Clinical characteristics.

FASTKD2-related combined oxidative phosphorylation deficiency (FASTKD2-COXPD) is a multisystem disorder that can present from infancy to adulthood with developmental delay with regression that is often triggered by febrile illness and/or seizures. Additional neurologic findings include movement disorder, episodes of acute encephalomyopathy, abnormal muscle tone, and/or stroke-like episodes. Reported ocular manifestations include optic atrophy, nystagmus, strabismus, and visual impairment. Cardiac abnormalities (hypertrophic cardiomyopathy, arrythmia) and impaired kidney function (chronic kidney disease / acute kidney failure) with or without neurologic manifestations have been reported.

Diagnosis/testing.

The diagnosis of FASTKD2-COXPD is established in a proband with suggestive findings and biallelic pathogenic variants in FASTKD2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Routine outpatient treatment includes developmental and educational support; standard treatment of seizures and movement disorder by an experienced neurologist; physical therapy and orthopedic rehabilitation for hypotonia and spasticity; medical and surgical therapies as needed for spasticity; treatment of ocular manifestations per experienced ophthalmologist with referral to early intervention services and community vision services; standard treatment of cardiomyopathy and arrhythmias; management of kidney disease per nephrologist; treatment for musculoskeletal manifestations per orthopedist; management of hearing loss per otolaryngologist; develop transitional care plan; social work support and coordination of care. Emergency outpatient treatment for mildly increased catabolism includes oral feeds if not vomiting, carbohydrate supplementation, and hydration; antipyretics for fever and/or inflammation; antiemetics for occasional vomiting; prompt empiric antibiotics/antiviral therapy guided by suspected infection. Acute inpatient treatment includes intravenous glucose for increased catabolism and hypoglycemia with cofactor supplementation; standard treatment for neurologic manifestations; management of cardiomyopathy per cardiologist; ventilatory support as needed for respiratory compromise; treatment of multiorgan failure per intensivist including assessment for infection, laboratory assessment for thyroid, liver, and kidney dysfunction, and evidence of myopathy.

Surveillance: Assessment of developmental progress, educational needs, neurologic manifestations, growth, and nutritional status at each visit or as clinically indicated; ophthalmology evaluation every six to 12 months or as recommended by ophthalmologist; blood pressure annually or as clinically indicated; EKG and echocardiogram annually or as clinically indicated in those with cardiac disease; kidney function tests and abdominal ultrasound annually or as clinically indicated especially in those with electrolyte imbalance and proteinuria; complete blood count, liver function tests, and liver transaminases annually or as clinically indicated; audiology evaluation every one to two years or as clinically indicated; assess family needs and provide family education at each visit.

Agents/circumstances to avoid: Avoid sodium valproate; other drugs should be used with caution (statins, metformin, high-dose acetaminophen, aminoglycosides, linezolid, tetracycline, azithromycin, and erythromycin); anesthesia can aggravate respiratory manifestations and precipitate respiratory failure; avoid propofol; catabolism should be prevented; medication dose adjustment is needed in those with kidney impairment; avoid neuromuscular-blocking drugs in individuals with muscle disease; avoid lactate-containing agents (e.g., Ringer lactate); exercise programs require cardiac clearance in those with hypertrophic cardiomyopathy, exercise intolerance, or exercise-induced rhabdomyolysis.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from avoidance of agents/circumstances that may further impair mitochondrial function and who may be at risk for seizures (including status epilepticus), acute metabolic decompensation, and other system involvement.

Genetic counseling.

