C12orf65 (chromosome 12 open reading frame 65) gene encodes a mitochondrial matrix protein essential for the release of newly synthesized proteins from mitochondrial ribosomes. Biallelic pathogenic variants result in loss of function in the protein complex necessary for oxidative phosphorylation. Pathogenic C12orf65 variants have been associated with various inherited neurological diseases, including Behr syndrome, Leigh syndrome, combined oxidative phosphorylation deficiency 7, and hereditary spastic paraplegia. This was a retrospective case series of 4 children with C12orf65 mutation from 3 unrelated pedigrees of Chinese descent. Clinical and diagnostic data were collected via retrospective medical record review. The phenotypic manifestations were systematically documented, and the genotypic data were analyzed in conjunction with previous reports. Four subjects exhibited optic nerve atrophy, strabismus, progressive lower limb dystonia, and abnormal gait. Whole exome sequencing revealed the c.394C>T variant in C12orf65 in all 4 patients. Three of the patients had coexisting novel MT-ND4 (m.11696 G>A) and OPA1 (c.1817G>A) variants. We analyzed the gene-phenotypic associations of 4 patients in conjunction with previous reports which added to the current understanding of C12orf65-related neurodegenerative disorders. The superimposed mutations in 2 of these patients suggest that the heterogeneity of optic neuropathy and the systemic features associated with C12orf65 pathogenic variants may be altered by the genetic background of mitochondrial or nuclear genes that influence mitochondrial function. We recommend genetic evaluation of C12ORF65-related diseases, including other genes responsible for optic neuropathy, and not just limited to Sanger sequencing.

Behr syndrome is associated with compound heterozygous dysfunction in OPA1 gene and typically presents with a constellation of visual impairment due to early onset optic atrophy, cerebellar ataxia, peripheral neuropathy, deafness, and gastrointestinal motility problems. Our patient with biallelic variants in OPA1 gene had delayed motor milestones, cerebellar ataxia, and optic atrophy in infancy. At the age of 7 years, he presented with recurrent episodes of super-refractory status epilepticus and metabolic stroke due to underlying mitochondrial dysfunction associated with OPA1 gene dysfunction. Besides the two rare prior case reports of focal and myoclonic seizures in patients with Behr syndrome, epilepsy in general is not well described in the typical phenotypic spectrum and to the best of our knowledge. Dramatic clinical presentation with recurrent super-refractory status epilepticus and metabolic stroke has not been reported previously. There is only one prior report of metabolic stroke in a patient with Behr syndrome due to OPA1 gene dysfunction.

Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a progressive decrease in vision, central visual field defects, and retinal ganglion cell loss. A biallelic mode of inheritance causes syndromic DOA or Behr phenotype, MIM # 605290. This case report details a family with Biallelic Optic Atrophy 1 (OPA1). The proband is a child with a severe phenotype and two variants in the OPA1 gene. He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia, and was found to have two likely pathogenic variants in his OPA1 gene: c.2287del (p.Ser763Valfs*15) maternally inherited and c.1311A>G (p.lIle437Met) paternally inherited. The first variant is predicted to be pathogenic and likely to cause DOA. In contrast, the second is considered asymptomatic by itself but has been reported in patients with DOA phenotype and is presumed to act as a phenotypic modifier. On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes. A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported. All share an early-onset, severe ocular phenotype and systemic features, which seem to be the hallmark of the disease.

Optic atrophy 1 (OPA1) gene mutations are associated with dominantly inherited optic neuropathy resulting in a progressive loss of visual acuity. Compound heterozygous or homozygous variants that lead to severe phenotypes, including Behr syndrome, have been reported rarely. Here, we present a 14-month-old boy with early onset optic atrophy, congenital cataracts, neuromuscular disorders, mental retardation, and developmental delay. Combined genetic testing, including whole exome sequencing (WES) and chromosomal microarray analysis, revealed a concurrent OPA1 variant (c.2189 T > C p.Leu730Ser) and de novo chromosome 3q deletion as pathogenic variants leading to the severe phenotype. Our case is the first reporting a novel missense OPA1 variant co-occurring with a chromosomal microdeletion leading to a severe phenotype reminiscent of Behr syndrome. This expands the mutation spectrum of OPA1 and inheritance patterns of this disease.

Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing. Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother. Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30's, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1. The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.