Costeff Syndrome
Summary
Clinical characteristics.
Costeff syndrome is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive decrease in visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.
Diagnosis/testing.
The diagnosis of Costeff syndrome is established in a proband with suggestive findings by identification of biallelic OPA3 pathogenic variants on molecular genetic testing.
Management.
Treatment of manifestations: 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.
Genetic counseling.
Costeff syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an OPA3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. When both OPA3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
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.
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.
Establishing the Diagnosis
The diagnosis of Costeff syndrome is established in a proband with suggestive findings and biallelic OPA3 pathogenic variants identified by molecular genetic testing (Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Costeff syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Costeff syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
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.
Table 1.
Molecular Genetic Testing Used in Costeff Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| OPA3 | Targeted analysis for the c.143-1G>C pathogenic variant in the Iraqi Jewish population 3 | 100% |
| Sequence analysis 4 | 100% 5 | |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
The variant c.143-1G>C accounts for 100% of pathogenic variants in the Iraqi Jewish population [Anikster et al 2001].
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
Most individuals with Costeff syndrome present within the first ten years of life with decreased visual acuity and/or choreoathetoid movement disorder. Although most develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.
The following description of the phenotypic features of Costeff syndrome is based on two reports:
- Elpeleg et al [1994] reported on 36 affected individuals, 11 of whom were previously unreported and 25 of whom had been previously reported.
- Yahalom et al [2014] reported on 28 individuals (age range: 6 months – 68 years) six of whom were previously unreported and 22 of whom had been previously reported by Elpeleg et al [1994].
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.
Genotype-Phenotype Correlations
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 (c.143-1G>C); however, phenotypic severity varies, even within the same family.
Nomenclature
Costeff syndrome has also been referred to as "optic atrophy plus syndrome" and "Costeff optic atrophy syndrome."
Prevalence
Costeff syndrome has been reported in more than 40 individuals of Iraqi Jewish origin [Anikster et al 2001], but also in pan ethnic populations, including families of Kurdish-Turkish descent [Kleta et al 2002], Afghani descent [Gaier et al 2019], and others. Of note, as the vast majority of affected individuals are still of Iraqi Jewish descent residing in Israel, it must be underscored that some families originate from the Iraqi area, including Iran and Syria. Individuals with Costeff syndrome have also been diagnosed from outside of Israel, including recently in the United States [Author, personal observation].
The carrier rate in Iraqi Jews was initially estimated at 1:10 [Anikster et al 2001]; however, subsequent screening tests showed the carrier rate to be 1:20-1:30 [Author, personal observation].
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 [Gunay-Aygun 2005]. 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism (Figure 1).
Figure 1.
Metabolic pathway diagram showing branched-chain organic acid 3-MGC as an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA
A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by Wortmann et al [2013a] and Wortmann et al [2013b]. Clinical features (Table 2) 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
| 3-MGCA | Gene | MOI | Disorder | Key Clinical Characteristics in Addition to 3-MGCA 1 |
|---|---|---|---|---|
| Discriminating feature 2 | AGK | AR | Sengers syndrome (see Mitochondrial DNA Maintenance Defects Overview) | Cataracts; cardiomyopathy (DD) |
| AUH | AR | AUH defect (OMIM 250950) |
| |
| CLPB | AR | CLPB deficiency | Cataracts; central hypopnea; DD & ID; movement disorder; neutropenia (epilepsy) | |
| DNAJC19 | AR | DNAJC19 defect (DCMA syndrome) (OMIM 610198) |
| |
| HTRA2 | AR | MGCA8 (OMIM 617248) | Cataracts; central hypopnea; DD & ID; epilepsy; movement disorder; neutropenia | |
| OPA3 | AR | Costeff syndrome | DD; movement disorders; optic atrophy | |
| SERAC1 | AR | SERAC1 defect (MEGDEL syndrome) | DD & ID; deafness; movement disorder (epilepsy & optic atrophy) | |
| TAZ | XL | TAZ defect (Barth syndrome) | Cardiomyopathy 5; skeletal myopathy; DD; growth restriction; neutropenia | |
| TIMM50 | AR | MGCA9 (OMIM 617698) | DD & ID; epilepsy | |
| TMEM70 | AR | TMEM70 defect | Cardiomyopathy; DD & ID | |
| Occasional feature | POLG | POLG disorders | Encephalopathy w/intractable epilepsy & hepatic failure; DD or dementia, lactic acidosis, & myopathy | |
| SUCLA2 | AR | SUCLA2 mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria | Hypotonia; epilepsy; muscular atrophy; movement disorder; growth retardation | |
| SUCLG1 | AR | SUCLG1 mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria | Hypotonia; uncontrolled movement; hearing loss; DD |
3-MGCA = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Features shown in ( )s are rare.