FASTKD2-COXPD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a FASTKD2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FASTKD2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

FASTKD2-COXPD should be suspected in probands with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

• Developmental delay with regression often triggered by febrile illness and/or seizures
• Seizures: generalized tonic-clonic, myoclonic, gelastic, epileptic spasms, status epilepticus, atypical absence
• Movement disorder: dystonic posturing, dyskinesia, spastic ataxic gait, cerebellar ataxia
• Acute metabolic decompensation / acute encephalomyopathy may be triggered by febrile illness and/or seizures
• Abnormal muscle tone: hypotonia, spastic hemiparesis/hemiplegia, spastic paraplegia, spastic tetraparesis
• Ocular manifestations: optic atrophy, nystagmus, strabismus, visual impairment
• Stroke-like episodes
• Other system involvement: chronic kidney disease and/or hypertrophic cardiomyopathy with or without neurologic manifestations

Laboratory findings

• Serum and/or cerebrospinal fluid lactate may be increased.
• Deficiency of single or multiple complexes on oxidative phosphorylation (OXPHOS) complex assays in muscle, skin, and/or lymphocytes. OXPHOS deficiency was documented in seven of 18 individuals; four of those seven had single complex deficiency (all involving complex IV) and the other three had multiple OXPHOS complex deficiencies [Ghezzi et al 2008, Wei et al 2020, Benkirane et al 2021, Wu et al 2022, Gonçalves et al 2025, Kaur et al 2025]. Different results have been noted between skin and muscle tissue; results can also be normal.

Imaging findings

• T₂-weighted hyperintensities in the basal ganglia and brain stem
• Diffuse atrophy involving the cerebrum and, less often, cerebellum and brain white matter
• Cerebral infarcts

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs of either sex and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of FASTKD2-COXPD is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in FASTKD2 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / 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 biallelic FASTKD2 variants of uncertain significance (or of one known FASTKD2 pathogenic variant and one FASTKD2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene 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).

Clinical Description

FASTKD2-related combined oxidative phosphorylation deficiency (FASTKD2-COXPD) is a multisystem disorder that can present from infancy to adulthood with developmental delay with regression that is often triggered by febrile illness and/or seizures. Additional neurologic findings include episodes of acute encephalomyopathy, abnormal muscle tone, movement disorder, and/or stroke-like episodes. Reported ocular manifestations include optic atrophy, nystagmus, strabismus, and visual impairment. Cardiac dysfunction (hypertrophic cardiomyopathy, arrythmia), impaired kidney function, and hematologic abnormalities have all been reported. To date, 19 individuals have been identified with biallelic pathogenic variants in FASTKD2 [Ghezzi et al 2008, Yoo et al 2017, Lyons et al 2019, Wei et al 2020, Benkirane et al 2021, Shah & Balasubramaniam 2021, Wu et al 2022, Astner-Rohracher et al 2023, Ma et al 2023, Simões et al 2023, Gouiza et al 2024, Gonçalves et al 2025, Kaur et al 2025].

Onset. The age of onset varies from early infancy to late adulthood (6 months to 42 years). However, most individuals presented in the first decade of life (13/19, 68.5%) and six individuals (46%) presented prior to age one year.

Developmental delay and intellectual disability. In most individuals, there was an initial period of normal development (11/18; observed in both children and adults) [Ghezzi et al 2008, Yoo et al 2017, Wei et al 2020, Benkirane et al 2021, Wu et al 2022, Astner-Rohracher et al 2023, Gouiza et al 2024, Gonçalves et al 2025, Kaur et al 2025].

Prior to the onset of the disease process, a history of developmental delay was observed in a subset of individuals (7/18); three individuals had delay of speech and motor development, two individuals had speech delay, and two had unspecified developmental delay [Lyons et al 2019, Wei et al 2020, Shah & Balasubramaniam 2021, Ma et al 2023].

A clinical trigger led to neurologic regression or cognitive decline in most individuals (11/18 individuals). Clinical triggers include seizures with or without fever (7 individuals) and febrile illness (6 individuals) [Ghezzi et al 2008, Yoo et al 2017, Wei et al 2020, Shah & Balasubramaniam 2021, Wu et al 2022, Astner-Rohracher et al 2023, Gouiza et al 2024, Kaur et al 2025].

