Costeff syndrome

Definition

Costeff syndrome is an inherited condition characterized by vision loss, delayed development, and movement problems.

Summary

Costeff syndrome is associated with increased levels of a substance called 3-methylglutaconic acid in the urine (3-methylglutaconic aciduria). The amount of this substance does not appear to influence the signs and symptoms of the condition. Costeff syndrome is one of a group of metabolic disorders that can be diagnosed by the presence of 3-methylglutaconic aciduria. People with Costeff syndrome also have high levels of another acid called 3-methylglutaric acid in their urine.

Alternate names

• 3-methylglutaconic aciduria type 3
• 3-methylglutaconic aciduria type III
• autosomal recessive OPA3
• autosomal recessive optic atrophy 3
• Costeff optic atrophy syndrome
• infantile optic atrophy with chorea and spastic paraplegia
• Iraqi Jewish optic atrophy plus
• MGA, type III
• MGA3
• OPA3 defect
• optic atrophy plus syndrome

Epidemiology

Costeff syndrome affects an estimated 1 in 10,000 individuals in the Iraqi Jewish population, in which at least 40 cases have been described. Outside this population, only a few affected individuals have been identified.

Cause

Mutations in a gene called OPA3 cause Costeff syndrome. The OPA3 gene provides instructions for making a protein whose exact function is unknown. The OPA3 protein is found in structures called mitochondria, which are the energy-producing centers of cells. It is thought to play a role in the organization of the shape and structure of mitochondria and in controlled cell death (apoptosis).

Gene mutations

• OPA3 gene mutations that result in Costeff syndrome lead to a loss of OPA3 protein function. Cells without any functional OPA3 protein have abnormally shaped mitochondria. These cells likely have reduced energy production and die prematurely, decreasing energy availability in the body's tissues.
• Cells in the eyes and brain have high energy demands, and it is likely that they are particularly vulnerable to cell death due to dysfunctional mitochondria and reduced energy production.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Vision loss is primarily caused by degeneration (atrophy) of the optic nerves, which carry information from the eyes to the brain. This optic nerve atrophy often begins in infancy or early childhood and results in vision impairment that worsens over time. Some affected individuals have rapid and involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus). Development of motor skills, such as walking, is often delayed in people with Costeff syndrome. Affected individuals may also have speech difficulties (dysarthria). While some people with Costeff syndrome have mild to moderate intellectual disability, many have normal intelligence. Movement problems in people with Costeff syndrome develop in late childhood and include muscle stiffness (spasticity), impaired muscle coordination (ataxia), and involuntary jerking movements (choreiform movements). As a result of these movement difficulties, individuals with Costeff syndrome may require wheelchair assistance.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• 3-Methylglutaconic aciduria
• Choreoathetosis
• Visual impairment(Impaired vision)

30%-79% of people have these symptoms

• Ataxia
• Dysarthria(Difficulty articulating speech)
• Intellectual disability(Mental deficiency)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Spastic paraparesis

5%-29% of people have these symptoms

• Gait disturbance(Abnormal gait)

Diagnosis

The diagnosis of Costeff syndrome is suspected in a child with the following clinical and laboratory findings and family history consistent with autosomal recessive inheritance.[1].

Clinical Findings Early in the disease course

• Relatively normal early development and growth
• Bilateral early-onset optic atrophy (pathologically pale optic discs, attenuated papillary vasculature, and visual evoked potentials that show bilateral prolonged latencies consistent with optic atrophy)
• Choreoathetoid movement disorder

Later in the disease course

• Progressive spasticity
• Cerebellar ataxia
• Cognitive deterioration (in a minority of individuals)

Laboratory Findings

• Increased urinary excretion of 3-methylglutaconate (3-MGC) and 3-methylglutaric acid (3-MGA).
• In Costeff syndrome, urinary 3-MGC and 3-MGA (measured using gas chromatography-mass spectrometry) are mildly increased.
• The diagnosis of Costeff syndrome is established in a proband with suggestive findings and biallelic OPA3 pathogenic variants identified by molecular genetic testing.

Treatment

Supportive and often provided by a multidisciplinary team; treatment of visual impairment, spasticity, and movement disorder as in the general population.

Agents/circumstances to avoid: Use of tobacco, alcohol, and medications known to impair mitochondrial function.

Prognosis

The long-term prognosis remains unknown: although the disease progresses during childhood, it appears to stabilise during early adulthood.

NIH genetic and rare disease info

• NIH info on Costeff syndrome

Costeff syndrome is a rare disease.

Costeff syndrome Resources
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