Costeff syndrome

Overview

Costeff syndrome, also known as 3-methylglutaconic aciduria type III, is a rare inherited neuro-ophthalmologic disorder characterized by a combination of optic atrophy (progressive vision loss), movement disorders (such as dystonia and spasticity), and elevated levels of 3-methylglutaconic acid in the urine. The condition was first described by Dr. Hanan Costeff in 1989 and is particularly prevalent in individuals of Iraqi Jewish descent. It typically presents in early childhood and progresses slowly over time.

Causes

Costeff syndrome is caused by mutations in the OPA3 gene, which is located on chromosome 19. The OPA3 gene is involved in mitochondrial function, particularly in maintaining the health and function of nerve cells. The disorder follows an autosomal recessive inheritance pattern, meaning that an affected individual must inherit one mutated copy of the gene from each parent. Carriers (those with only one mutated copy) do not show symptoms.

Symptoms

Symptoms of Costeff syndrome usually begin in early childhood and progress gradually. Common features include:

• Optic atrophy: Progressive loss of optic nerve fibers leading to decreased visual acuity and eventual visual impairment

• Extrapyramidal movement disorders: Such as dystonia (involuntary muscle contractions), chorea (involuntary, jerky movements), and ataxia (poor coordination)

• Spasticity: Increased muscle tone and stiffness, especially in the lower limbs

• Developmental delays: Mild delays in motor milestones or speech in some cases

• Gait disturbances: Walking difficulties due to spasticity and coordination issues

• Elevated urinary 3-methylglutaconic acid: A key biochemical marker of the condition

Intellectual development is typically normal, although mild cognitive issues may occur in some individuals.

Diagnosis

Diagnosis of Costeff syndrome involves a combination of clinical evaluation, biochemical testing, and genetic analysis. Steps include:

• Ophthalmologic examination: To assess for optic nerve atrophy and visual impairment

• Neurological evaluation: To identify movement disorders, spasticity, and coordination issues

• Urine organic acid analysis: Detects elevated levels of 3-methylglutaconic acid, which is characteristic of the syndrome

• Genetic testing: Confirms the diagnosis by identifying biallelic mutations in the OPA3 gene

• Brain imaging (MRI): May show mild abnormalities such as cerebellar atrophy or basal ganglia changes

Treatment

There is no cure for Costeff syndrome, and treatment is symptomatic and supportive. A multidisciplinary team approach is often required to manage the various aspects of the condition. Treatment strategies include:

• Visual support: Use of corrective lenses, magnifiers, or visual aids for low vision

• Physical therapy: To improve mobility, balance, and muscle strength

• Occupational therapy: To assist with daily activities and fine motor skills

• Speech therapy: For individuals with speech or swallowing difficulties

• Medications: To control dystonia or spasticity (e.g., baclofen, anticholinergics, or botulinum toxin injections)

• Regular monitoring: By ophthalmologists, neurologists, and other specialists to track progression and manage complications

Prognosis

The prognosis for individuals with Costeff syndrome varies depending on the severity of symptoms. While the condition is progressive, it is not typically life-threatening, and many individuals can live into adulthood. Visual impairment tends to worsen over time, but cognitive abilities are often preserved. Early intervention and supportive therapies can greatly improve quality of life and help maintain functional independence for as long as possible.