After the onset of the disease, the majority of individuals (67%) showed mild-to-severe developmental delay / cognitive involvement or developmental regression (10/17 individuals). The remaining individuals (7/17) showed no neurologic regression or psychomotor delay; however, they continued to experience persistent seizures, recurrent episodes of acute metabolic decompensation / acute encephalomyopathy, and spastic ataxia [Yoo et al 2017, Benkirane et al 2021, Kaur et al 2025].

Gastrointestinal function, feeding, and nutrition. One individual was reported to require gastrostomy tube feeding due to a diminished gag reflex. This individual was profoundly neurologically impaired with no voluntary movements or communication [Ghezzi et al 2008]. Although feeding difficulties and poor weight gain are not universally reported among individuals with FASTKD2-COXPD, given the natural history of the disorder in most individuals – characterized by progressive neurologic decline, episodes of metabolic decompensation or acute encephalomyelopathy, seizures, and febrile illnesses – affected individuals are inherently at risk for feeding challenges and subsequent nutritional deficiencies, particularly in early childhood. Consequently, regular monitoring of gastrointestinal function, feeding ability, and nutritional status is warranted.

Epilepsy. Seizures of varying types and severity were noted in 13/19 individuals. The age of onset of seizures varies, from infancy to late adulthood (7 months to 42 years). Types of seizures included generalized tonic-clonic (3/13), myoclonic (3/13), focal motor seizures, and atypical absence seizures. Six individuals experienced status epilepticus (age of onset: 2.5 years to 18 years). New-onset refractory status epilepticus (NORSE) was reported in a previously healthy child at age 14 years [Astner-Rohracher et al 2023]. Based on clinical descriptions, Lennox-Gastaut syndrome [Wu et al 2022] and Dravet syndrome [Ghezzi et al 2008] were each reported in one individual. Abnormal EEG findings were documented in five individuals, with lateralization reported in most individuals [Ghezzi et al 2008, Yoo et al 2017, Wei et al 2020, Wu et al 2022, Astner-Rohracher et al 2023]. In the majority of affected individuals (8/13), seizures were persistent and either poorly or only partially controlled, often refractory to anti-seizure medications; in some individuals, seizures contributed to early mortality.

Movement disorders were documented in some individuals (9/19) including tremor (3), dystonia (2), dyskinesia (2), and ataxia (2) [Ghezzi et al 2008, Lyons et al 2019, Wei et al 2020, Benkirane et al 2021, Shah & Balasubramaniam 2021, Astner-Rohracher et al 2023, Gouiza et al 2024].

Episodes of acute metabolic decompensation / acute encephalomyopathy are often triggered by febrile illness with or without seizures (age of onset: 5 months to 14 years) and characterized by multiorgan failure (cardiomyopathy and/or nephropathy), sepsis, elevated transaminases, altered sensorium, and episodic lower-limb weakness [Ghezzi et al 2008, Astner-Rohracher et al 2023, Gouiza et al 2024, Kaur et al 2025]. The episodes typically led to progression of neurologic abnormalities. However, two sibs completely recovered from acute episodes and had normal cognitive abilities without neurologic deficit in between acute episodes [Kaur et al 2025].

Abnormal muscle tone. Hypotonia was reported in 4/17 individuals [Ghezzi et al 2008, Wei et al 2020, Ma et al 2023]. Spasticity was observed in 4/17 individuals, including spastic paraplegia, spastic hemiparesis, spastic tetraparesis, and spastic ataxic gait [Ghezzi et al 2008, Benkirane et al 2021, Astner-Rohracher et al 2023, Gouiza et al 2024].

Ophthalmologic involvement. Bilateral optic atrophy is the most common eye finding (6/17 individuals) [Ghezzi et al 2008, Yoo et al 2017, Wei et al 2020, Astner-Rohracher et al 2023, Gouiza et al 2024] and was associated with poor vision and nystagmus. Strabismus has also been reported [Wei et al 2020, Benkirane et al 2021, Astner-Rohracher et al 2023, Gouiza et al 2024].

