Pathological EXOSC3 mutation and its neurological manifestations: a case report

Case presentation: AMD, 12 year-old male presented with developmental delay starting at 4 months-old, with motor difficulties, hypotonia, significant weight gain and 2 episodes of febrile convulsion. Unplanned pregnancy of a non-consanguineous marriage. Delivery at 7 months of pregnancy, APGAR 9/10, no further complications presented. Physical examination showed more pronounced hypotonia on upper limbs in comparison to lower limbs, but normal reflexes on the latter, currently walking with support. Skull and spine MR showed moderate to severe atrophy of cerebellar hemispheres and superior vermis; inferior vermis agenesis, discrete pontine atrophy, arachnoid cyst, sulcal widening and an increase in the supratentorial ventricular system's amplitude. The spine presented a slight dorsal scoliosis and bilateral posterior paravertebral hypotrophy in the lumbar region. An increase in triglycerides, cholesterol and glucose was also identified. Array-CGH examination showed a heterozygotic duplication of around 228Kb of the short arm of the X chromosome, including the PPP2R3B gene - of uncertain significance. A complete exome sequencing showed a pathogenic EXOSC3 mutation.

Discussion: EXOSC3 mutations have been recently defined as one of the main causes of pontocerebellar hypoplasia subtype 1, which is characterized by cerebellar atrophy and hypoplasia, variable pontine atrophy, as well as severe motor and mental disorders. This case report shows the importance and complexity of the genotype-phenotype correlations. The exosome complex is involved in the processing and synthesis of RNA. Hence, an alteration of this functional axis can lead to mutations of this process. It is suggested that the EXOSC3 unit is essential to the survival of cerebellar and spinal neurons’ motor function. Therefore, an anomaly of this subunit could cause a deregulation of RNA's metabolism, leading to developmental delay, pyramidal, extrapyramidal and/or cerebellar damage.

Final comments: EXOSC3 gene mutations are directly correlated to pontocerebellar hypoplasia subtype 1, presenting itself on patients with ataxia and motor disorders. This case report promotes attention to premature patients with abnormal neurological examination with no other reasonable cause for alterations, which is relevant to the investigation of a genetic cause, to find an etiological conclusion for symptoms, correct diagnosis and patient treatment.

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023