Behr Syndrome

Behr syndrome (BS) is a genetic disorder that primarily causes optic atrophy as well as neurological symptoms. It has been linked to optic atrophy 1 (OPA1) and optic atrophy 3 (OPA3) gene mutations, which lead to autosomal dominant and recessive inheritance respectively [1] [2]. The C12ORF65 (chromosome 12 open reading frame 65) and C19ORF12 (chromosome 19 open reading frame 12) genes have also been implicated [3]. Despite the discovery of genetic predisposition, most known cases of the disease are sporadic [4]. BS does not have a male or female preponderance, and its prevalence is unknown. Furthermore, it shares numerous features with Costeff syndrome, which presents with additional metabolic derangements.

The development of optic atrophy is usually seen in childhood and does not worsen during the course of the disease. Neurological features vary between individuals, and between families. Ocular signs of neuropathy include nystagmus, ophthalmoparesis, and other gaze palsies. Additional neurological complaints are ataxia, paraparesis, loss of sensation, speech disarticulation, epilepsy, peripheral neuropathy, intellectual impairment, spastic paraplegia, extrapyramidal signs, and contractures often in the lower extremities [5]. These are progressive and become more pronounced in early adulthood [3]. Patients with BS will also have central nervous system abnormalities that are visible on neuroimaging, such as cerebellar atrophy.

Varying degrees of poor vision are seen from childhood, while mobility is moderately or severely affected in adulthood. The latter may be an indication for surgical intervention. In the variant of the disease stemming from OPA1 mutation, patients may present solely with optic atrophy.

Diagnosis of Behr syndrome is made clinically [6]. Patients who present with features known to occur in BS should be investigated for the disease. Moreover, BS should be considered as a differential diagnosis in patients presenting with inherited neurological complaints, more so if they have coexisting optic atrophy. Currently, it is not possible to predict the phenotypic expression of BS based on an individual's genotype [7].

Other diagnostic modalities entail:

• Biopsy and histological analysis: These may show COX-negative (cytochrome oxidase negative) fibers.
• Genetic testing: Polymerase chain reaction (PCR) and Southern blot are the techniques used. These are able to detect damage to mitochondrial deoxyribonucleic acid (DNA) [8]. In BS, DNA deletions are the usual cause mutations.
• Urine analysis: Abnormal excretion of organic acids should prompt further genetic testing.

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.
2. Marelli C, Amati-Bonneau P, Reynier P, et al. Heterozygous OPA1 mutations in Behr syndrome. Brain. 2011;134(Pt 4):e169. author reply e170.
3. Kleffner I, Wessling C, Gess B, et al. Behr syndrome with homozygous C19ORF12 mutation. J Neurol Sci. 2015;357(1-2):115-118.
4. Felicio AC, Godeiro-Junior C, Alberto LG, et al. Familial Behr syndrome-like phenotype with autosomal dominant inheritance. Parkinsonism Relat Disord. 2008;14(4):370–372.
5. Orphanet. Behr syndrome. Orphanet. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1239. Updated March 2005. Accessed July 14, 2017.
6. 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.
7. Cecilia Marelli, Patrizia Amati-Bonneau, Pascal Reynier, et al. Heterozygous OPA1 mutations in Behr syndrome. Brain. 2011;134(4):e169.
8. Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133(Pt 3):771-786.