Hereditary spastic paraplegia 28

Summary

Hereditary spastic paraplegia 28 (MONDO:0012256) is a disease caused by DDHD1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DDHD1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 396
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0006944	Abolished vibration sense	Frequent (30-79%)
HP:0007021	Pain insensitivity	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0010830	Impaired tactile sensation	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 28
Mondo ID	MONDO:0012256
MeSH	C563732
OMIM	609340
Orphanet	101008
DOID	DOID:0110779
SNOMED CT	763376002
UMLS	C1836295
MedGen	332174
GARD	0016941
Is cancer (heuristic)	no

Also known as: autosomal recessive pure spastic paraplegia caused by mutation in DDHD1 · autosomal recessive spastic paraplegia type 28 · DDHD1 autosomal recessive pure spastic paraplegia · hereditary spastic paraplegia 28 · hereditary spastic paraplegia type 28 · spastic paraplegia 28, autosomal recessive · SPG28

Data availability: 396 ClinVar variants · 5 GenCC gene-disease records.

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 › pure hereditary spastic paraplegia › hereditary spastic paraplegia 28

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 8, hereditary spastic paraplegia 12, hereditary spastic paraplegia 19, hereditary spastic paraplegia 37, hereditary spastic paraplegia 42, hereditary spastic paraplegia 41, hereditary spastic paraplegia 72, hereditary spastic paraplegia 62, hereditary spastic paraplegia 73, autosomal recessive spastic paraplegia type 71

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

396 retrieved; paginated sample, class counts are floors:

182 uncertain significance, 151 likely benign, 22 pathogenic, 14 benign, 12 conflicting classifications of pathogenicity, 10 benign/likely benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071245	NM_001160148.2(DDHD1):c.5dup (p.Asn2fs)	DDHD1	Pathogenic	criteria provided, single submitter
1120268	NM_001160148.2(DDHD1):c.1637_1638dup (p.Met547Ter)	DDHD1	Pathogenic	no assertion criteria provided
2015090	NM_001160148.2(DDHD1):c.1371G>A (p.Trp457Ter)	DDHD1	Pathogenic	criteria provided, single submitter
2020629	NM_001160148.2(DDHD1):c.184del (p.Glu62fs)	DDHD1	Pathogenic	criteria provided, single submitter
2099568	NM_001160148.2(DDHD1):c.456_463dup (p.His155fs)	DDHD1	Pathogenic	criteria provided, single submitter
2158823	NM_001160148.2(DDHD1):c.1729C>T (p.Arg577Ter)	DDHD1	Pathogenic	criteria provided, single submitter
2699071	NM_001160148.2(DDHD1):c.731del (p.His244fs)	DDHD1	Pathogenic	criteria provided, single submitter
2815864	NM_001160148.2(DDHD1):c.1996del (p.Tyr666fs)	DDHD1	Pathogenic	criteria provided, single submitter
3338263	NM_001160148.2(DDHD1):c.1824dup (p.Pro609fs)	DDHD1	Pathogenic	criteria provided, single submitter
3706662	NM_001160148.2(DDHD1):c.1473del (p.Met491fs)	DDHD1	Pathogenic	criteria provided, single submitter
3720709	NM_001160148.2(DDHD1):c.344dup (p.Leu115fs)	DDHD1	Pathogenic	criteria provided, single submitter
3721963	NM_001160148.2(DDHD1):c.702_708del (p.Cys235fs)	DDHD1	Pathogenic	criteria provided, single submitter
39671	NM_001160148.2(DDHD1):c.1766G>A (p.Arg589Gln)	DDHD1	Pathogenic	no assertion criteria provided
39672	NM_001160148.2(DDHD1):c.1874del (p.Pro624_Leu625insTer)	DDHD1	Pathogenic	no assertion criteria provided
39673	NM_001160148.2(DDHD1):c.1249C>T (p.Gln417Ter)	DDHD1	Pathogenic	no assertion criteria provided
39674	NM_001160148.2(DDHD1):c.2522-1G>T	DDHD1	Pathogenic	no assertion criteria provided
422933	NM_001160148.2(DDHD1):c.1754dup (p.Thr586fs)	DDHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4810778	NM_001160148.2(DDHD1):c.259G>T (p.Glu87Ter)	DDHD1	Pathogenic	criteria provided, single submitter
951954	NM_001160148.2(DDHD1):c.1044dup (p.Val349fs)	DDHD1	Pathogenic	criteria provided, single submitter
954039	NM_001160148.2(DDHD1):c.971del (p.Asn324fs)	DDHD1	Pathogenic	criteria provided, single submitter
989056	NM_001160148.2(DDHD1):c.246del (p.Cys83fs)	DDHD1	Pathogenic	criteria provided, single submitter
989057	NM_001160148.2(DDHD1):c.395dup (p.Gly133fs)	DDHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
989058	NM_001160148.2(DDHD1):c.510G>A (p.Trp170Ter)	DDHD1	Pathogenic	criteria provided, single submitter
1299394	NM_001160148.2(DDHD1):c.1842+1G>A	DDHD1	Likely pathogenic	criteria provided, single submitter
3779563	NM_001160148.2(DDHD1):c.1762C>T (p.Arg588Ter)	DDHD1	Likely pathogenic	criteria provided, single submitter
3899853	NM_001160148.2(DDHD1):c.1993_2437+5del	DDHD1	Likely pathogenic	criteria provided, single submitter
800955	NM_001160148.2(DDHD1):c.2444G>A (p.Arg815Lys)	DDHD1	Likely pathogenic	no assertion criteria provided
1139915	NM_001160148.2(DDHD1):c.941A>G (p.Asn314Ser)	DDHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344285	NM_001160148.2(DDHD1):c.1014T>C (p.Ala338=)	DDHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344286	NM_001160148.2(DDHD1):c.1142-7T>C	DDHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
DDHD1	Definitive	Autosomal recessive	hereditary spastic paraplegia 28	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDHD1	Orphanet:101008	Autosomal recessive spastic paraplegia type 28
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDHD1	HGNC:19714	ENSG00000100523	Q8NEL9	Phospholipase DDHD1	gencc,clinvar
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDHD1	Phospholipase DDHD1	Phospholipase A1 (PLA1) that hydrolyzes ester bonds at the sn-1 position of glycerophospholipids producing a free fatty acid and a lysophospholipid.
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDHD1	Enzyme (other)	yes	3.1.1.118	DDHD_dom, PA-PLA1
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
sperm	1
subthalamic nucleus	1
pigmented layer of retina	1
rectum	1
retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDHD1	250	ubiquitous	marker	sperm, corpus callosum, subthalamic nucleus
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP4	4,425
DDHD1	1,219

