SPG35 Gene

SPG35 - FA2H (Fatty Acid 2-Hydroxylase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SPG35</th></tr> [@fa2h_discovery_2008]
<tr><td><b>Full Name</b></td><td>FA2H (Fatty Acid 2-Hydroxylase)</td></tr> [@fa2h_structure_2012]
<tr><td><b>Chromosomal Location</b></td><td>16q23.3</td></tr> [@fa2h_discovery_2008]
<tr><td><b>NCBI Gene ID</b></td><td>[64080](https://www.ncbi.nlm.nih.gov/gene/64080)</td></tr>
<tr><td><b>OMIM</b></td><td>[610672](https://www.omim.org/entry/610672)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q8IWA4](https://www.uniprot.org/uniprotkb/Q8IWA4/entry)</td></tr>
<tr><td><b>Category</b></td><td>Lipid Metabolism</td></tr>
<tr><td><b>Protein Length</b></td><td>383 amino acids</td></tr> [@fa2h_isoforms_2024]
<tr><td><b>Inheritance</b></td><td>Autosomal recessive</td></tr> [@spg35_phenotype_2021]
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

The SPG35 gene encodes fatty acid 2-hydroxylase (FA2H), a critical enzyme involved in the synthesis of 2-hydroxy fatty acids (2-OH FAs) that are essential components of myelin lipids. FA2H is a member of the fatty acid hydroxylase family and plays a vital role in maintaining myelin integrity in the central nervous system (CNS) [@myelin_lipids_2011].

SPG35 - FA2H (Fatty Acid 2-Hydroxylase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SPG35</th></tr> [@fa2h_discovery_2008]
<tr><td><b>Full Name</b></td><td>FA2H (Fatty Acid 2-Hydroxylase)</td></tr> [@fa2h_structure_2012]
<tr><td><b>Chromosomal Location</b></td><td>16q23.3</td></tr> [@fa2h_discovery_2008]
<tr><td><b>NCBI Gene ID</b></td><td>[64080](https://www.ncbi.nlm.nih.gov/gene/64080)</td></tr>
<tr><td><b>OMIM</b></td><td>[610672](https://www.omim.org/entry/610672)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q8IWA4](https://www.uniprot.org/uniprotkb/Q8IWA4/entry)</td></tr>
<tr><td><b>Category</b></td><td>Lipid Metabolism</td></tr>
<tr><td><b>Protein Length</b></td><td>383 amino acids</td></tr> [@fa2h_isoforms_2024]
<tr><td><b>Inheritance</b></td><td>Autosomal recessive</td></tr> [@spg35_phenotype_2021]
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

The SPG35 gene encodes fatty acid 2-hydroxylase (FA2H), a critical enzyme involved in the synthesis of 2-hydroxy fatty acids (2-OH FAs) that are essential components of myelin lipids. FA2H is a member of the fatty acid hydroxylase family and plays a vital role in maintaining myelin integrity in the central nervous system (CNS) [@myelin_lipids_2011].

Mutations in FA2H cause a complex form of hereditary spastic paraplegia (HSP) designated SPG35, which is characterized by progressive lower limb spasticity, often accompanied by neurological complications including seizures, cognitive impairment, and in some cases, neurodegeneration with brain iron accumulation (NBIA) [@fa2h_nb2010]. The disease typically presents in childhood with a variable phenotype that reflects the complex interplay between FA2H function in lipid metabolism, iron homeostasis, and myelin maintenance.

FA2H deficiency represents a unique intersection between white matter disorders and iron metabolism disorders, making it an important model for understanding how lipid dysregulation contributes to neurodegenerative processes.

Gene Structure and Molecular Biology

Genomic Organization

The FA2H gene is located on chromosome 16q23.3 and consists of 13 exons spanning approximately 30 kb of genomic DNA [@fa2h_discovery_2008]. The gene encodes a protein of 383 amino acids with a molecular weight of approximately 44 kDa. Several pathogenic variants have been identified throughout the gene, including missense, nonsense, and splice-site mutations.

Alternative Splicing

Recent studies have identified multiple alternatively spliced isoforms of FA2H that demonstrate tissue-specific expression patterns [@fa2h_isoforms_2024]:

• Isoform 1 (canonical): Full-length 383 amino acids, predominantly expressed in brain
• Isoform 2: Lacks exon 6, expressed in peripheral tissues
• Isoform 3: Alternative start site, truncated variant

Protein Structure

FA2H is an integral membrane protein with several structural features [@fa2h_structure_2012]:

The enzyme localizes primarily to the endoplasmic reticulum (ER) where it catalyzes the 2-hydroxylation of very-long-chain fatty acids (VLCFAs) and very-long-chain fatty acids (C20-C26).

