Clinical characteristics.

AFG3L2-related neurologic disorders comprise four phenotypes. Spinocerebellar ataxia type 28 (SCA28), the most common phenotype, is characterized by young adult onset (26.5 ± 17.2 years); the onset range is from birth to 74 years of a cerebellar syndrome manifesting initially as very slowly progressive gait and limb ataxia resulting in incoordination and balance problems. Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding. Pyramidal syndrome (increased and brisk reflexes, extensor plantar reflex, and spasticity) is commonly observed in individuals with longer disease duration. Although cognitive impairment, spasticity, and ophthalmologic signs can occur with disease progression, most individuals remain ambulatory and fully independent throughout their lives.

Spastic ataxia type 5 (SPAX5), reported in 14 individuals to date, ranges from severe neurodegeneration with microcephaly, poor weight gain, developmental delay, developmental regression around age nine months, and death as early as age 2.5 years. Milder presentations range from onset in infancy to an early-onset complex cerebellar ataxia with myoclonic epilepsy.

AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR), reported in two individuals to date, is a late-onset ataxia with a clinical phenotype closely resembling that of SCA28.

Optic atrophy type 12 (OPA12) manifests as decreased visual acuity (variable but frequently ranging from 0.2/10 to 2/10), photophobia, and impaired color vision. Ophthalmologic findings are optic nerve pallor and highly reduced retinal nerve fiber layer on optical coherence tomography. Although affected individuals do not present with ataxia, some may exhibit sensorineural hearing loss, neurodevelopmental disorders, dystonia, and spasticity.

Diagnosis/testing.

The diagnoses of SCA28 and OPA12 are established in a proband with suggestive findings and a heterozygous pathogenic variant in AFG3L2 identified by molecular genetic testing.

The diagnoses of SPAX5 and AFG3L2-SCAR are established in a proband with suggestive findings and biallelic pathogenic variants in AFG3L2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields including neurologists (to address pharmacologic treatment of myoclonic epilepsy, spasticity, movement disorders); occupational therapists (to optimize activities of daily living and home safety); physiatrists and physical therapists (to help maintain independence and mobility); nutritionists and feeding therapy programs (to assess the risks of aspiration and need for gastrostomy tube placement for those with dysphagia); speech-language therapists (to address communication for individuals who have expressive language difficulties), ophthalmologists (to consider surgery for ptosis); low vision clinics (for those with optic atrophy); and social workers and psychologists (depending on any cognitive or psychologic manifestations).

Surveillance: Routinely scheduled follow-up appointments with treating clinicians are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Agents/circumstances to avoid: Alcohol consumption and sedatives such as benzodiazepines that may worsen gait ataxia and coordination. Carbamazepine and phenytoin may exacerbate myoclonus in SPAX5.

Genetic counseling.

SCA28 and OPA12 are inherited in an autosomal dominant manner. AFG3L2-SCAR and SPAX5 are inherited in an autosomal recessive manner.

Autosomal dominant inheritance: Most individuals diagnosed with SCA28, and some individuals diagnosed with OPA12, have an affected parent. Some individuals diagnosed with an autosomal dominant AFG3L2-related neurologic disorder have the disorder as the result of a de novo pathogenic variant. Each child of an individual with an autosomal dominant AFG3L2-related neurologic disorder has a 50% risk of inheriting the pathogenic variant. If the reproductive partner of an individual with an autosomal dominant AFG3L2-related neurologic disorder also has an AFG3L2 pathogenic variant, offspring are at risk of inheriting biallelic pathogenic variants and having an autosomal recessive AFG3L2-related neurologic disorder. Once the AFG3L2 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Autosomal recessive inheritance: The parents of a child with an autosomal recessive AFG3L2-related neurologic disorder are presumed to be heterozygous for an AFG3L2 pathogenic variant. If both parents are known to be heterozygous for an AFG3L2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial AFG3L2 pathogenic variants. Heterozygous family members of an individual with an autosomal recessive AFG3L2-related neurologic disorder are typically asymptomatic and the risk of developing an AFG3L2-related neurologic disorder appears to be low. Once the AFG3L2 pathogenic variants has been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of an AFG3L2-related neurologic disorder should be considered in probands with the following clinical and imaging findings and family history.

Clinical findings

• Onset generally in young adulthood (range: 0-76 years)
• Neurologic examination demonstrating any of the following:
  • Progressive cerebellar ataxia
  • Slowly progressive gait disorder
  • Slowly progressive limb ataxia
  • Cerebellar dysarthria
  • Hyperreflexia or brisk deep tendon reflexes, increased muscle tone in the lower limbs (spasticity), extensor plantar responses
  • Oculomotor abnormalities including smooth pursuit abnormalities, dysmetric and slow saccades, ophthalmoparesis, and gaze-evoked nystagmus
  • Dystonia and/or chorea
  • Parkinsonism
  • Myoclonic epilepsy
  • Mild cognitive impairment and/or neurodevelopmental delay
  • Axonal peripheral sensorimotor neuropathy
• Ophthalmologic examination demonstrating findings of any of the following:
  • Ptosis
  • Optic nerve atrophy and decreased thickness of the retinal nerve fiber layer identified on optical coherence tomography
  • Pale optic discs

Imaging. Brain MRI demonstrating findings of any of the following:

• Cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem
• Abnormal signal in the globus pallidus

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) or autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of spinocerebellar ataxia type 28 (SCA28) or optic atrophy type 12 (OPA12) is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in AFG3L2 identified by molecular genetic testing (see Table 1).

