We report two patients with novel mutations in SPATA5 who demonstrate biochemical evidence of mitochondrial dysfunction.

Mutations in SPATA5 gene are associated with “Epilepsy, Hearing Loss and Mental Retardation Syndrome” (EHLMRS). There is recent experimental evidence from animal models that the SPATA5 gene is involved in mitochondrial remodeling, ATP production and brain development.

Both patients presented with seizures, sensorineural hearing loss, global developmental delays, and hypotonia.

Patient 1 and 2 underwent extensive biochemical workup and neuroimaging.

Patient 2 had a chromosome microarray which showed a 51 kb loss of 4q28.1, which involved a portion of the SPATA5 gene – at the time, thought to be benign.

Both Patient 1 and Patient 2 underwent testing for mitochondrial dysfunction using buccal swab analysis for three enzymes: citrate synthase to to evaluate overall mitochondrial content, and Complex I and IV activity levels.

Finally, both patients underwent Whole Exome Sequencing.

Patient 1 revealed normal citrate synthase levels, normal Complex I and low Complex IV levels.

Patient 2 buccal swab testing revealed very high citrate synthase levels, with low Complex I and IV.

Patient 1 had two compound heterozygous mutations in the SPATA5 gene: p.G357X (c.1069 G>T in exon 5) and p.P102S (c.304 C>T in exon 3).

Patient 2 had a maternally inherited deletion of Exons 12-13, as well as a “variant of uncertain significance” p.Lys638Glu (c.1912 A>G in exon 11) in the SPATA5 gene.

Our patients’ novel mutations and unusual phenotypes demonstrate that SPATA5 deficiency leads to altered mitochondria respiratory function, supporting experimental evidence that it delays development of cortical neurons. We suggest that SPATA5 mutations be considered in the work up of a patient with presumptive mitochondrial encephalopathy.