Behr Syndrome
A number sign (#) is used with this entry because of evidence that Behr syndrome (BEHRS) is caused by homozygous or compound heterozygous mutations in the OPA1 gene (605290) on chromosome 3q29.
Description'Behr syndrome' is a clinical term that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation (Behr, 1909; Thomas et al., 1984).
Patients with mutations in genes other than OPA1 can present with clinical features reminiscent of Behr syndrome. Mutations in one of these genes, OPA3 (606580), result in type III 3-methylglutaconic aciduria (MGCA3; 258501). Lerman-Sagie (1995) noted that the abnormal urinary pattern in MGCA3 may not be picked up by routine organic acid analysis, suggesting that early reports of Behr syndrome with normal metabolic features may actually have been 3-methylglutaconic aciduria type III.
Clinical FeaturesEarly Clinical Descriptions
Behr (1909) described a syndrome of optic atrophy beginning in early childhood, associated with ataxia, spasticity, and mental retardation. Posterior column sensory loss was also reported. After a period of progression, the symptoms remained static. Involvement of multiple brothers and sisters with normal parents and parental consanguinity suggested autosomal recessive inheritance. Van Bogaert and Andre-Van Leeuwen (1942) reported necropsy findings. In their pedigree, mild manifestations were evident in heterozygotes.
Horoupian et al. (1979) reported 2 sisters with Behr syndrome. Postmortem examination of 1 patient showed central atrophy of the optic nerves and total disarray of the normal laminar pattern of the lateral geniculate nucleus, neuronal loss, and gliosis. Numerous axonal spheroids were also present. The authors suggested that Behr syndrome is a manifestation of a heterogeneous group of disorders.
Thomas et al. (1984) described a consanguineous Oriental family in which 2 males and 3 females in 2 generations were affected with Behr syndrome. Salient clinical features included mental retardation and dementia, optic atrophy, cerebellar ataxia, pyramidal signs, and peripheral neuropathy. Nerve biopsy from the index case showed a chronic neuropathy with axonal degeneration and regeneration, and muscle biopsy showed multiple inclusions composed of spiral cylindrical structures. The parents of the 3 affected persons in the first of these generations were first cousins, and those affected in the second generation were offspring of a brother of the elder affected persons who was married to a first cousin once removed. Most of the patients were adults, the proband being 46 years old.
Copeliovitch et al. (2001) reported the management of musculoskeletal abnormalities in 17 patients with Behr syndrome. All were born in Israel to Iraqi Jewish immigrants. The main clinical features were optic atrophy diagnosed during the first decade of life, nystagmus (apparent in the first year of life), and spastic ataxic gait. Seventy percent of patients had severe lower limb muscle contractures leading to frequent falls and requiring surgery. Achilles tendon lengthening was effective in 11 patients who received it. Hamstring lengthening and surgery to improve hip adduction were not as effective in improving the pattern of gait. Copeliovitch et al. (2001) found that the ataxia and spasticity were progressive in their patients and became more prominent in the second decade of life. At follow-up at an average age of 21.7 years, 13 of the patients were housebound walkers, 2 were nonfunctional walkers, 2 were nonwalkers, and all patients resided in special homes for the handicapped.
Pizzatto and Pascual-Castroviejo (2001) reported 7 cases of Behr syndrome, 6 of whom were 3 pairs of sibs. Biochemical investigations were reportedly normal. MRI of 5 patients showed marked cerebellar atrophy in 3 and moderate cerebellar atrophy in 2.
Patients with Mutations in the OPA1 Gene
Yu-Wai-Man et al. (2010) reported 2 adult sibs of Norwegian origin, 60 and 64 years old, with early-onset optic atrophy, ataxia, myopathy, neuropathy, and spasticity who were compound heterozygous for 2 missense mutations in the OPA1 gene (S256R and Q285R).
Schaaf et al. (2011) reported a family in which 2 sibs presented in early childhood (about age 3 years) with a severe neurologic disorder characterized by early-onset optic atrophy, hypotonia, delayed motor development, ataxia, dysphagia, and gastrointestinal disability. Skeletal muscle biopsy of 1 patient showed ragged-red fibers, increased numbers of mitochondria, rimmed vacuoles, and rare COX-depleted fibers, suggestive of mitochondrial dysfunction, but there were no mtDNA deletions and respiratory enzyme activity was normal. Genetic analysis revealed compound heterozygosity for 2 mutations in the OPA1 gene (c.2708delTTAG, 605290.0003 and I382M, 605290.0018) in both sibs. Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy, color vision dysfunction, and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, without evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) concluded that the missense mutation may be a mild mutation that shows strong additive effects when combined with a second mutation. The findings suggested either semidominant or recessive inheritance.
Bonneau et al. (2014) reported 4 unrelated children with features compatible with Behr syndrome. They had onset of optic atrophy in infancy or the first years of life, axonal sensorimotor peripheral neuropathy, and cerebellar ataxia, usually associated with cerebellar atrophy. More variable features included delayed development, hearing loss, dysmetria, and dysarthria. Only 1 of the patients was reported to have deafness. In 1 of 2 patients investigated, respiratory complex I activity was reduced in fibroblasts but not in skeletal muscle. Two of the 8 parents had mild optic atrophy.
Carelli et al. (2015) reported a 20-year-old Italian man who presented at birth with congenital nystagmus and developed optic atrophy in the first year of life. He showed delayed motor development, ataxic-spastic gait resulting in loss of independent ambulation, hyperreflexia, extensor plantar responses, pes cavus, and a sensorimotor peripheral neuropathy. Sural nerve biopsy showed a reduction in large diameter myelinated axons. He also had cerebellar signs, including dysmetria, dysdiadochokinesis, and nystagmus. The patient had mild cerebellar atrophy and accumulation of lactate in the cerebrospinal fluid. Muscle biopsy and mitochondrial respiratory enzyme activities were normal, but cultured fibroblasts from the patient showed an abnormally fragmented mitochondrial network and impaired ATP synthesis through complex I. The findings were consistent with impaired mitochondrial function. Laboratory studies showed mildly increased 3-methylglutaconic aciduria, but pathogenic mutations in the OPA3 gene were not found. Family history revealed that isolated optic atrophy segregated as a dominant trait with incomplete penetrance in the maternal side of the family.
Molecular GeneticsIn 4 unrelated children with a phenotype consistent with Behr syndrome, Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene (see, e.g., 605290.0018; 605290.0020-605290.0021). Three of the children carried the same missense mutation (I382M; 605290.0018). Three of the 4 patients carried a truncating mutation on 1 allele and a missense mutation on the other allele. Functional studies of the variants were not performed. Yu-Wai-Man and Chinnery (2014) commented that co-occurrence of a truncating OPA1 with a missense OPA1 mutation may result in a dominant-negative effect and a more severe phenotype, particularly if the missense mutation occurs in the GTPase domain of the protein, as does I382M.
In an Italian man with Behr syndrome, Carelli et al. (2015) identified compound heterozygous mutations in the OPA1 gene: I382M (605290.0018) and a splice site mutation (605290.0022).