The diagnosis of AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR) or spastic ataxia type 5 (SPAX5) is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in AFG3L2 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of AFG3L2 variants of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of AFG3L2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended, as the associated phenotypes are not pathognomonic for this gene.

Clinical Description

To date, hundreds of individuals have been identified with an AFG3L2-related neurologic disorder [Cagnoli et al 2006, Cagnoli et al 2010, Eskandrani et al 2017, Caporali et al 2020, Charif et al 2020, Dosi et al 2020, Cunha et al 2023, Zheng et al 2025]. The following description of the phenotypic features associated with these conditions is based on these reports and highlights the four distinct clinical presentations associated with AFG3L2-related neurologic disorders.

Genotype-Phenotype Correlations

Variant locations. Reported phenotype correlations with variant locations to date include the following [Caporali et al 2020]:

• Most reported SCA28-related pathogenic variants affect the proteolytic domain (exons 15 and 16).
• The five SPAX5-related pathogenic variants described to date are in the proteolytic domain (exons 15 and 16).
• SCAR-related pathogenic variants, identified in two individuals to date, are compound heterozygous variants – p.[Tyr616Cys];[p.Val723Met] [Tunc et al 2019] and p.[Arg632Ter];p.[Val723Met] [Chiang et al 2021] – located in the proteolytic domain (exons 15 and 16).
• OPA12-related pathogenic variants cluster in the ATPase domain (exons 9 to 12).

SCA28. Individuals heterozygous for the pathogenic variants p.Met666Arg, p.Glu700Lys, and p.Gly671Arg have early-onset disease (i.e., in infancy/childhood), whereas other SCA28-related heterozygous pathogenic missense variants are mainly associated with onset in the second to fourth decade [Mariotti et al 2008, Cagnoli et al 2010, Edener et al 2010, Szpisjak at al 2017].

Penetrance

SCA28. Based on studies published to date, penetrance appears to be complete [Di Bella et al 2010].

OPA12. Reduced penetrance or subclinical phenotypes are suggested by published data [Caporali et al 2020].

Prevalence

SCA28 accounts for approximately 1%-3% of autosomal dominant cerebellar ataxia (ADCA) in individuals of European origin [Cagnoli et al 2010, Hersheson et al 2012], with an estimated incidence of 0.045 in 100,000 individuals.

OPA12 accounts for approximately 4%-5% of autosomal dominant optic atrophy [Caporali et al 2020, Zheng et al 2025].

The other two AFG3L2-related neurologic disorders are extremely rare: to date, only 14 individuals have been reported with SPAX5 and two with AFG3L2-SCAR.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an AFG3L2-related neurologic disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no specific treatment for AFG3L2-related neurologic disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields including neurology, occupational therapy, physical therapy, physiatry, orthopedics, nutrition, speech therapy, social work, and psychology depending on the clinical manifestations (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Alcohol consumption and sedatives such as benzodiazepines may worsen gait ataxia and coordination difficulties.

Carbamazepine and phenytoin may exacerbate myoclonus in spastic ataxia type 5 (SPAX5).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

When women with SPAX5 have epilepsy, anti-seizure medications should be monitored regularly and adjusted to avoid exposure to teratogenic medications during pregnancy and medications harmful when breastfeeding.

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.

Mode of Inheritance

AFG3L2-related spinocerebellar ataxia is inherited in an autosomal dominant (spinocerebellar ataxia type 28; SCA28) or autosomal recessive (AFG3L2-related autosomal recessive spinocerebellar ataxia; AFG3L2-SCAR) manner.

Spastic ataxia type 5 (SPAX5) is inherited in an autosomal recessive manner.

