OPA3

Optic Atrophy 3 and Cataracts

Clinical Characteristics
Ocular Features: 

There is considerable variation in age of onset and severity of clinical disease.  Cataracts may be evident in the first decade of life but in most cases by the second decade.  They are usually described as anterior or posterior cortical opacities.  Progression of opacification is slow and most patients do not require removal until late adulthood and some never require surgery. Visual impairment from optic atrophy may be evident in infancy and some patients experience a worsening in late adulthood.  Visual acuity is highly variable.  Temporal pallor may be present in childhood or later.

Systemic Features: 

Neurologic signs such as tremor, extrapyramidal rigidity in the upper extremities, and ataxia are seldom present until after the age of 50 years.  However not all patients have neurologic disease.

Genetics

This disorder is inherited in an autosomal dominant pattern as a result of a mutation in the OP3 gene (19q13.2-q13.3) encoding an inner membrane mitochondrial protein.  It is allelic to autosomal recessive optic atrophy-3, or 3-methylglutaconic aciduria type III (258501), sometimes called Behr early onset optic atrophy (210000). 

Optic atrophy 3 is less severe than in Behr optic atrophy and the presence of cataracts is an important distinguishing feature.  For these reasons, optic atrophy 3 is discussed as a separate disorder here.   However, the nosology remains unclear since not all individuals with Behr optic atrophy have 3-methylglutaric acidemia.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available for the optic atrophy.  Cataract surgery may be necessary for visually significant lens opacities.

References
Article Title: 

OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract

Reynier P, Amati-Bonneau P, Verny C, Olichon A, Simard G, Guichet A, Bonnemains C, Malecaze F, Malinge MC, Pelletier JB, Calvas P, Dollfus H, Belenguer P, Malthi?(r)ry Y, Lenaers G, Bonneau D. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004 Sep;41(9):e110.

PubMed ID: 
15342707

[On a heredo-familial disease combining cataract, optic atrophy, extrapyramidal symptoms and certain defects of Friedreich's disease]

GARCIN R, RAVERDY P, DELTHIL S, MAN HX, CHIMENES H. [On a heredo-familial disease combining cataract, optic atrophy, extrapyramidal symptoms and certain defects of Friedreich's disease. (Its nosological position in relation to the Behr's syndrome, the Marinesco-Sjogren syndrome and Friedreich's disease with ocular symptoms.]. Rev Neurol (Paris). 1961 May;104:373-9. French.

PubMed ID: 
13703570

Behr Early Onset Optic Atrophy Syndromes

Clinical Characteristics
Ocular Features: 

Optic atrophy is the earliest sign in Behr syndrome and may be evident in early childhood.  Nystagmus is a variable feature.  Acuity in the first decade is in the 20/70 to 20/100 range with little worsening in patients followed for a decade or more even though the disc pallor may increase with loss of papillary vasculature.  ERGs are normal but VEPs are usually abnormal.

Systemic Features: 

The nosology of infantile optic atrophy is unclear.   There is no doubt that some familial cases with likely autosomal recessive inheritance lacked (or were not tested for) urinary metabolites considered diagnostic for an optic atrophy disorder with 3-methylglutaconate aciduria (258501) and labeled methylglutaconic aciduria type III (and sometimes Costeff optic atrophy syndrome).  Excretion of 3-methylglutaric acid may also be increased.  But it is also possible that another form of infantile optic atrophy without aminoaciduria also exists.  Early onset (early childhood) optic atrophy, with later (second decade) spasticity, ataxia, extrapyramidal signs and cognitive defects to some degree are common to both.  Dementia, posterior column signs and peripheral neuropathy are more variable clinical signs.  Nerve biopsies and postmortem studies show widespread disease with evidence of chronic neuropathy, neuronal loss, and gliosis.  In Behr's report, the neurologic symptoms remained static after a period of progression.   Others have reported progression with the majority of patients severely handicapped by the third decade of life.

Genetics

Sibs born to consanguineous parents suggest autosomal recessive inheritance in both Behr syndrome with ataxia and in 3-methylglutaconic aciduria, type III.  The latter is most commonly found among Iraqi Jews and is the result of a mutation in the OPA3 gene (19q13.2-q13.3).  The genetic basis for simple Behr infantile optic atrophy is unclear and it is likely that multiple unique entities exist.  This disorder is allelic to an autosomal dominant disorder called Optic Atrophy 3 and Cataracts (165300) but the uniqueness of the latter entity is uncertain.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None known

References
Article Title: 
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