Hearing Loss Is Not an Obligatory Hallmark of SPATA5 Early-Onset Epileptic Encephalopathy with Microcephaly and Hypomyelination

Objectives: Introduction SPATA5 is a newly reported cause of early-onset epileptic encephalopathy with typical characteristics, including hearing loss which was considered as a hallmark for this disorder.

Content: Method: We report here a 6-year-old boy born from first cousins healthy Kurdish Iraqi parents. His maternal aunt in Canada has unexplained severe cerebral palsy with childhood-onset epilepsy. He was diagnosed soon after birth with galactosemia and appropriate diet was introduced. From the age of 5 months, developmental decline associated with poor eye contact and pyramidal signs and later spasticity were observed. MRI at the age of 9 months demonstrated delayed myelination. At the age of 13 months, late-onset infantile spams occurred associated with severely abnormal EEG. In the follow-up, multiple daily polymorphic seizures appeared soon refractory to all antiepileptic medications including ketogenic diet. In parallel, postnatal microcephaly became apparent. Apart from mild esotropia, ophthalmological examination, including fundoscopy and ERG, was fully normal. Hearing was preserved and this was confirmed by normal auditory evoked potentials. Initial metabolic and genetic investigations were negative and completed by targeted whole-exome sequencing.

Results: Further analysis was able to identify an homozygous splicing-site variant (c.2214–5A > G) within the SPATA5 gene. Both parents were healthy carriers. His aunt exhibited the same mutation and similar clinical profile and radiological findings according to charts and imaging review from Ottawa Children's Hospital. Due to the atypical findings of preserved hearing in both affected patients, RNA studies in the skin biopsy from the proband were conducted that confirmed the pathogenicity of the variant.

Conclusion: SPATA5 is now recognized as one of the causative gene responsible for recessive forms of early onset epileptic encephalopathy. Microcephaly and hypomyelination are typical findings. Hearing loss is not an obligatory feature. Severe disability and refractory epilepsy are common.

Publication History

Article published online:
16 March 2022