Optic atrophy type 12 (OPA12) is inherited in an autosomal dominant manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SCA28 have an affected parent. Some individuals diagnosed with OPA12 have an affected parent.
• Some individuals diagnosed with an autosomal dominant AFG3L2-related neurologic disorder have the disorder as the result of a de novo pathogenic variant. The proportion of probands diagnosed with SCA28 or OPA12 who have the disorder as the result of de novo pathogenic variant is unknown. However, such events appear to be rare in SCA28, with only a single individual with a de novo pathogenic variant reported to date [Di Bella et al 2010]. A de novo pathogenic variant was identified in two of 12 families with OPA12 in one study [Caporali et al 2020].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
  Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members with milder phenotypes (subclinical OPA12 phenotypes are suggested by published data [Caporali et al 2020]), early death of a parent before the onset of manifestations, or late onset of the disease in an affected parent. Therefore, de novo occurrence of an AFG3L2 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the AFG3L2 pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an AFG3L2 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The penetrance of SCA28 appears to be complete; however, intrafamilial variability has been reported in age of onset and clinical severity [Di Bella et al 2010]. Reduced penetrance and subclinical manifestations have been reported in heterozygous family members of individuals with OPA12 [Caporali et al 2020].
• If the AFG3L2 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the AFG3L2 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for an autosomal dominant AFG3L2-related neurologic disorder because of the possibility of reduced penetrance in a heterozygous parent of a proband with OPA12 and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with an autosomal dominant AFG3L2-related neurologic disorder has a 50% risk of inheriting the pathogenic variant.
• If the reproductive partner of an individual with an autosomal dominant AFG3L2-related neurologic disorder also has an AFG3L2 pathogenic variant, offspring are at risk of inheriting biallelic AFG3L2 pathogenic variants and having an autosomal recessive AFG3L2-related neurologic disorder. A child diagnosed with SPAX5 inherited biallelic AFG3L2 pathogenic variants: one from a parent with OPA12 and one from an unaffected parent with an AFG3L2 pathogenic variant located in the proteolytic domain [Caporali et al 2020].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the AFG3L2 pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with an autosomal recessive AFG3L2-related neurologic disorder are presumed to be heterozygous for an AFG3L2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an AFG3L2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous family members of an individual with an autosomal recessive AFG3L2-related neurologic disorder are typically asymptomatic and the risk of developing an AFG3L2-related neurologic disorder appears to be low. However, milder clinical features such as isolated cerebellar atrophy on brain MRI [Tunc et al 2019] or isolated optic atrophy [Caporali et al 2020] have been reported in some heterozygous family members.

Sibs of a proband

• If both parents are known to be heterozygous for an AFG3L2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial AFG3L2 pathogenic variants.
• Heterozygous family members of an individual with an autosomal recessive AFG3L2-related neurologic disorder are typically asymptomatic and the risk of developing an AFG3L2-related neurologic disorder appears to be low. However, milder clinical features such as isolated cerebellar atrophy on brain MRI [Tunc et al 2019] or isolated optic atrophy [Caporali et al 2020] have been reported in some heterozygous family members.

Offspring of a proband. Unless an affected individual's reproductive partner also has an AFG3L2 pathogenic variant, offspring will be obligate heterozygotes for a pathogenic variant in AFG3L2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AFG3L2 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the AFG3L2 pathogenic variants in the family.

Related Genetic Counseling Issues

Predictive testing for autosomal dominant AFG3L2-related neurologic disorders (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the AFG3L2 pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors for autosomal dominant AFG3L2-related neurologic disorders (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having AFG3L2 pathogenic variant(s).

Prenatal Testing and Preimplantation Genetic Testing

Once the AFG3L2 pathogenic variant(s) has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

AFG3L2 is a nuclear gene that encodes a subunit of the mitochondrial matrix AAA metalloprotease (m-AAA) complex. The AFG3L2 subunit can form homo-oligomeric or hetero-oligomeric protein complexes with the SPG7 protein. The m-AAA complex, located in the inner membrane of the mitochondria, has important functions in proteolysis, protein folding, and membrane trafficking of mitochondrial proteins [Koppen et al 2007, Ghosh Dastidar et al 2024].

Mechanism of disease causation

• SCA28. Most pathogenic variants reported to date exert a dominant-negative effect [Di Bella et al 2010]. Nearly all SCA28-associated variants are localized within the central protease loops and are thought to destabilize its structure, which is essential for substrate unfolding and degradation [Puchades et al 2019].
• SPAX5 is caused by biallelic loss-of-function variants [Pierson et al 2011]. SPAX5-associated variants are close to the protease active site and are involved in substrate cleavage [Puchades et al 2019].
• OPA12-associated pathogenic variants are located in the ATPase domain and indirectly disrupt OPA1 processing, leading to mitochondrial fragmentation [Caporali et al 2020].

Author Notes

Dr Giulia Coarelli is actively involved in clinical research at Paris Brain Institute (ICM, https://institutducerveau.org) regarding individuals with spinocerebellar ataxias and spastic paraplegias. She would be happy to communicate with persons who have any questions regarding the diagnosis of these disorders.

Dr Charlotte Mouraux is actively involved in clinical research within the Rare Movement Disorders Research Group (RMD, GIGA CRC Human Imaging, University of Liege, Belgium) regarding individuals with inherited movement disorders. She would be happy to communicate with persons who have any questions regarding diagnosis of these disorders.

Acknowledgments

We sincerely thank our patients and their families for their willingness to collaborate with us.

Author History

Alfredo Brusco, PhD; University of Turin (2011-2025)
Alessandro Brussino, MD; University of Turin (2011-2025)
Giulia Coarelli, MD, PhD (2025-present)
Alexandra Durr, MD, PhD; Pitié-Salpêtrière University Hospital (2011-2025)
Cecilia Mancini, PhD; University of Turin (2018-2025)
Charlotte Mouraux, MD (2025-present)

Revision History

• 18 September 2025 (bp) Comprehensive update posted live
• 22 March 2018 (ha) Comprehensive update posted live
• 17 May 2011 (me) Review posted live
• 7 February 2011 (ab) Original submission

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