cuthbertson D., Lopez M., Smolen A., Braveran N. E. Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review.
Paul R. Lee, MD, PhD, and Gerald V. Raymond, MD. Child Neurology: Zellweger syndrome

Palavras Chave

PEX6; Peroxisome; Zellweger syndrome