Behr syndrome secondary to compound heterozygosis mutation of the OPA1 gene: rare disease reported in a neuropediatric patient with early presentation

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Abstract

Case Presentation: Female child, 13 years old, born at term, childbirth without intercurrences. Daughter of non-consanguineous and healthy parents. With onset of symptoms in early childhood, with neuropsychomotor development delay progressive optic nerve atrophy, Ophthalmoplegia and ataxia. Evolves with epilepsy, stroke at age 5, hypothyroidism and demyelinating sensorimotor polyneuropathy. Brain MRI with hypoplasia of the inferior vermis, volumetric reduction of the visualized portions of the bulbomedullary junction, atrophy of the nerves and optic chiasm. In genomic sequencing, a pathogenic variant c.1146A>G, p.(Ile382Met), was found in exon 12 of the OPA1 gene and a variant of uncertain significance, c.2614-6T>G, was found in the intronic region that precedes exon 26 of the OPA1 gene, both heterozygosis.

Discussion: The OPA1 gene provides instructions for making a protein called mitofusin-1, which is found in cells and tissues throughout the body. It is located in the inner mitochondrial membrane and is involved in mitochondrial dynamics and mtDNA maintenance. Retinal ganglion cells appear to be particularly sensitive to the effects of OPA1 gene mutations, and consequent changes in mitochondrial function and decreases in energy production. However, some patients have multisystem manifestations with varying levels of severity. Behr syndrome is a clinical term, caused by homozygous or compound heterozygous mutations in the OPA1 gene on chromosome 3q29, that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation. In the case of the patient in question, two mutations were found in the OPA 1 gene, one known to be pathogenic and the other variant of uncertain significance, affecting the intronic region of that gene. Furthermore, this patient evolved with comorbidities little reported in the literature associated with Behr syndrome, with epilepsy and ischemic stroke.

Final Comments: Behr syndrome is a rare disease, but one that can have a significant impact on the quality of life of affected patients. Our report confirms the broad in the phenotypic spectrum associated with recessive OPA1 mutations and it reinforces the questioning of the role of mutations in intronic regions in the severity of the clinical presentation.

Publication History

Article published online:
12 May 2025