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.

• Recurrent Vomiting

  The disease started at age 1 year with sudden trunk ataxia, abnormal ocular movement and recurrent vomiting episodes. At that time, fundoscopy, lactate levels in the CSF, and the brain MRI were all normal. [doi.org]

• Muscle Contracture

  The ataxia, spasticity, and muscle contractures, mainly of the hip adductors, hamstrings, and soleus, are progressive and become more prominent in the second decade. [ncbi.nlm.nih.gov]

  For instance, people who develop muscle contractures may have to undergo surgery. Also, treatment depends on the specific signs and symptoms seen in the patient. Resources - Behr syndrome [checkorphan.org]

• Central Scotoma

  Central scotomas and dyschromatopsia may be present. Visual impairment is often severe but the progression can plateau in early midlife and remains static as first reported by Behr. [disorders.eyes.arizona.edu]

• Neonate-Onset

  Finally, Schaaf et al. (2011) reported two siblings, 3 and 8 years old, presenting with a severe neonatal-onset disorder associating severe optic atrophy, ataxia, hypotonia, gastrointestinal dysmotility and dysphagia. [doi.org]

• Ataxia

  Behr syndrome is characterized by optic atrophy beginning in early childhood associated with ataxia, spasticity, mental retardation, and posterior column sensory loss. [ncbi.nlm.nih.gov]

• Babinski Sign

  Other characteristics include optic atrophy (prevalent in males), nystagmus, scotoma, progressive temporal nerve atrophy, bilateral retrobulbar neuritis, increased tendon reflexes, Babinski sign, and incoordination. [whonamedit.com]

  Unusual foot reflexes (a positive Babinski sign) may also be experienced by the patient when the sole is stimulated. Increasing tremors in both hands are also symptoms of this disease. [medigest.uk]

  Symptoms can include rapid involuntary eye movements (nystagmus), progressive damage to nerves, nerve inflammation and unusual foot reflexes when the sole is stimulated (positive Babinski sign). [the-medical-dictionary.com]

  Behr syndrome is a disorder characterized by early-onset optic atrophy along with neurological features, including ataxia, spasticity, and intellectual disability. 0001771 Adductor longus contractures 0006366 Autosomal recessive inheritance 0000007 Babinski [rarediseases.info.nih.gov]

• Pyramidal Tract Signs

  Behr syndrome was first described in 1909 as a syndrome of heredofamilial optic atrophy, visual disturbances, nystagmus, and variable pyramidal tract signs. The syndrome has been reported in both sexes. [ncbi.nlm.nih.gov]

  Case Report First Online: 25 March 2005 70 Downloads 13 Citations Summary Behr syndrome was first described in 1909 as a syndrome of heredofamilial optic atrophy, visual disturbances, nystagmus, and variable pyramidal tract signs. [doi.org]

  Newman, MD, Emory Eye Center Description In 1909, Behr described a syndrome of heredofamilial optic atrophy beginning in early childhood and associated with variable pyramidal tract signs, ataxia, mental retardation, urinary incontinence, and pes cavus [collections.lib.utah.edu]

  Case Report First Online: 25 March 2005 70 Downloads 10 Citations Summary Behr syndrome was first described in 1909 as a syndrome of heredofamilial optic atrophy, visual disturbances, nystagmus, and variable pyramidal tract signs. [link.springer.com]

  Definition Behr's Syndrome is a rare inherited neurological condition named after Carl Behr, who first described it in 1909 as a syndrome of variable pyramidal tract signs. It is characterized by spastic paraplegia and sometimes optic atrophy. [medigest.uk]

• Dysmetria

  […] along with neurological features, including ataxia, spasticity, and intellectual disability. 0001771 Adductor longus contractures 0006366 Autosomal recessive inheritance 0000007 Babinski sign 0003487 Cerebellar atrophy Degeneration of cerebellum 0001272 Dysmetria [rarediseases.info.nih.gov]

  Thereafter, she developed cerebellar ataxia without dysmetria and needed support for walking. Her speech was affected by mild dysarthria but she had no cognitive impairment. [doi.org]

• Abnormal Gait

  gait Abnormal walk Impaired gait [3] This gene provides instructions for making a protein that helps determine the shape and structure of mitochondria, the energy-producing centers within cells. [rarediseases.info.nih.gov]

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.

• Central Scotoma

  Central scotomas and dyschromatopsia may be present. Visual impairment is often severe but the progression can plateau in early midlife and remains static as first reported by Behr. [disorders.eyes.arizona.edu]

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.