Clinical Diagnosis

The diagnosis of fatty acid hydroxylase-associated neurodegeneration (FAHN) may be suspected in individuals with in the first- or second-decade onset of the hallmark features: corticospinal tract involvement, movement disorder, and suggestive neuroimaging findings. See Figure 1.

Figure

Figure 1. Neuroimaging features of FAHN (A) vs PKAN (B)

The two forms of NBIA share T₂/GRE hypointensity. Distinguishing features include diffuse cerebral atrophy (seen in FAHN) and central globus pallidus T₂ hyperintensity (seen in PKAN), (more...)

Molecular Genetic Testing

Gene. FA2H is the only gene in which mutations are known to cause fatty acid hydroxylase-associated neurodegeneration (FAHN).

Clinical testing

• Sequence analysis is performed using primers spanning all seven exons and intron-exon boundaries of FA2H with comparison to reference sequence [Kruer et al 2010].

Table 1. Summary of Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
FA2H	Sequence analysis	Sequence variants 2	>95%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results

• When only one mutation is identified in an individual with clinical and neuroimaging features of FAHN, a diagnosis of ‘suspected FAHN’ is appropriate.

• For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of FAHN may be clinically suspected when the following are present:

• A mixed movement disorder (ataxia/dystonia) and corticospinal tract findings

• Corroborative ophthalmologic features: optic atrophy, strabismus, nystagmus, and supranuclear gaze palsy

• Supportive findings on neuroimaging: T₂ hypointensity of the globus pallidus, T₂ subcortical white matter hyperintensity, and atrophy of the corpus callosum, brain stem, and cerebellum

On the basis of this constellation of features, molecular genetic testing of FA2H should be considered.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Two phenotypes previously identified as distinct disorders are now included in the phenotypic spectrum of FAHN (see Clinical Description, Leukodystrophy and hereditary spastic paraplegia 35).

No other phenotypes are known to be associated with mutations in FA2H.

Natural History

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is considered to represent a subtype of neurodegeneration with brain iron accumulation (NBIA), a class of disorders that also includes pantothenate kinase-associated neurodegeneration (PKAN) and neuroaxonal dystrophy (NAD; see Infantile Neroaxonal Dystrophy).

The signs and symptoms of FAHN are largely confined to the central nervous system and include corticospinal tract involvement, movement disorder, and eye findings. To date, a total of 25 individuals from seven families of diverse ethnicity with FAHN have been described [Dick et al 2008, Edvardson et al 2008, Dick et al 2010, Kruer et al 2010]; therefore, information on the extent of the phenotype and natural history are limited. (See Table 2.)

The most frequent presenting finding is a subtle change in gait that may lead to increasingly frequent falls. This typically occurs in childhood or adolescence and may be the result of focal dystonia and/or corticospinal tract involvement.

The degree of spasticity resulting from corticospinal tract involvement may vary among persons with FAHN. Individuals affected to a lesser degree may develop spastic paraparesis but retain the ability to walk, while individuals with more severe disease may demonstrate a spastic quadriplegic pattern of disability and lose their ability to ambulate, instead relying on a wheelchair.

Dystonia may begin focally (e.g., affecting one foot) but typically spreads to assume a generalized pattern. The degree of dystonia seen in FAHN is generally milder than that in other forms of NBIA, such as PKAN, in which status dystonicus occurs.

Ataxia typically begins in childhood or adolescence and may emerge along with dystonia and/or spasticity. The ataxia that occurs in FAHN may affect both axial and appendicular function and, along with both dystonia and spasticity, can markedly impair gait.

Dysarthria may be prominent in FAHN. In some individuals, expressive speech can be impaired to the point of anarthria. Dysphagia, potentially necessitating gastrostomy tube placement, can also occur.

Optic atrophy in FAHN may begin as a subtle loss of visual acuity in childhood, but may progress to the point of functional blindness. The oculomotor abnormalities seen in FAHN may impair functional vision as well.

Seizures are not typically seen in the early stages of disease, but may occur later in the disease course. When present, seizures tend to be complex partial or generalized in nature but are typically infrequent and respond relatively well to anticonvulsants.

Progressive intellectual impairment is reported in most persons with FAHN, although more detailed data on the cognitive phenotype and natural history are needed.