Function in Normal Cells

Lipid Metabolism

FA2H catalyzes the 2-hydroxylation of very-long-chain fatty acids (VLCFAs), a critical step in the synthesis of 2-hydroxy sphingolipids [@myelin_lipids_2011]:

• Substrate specificity: Prefers C24 and C26 fatty acids
• Product formation: 2-hydroxy VLCFAs are incorporated into cerebrosides and sulfatides
• Cellular location: Endoplasmic reticulum membrane

• Membrane stability: Proper lipid raft organization
• Myelin compaction: Formation of the multilayered myelin structure
• Node of Ranvier organization: Maintenance of saltatory conduction
• Protein trafficking: Lipid-dependent membrane protein sorting

Myelin Synthesis

FA2H is essential for proper myelin formation and maintenance [@oligodendrocyte_2019]:

• Oligodendrocyte function: Critical for myelin-producing cells
• Myelin lipid composition: Determines myelin physical properties
• Axonal support: Myelin provides metabolic support to axons
• Saltatory conduction: Enables rapid nerve impulse transmission

Iron Metabolism

FA2H is involved in brain iron homeostasis [@iron_metabolism_2020]:

• Ferritin regulation: Affects iron storage protein expression
• Iron transport: Modulates transferrin receptor expression
• Divalent metal transporter 1 (DMT1): Regulates cellular iron uptake

Molecular Mechanisms of SPG35 Pathogenesis

Lipid Abnormalities

The primary pathogenic mechanism involves disruption of myelin lipid metabolism:

Myelin Dysfunction

The myelin abnormalities in SPG35 include [@white_matter_2017]:

• Hypomyelination: Reduced myelin volume in CNS
• Vacuolization: Formation of myelin vacuoles
• Periaxonal edema: Fluid accumulation between myelin layers
• Axonal loss: Secondary degeneration

Iron Accumulation

The mechanism of brain iron accumulation in SPG35 involves [@nbia_disorders_2015]:

• Dysregulated iron metabolism: Altered expression of iron regulatory proteins
• Increased iron uptake: Upregulation of DMT1
• Reduced ferritin: Inadequate iron sequestration
• Oxidative stress: Iron-catalyzed ROS production

Oligodendrocyte Dysfunction

FA2H deficiency leads to oligodendrocyte impairment [@fa2h_cellular_2016]:

• ER stress: Accumulation of misfolded proteins
• Unfolded protein response (UPR): Activation of adaptive pathways
• Apoptosis: Cell death in severe cases
• Metabolic dysfunction: Impaired energy metabolism

Disease Phenotype

Core Clinical Features

The presentation of SPG35 is variable but includes [@spg35_phenotype_2021]:

Spastic Paraplegia

• Progressive spasticity: Bilateral lower limb involvement
• Motor regression: Loss of ambulation over time
• Hypertonia: Increased muscle tone
• Babinski sign: Positive plantar response

Neurological Complications

• Cognitive impairment: Variable intellectual disability
• Seizures: Present in approximately 50% of patients
• Dystonia: Involuntary muscle contractions
• Ataxia: Cerebellar involvement

White Matter Abnormalities

Neuroimaging reveals characteristic findings [@white_matter_2017]:

• T2 hyperintensity: White matter signal changes
• Diffusion abnormalities: Altered water diffusion
• Atrophy: Progressive white matter volume loss
• Calcifications: In some cases

Neurodegeneration with Iron Accumulation

Some patients develop NBIA features [@nbia_disorders_2015]:

• Brain iron deposition: MRI evidence in basal ganglia
• Progressive movement disorders: Dystonia-parkinsonism
• Cognitive decline: Progressive dementia
• Visual impairment: Optic atrophy in some cases

Disease Course

• Onset: Typically in childhood (ages 2-10 years)
• Progression: Gradual decline over decades
• Ambulation: Many become wheelchair-dependent
• Life expectancy: Variable, often reduced

Therapeutic Approaches

Lipid Replacement Therapy

Therapeutic strategies focus on restoring normal lipid metabolism [@lipid_therapy_2022]:

• 2-hydroxy fatty acid supplementation: Dietary 2-OH VLCFAs
• Lecithin supplementation: Phosphatidylcholine precursor
• Omega-3 fatty acids: Anti-inflammatory effects
• Cholesterol supplementation: Myelin membrane stability

Myelin-Targeted Therapies

Approaches to promote remyelination [@myelin_biogenesis_2023]:

• Clemastine: Promoting oligodendrocyte differentiation
• Opicinumab: Anti-LINGO-1 antibody
• Q-206: Small molecule remyelination promoter
• Cell therapy: Oligodendrocyte precursor transplantation