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BMP4	P12644	79.12
DDHD1	Q8NEL9	67.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 2 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
Formation of lateral plate mesoderm	1	1142.0×	0.009	BMP4
Formation of intermediate mesoderm	1	713.8×	0.009	BMP4
Specification of primordial germ cells	1	439.2×	0.009	BMP4
Kidney development	1	407.9×	0.009	BMP4
Germ layer formation at gastrulation	1	335.9×	0.009	BMP4
Formation of the nephric duct	1	317.2×	0.009	BMP4
Specification of the neural plate border	1	317.2×	0.009	BMP4
Formation of the ureteric bud	1	248.3×	0.010	BMP4
Formation of paraxial mesoderm	1	203.9×	0.011	BMP4
Elastic fibre formation	1	167.9×	0.011	BMP4
Molecules associated with elastic fibres	1	154.3×	0.011	BMP4
Synthesis of PA	1	146.4×	0.011	DDHD1
Gastrulation	1	129.8×	0.012	BMP4
Reproduction	1	95.2×	0.015	BMP4
Post-translational protein phosphorylation	1	50.1×	0.026	BMP4
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.029	BMP4
Extracellular matrix organization	1	31.6×	0.037	BMP4
Post-translational protein modification	1	9.6×	0.113	BMP4
Developmental Biology	1	7.2×	0.141	BMP4
Metabolism of proteins	1	6.2×	0.155	BMP4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate mesodermal cell differentiation	1	8426.0×	0.002	BMP4
positive regulation of cardiac muscle fiber development	1	8426.0×	0.002	BMP4
bronchus development	1	8426.0×	0.002	BMP4
bud dilation involved in lung branching	1	8426.0×	0.002	BMP4
mammary gland formation	1	8426.0×	0.002	BMP4
negative regulation of mesenchymal cell proliferation involved in ureter development	1	8426.0×	0.002	BMP4
negative regulation of glomerulus development	1	8426.0×	0.002	BMP4
regulation of mesodermal cell differentiation	1	8426.0×	0.002	BMP4
negative regulation of metanephric S-shaped body morphogenesis	1	8426.0×	0.002	BMP4
negative regulation of metanephric comma-shaped body morphogenesis	1	8426.0×	0.002	BMP4
tendon cell differentiation	1	4213.0×	0.002	BMP4
positive regulation of branching involved in lung morphogenesis	1	4213.0×	0.002	BMP4
negative regulation of glomerular mesangial cell proliferation	1	4213.0×	0.002	BMP4
negative regulation of branching involved in ureteric bud morphogenesis	1	4213.0×	0.002	BMP4
positive regulation of primary miRNA processing	1	4213.0×	0.002	BMP4
mesodermal cell fate determination	1	2808.7×	0.002	BMP4
specification of animal organ position	1	2808.7×	0.002	BMP4
regulation of cell fate commitment	1	2808.7×	0.002	BMP4
deltoid tuberosity development	1	2808.7×	0.002	BMP4
trachea development	1	2808.7×	0.002	BMP4
glomerular capillary formation	1	2808.7×	0.002	BMP4
nephric duct formation	1	2808.7×	0.002	BMP4
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis	1	2808.7×	0.002	BMP4
lens induction in camera-type eye	1	2106.5×	0.002	BMP4
prostatic bud formation	1	2106.5×	0.002	BMP4
epithelial-mesenchymal cell signaling	1	2106.5×	0.002	BMP4
negative regulation of prostatic bud formation	1	2106.5×	0.002	BMP4
regulation of protein import into nucleus	1	1685.2×	0.002	BMP4
negative regulation of striated muscle tissue development	1	1685.2×	0.002	BMP4
regulation of smooth muscle cell differentiation	1	1685.2×	0.002	BMP4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDHD1	0	0
BMP4	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
BMP4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDHD1	3.1.1.118, 3.1.1.32	phospholipid sn-1 acylhydrolase, phospholipase A1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	DDHD1
E	Difficult family or no structure, no drug	1	BMP4

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)
DDHD1	0	—
BMP4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.