Costeff Syndrome

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. Note: (1) In Costeff syndrome, the excretion of 3-MGC and 3-MGA is variable, sometimes even overlapping that of normal controls; furthermore, 3-MGC and 3-MGA are not always easy to detect on urine organic acid analysis. (2) Because laboratories both within and between countries use different methods, they have very different reference ranges; thus, the gender- and age-specific reference range determined by each reference laboratory should be used.

Option 1

Single-gene testing. Sequence analysis of OPA3 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step could be to perform gene-targeted deletion/duplication analysis to detect (multi)exon and whole-gene deletions or duplications; to date, however, deletions/duplications have not been identified as a cause of Costeff syndrome.

Note: Targeted analysis for the c.143-1G>C pathogenic variant, which has been identified in all affected individuals of Iraqi Jewish descent, can be performed first in this population.

A multigene panel that includes OPA3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis; to date, however, deletions/duplications have not been identified as a cause of Costeff syndrome.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Optic Atrophy

Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus.

In 36 individuals with Costeff syndrome, visual acuity decreased with age:

• In two children age two years, visual acuity appeared to be normal.
• In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
• In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.

Some children have strabismus and gaze apraxia.

Motor Disability

Motor disability is primarily caused by extrapyramidal dysfunction and spasticity.

Extrapyramidal dysfunction. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. In 36 individuals with Costeff syndrome, extrapyramidal involvement caused the following in 32 individuals:

• Major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
• Minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
• Mild manifestations with no resulting disability in three individuals age 15 to 36 years

No extrapyramidal involvement was observed in four individuals ages 13 to 32 years.

Spasticity. Unstable spastic gait, increased tendon reflexes, and Babinski sign may be seen. In 36 individuals with Costeff syndrome, spasticity was age-related:

• Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
• Four individuals age 11 to 26 years had mild spasticity but no related disability.
• Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
• Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.

Cerebellar dysfunction is usually mild. Ataxia and dysarthria caused mostly mild disability in 18 of the 36 individuals reported by Elpeleg et al [1994].

Cognitive Impairment

Cognitive impairment was previously noted in some individuals. Of 36 individuals:

• Nineteen individuals age two to 36 years (16.±18.7) had an IQ of 71 or higher.
• Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
• Four individuals age nine to 26 years had an IQ between 40 and 54.

More recently, however, a study of the neuropsychological profile of 16 adults with Costeff syndrome reported intact global cognition and learning abilities and strong auditory memory performance [Sofer et al 2015].

Other

Several affected individuals were reported to have married, four of whom (all female) had healthy offspring [Yahalom et al 2014].

Affected adults in the seventh decade of life have been reported [Yahalom et al 2014]; life expectancy beyond the seventh decade is unknown.

Seizures are not typical in Costeff syndrome. Partial seizures were reported in one individual. In addition, two individuals with Costeff syndrome were reported with electrical status epilepticus during slow-wave sleep (ESESS) (also known as continuous spike-wave of slow sleep (CSWSS) [Carmi et al 2015, Kessi et al 2018].

Cranial nerve functions, sensation, and muscle tone are normal.

No cardiac or structural brain abnormalities have been reported.

The level of 3-methylglutaconate (3-MGC) or 3-methylglutaric acid (3-MGA) in urine does not correlate with the degree of neurologic damage.

Electroretinogram is normal.

Developmental Disability / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

• Individualized education plan (IEP) services:
  • An IEP provides specially designed instruction and related services to children who qualify.
  • IEP services will be reviewed annually to determine whether any changes are needed.
  • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
  • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
  • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
  • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox^®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range