Clinical Guidance

Genotype-phenotype correlations cannot be made due to the limited number of OPA3 pathogenic variants identified to date. All individuals of Iraqi Jewish origin with Costeff syndrome have the same pathogenic variant; however, phenotypic severity varies, even within the same family.

Source: GeneReviews — "Costeff Syndrome"

Diagnostic Criteria

Suggestive Findings

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

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 g...

Source: GeneReviews — "Costeff Syndrome"

Differential Diagnosis

3-Methylglutaconic Aciduria Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism . 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism. A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by and . Clinical features and biochemical findings of syndromes associated with 3-MGCA vary. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected. The only disorder in which the exact source of 3-MGC is known (a block of leucine degradation) is AUH defect, the rarest 3-MGCA, caused by primary deficiency of the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase (3-MGCH). Table 2. Inborn Errors of Metabolism Associated with 3-Methylglutaconic Aciduria

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Costeff syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Costeff Syndrome

Source: GeneReviews — "Costeff Syndrome"

Clinical Guidance

The following should be avoided:

• Tobacco and alcohol use

• Medications known to impair mitochondrial function

Source: GeneReviews — "Costeff Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Costeff Syndrome"

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with Costeff Syndrome

System/Concern | Evaluation | Frequency

Visual impairment

|

• Ophthalmologic exam incl best corrected visual acuity, color vision testing, visual field testing

• Appropriateness of visual aids

| Annually

Pyramidal dysfunction / Spasticity / Cerebellar dysfunction

|

• Neurologic exam for progression of findings

• Orthopedics (eval of Achilles tendon shortening); OT/PT eval

• Speech language assessment

Feeding nutrition

| By feeding team | As needed

Orthopedic involvement1

| Eval by orthopedic surgeon

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) care coordination. | At each visit

OT = occupational therapy; PT = physical therapy

1. Shortening of Achilles tendon

Source: GeneReviews — "Costeff Syndrome"