Iron Chelation

For patients with iron accumulation:

• Deferoxamine: Iron chelation therapy
• Deferasirox: Oral chelator
• Ferroportin modulators: Iron export enhancement

Gene Therapy

Future therapeutic approaches include [@fa2h_therapy_2018]:

• AAV-mediated FA2H delivery: Gene replacement
• CRISPR-based correction: Direct gene editing
• mRNA delivery: Transient protein expression
• Small molecule correctors: Pharmacological chaperones

Symptomatic Management

Supportive care includes:

• Spasticity management: Baclofen, botulinum toxin
• Seizure control: Antiepileptic medications
• Physical therapy: Maintaining mobility
• Occupational therapy: Daily living adaptations

Animal Models

Several animal models have been developed to study FA2H deficiency:

Knockout Mouse

The FA2H-null mouse model demonstrates:

• Severe hypomyelinaton: Near absence of CNS myelin
• Motor deficits: Ataxia and spasticity
• Premature death: Reduced lifespan
• Iron accumulation: Brain iron deposition

Conditional Knockout

Tissue-specific knockouts reveal:

• Oligodendrocyte-specific deletion: Myelin phenotype
• Astrocyte-specific deletion: Mild phenotype
• Neuron-specific deletion: No significant phenotype

Zebrafish Model

Zebrafish studies demonstrate:

• Developmental myelination defects: Visible in live animals
• Behavioral abnormalities: Swimming deficits
• Drug screening: Platform for therapeutic discovery

Protein Interactions and Pathway Involvement

FA2H-Interacting Proteins

FA2H interacts with several key proteins involved in lipid metabolism and myelin maintenance:

Lipid Metabolism Enzymes

• CYP4F2: Omega-hydroxylase that acts in parallel with FA2H
• ELOVL4: Elongase involved in very-long-chain fatty acid synthesis
• SCD1: Stearoyl-CoA desaturase for monounsaturated fatty acid synthesis
• FASN: Fatty acid synthase for de novo fatty acid synthesis

Myelin Proteins

• PLP1 (Proteolipid protein 1): Major myelin protein requiring proper lipid environment
• MBP (Myelin basic protein): Stabilizes myelin multilayers
• CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase): Associates with myelin membranes
• MAG (Myelin-associated glycoprotein): Axonal recognition and maintenance

Iron Metabolism Proteins

• Ferritin (FTH/FTL): Iron storage protein
• Transferrin receptor (TFRC): Cellular iron uptake
• DMT1 (SLC11A2): Divalent metal transporter
• Ferroportin (SLC40A1): Cellular iron export

Signaling Pathways Affected

FA2H deficiency impacts several cellular signaling pathways:

PI3K/Akt Pathway

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is dysregulated:

• Akt phosphorylation: Reduced in FA2H-deficient oligodendrocytes
• mTOR signaling: Altered downstream of Akt
• Cell survival: Pro-apoptotic signaling predominates

MAPK/ERK Pathway

The mitogen-activated protein kinase pathway shows changes:

• ERK1/2 activation: Reduced phosphorylation
• Cell differentiation: Impaired oligodendrocyte maturation
• Myelin gene expression: Downregulated PLP1, MBP

AMPK Pathway

Adenosine monophosphate-activated protein kinase (AMPK) is affected:

• Energy sensing: Activated due to metabolic stress
• mTORC1 inhibition: Attempts to restore homeostasis
• Autophagy induction: May contribute to oligodendrocyte death

Cellular Processes Affected

ER Stress Response

FA2H deficiency induces endoplasmic reticulum stress:

• UPR activation: Unfolded protein response pathways
• CHOP expression: Pro-apoptotic transcription factor
• XBP1 splicing: Adaptive UPR response
• Apoptosis: Cell death in severely affected cells

Autophagy

Autophagy is dysregulated:

• LC3 conversion: Altered autophagosome formation
• p62 accumulation: Impaired autophagic clearance
• Mitophagy: Mitochondrial quality control affected

Mitochondrial Function

Mitochondria are impacted:

• ATP production: Reduced efficiency
• ROS generation: Increased reactive oxygen species
• Membrane potential: Altered mitochondrial transmembrane potential

Cellular Vulnerability Patterns

Oligodendrocyte-Specific Vulnerabilities

Oligodendrocytes show particular sensitivity to FA2H loss:

Development

• Precursor differentiation: Impaired maturation to mature oligodendrocytes
• Process extension: Reduced myelin sheet formation
• Survival: Increased apoptosis during differentiation

Function

• Myelin synthesis: Unable to produce proper myelin lipids
• Axonal support: Failure to provide metabolic support to axons
• Node of Ranvier: Altered paranodal organization

