Behr syndrome is a rare genetic disorder first reported in 1909 by ophthalmologist Carl Behr 1). It follows an autosomal recessive inheritance pattern.
This syndrome is caused by biallelic pathogenic variants in the OPA1 gene 1). Cases caused by mutations in OPA3 or C12orf65 have also been reported. When caused by OPA3 gene mutations, it is associated with 3-methylglutaconic aciduria and is also called Costeff syndrome.
The core feature is optic atrophy that begins in childhood, along with various neurological symptoms such as cerebellar ataxia, spastic paraplegia, peripheral neuropathy, and intellectual disability. The combination of symptoms varies depending on the causative gene.
Monoallelic (heterozygous) mutations in the OPA1 gene cause autosomal dominant optic atrophy (ADOA). ADOA primarily involves optic neuropathy, but severe cases present a “DOA plus” phenotype with hearing loss, ataxia, peripheral neuropathy, and progressive external ophthalmoplegia 1).
ADOA is caused by a monoallelic mutation (heterozygous) in the OPA1 gene and primarily involves slowly progressive optic neuropathy. Behr syndrome differs in that it results from biallelic mutations (compound heterozygous) and presents with multisystem neurological symptoms such as ataxia, spasticity, and peripheral neuropathy in addition to optic atrophy.
The following symptoms appear from infancy.
Ocular Findings
Bilateral optic atrophy: Onset in infancy. Pallor of the optic disc is observed.
Nystagmus: Appears congenitally or in early infancy. May worsen over time1).
Decreased visual acuity: In some cases, decreases to approximately 20/2601). Scotopic electroretinogram responses are also reduced.
Retinal pigment epithelium atrophy: Extensive areas of atrophy have been reported1).
Neurological Findings
Cerebellar ataxia: Presents with intention tremor, dysmetria, and wide-based gait1).
Spastic paraparesis: Increased muscle tone and hyperreflexia in the lower limbs.
Peripheral neuropathy: May present as decreased deep tendon reflexes throughout the body1).
Intellectual disability: Severity varies by case. Language development may be preserved in some cases1).
Lower limb muscle contractures (hip adductors, hamstrings, soleus, Achilles tendon) may occur. Gastrointestinal dysmotility has also been reported1).
Rare but reported. Myoclonic seizures and focal seizures have been described, and cases of refractory status epilepticus have also been reported1). See “Pathophysiology and Detailed Mechanisms” section for details.
The cause of Behr syndrome is biallelic pathogenic variants in the OPA1 gene 1). Due to autosomal recessive inheritance, both parents are typically carriers and asymptomatic.
The main causative genes and their corresponding phenotypes are shown below.
| Causative gene | Inheritance pattern | Characteristic phenotype |
|---|---|---|
| OPA1 | Autosomal recessive | Optic atrophy + neurological symptoms |
| OPA3 | Autosomal recessive | +3-methylglutaconic aciduria |
| C12orf65 | Autosomal recessive | Typical Behr syndrome findings |
In one case, a compound heterozygous mutation of c.2287del (p.Ser763Valfs*15) and c.1311A>G (p.Ile437Met) in the OPA1 gene was confirmed 1). The former was inherited from the mother and the latter from the father.
More than 500 types of pathogenic variants have been identified in the OPA1 gene. In ADOA, c.2708_2711delTTAG is known as a hotspot and is also frequent in Japanese individuals.
Suspect this syndrome when bilateral optic atrophy of childhood onset is accompanied by the following neurological findings.
A definitive diagnosis is made by identifying biallelic pathogenic variants in the OPA1 gene 1). Optic atrophy panel testing or whole exome sequencing is used. In addition to OPA1, OPA3 and C12orf65 are also examined.
OPA1 genetic testing is not widely available as a routine commercial test. It must be referred to major facilities such as university hospitals. In recent years, the availability of whole exome sequencing has increased testing opportunities.
No specific treatment has been established for this syndrome. Management focuses on symptomatic and supportive therapy for each symptom.
Surgical intervention may be performed for lower limb muscle contractures.
Currently, there is no established treatment to reverse optic atrophy. Support through low vision care is the mainstay. Gene therapy research for OPA1-related optic neuropathy is ongoing and is expected as a future treatment option.
The OPA1 gene encodes a mitochondrial protein belonging to the dynamin-related GTPase family 1). The OPA1 protein is localized to the inner mitochondrial membrane and performs the following important functions.
OPA1 protein is also involved in synapse formation of retinal ganglion cells through the balance of mitochondrial fusion and fission. Loss of these functions due to biallelic mutations leads to degeneration and cell death of neurons (especially retinal ganglion cells)1).
The prevalence of seizures in mitochondrial disease is reported to be 20–60%1). ATP deficiency due to impaired oxidative phosphorylation leads to an imbalance between excitatory and inhibitory neurons, resulting in excessive neuronal excitation and epilepsy1).
Characteristics of epilepsy associated with mitochondrial disease include onset from the occipital region, nonconvulsive status epilepticus, and epilepsia partialis continua1). Refractory cases may progress to progressive neurodegeneration and epileptic encephalopathy1).
The pathophysiology of stroke-like episodes (SLE) in mitochondrial disease has not been fully elucidated. The proposed mechanisms are as follows1).
Jagadish et al. (2024) reported a case of a patient with Behr syndrome carrying biallelic mutations in the OPA1 gene who presented with recurrent super-refractory status epilepticus and metabolic stroke at age 7. Head MRI showed diffusion restriction in the left thalamus, left parieto-occipital cortex, and left frontal cortex, not conforming to vascular territories. Status epilepticus had not been previously reported in Behr syndrome, and only one case of metabolic stroke had been reported1).
In autopsy cases, central atrophy of the optic nerve and axonal spheroids in the neuropil have been observed. Spheroids with cell loss and gliosis are found in the thalamic nuclei and globus pallidus, and disruption of normal laminar structure and gliosis have been reported in the lateral geniculate body.
For optic neuropathy caused by OPA1 mutations, early clinical trials using mutation-independent gene expression regulation technology are underway 2). These primarily target autosomal dominant optic atrophy (ADOA), but future applications to Behr syndrome are also expected.
The following therapeutic approaches are being studied for hereditary optic neuropathies in general 2).
Vail syndrome is an extremely rare disease, and conducting large-scale clinical trials faces challenges such as genetic heterogeneity, disease variability, and optimization of patient selection2).
Ganetzky et al. (2018) reported a retrospective analysis of intravenous arginine therapy in 9 pediatric patients with mitochondrial disease (a total of 17 SLE episodes). Clinical improvement was observed in approximately 47% of acute SLE episodes, and the therapy was effective in preventing progression and recurrence of SLE. No adverse events were noted1).
Ketogenic diet therapy has also been reported to be effective in treating seizures in mitochondrial disease1). Decreased nitric oxide synthesis and deficiency of its precursors (arginine and citrulline) are thought to contribute to SLE1), and research on supplementation therapy is ongoing.