Neuroimaging. Abnormal neuroimaging findings were documented in most individuals (16/18) [Ghezzi et al 2008, Yoo et al 2017, Lyons et al 2019, Wei et al 2020, Benkirane et al 2021, Shah & Balasubramaniam 2021, Wu et al 2022, Astner-Rohracher et al 2023, Ma et al 2023, Gouiza et al 2024, Gonçalves et al 2025]. Reported findings include:

• Multiple areas of bilateral and symmetrical T₂ hyperintensities / diffusion restriction in cortical regions (globus pallidus, caudate nucleus, thalamic, subthalamic nuclei, cerebral peduncle, substantia nigra, and medulla oblongata) leading to the diagnosis of Leigh syndrome and/or suspicion of a mitochondrial disorder
• Occipital lobe infarction
• Generalized cerebral atrophy (symmetrical or asymmetrical)
• Dilatation of the lateral ventricles and basal cisternae
• MR spectroscopy showing increased lactate
• Widened cerebellar sulcus
• Generalized cerebellar atrophy

Stroke-like episodes, characterized by acute or subacute onset of unilateral limb hemiparesis/hemiplegia with or without vision involvement and cranial nerve palsies, were reported in four individuals [Ghezzi et al 2008, Yoo et al 2017, Wei et al 2020, Shah & Balasubramaniam 2021]. Brain MRI findings in those with stroke-like episodes included contralateral severe brain atropy [Ghezzi et al 2008], right occipital lobe infarction [Yoo et al 2017], typical imaging findings of Leigh-like disease [Wei et al 2020], and diffusion restriction in the left temporal lobe, insular cortex, and left lentiform nucleus, which completely resolved on follow-up imaging after one month [Shah & Balasubramaniam 2021].

Cardiac abnormalities have included hypertrophic cardiomyopathy, sinus tachycardia, and supraventricular tachycardia [Wei et al 2020, Kaur et al 2025, Gonçalves et al 2025]. Hypertrophic cardiomyopathy was identified in one child [Wei et al 2020]. Onset of hypertrophic cardiomyopathy in adulthood was reported in one individual [Gonçalves et al 2025] along with chronic kidney disease without neurologic manifestations. Supraventricular tachycardia has been reported in one child [Kaur et al 2025].

Abnormal kidney function. Acute kidney failure in one individual occurred as part of multiorgan dysfunction [Kaur et al 2025]. Late-onset (in adolescence and adulthood) nephropathy and proteinuria with chronic kidney disease were reported in three individuals [Lyons et al 2019, Gonçalves et al 2025]. One of the individuals with chronic kidney disease had hypertrophic cardiomyopathy and no neurologic disease [Gonçalves et al 2025]. The other two individuals (sibs) had chronic kidney disease with neurologic disease (one with tremors and neuroregression, the other with only tremors) [Lyons et al 2019].

Hematologic abnormalities. Thrombocytopenia, anemia, and pancytopenia were reported in affected sibs [Kaur et al 2025].

Musculoskeletal abnormalities have included the following in one individual each: joint contractures [Ghezzi et al 2008], joint hypermobility and pes cavus [Astner-Rohracher et al 2023], bilateral valgus deformity of the feet and joint laxity of the knee and ankles [Ma et al 2023], congenital hip dislocation [Ghezzi et al 2008], and scoliosis [Gouiza et al 2024].

Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.

Other. Hearing loss was reported in one individual [Gouiza et al 2024].

Prognosis. Most individuals experienced progressive encephalomyopathy of variable clinical severity. Early death in childhood has been reported due to metabolic decompensation / status epilepticus [Shah & Balasubramaniam 2021, Gouiza et al 2024, Kaur et al 2025].

Adult-onset individuals with or without a milder FASTKD2-COXPD phenotype may not experience early mortality [Benkirane et al 2021, Astner-Rohracher et al 2023, Gonçalves et al 2025]. The oldest reported surviving individual was age 50 years at the time of the last evaluation with age of onset at 42 years [Benkirane et al 2021].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified to date given the limited affected individuals identified.

Prevalence

FASTKD2-COXPD is a rare condition, with only 19 individuals from 15 families described to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FASTKD2-COXPD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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 (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 7 are recommended.

