OPA1

Behr Syndrome

Clinical Characteristics
Ocular Features: 

Optic atrophy is the hallmark of this condition.  It is usually considered infantile in onset which may be helpful in the clinical diagnosis as many other forms of optic atrophy have their onset somewhat later.   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.

Systemic Features: 

A wide range of neurologic non-specific signs and symptoms may be present.  Behr's patients had ataxia, spasticity, sensory loss, and cognitive deficits.  Deafness has been reported in some patients.  All these may progress for a period of time and then remain static.  Heterozygous carriers have been reported to have mild neurologic manifestations.

It is important to emphasize that case descriptions reported in the literature often cannot be accurately assigned to a specific condition without genotyping.   For this reason histological reports of retinal ganglion cell loss and histological alterations in the brain such as gliosis and neuronal loss may or may not be a part of Behr syndrome.  Further studies should clarify what is now a confusing category of clinical disease.

Genetics

Homozygous or compound heterozygous mutations in the OPA1 gene (3q29) have been found in families with early-onset atrophy called Behr optic atrophy.  However, heterozygous mutations in the same gene have also been associated with optic atrophy (165500).  

Optic atrophy is a common sign among neurologic disorders such as spinocerebellar ataxias and in developmental (e.g., microphthalmia), and degenerative (e.g., retinal dystrophies) disorders of the eye.  More than 130 conditions with optic atrophy are described in this database.  Because of the overlapping clinical features, genotyping may be necessary to accurately determine which disorder is present.

See 165500 for a summary of the genetic heterogeneity of optic atrophy with links to other heritable forms OPA2 through OPA8.

See Behr Early Onset Optic Atrophy Syndromes in this database for more information on phenotypes and genotypes.

Homozygous mutations in OPA1 are also responsible for the mitochondrial DNA depletion syndrome 14 (616896) reported in a single family.  The clinical features include encephalomypathy, hypertrophic cardiomyopathy, and abnormal pursuit movements with optic atrophy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation

Spiegel R, Saada A, Flannery PJ, Burte F, Soiferman D, Khayat M, Eisner V, Vladovski E, Taylor RW, Bindoff LA, Shaag A, Mandel H, Schuler-Furman O, Shalev SA, Elpeleg O, Yu-Wai-Man P. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet. 2016 Feb;53(2):127-31.

PubMed ID: 
26561570

Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Bonneau D, Colin E, Oca F, Ferre M, Chevrollier A, Gueguen N, Desquiret-Dumas V, N'Guyen S, Barth M, Zanlonghi X, Rio M, Desguerre I, Barnerias C, Momtchilova M, Rodriguez D, Slama A, Lenaers G, Procaccio V, Amati-Bonneau P, Reynier P. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain. 2014 Oct;137(Pt 10):e301.

PubMed ID: 
25012220

Multi-system neurological disease is common in patients with OPA1 mutations

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133(Pt 3):771-86.

PubMed ID: 
20157015

Optic Atrophy, Ophthalmoplegia, Myopathy, and Neuropathy

Clinical Characteristics
Ocular Features: 

Visual symptoms have an insidious onset in childhood with vision loss and progressive external ophthalmoplegia.  Ptosis may be evident later.  The optic atrophy is progressive.   ERG abnormalities have been reported but no pigmentary retinopathy has been seen.  Myopia is sometimes present.

Systemic Features: 

The extraocular signs and symptoms are variable and generally have a later onset.  Some patients have an early onset of sensorineural hearing loss.  Muscle cramps and hyperreflexia may occur with clonus and a spastic gait.  Ataxia seems to be common.  The neurological phenotype has been likened to muscular sclerosis, Kearns-Sayre syndrome, and spastic paraplegia.  Muscle biopsies show variable-sized and atrophic fibers.

Genetics

This is generally considered an autosomal dominant disorder secondary to mutations in the OPA1 gene.  It is allelic to optic atrophy 1 (165500) but may also be the same condition since the p.Arg247His mutation has been found in patients with both disorders.  This syndromic form of optic atrophy may also result from biallelic mutations in OPA1 in which the clinical disease is more severe and earlier in onset. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the neurological disease but low vision aids should be considered to selected patients especially during childhood educational activities.

References
Article Title: 

Multi-system neurological disease is common in patients with OPA1 mutations

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010 Mar;133(Pt 3):771-86.

PubMed ID: 
20157015

Optic Atrophy 1

Clinical Characteristics
Ocular Features: 

This form of bilateral optic atrophy may have its onset in early childhood with optic disc pallor, loss of acuity, loss of color vision, and centrocecal scotomas.  However, it is often not manifest until the second decade of life.  Moderate to severe temporal or diffuse pallor can be seen.  The optic disc has been described as normal in 29% of documented carriers and 20% have no visual field defect.  Pallor of the complete disc is found in only 10%.  Consequently, the phenotype is variable, with some individuals having minimal symptoms while others have severe vision loss.  The disease is progressive in some but not all families.  The median visual acutity is 20/70 but ranges from normal to hand motions.  

Histologic studies show atrophy of ganglion cells in the retina and loss of myelin sheaths in the optic nerve.   VEPs are absent or subnormal.  Optical coherence tomography reveals a significant reduction in retinal nerve fiber layer and ganglion cell layer thickness, most marked in the temporal quadrants.

Systemic Features: 

OPA1 is generally not associated with systemic disease.  However, some have sensorineural deafness, ataxia, ptosis, and ophthalmoplegia.  Families with both early and late onset have been reported.  Some (~20%) individuals have a myopathy as well.

Genetics

This is an autosomal dominant disorder resulting from mutations in a nuclear gene, OPA1 (3q28-q29).  The gene product is attached to the mitochondrial cristae of the inner membrane and metabolic studies have implicated the oxidative phosphorylation pathway which seems to be defective with reduced efficiency of ATP synthesis.  Penetrance approaches 90% but this is, of course, age dependent to some extent.

An allelic disorder (125250) is associated with sensorineural deafness, ataxia, and ophthalmoplegia but its uniqueness remains to be established since the same mutations in OPA1 have been found in both conditions.

Other autosomal dominant optic atrophy disorders include OPA5 (610708) and OPA4 (605293).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

OPA1 in multiple mitochondrial DNA deletion disorders

Stewart JD, Hudson G, Yu-Wai-Man P, Blakeley EL, He L, Horvath R, Maddison P, Wright A, Griffiths PG, Turnbull DM, Taylor RW, Chinnery PF. OPA1 in multiple mitochondrial DNA deletion disorders. Neurology. 2008 Nov 25;71(22):1829-31.

PubMed ID: 
19029523
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