Astrocyte Interactions

Astrocytes respond to FA2H deficiency:

• Reactive gliosis: Astrocyte activation and proliferation
• Cytokine release: Pro-inflammatory cytokine production
• Iron regulation: Altered brain iron handling

Neuronal Involvement

Neurons show secondary degeneration:

• Axonal transport defects: Impaired cargo trafficking
• Synaptic dysfunction: Altered neurotransmitter release
• Wallerian degeneration: Secondary to myelin loss

Biochemical Abnormalities

Lipid Profile Changes

FA2H deficiency leads to characteristic lipid alterations:

• 2-hydroxy fatty acids: Severely reduced in brain tissue
• C24:0 and C26:0 fatty acids: Accumulate as compensatory mechanism
• Cerebrosides: Reduced galactosylceramide and sulfatides
• Cholesterol: Altered membrane distribution

Metal Ion Dysregulation

Iron and other metals are affected:

• Brain iron: Increased accumulation in basal ganglia
• Zinc: Altered cellular distribution
• Copper: Potential secondary dysregulation
• Manganese: May show altered handling

Oxidative Stress Markers

Oxidative stress is elevated:

• 8-OHdG: Increased DNA oxidation
• 4-HNE: Lipid peroxidation product
• Protein carbonyls: Oxidized protein accumulation
• Glutathione: Reduced antioxidant capacity

Management Considerations

Multidisciplinary Care

Comprehensive management requires multiple specialties:

• Neurology: Primary care, medication management
• Genetics: Genetic counseling, family planning
• Ophthalmology: Visual assessment, monitoring for optic atrophy
• Orthopedics: Management of contractures, scoliosis
• Psychiatry/psychology: Cognitive and behavioral support

Emerging Therapies

Several therapeutic approaches are under investigation:

Small Molecule Therapies

• Fingolimod (FTY720): Promotes oligodendrocyte precursor differentiation
• Liraglutide: GLP-1 receptor agonist with neuroprotective effects
• Clemanstine: Promyelination through M1 muscarinic antagonism

Cell-Based Therapies

• OPC transplantation: Oligodendrocyte precursor cell delivery
• Mesenchymal stem cells: Paracrine neuroprotective effects
• iPSC-derived oligodendrocytes: Patient-specific cell therapy

Nutritional Interventions

• Dietary VLCFA supplementation: Exogenous 2-hydroxy fatty acids
• Phosphatidylcholine: Myelin membrane precursor
• Omega-3 fatty acids: Anti-inflammatory, pro-myelination
• Coenzyme Q10: Mitochondrial support

Key Publications

Diagnostic Considerations

Genetic Testing

Molecular diagnosis involves:

• Sequencing: Full FA2H coding region
• Deletion/duplication analysis: Detects larger rearrangements
• Panel testing: Multi-gene HSP panels
• Whole exome sequencing: For variant identification

Biomarkers

Investigational biomarkers include:

• 2-hydroxy sphingolipids: Reduced in serum/CSF
• VLCFA levels: Elevated very-long-chain fatty acids
• Neurofilament light chain (NfL): Marker of axonal injury
• Ferritin: Elevated in NBIA phenotype

Imaging

Neuroimaging findings:

• MRI brain: White matter abnormalities, iron deposition
• MRS: Metabolic changes in affected regions
• DTI: Diffusion tensor abnormalities
• SWI: Susceptibility-weighted imaging for iron

Key Publications

See Also

• [Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia)
• [Hereditary Spastic Paraplegia 35](/diseases/hereditary-spastic-paraplegia-35)
• [Spastic Paraplegia 35 with Iron Accumulation](/diseases/spastic-paraplegia-35-with-iron-accumulation)
• [Neurodegeneration with Brain Iron Accumulation](/diseases/neurodegeneration-brain-iron-accumulation)
• [White Matter Disorders](/diseases/white-matter-disorders)
• [Myelin Disorders](/mechanisms/myelin-disorders)
• [Lipid Metabolism in Neurodegeneration](/mechanisms/lipid-metabolism-neurodegeneration)
• [Oligodendrocyte Function](/cell-types/oligodendrocytes)
• [Mitochondrial Disorders](/diseases/mitochondrial-disorders)

External Links

• [NCBI Gene: SPG35](https://www.ncbi.nlm.nih.gov/gene/64080)
• [UniProt: SPG35](https://www.uniprot.org/uniprotkb/Q8IWA4/entry)
• [OMIM: 610672](https://www.omim.org/entry/610672)
• [GeneReviews: FA2H-Related HSP](https://www.ncbi.nlm.nih.gov/books/NBK1245/)
• [HSP Foundation](https://www.hsp-research.org/)

References