Agents/Circumstances to Avoid

In general, for any primary mitochondrial disorder, the following precautions are recommended to prevent further deterioration of mitochondrial function, as suggested by a Delphi consensus review on mitochondrial disorders [Parikh et al 2017, De Vries et al 2020, Sue et al 2022].

• Sodium valproate should be avoided, if possible, because of its inhibitory effect on respiratory chain enzymes. Other drugs should be used with caution, including statins, metformin, high-dose acetaminophen, and selected antibiotics such as aminoglycosides, linezolid, tetracycline, azithromycin, and erythromycin.
• Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use.
• Propofol use should be avoided or limited to short procedures due to risk of propofol infusion syndrome including lactic acidosis.
• Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet).
• Medication dose adjustment should be considered in those with impaired kidney function, particularly when active drug moieties are renally cleared.
• Neuromuscular-blocking drugs should be avoided in individuals with muscle disease or, if necessary, used under strict monitoring.
• Avoid lactate-containing agents (e.g., Ringer lactate) when there is risk of lactic acidosis.
• Cardiac screening prior to beginning an exercise program, along with supervised exercise program if it is considered safe, particularly for those with hypertrophic cardiomyopathy, exercise intolerance, or exercise-induced rhabdomyolysis.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from avoidance of agents/circumstances that may further impair mitochondrial function and who may be at risk for seizures (including status epilepticus), acute metabolic decompensation, and other system involvement.

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

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

FASTKD2-related combined oxidative phosphorylation deficiency (FASTKD2-COXPD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a FASTKD2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a FASTKD2 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 [Ma et al 2023].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a FASTKD2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has FASTKD2-COXPD or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in FASTKD2.
• Reproductive fitness may be reduced in severely affected individuals (particularly those with pronounced neurologic involvement).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a FASTKD2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FASTKD2 pathogenic variants in the family.

Related Genetic Counseling Issues

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, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the FASTKD2 pathogenic variants have 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 use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FASTKD2 encodes FAST kinase domain-containing protein 2, mitochondrial (FASTKD2), a mitochondrial RNA-binding protein that includes three domains: two FAST-like domains, FAST1 (456-528) and FAST2 (538-619), and a highly conserved RNA-binding domain (RAP) domain (636-692) [Lee & Hong 2004, Simarro et al 2010]. FASTKD2 plays a role in mitochondrial RNA processing, mitochondrial protein synthesis, and mitochondrial apoptosis [Ghezzi et al 2008, Simarro et al 2010, Popow et al 2015].

Knockdown of FASTKD2 in zebra fish has been shown to lead to multiple oxidation phosphorylation (OXPHOS) deficiencies [Wei et al 2020]. Thus, defective FASTKD2 protein would perturb global mitochondrial protein synthesis, which would result in decreased activity of OXPHOS protein complexes [Antonicka & Shoubridge 2015, Jourdain et al 2015, Popow et al 2015].

Mechanism of disease causation. Loss of function

Author Notes

Dr Siddaramappa J Patil (moc.liamg@litapjsrd) is actively involved in clinical research on rare genetic disorders and is particularly interested in identifying additional individuals to expand the genotypic and phenotypic spectrum of FASTKD2-related combined oxidative phosphorylation deficiency.

Dr Patil and Dr Anju Shukla (ude.lapinam@alkuhs.ujna) are interested in hearing from clinicians treating families in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in combined oxidative phosphorylation deficiency disorders.

Contact Dr Patil and Dr Shukla to inquire about review of FASTKD2 variants of uncertain significance.

Society for Mitochondrial Research and Medicine. The Society for Mitochondria Research and Medicine, India (SMRM) is a nonprofit organization of scientists, clinicians, and academicians. The purpose of SMRM is to foster research on basic science of mitochondria, mitochondrial pathogenesis, prevention, diagnosis, and treatment throughout India and abroad.

Revision History

• 4 December 2025 (sw) Review posted live
• 4 August 2025 (sp) Original submission

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