- 2.
Adapted from Kovacs-Nagy et al [2018], Table 1
- 3.
Sweetman & Williams [2001], Ijlst et al [2002], Illsinger et al [2004]
- 4.
Davey et al [2006]
- 5.
Dilated cardiomyopathy presents within the first year of life or even prenatally [Barth et al 2004].
Clinical Findings of Costeff Syndrome
Behr syndrome. The clinical picture of Behr syndrome is most similar to Costeff syndrome [Copeliovitch et al 2001]. Behr syndrome is an autosomal recessive disorder caused by pathogenic variants in OPA1 (OMIM 210000) associated with childhood-onset optic atrophy and spinocerebellar degeneration characterized by ataxia, spasticity, intellectual disability, posterior column sensory loss, and peripheral neuropathy.
Ataxia, an obligatory finding in Behr syndrome, is not seen in approximately half of individuals with Costeff syndrome; conversely, most individuals with Behr syndrome do not manifest extrapyramidal dysfunction, one of the major features of Costeff syndrome. Given that some individuals with Costeff syndrome do not have extrapyramidal dysfunction, it is not possible to distinguish Behr syndrome from Costeff syndrome based on clinical findings alone. Costeff syndrome can be distinguished from Behr syndrome by the presence of elevated excretion of 3-MGC and 3-MGA in urine.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Costeff syndrome, the evaluations summarized in Table 3 (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
| System/Concern | Evaluation | Comment |
|---|---|---|
| Optic atrophy | Complete ophthalmologic exam | Assess:
|
| Motor disability | Complete neurologic exam | Assess for extrapyramidal dysfunction, spasticity, cerebellar dysfunction |
| Refer to neuromuscular clinic (OT/PT / rehabilitation specialist). | To assess:
| |
| Feeding difficulties | Gastroenterology/nutrition/ feeding team eval | To incl eval of aspiration risk & nutritional status |
| Development (children) | Developmental assessment |
|
| Cognitive impairment (older children & adults) | To incl motor, speech/language eval; general cognitive skills | Frontotemporal & executive deficits; perform formal neuropsychological eval. |
| Genetic counseling | By genetics professionals 1 | To inform individuals & families re nature, MOI, & implications of Costeff syndrome in order to facilitate medical & personal decision making |
| Family support/ Resources | Contact w/a patient advocacy organization may provide additional benefit. Assess need for:
|
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Treatment is supportive. A multidisciplinary team including a neurologist, orthopedic surgeon, ophthalmologist, biochemical geneticist, and physical therapist is required for the care of affected individuals.
Table 4.
Treatment of Manifestations in Individuals with Costeff Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Visual impairment | Standard treatment(s) as recommended by ophthalmologist |
|
| Spasticity | Orthopedics / physical medicine & rehabilitation / PT/OT incl stretching to help avoid contractures & falls | Consider need for positioning & mobility devices, disability parking placard. |
| Poor weight gain / Failure to thrive | Feeding therapy | Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia |
| DD | See DD/ID Management Issues. | |
| Family/Community |
|
|
DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
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