Leukodystrophy and hereditary spastic paraplegia 35 (HSP35) are two phenotypes previously identified as distinct disorders but now included in the phenotypic spectrum of FAHN:

• Mutations in FA2H were first identified in a family with progressive dystonia and intellectual decline [Edvardson et al 2008]. Neuroimaging revealed widespread T₂ white matter hyperintensities consistent with a clinical diagnosis of leukodystrophy. Further review of neuroimaging revealed T₂ hypointensities in the globus pallidus [Kruer et al 2010]. This phenotype likely represents a variant of FAHN.

• Dick et al [2008] described spastic paraplegia and dystonia in a consanguineous Omani family. They mapped the disease-associated locus, which they designated SGP35, to 16q21-23. Subsequently, Dick et al [2010] identified mutations in FA2H in the index family as well as in an additional family from Pakistan. Affected individuals exhibited spastic paraplegia, dystonia, and optic atrophy, leading to the characterization of the SPG35-associated phenotype as a ‘complicated’ form of HSP.

Although FAHN is progressive, declines may be intermittent and punctuated by periods of relative clinical stability. However, lost skills are not usually regained. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence.

Although premature death often occurs in the 20s or 30s secondary to a combination of nutrition-related immunodeficiency and respiratory compromise, life span is variable.

Neuropathologic features for FAHN have not yet been reported.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been observed for mutations in FA2H.

Nomenclature

FAHN was called ‘hereditary spastic paraplegia 35 (HSP35)’ by Dick et al [2008]. More recently Dick et al [2010] identified FA2H mutations in two families with HSP35 (see Clinical Description, Leukodystrophy and hereditary spastic paraplegia 35).

Prevalence

No reliable prevalence data on this rare disorder have been collected. However, the prevalence is estimated to be less than one in 1,000,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the following evaluations may be useful:

• Neurologic examination for dystonia, ataxia, and spasticity, including formal evaluation of ambulation, speech, and feeding

• Ophthalmologic assessment for evidence of optic atrophy or eye movement abnormalities

• Screening developmental assessment, with referral for more formal testing if delay is indicated

• Assessment for physical therapy, occupational therapy, and/or speech therapy and appropriate assistive devices

Prevention of Primary Manifestations

Pharmacologic and surgical interventions have focused on palliation of symptoms.

Weighted gloves can sometimes be used to assist with dysmetria.

Symptomatic treatment is aimed primarily at the dystonia, which can be debilitating. Therapies to manage dystonia in affected individuals that have been used with varying success include the following:

• Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene

• Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups

• Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [Justesen et al 1999]. (For discussion of deep brain stimulation [DBS] see Therapies Under Investigation.)

It is important to help affected individuals to maintain independence whenever possible.

• Affected individuals should be referred to appropriate community resources for financial services, services for the visually impaired (if optic atrophy is present), and special education.

• As needed, individuals should be referred for adaptive aids such as a walker or wheelchair for gait abnormalities and augmentative communication devices.

Prevention of Secondary Complications

Swallowing evaluation and regular dietary assessments are indicated to assure adequate nutrition and prevent aspiration. Once the individual can no longer maintain an adequate diet orally, gastrostomy tube placement is indicated.

Surveillance

The following should be performed on a regular basis:

• Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status

• Ophthalmologic assessment. Fundus photography may be helpful in characterizing changes in the optic nerve over time.

• Assessment of ambulation, speech, and swallowing

• Regular review of communication needs and environmental adaptations

Testing of Relatives at Risk

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

Therapies Under Investigation

Deep brain stimulation (DBS). To the authors’ knowledge, DBS has not yet been employed in the treatment of dystonia secondary to FAHN. Ongoing studies in the use of DBS for the management of other forms of NBIA suggest that it does provide benefit to a subset of affected individuals [Timmermann et al 2010]. Future studies will be necessary to determine whether DBS may be similarly useful for dystonia in FAHN.

Intrathecal baclofen pump. The implantable intrathecal baclofen pump has shown efficacy in ameliorating dystonia in some forms of NBIA. The intraventricular baclofen pump has been used successfully in at least one person with NBIA among a cohort of individuals with refractory dystonia [Albright & Ferson 2009]. Additional experience is necessary to better define the optimal mode of drug delivery and risk/benefit ratio.

Iron chelation. Interest in iron chelation has reemerged as trials using deferiprone have been published in other disorders of brain iron accumulation, including Friedreich ataxia [Boddaert et al 2007] and superficial siderosis [Levy & Llinas 2011]. Deferiprone can cross the blood-brain barrier and remove intracellular iron.

