Hereditary spastic paraplegia 35

Summary

Hereditary spastic paraplegia 35 (MONDO:0012866) is a disease caused by FA2H (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FA2H (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 137
• Phenotypes (HPO): 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		38	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0009027	Foot dorsiflexor weakness	Very frequent (80-99%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001285	Spastic tetraparesis	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0006895	Lower limb hypertonia	Frequent (30-79%)
HP:0007325	Generalized dystonia	Frequent (30-79%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Frequent (30-79%)
HP:0007371	Corpus callosum atrophy	Frequent (30-79%)
HP:0011448	Ankle clonus	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000298	Mask-like facies	Occasional (5-29%)
HP:0000467	Neck muscle weakness	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002454	Eye of the tiger anomaly of globus pallidus	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0005656	Positional foot deformity	Occasional (5-29%)
HP:0006879	Pontocerebellar atrophy	Occasional (5-29%)
HP:0010677	Enuresis nocturna	Occasional (5-29%)
HP:0011096	Peripheral demyelination	Occasional (5-29%)
HP:0100515	Pollakisuria	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 35
Mondo ID	MONDO:0012866
MeSH	C567311
OMIM	612319
Orphanet	171629
DOID	DOID:0110786
SNOMED CT	764688002
UMLS	C3496228
MedGen	501249
GARD	0010538
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 35 · FA2H hereditary spastic paraplegia · hereditary spastic paraplegia 35 · hereditary spastic paraplegia caused by mutation in FA2H · hereditary spastic paraplegia type 35 · spastic paraplegia 35, autosomal recessive · SPG35

Data availability: 137 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › hereditary spastic paraplegia 35

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

137 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 25 conflicting classifications of pathogenicity, 16 likely pathogenic, 14 pathogenic/likely pathogenic, 13 benign, 12 pathogenic, 6 benign/likely benign, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012406	NM_024306.5(FA2H):c.379C>T (p.Arg127Ter)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1041793	NM_024306.5(FA2H):c.941_945del (p.Thr314fs)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1043	NM_024306.5(FA2H):c.786+1G>A	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210342	NM_024306.5(FA2H):c.131del (p.Pro44fs)	FA2H	Pathogenic	criteria provided, multiple submitters, no conflicts
1373656	NM_024306.5(FA2H):c.1A>G (p.Met1Val)	FA2H	Pathogenic	criteria provided, multiple submitters, no conflicts
1685805	NM_024306.5(FA2H):c.506+1G>C	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705931	NM_024306.5(FA2H):c.674T>C (p.Leu225Pro)	FA2H	Pathogenic	criteria provided, single submitter
1803968	NM_024306.5(FA2H):c.786G>A (p.Lys262=)	FA2H	Pathogenic	criteria provided, single submitter
208728	NM_024306.5(FA2H):c.565C>T (p.Arg189Ter)	FA2H	Pathogenic	criteria provided, multiple submitters, no conflicts
2637704	NM_024306.5(FA2H):c.911dup (p.Leu305fs)	FA2H	Pathogenic	criteria provided, multiple submitters, no conflicts
2671835	NM_024306.5(FA2H):c.363+2T>C	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30871	NM_024306.5(FA2H):c.159_176del (p.Arg53_Ile58del)	FA2H	Pathogenic	criteria provided, multiple submitters, no conflicts
30873	NM_024306.5(FA2H):c.510_511del (p.Tyr170_Ser171delinsTer)	FA2H	Pathogenic	criteria provided, multiple submitters, no conflicts
31624	NM_024306.5(FA2H):c.707T>C (p.Phe236Ser)	FA2H	Pathogenic	no assertion criteria provided
31625	NG_017070.1:g.(39810_52446)(66877?)del	FA2H	Pathogenic	no assertion criteria provided
3776207	NM_024306.5(FA2H):c.581del (p.Gly194fs)	FA2H	Pathogenic	criteria provided, single submitter
406877	NM_024306.5(FA2H):c.443C>T (p.Pro148Leu)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449574	NM_024306.5(FA2H):c.130C>T (p.Pro44Ser)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4540448	NM_024306.5(FA2H):c.704G>A (p.Arg235His)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488512	NM_024306.5(FA2H):c.102C>G (p.Tyr34Ter)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803271	NM_024306.5(FA2H):c.340_363+8del	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930104	NM_024306.5(FA2H):c.620C>T (p.Thr207Met)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
936701	NM_024306.5(FA2H):c.589C>T (p.Arg197Ter)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
948467	NM_024306.5(FA2H):c.806G>A (p.Arg269His)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989137	NM_024306.5(FA2H):c.190G>T (p.Gly64Trp)	FA2H	Pathogenic	criteria provided, single submitter
989138	NM_024306.5(FA2H):c.822del (p.Val275fs)	FA2H	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424726	NM_024306.4(FA2H):c.[117C>A];[150_159dupGCGGGCCAGG]		Likely pathogenic	no assertion criteria provided
1184459	NM_024306.5(FA2H):c.798C>G (p.Asp266Glu)	FA2H	Likely pathogenic	no assertion criteria provided
1184460	NM_024306.5(FA2H):c.782dup (p.His261fs)	FA2H	Likely pathogenic	no assertion criteria provided
1684571	NM_024306.5(FA2H):c.115_121del (p.Phe39fs)	FA2H	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FA2H	Definitive	Autosomal recessive	hereditary spastic paraplegia 35	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FA2H	Orphanet:171629	Autosomal recessive spastic paraplegia type 35
FA2H	Orphanet:329308	Fatty acid hydroxylase-associated neurodegeneration

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FA2H	HGNC:21197	ENSG00000103089	Q7L5A8	Fatty acid 2-hydroxylase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FA2H	Fatty acid 2-hydroxylase	Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FA2H	Enzyme (other)	yes	1.14.18.6	Cyt_B5-like_heme/steroid-bd, Fatty_acid_hydroxylase, Scs7

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FA2H	213	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FA2H	2,099

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FA2H	Q7L5A8	85.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sphingolipid de novo biosynthesis	1	285.5×	0.004	FA2H

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of sebum secreting cell proliferation	1	8426.0×	7e-04	FA2H
regulation of acinar cell proliferation	1	8426.0×	7e-04	FA2H
sebaceous gland cell differentiation	1	5617.3×	7e-04	FA2H
glucosylceramide biosynthetic process	1	5617.3×	7e-04	FA2H
galactosylceramide biosynthetic process	1	3370.4×	8e-04	FA2H
central nervous system myelin maintenance	1	2808.7×	8e-04	FA2H
plasma membrane raft organization	1	2808.7×	8e-04	FA2H
regulation of hair cycle	1	2407.4×	8e-04	FA2H
lipid modification	1	1872.4×	9e-04	FA2H
peripheral nervous system myelin maintenance	1	1532.0×	1e-03	FA2H
establishment of skin barrier	1	455.5×	0.003	FA2H
ceramide biosynthetic process	1	421.3×	0.003	FA2H
sphingolipid biosynthetic process	1	358.6×	0.003	FA2H
fatty acid biosynthetic process	1	351.1×	0.003	FA2H
fatty acid metabolic process	1	193.7×	0.005	FA2H

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FA2H	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FA2H	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FA2H	1.14.18.6	4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	FA2H
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FA2H	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.