Behr Syndrome
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Disease Entity
Behr syndrome is a clinically and genetically heterogeneous neuro-ophthalmic syndrome characterized by childhood-onset optic atrophy accompanied by variable neurological manifestations, most commonly spastic paraparesis, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, and developmental or cognitive impairment. The term describes a clinical phenotype that can result from several different genetic disorders. The syndrome was first described by German ophthalmologist Carl Behr in 1909 [1][2][3].
Genetics
Behr syndrome may result from pathogenic variants in several genes involved in mitochondrial function and neurodegeneration. Autosomal recessive inheritance is common, although the inheritance pattern and associated clinical features depend on the underlying gene[1][2][3][4][5].
Biallelic pathogenic variants in C12orf65 have been identified in patients with the classical Behr syndrome phenotype. C12orf65 encodes a mitochondrial protein involved in mitochondrial translation. Affected individuals typically develop childhood-onset optic atrophy followed by variable spasticity, distal weakness, peripheral neuropathy, and ophthalmoparesis[1].
Biallelic variants in OPA1 can produce a severe, early-onset syndromic optic neuropathy consistent with a Behr phenotype. OPA1 encodes a mitochondrial inner-membrane GTPase that plays an important role in mitochondrial membrane stabilization and mitochondrial DNA maintenance[3][4]. In contrast, a single pathogenic OPA1 variant more commonly causes autosomal dominant optic atrophy. When additional neurologic manifestations are present, this is referred to as dominant optic atrophy plus[3]. Patients with biallelic OPA1-related disease generally have earlier and more severe visual impairment, often accompanied by ataxia, spasticity, peripheral neuropathy, ophthalmoplegia, hearing loss, or other neurologic abnormalities[3][4].
Biallelic OPA3 variants cause OPA3-related 3-methylglutaconic aciduria, also known as Costeff syndrome[6][7]. This is a distinct but overlapping neuro-ophthalmic disorder characterized by early-onset bilateral optic atrophy, followed by variable spasticity, ataxia, and extrapyramidal movement abnormalities. Increased urinary excretion of 3-methylglutaconic and 3-methylglutaric acids is a characteristic biochemical finding that may assist in diagnosis[7]. Heterozygous OPA3 variants can cause autosomal dominant optic atrophy, often associated with early-onset cataract but without the typical systemic manifestations of Costeff syndrome[8][9].
Less common genetic associations include biallelic variants in C19orf12 and UCHL1, which have been reported in individuals with Behr-like phenotypes. C19orf12-related disease falls within the spectrum of neurodegeneration with brain iron accumulation, specifically mitochondrial membrane protein-associated neurodegeneration, whereas biallelic UCHL1 variants are associated with hereditary spastic paraplegia[2][5]. These reports further support Behr syndrome as a genetically heterogeneous phenotype that overlaps with other inherited neurodegenerative disorders.
Treatment and Management
There is currently no established disease-modifying treatment for Behr syndrome. Management is supportive, individualized according to the underlying genetic diagnosis and clinical manifestations, and often involves a multidisciplinary team. Ophthalmic management includes correction of refractive errors, periodic assessment of visual function, low-vision rehabilitation, educational accommodations, and mobility support[3]. Physical and occupational therapy may help preserve mobility and function, while orthopedic surgery may be considered for significant lower-extremity contractures or deformities[10]. Deep brain stimulation of the ventral intermediate thalamic nucleus has been reported to improve severe tremor in a single patient, but evidence remains limited and this is not considered standard treatment[11]. Prognosis is variable and depends on the underlying genetic cause and the severity and progression of neurologic involvement[1][3][4].
References
- ↑ 1.0 1.1 1.2 1.3 Pyle A, Ramesh V, Bartsakoulia M, et al. Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene. J Neuromuscul Dis. 2014;1(1):55-63. doi:10.3233/JND-140003
- ↑ 2.0 2.1 2.2 Kleffner I, Wessling C, Gess B, et al. Behr syndrome with homozygous C19orf12 mutation. J Neurol Sci. 2015;357(1-2):115-118. doi:10.1016/j.jns.2015.07.009
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Othman BA, Ong JE, Dumitrescu AV. Biallelic Optic Atrophy 1 (OPA1) Related Disorder-Case Report and Literature Review. Genes (Basel). 2022;13(6):1005. Published 2022 Jun 2. doi:10.3390/genes13061005
- ↑ 4.0 4.1 4.2 4.3 Bonneau D, Colin E, Oca F, et al. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain. 2014;137(Pt 10):e301. doi:10.1093/brain/awu184
- ↑ 5.0 5.1 McMacken G, Lochmüller H, Bansagi B, et al. Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion. J Neurol. 2020;267(12):3643-3649. doi:10.1007/s00415-020-10059-3
- ↑ Yahalom G, Anikster Y, Huna-Baron R, et al. Costeff syndrome: clinical features and natural history. J Neurol. 2014;261(12):2275-2282. doi:10.1007/s00415-014-7481-x
- ↑ 7.0 7.1 Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet. 2001;69(6):1218-1224. doi:10.1086/324651
- ↑ Reynier P, Amati-Bonneau P, Verny C, et al. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004;41(9). doi:10.1136/jmg.2003.016576.
- ↑ Gaier ED, Sahai I, Wiggs JL, McGeeney B, Hoffman J, Peeler CE. Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy. Ophthalmic Genet. 2019;40(6):570-573. doi:10.1080/13816810.2019.1711428
- ↑ Copeliovitch L, Katz K, Arbel N, et al. Musculoskeletal deformities in Behr Syndrome. J Pediatr Orthop. 2001;21(4):512-514
- ↑ Schramm P, Scheihing M, Rasche D, Tronnier VM. Behr syndrome variant with tremor treated by VIM stimulation. Acta Neurochir (Wien). 2005;147(6):679-683. doi:10.1007/s00701-005-0508-4
