Hereditary spastic paraplegia 54

Summary

Hereditary spastic paraplegia 54 (MONDO:0014018) is a disease caused by DDHD2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DDHD2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 259
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0007766	Optic disc hypoplasia	Frequent (30-79%)
HP:0008366	Foot joint contracture	Frequent (30-79%)
HP:0030891	Periventricular white matter hyperintensities	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006970	Periventricular leukomalacia	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 54
Mondo ID	MONDO:0014018
OMIM	615033
Orphanet	320380
DOID	DOID:0110806
SNOMED CT	723824005
UMLS	C3539495
MedGen	761341
GARD	0017475
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in DDHD2 · autosomal recessive spastic paraplegia type 54 · DDHD2 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 54 · spastic paraplegia 54, autosomal recessive · SPG54

Data availability: 259 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 54

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

259 retrieved; paginated sample, class counts are floors:

103 uncertain significance, 97 likely benign, 20 pathogenic, 13 conflicting classifications of pathogenicity, 10 likely pathogenic, 8 benign/likely benign, 4 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101083	NM_015214.3(DDHD2):c.1057+5C>G	DDHD2	Pathogenic	criteria provided, single submitter
1076234	NC_000008.10:g.(?38095036)(38095747_?)del	DDHD2	Pathogenic	criteria provided, single submitter
1344306	NM_015214.3(DDHD2):c.856C>T (p.Gln286Ter)	DDHD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2067256	NM_015214.3(DDHD2):c.196C>T (p.Gln66Ter)	DDHD2	Pathogenic	criteria provided, single submitter
2202619	NM_015214.3(DDHD2):c.815G>A (p.Trp272Ter)	DDHD2	Pathogenic	criteria provided, single submitter
2694153	NM_015214.3(DDHD2):c.453_454del (p.Lys152fs)	DDHD2	Pathogenic	criteria provided, single submitter
3068415	NM_015214.3(DDHD2):c.819_820del (p.His273fs)	DDHD2	Pathogenic	criteria provided, single submitter
3665854	NM_015214.3(DDHD2):c.344G>A (p.Trp115Ter)	DDHD2	Pathogenic	criteria provided, single submitter
39676	NM_015214.3(DDHD2):c.1803dup (p.Thr602fs)	DDHD2	Pathogenic	no assertion criteria provided
39677	NM_015214.3(DDHD2):c.2057del (p.Glu686fs)	DDHD2	Pathogenic	no assertion criteria provided
39679	NM_015214.3(DDHD2):c.1978G>C (p.Asp660His)	DDHD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39680	NM_015214.3(DDHD2):c.1546C>T (p.Arg516Ter)	DDHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
39681	NM_015214.3(DDHD2):c.859C>T (p.Arg287Ter)	DDHD2	Pathogenic/Likely pathogenic	no assertion criteria provided
452548	NM_015214.3(DDHD2):c.985C>T (p.Arg329Ter)	DDHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
473074	NM_015214.3(DDHD2):c.371del (p.Lys124fs)	DDHD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4738058	NM_015214.3(DDHD2):c.1240_1243del (p.Glu414fs)	DDHD2	Pathogenic	criteria provided, single submitter
503722	NM_015214.3(DDHD2):c.1386dup (p.Ile463fs)	DDHD2	Pathogenic	criteria provided, single submitter
540287	NM_015214.3(DDHD2):c.1803del (p.Phe601fs)	DDHD2	Pathogenic	criteria provided, single submitter
634496	NM_015214.3(DDHD2):c.694C>T (p.Arg232Ter)	DDHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
638323	NM_015214.3(DDHD2):c.334C>T (p.Arg112Ter)	DDHD2	Pathogenic	criteria provided, single submitter
653596	NM_015214.3(DDHD2):c.420C>A (p.Tyr140Ter)	DDHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
655242	NC_000008.11:g.(?38242230)(38247855_?)del	DDHD2	Pathogenic	criteria provided, single submitter
988995	NM_015214.3(DDHD2):c.1529G>A (p.Gly510Glu)	DDHD2	Pathogenic	criteria provided, single submitter
988996	NC_000008.10:g.(?38090513)(38117639_?)del	DDHD2	Pathogenic	criteria provided, single submitter
3897894	NM_015214.3:c.[1517G>A];[694C>T]		Likely pathogenic	criteria provided, single submitter
1696332	NM_015214.3(DDHD2):c.1126-2A>G	DDHD2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709490	NM_015214.3(DDHD2):c.1217_1218del (p.Ile405_Phe406insTer)	DDHD2	Likely pathogenic	criteria provided, single submitter
2025715	NM_015214.3(DDHD2):c.1617+1G>T	DDHD2	Likely pathogenic	criteria provided, single submitter
2439662	NM_015214.3(DDHD2):c.1901delinsTCTGTGGCAGTTAA (p.Thr634delinsIleCysGlySerTer)	DDHD2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068647	NM_015214.3(DDHD2):c.1887_1890dup (p.Asp631Ter)	DDHD2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DDHD2	Definitive	Autosomal recessive	hereditary spastic paraplegia 54	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDHD2	Orphanet:320380	Autosomal recessive spastic paraplegia type 54
ADAM9	Orphanet:1872	Cone rod dystrophy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDHD2	HGNC:29106	ENSG00000085788	O94830	Triacylglycerol hydrolase DDHD2	gencc,clinvar
ADGRA2	HGNC:17849	ENSG00000020181	Q96PE1	Adhesion G protein-coupled receptor A2	clinvar
ADAM9	HGNC:216	ENSG00000168615	Q13443	Disintegrin and metalloproteinase domain-containing protein 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDHD2	Triacylglycerol hydrolase DDHD2	Diacylglycerol (DAG) and triacylglycerol (TAG) lipase required for proper lipid homeostasis in the central nervous system.
ADGRA2	Adhesion G protein-coupled receptor A2	Endothelial receptor which functions together with RECK to enable brain endothelial cells to selectively respond to Wnt7 signals (WNT7A or WNT7B).
ADAM9	Disintegrin and metalloproteinase domain-containing protein 9	Metalloprotease that cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Protease	1	12.2×	0.180
GPCR	1	8.0×	0.180
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDHD2	Other/Unknown	no		SAM, WWE_dom, DDHD_dom
ADGRA2	GPCR	yes		GPS, Cys-rich_flank_reg_C, GPCR_2_secretin-like
ADAM9	Protease	yes	3.4.24.B9	EGF, Peptidase_M12B, Disintegrin_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	2
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
endocervix	1
seminal vesicle	1
gall bladder	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDHD2	294	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ADGRA2	226	ubiquitous	marker	stromal cell of endometrium, seminal vesicle, endocervix
ADAM9	215	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAM9	1,555
ADGRA2	1,345
DDHD2	1,153