• A single case report suggests regression of symptoms in an adult with NBIA of unknown cause [Forni et al 2008].

• A recently completed phase II deferiprone trial in Italy in persons with PKAN demonstrated after six months of treatment decreased T₂ hypointensity but no detectable change in clinical symptom severity [Zorzi et al 2011]. No serious treatment-related adverse events occurred.

Long-term clinical trials of deferiprone in specific forms of NBIA will be necessary to further assess safety and efficacy.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

The NBIA Disorders Association maintains a registry of families interested in participation in research, including families affected by FAHN:

NBIA Disorders Association Research Registry
Phone: 619-588-2315
Fax: 619-588-4093
Email: pwood/at/nbiadisorders.org
www.nbiadisorders.org/researchregistry.htm

An NBIA research registry and biological sample repository is maintained at Oregon Health & Science University:

Repository for NBIA and Related Disorders
Phone: 503-494-4344
Fax: 503-494-6886
Email: gregorya/at/ohsu.edu

Other

Riluzole, recently recommended for cerebellar ataxia [Ristori et al 2010], has not, to the authors’ knowledge, undergone a therapeutic trial in FAHN.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has 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 an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

• The offspring of an individual with FAHN are obligate heterozygotes (carriers) for a disease-causing mutation in FA2H.

• Unless an individual with FAHN has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a disease-causing mutation in FA2H.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Human FA2H encodes the fatty acid 2-hydroxylase, an enzyme that alpha-hydroxylates nascent fatty acids that are subsequently incorporated into several diverse lipid species. Mutations in FA2H are believed to lead to fatty acid hydroxylase-associated neurodegeneration (FAHN) through a loss-of-function mechanism. This is supported by the identification of mutations that lead to premature truncation of the protein [Kruer et al 2010], as well as in vitro evidence of decreased α-hydroxylation activity [Dick et al 2010] and decreased protein abundance [Kruer et al 2010] secondary to mutations associated with clinical FAHN.

In the peripheral nervous system, there is evidence that a second fatty acid-hydroxylating enzyme (perhaps phytanoyl coA 2-hydroxylase) may compensate for loss of FA2H activity [Edvardson et al 2008]. However, in the central nervous system, this redundancy does not seem to exist. A decrease in 2-OH fatty acids may lead to abnormal white matter, as 2-OH sphingomyelin is an important myelin constituent [Eckhardt et al 2005]. Deficiency of 2-OH fatty acids may also lead to an abnormal increase in membrane fluidity [Guo et al 2010], with implications for the regulation of autophagy via the endosomal-lysosomal system. An important cell-cycle signaling role for FA2H has also been shown [Alderson & Hama 2009]. However, further investigation is needed to better characterize the mechanism(s) by which loss of functional FA2H may lead to FAHN.

Normal allelic variants. The reference sequence NM_024306.4 has seven exons.

Pathologic allelic variants. No common sequence variants have been identified to date in persons with FAHN; all have been ‘private’ mutations.

Normal gene product. FA2H encodes a 43-kd protein of 372 amino acid residues that is a functional fatty acid hydroxylase [Alderson et al 2004]. This protein is known to localize to the endoplasmic reticulum and to require iron as a cofactor. Hydroxy fatty acids have important structural and signal transduction roles.

Abnormal gene product. Mutations can generally be categorized into null or missense alleles. Missense mutations in FA2H have been detected, leading to decreased protein abundance or enzyme activity. Null alleles have been detected as well.

