BASICS

DESCRIPTION

• Most common hereditary form of optic atrophy causing vision loss within the first decade of life. Vision loss tends to be insidious with slow progression described.

– May be referred to as Kjer type optic atrophy

– Vision is typically reduced to between 20/70–20/100, but range can be from 20/20 to counting fingers

EPIDEMIOLOGY

Prevalence

• 1:50,000 worldwide

• Most prevalent in Denmark 1:10,000

RISK FACTORS

Positive family history

Genetics

• Autosomal dominance inheritance pattern with incomplete penetrance and variable clinical expression

• OPA1 gene, chromosome 3q28 most commonly involved. Other loci include OPA3 (10q13.2), OPA4 (18q12.2), and OPA5 (22q12.1-q13.1)

PATHOPHYSIOLOGY

• Primary retinal ganglion cell degeneration

• The OPA1 gene on chromosome 3 produces a protein that is essential for maintaining the shape and structure of mitochondria. It is also involved in cellular apoptosis and maintenance of mitochondrial DNA. OPA 1 is also involved in oxidative phosphorylation.

• Mutations in the OPA1 gene lead to overall mitochondrial dysfunction and increased cell death (apoptosis). This leads to primary retinal ganglion cell degeneration and subsequent optic atrophy.

ETIOLOGY

Inherited mutation usually involving OPA1 gene of chromosome 3.

COMMONLY ASSOCIATED CONDITIONS

• Majority of patients are otherwise completely healthy.

• Recent studies suggest that up to 20% of OPA1 mutational carriers may have other extraocular neurological complications (1)

– Bilateral sensorineural deafness beginning in late childhood and early adulthood

– Ataxia

– Myopathy

– Peripheral neuropathy

– Progressive external ophthalmoplegia

– Spastic multiple sclerosis-like illness

– Mental retardation

DIAGNOSIS

HISTORY

• Vision loss is often insidious and may be found incidentally on routine examination in some children

• Mild photophobia may be present

• May have positive family history

PHYSICAL EXAM

• Decreased visual acuity (typically 20/70–20/100, range 20/20 – counting fingers)

– Decreased color vision (blue–yellow defect (tritanopia) most common, but other color defects may be present)

– Variable degree of optic atrophy (may range from mild temporal pallor to complete atrophy (2)

– Characteristic focal temporal excavation of optic discs is present in some patients.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

Genetic testing of OPA1 gene sequence is available. This detects mutations in 70–90% of familial cases and 50% of simplex cases.

Follow-up & special considerations

• Auditory testing – auditory brainstem responses, auditory evoked potentials

• Glucose tolerance test may be appropriate.

• Blue cone ERG may help distinguish from congenital tritanopia.

Imaging

MRI with attention to the optic nerves and chiasm may be necessary to rule out compressive lesion if diagnosis is questionable.

Diagnostic Procedures/Other

• Visual field testing is appropriate if the child is of appropriate maturity to reliably do this test. Most children are not able to respond reliably to this test below the age of 10 years. Static perimetry may be more sensitive than kinetic perimetry.

• Electroretinography – markedly reduced negative component with normal positive component

• Visual evoked potentials – decreased amplitude

Pathological Findings

Ganglion cell loss, primarily in the macula, and papillomacular bundle.

DIFFERENTIAL DIAGNOSIS

• Leber hereditary optic neuropathy

• Toxic deafness optic neuropathies

• Deafness-dystonia-optic neuronopathy syndrome

• Wolfram syndrome (AKA DIDMOAD) – Diabetes insipidus, Diabetes mellitus, optic atrophy

• Congenital tritanopia

• Optic atrophy secondary to retinal dystrophy

• Idiopathic intracranial hypertension

• Intracranial tumor

TREATMENT

MEDICATION

No medical therapy is available

ADDITIONAL TREATMENT

General Measures

Symptomatic treatment with low vision aids

Issues for Referral

• Audiology referral may be appropriate to detect associated hearing loss

• Low vision evaluation

COMPLEMENTARY & ALTERNATIVE THERAPIES

There are no known effective complementary or alternative therapies. Stem cell treatment (outside of US) has been proposed and tried without proven efficacy.

SURGERY/OTHER PROCEDURES

No known surgical procedures.

IN-PATIENT CONSIDERATIONS

Generally, does not require hospitalization.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Yearly ophthalmic evaluations

Patient Monitoring

• Visual field testing

• Monitor for possible sensorineural hearing loss

• Neurologic evaluation based on symptoms

PATIENT EDUCATION

Genetic counseling

PROGNOSIS

• Children seem to function better than expected for their given visual deficits

• Vision tends to remain stable or decrease imperceptibly beyond mid-teens