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAM9	Q13443	76.14
DDHD2	O94830	74.70
ADGRA2	Q96PE1	70.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PA	1	146.4×	0.023	DDHD2
Collagen degradation	1	87.8×	0.023	ADAM9
Degradation of the extracellular matrix	1	58.9×	0.023	ADAM9
Extracellular matrix organization	1	31.6×	0.031	ADAM9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 establishment of blood-brain barrier	1	2808.7×	0.010	ADGRA2
positive regulation of macrophage fusion	1	1123.5×	0.010	ADAM9
response to manganese ion	1	936.2×	0.010	ADAM9
regulation of chemotaxis	1	936.2×	0.010	ADGRA2
monocyte activation	1	624.1×	0.010	ADAM9
cell-cell adhesion mediated by integrin	1	510.7×	0.010	ADAM9
positive regulation of keratinocyte migration	1	432.1×	0.010	ADAM9
negative regulation of vascular endothelial growth factor signaling pathway	1	432.1×	0.010	ADGRA2
membrane protein intracellular domain proteolysis	1	401.2×	0.010	ADAM9
amyloid precursor protein catabolic process	1	401.2×	0.010	ADAM9
mitochondrial fission	1	351.1×	0.010	DDHD2
positive regulation of cell adhesion mediated by integrin	1	351.1×	0.010	ADAM9
lipid droplet organization	1	312.1×	0.010	DDHD2
positive regulation of membrane protein ectodomain proteolysis	1	312.1×	0.010	ADAM9
triglyceride catabolic process	1	267.5×	0.011	DDHD2
positive regulation of mitochondrial fission	1	255.3×	0.011	DDHD2
cell adhesion mediated by integrin	1	224.7×	0.011	ADAM9
membrane protein ectodomain proteolysis	1	216.1×	0.011	ADAM9
response to tumor necrosis factor	1	208.1×	0.011	ADAM9
sprouting angiogenesis	1	160.5×	0.013	ADGRA2
response to hydrogen peroxide	1	156.0×	0.013	ADAM9
regulation of angiogenesis	1	140.4×	0.014	ADGRA2
endothelial cell migration	1	137.0×	0.014	ADGRA2
positive regulation of protein secretion	1	114.6×	0.016	ADAM9
response to glucocorticoid	1	108.0×	0.016	ADAM9
response to calcium ion	1	106.0×	0.016	ADAM9
visual learning	1	102.1×	0.016	DDHD2
positive regulation of endothelial cell migration	1	83.8×	0.018	ADGRA2
keratinocyte differentiation	1	82.6×	0.018	ADAM9
locomotory behavior	1	59.8×	0.024	DDHD2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 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
ADAM9	3	2
DDHD2	0	0
ADGRA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ILOMASTAT	2	ADAM9
APRATASTAT	2	ADAM9
PEPSTATIN	2	ADAM9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADAM9	19	Binding:18, ADMET:1
DDHD2	2	Functional:2
ADGRA2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAM9	3.4.24.B9

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
ILOMASTAT	2	ADAM9
APRATASTAT	2	ADAM9
PEPSTATIN	2	ADAM9

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	1	ADAM9
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADGRA2
E	Difficult family or no structure, no drug	1	DDHD2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DDHD2	2	—
ADGRA2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.