Literature Cited

1. Albright AL, Ferson SS. Intraventricular baclofen for dystonia: techniques and outcomes. Clinical article. J Neurosurg Pediatr. 2009;3:11–4. [PubMed: 19119897]
2. Alderson NL, Rembiesa BM, Walla MD, Bielawska A, Bielawski J, Hama H. The human FA2H gene encodes a fatty acid 2-hydroxylase. J Biol Chem. 2004;279:48562–8. [PubMed: 15337768]
3. Alderson NL, Hama H. Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T schwannoma cells. J Lipid Res. 2009;50:1203–8. [PMC free article: PMC2681402] [PubMed: 19171550]
4. Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard JC, Munnich A, Cabantchik ZI. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007;110:401–8. [PubMed: 17379741]
5. Dale RC, Church AJ, Benton S, Surtees RA, Lees A, Thompson EJ, Giovannoni G, Neville BG. Post-streptococcal autoimmune dystonia with isolated bilateral striatal necrosis. Dev Med Child Neurol. 2002;44:485–9. [PubMed: 12162386]
6. Dick KJ, Al-Mjeni R, Baskir W, Koul R, Simpson MA, Patton MA, Raeburn S, Crosby AH. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology. 2008;71:248–52. [PubMed: 18463364]
7. Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat. 2010;31:E1251–60. [PubMed: 20104589]
8. Eckhardt M, Yaghootfam A, Fewou SN, Zöller I, Gieselmann V. A mammalian fatty acid hydroxylase responsible for the formation of alpha-hydroxylated galactosylceramide in myelin. Biochem J. 2005;388:245–54. [PMC free article: PMC1186713] [PubMed: 15658937]
9. Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, Korman SH, Taustein I, Saada A, Elpeleg O. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am J Hum Genet. 2008;83:643–8. [PMC free article: PMC2668027] [PubMed: 19068277]
10. Forni GL, Balocco M, Cremonesi L, Abbruzzese G, Parodi RC, Marchese R. Regression of symptoms after selective iron chelation therapy in a case of neurodegeneration with brain iron accumulation. Mov Disord. 2008;23:904–7. [PubMed: 18383118]
11. Guo L, Zhou D, Pryse KM, Okunade AL, Su X. Fatty acid 2-hydroxylase mediates diffusional mobility of Raft-associated lipids, GLUT4 level, and lipogenesis in 3T3-L1 adipocytes. J Biol Chem. 2010;285:25438–47. [PMC free article: PMC2919107] [PubMed: 20519515]
12. Harting I, Neumaier-Probst E, Seitz A, Maier EM, Assmann B, Baric I, Troncoso M, Mühlhausen C, Zschocke J, Boy NP, Hoffmann GF, Garbade SF, Kölker S. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain. 2009;132:1764–82. [PubMed: 19433437]
13. Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report. J Neurosurg. 1999;90:551–4. [PubMed: 10067928]
14. Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, Hayflick SJ. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol. 2010;68:611–8. [PubMed: 20853438]
15. Levy M, Llinas RH. Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis. AJNR Am J Neuroradiol. 2011;32:E1–2. [PubMed: 21051507]
16. Paisán-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E, Schneider SA, Schwingenschuh P, Bajaj N, Emre M, Singleton AB, Hardy J, Bhatia KP, Brandner S, Lees AJ, Houlden H. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord. 2010;25:1791–800. [PubMed: 20669327]
17. Quintana E, Mayr JA, García Silva MT, Font A, Tortoledo MA, Moliner S, Ozaez L, Lluch M, Cabello A, Ricoy JR, Koch J, Ribes A, Sperl W, Briones P. PDH E(1)beta deficiency with novel mutations in two patients with Leigh syndrome. J Inherit Metab Dis. 2009 [PubMed: 19924563]
18. Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M, Pontieri FE, Vanacore N, Salvetti M. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74:839–45. [PubMed: 20211908]
19. Timmermann L, Pauls KA, Wieland K, Jech R, Kurlemann G, Sharma N, Gill SS, Haenggeli CA, Hayflick SJ, Hogarth P, Leenders KL, Limousin P, Malanga CJ, Moro E, Ostrem JL, Revilla FJ, Santens P, Schnitzler A, Tisch S, Valldeoriola F, Vesper J, Volkmann J, Woitalla D, Peker S. Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation. Brain. 2010;133:701–12. [PMC free article: PMC2842517] [PubMed: 20207700]
20. Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz M, Clayton PT. Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia-A new metabolic disorder. J Inherit Metab Dis. 2008 [PubMed: 18392750]
21. Zeng WQ, Al-Yamani E, Acierno JS, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet. 2005;77:16–26. [PMC free article: PMC1226189] [PubMed: 15871139]
22. Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, Longo F, Garavaglia B, Aquino D, Savoiardo M, Solari A, Nardocci N. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: Results of a phase II pilot trial. Mov Disord. 2011;26:1756–9. [PubMed: 21557313]

Revision History

• 29 September 2011 (cd) Revision: prenatal diagnosis available clinically

• 28 June 2011 (me) Review posted live

• 3 January 2011 (mk) Original submission