Hereditary spastic paraplegia 63

Summary

Hereditary spastic paraplegia 63 (MONDO:0014305) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 381
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004325	Decreased body weight	Frequent (30-79%)
HP:0012407	Scissor gait	Frequent (30-79%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 63
Mondo ID	MONDO:0014305
OMIM	615686
Orphanet	401805
DOID	DOID:0110814
SNOMED CT	726610000
UMLS	C3810295
MedGen	816625
GARD	0017658
Is cancer (heuristic)	no

Also known as: AMPD2 autosomal recessive complex spastic paraplegia · autosomal recessive complex spastic paraplegia caused by mutation in AMPD2 · hereditary spastic paraplegia type 63 · spastic paraplegia 63, autosomal recessive · SPG63

Data availability: 381 ClinVar variants · 2 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 63

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 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, 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

381 retrieved; paginated sample, class counts are floors:

194 likely benign, 126 uncertain significance, 14 benign, 11 benign/likely benign, 11 likely pathogenic, 10 pathogenic, 9 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101075	NM_001368809.2(AMPD2):c.157del (p.Cys53fs)	AMPD2	Pathogenic	no assertion criteria provided
132813	NM_001368809.2(AMPD2):c.1859G>A (p.Arg620His)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1508575	NM_001368809.2(AMPD2):c.1698+1G>A	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705300	NM_001368809.2(AMPD2):c.1057C>T (p.Arg353Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723362	NM_001368809.2(AMPD2):c.646del (p.Leu216fs)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1991577	NM_001368809.2(AMPD2):c.-43_-24dup	AMPD2	Pathogenic	criteria provided, single submitter
2004862	NM_001368809.2(AMPD2):c.319C>T (p.Gln107Ter)	AMPD2	Pathogenic	criteria provided, single submitter
2500190	NM_001368809.2(AMPD2):c.265_277del (p.Ala89fs)	AMPD2	Pathogenic	criteria provided, single submitter
3758013	NM_001368809.2(AMPD2):c.42del (p.Lys14fs)	AMPD2	Pathogenic	criteria provided, single submitter
426650	NM_001368809.2(AMPD2):c.102_103del (p.Gly35fs)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4785536	NM_001368809.2(AMPD2):c.2007C>A (p.Tyr669Ter)	AMPD2	Pathogenic	criteria provided, single submitter
4787223	NM_001368809.2(AMPD2):c.886_887del (p.Tyr295_Pro296insTer)	AMPD2	Pathogenic	criteria provided, single submitter
4789804	NM_001368809.2(AMPD2):c.-90_-69dup	AMPD2	Pathogenic	criteria provided, single submitter
4790266	NM_001368809.2(AMPD2):c.-42dup	AMPD2	Pathogenic	criteria provided, single submitter
620339	NM_001368809.2(AMPD2):c.520G>T (p.Glu174Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2424031	NC_000001.10:g.(?108679275)(111674176_?)del	EPS8L3	Pathogenic	criteria provided, single submitter
2031731	NM_001368809.2(AMPD2):c.1408-3_1418del	AMPD2	Likely pathogenic	criteria provided, single submitter
3338426	GRCh37/hg19 1p13.3(chr1:110163633-110173775)x0	AMPD2	Likely pathogenic	no assertion criteria provided
3382962	NM_001368809.2(AMPD2):c.269del (p.Pro90fs)	AMPD2	Likely pathogenic	criteria provided, single submitter
3384023	NM_001368809.2(AMPD2):c.1471G>A (p.Gly491Arg)	AMPD2	Likely pathogenic	criteria provided, single submitter
3574021	NM_001368809.2(AMPD2):c.91+1G>T	AMPD2	Likely pathogenic	criteria provided, single submitter
3574117	NM_001368809.2(AMPD2):c.302del (p.Gln101fs)	AMPD2	Likely pathogenic	criteria provided, single submitter
3574181	NM_001368809.2(AMPD2):c.1782G>A (p.Trp594Ter)	AMPD2	Likely pathogenic	criteria provided, single submitter
3574229	NM_001368809.2(AMPD2):c.1984-2A>G	AMPD2	Likely pathogenic	criteria provided, single submitter
3751257	NM_001368809.2(AMPD2):c.861-2A>G	AMPD2	Likely pathogenic	criteria provided, single submitter
3896775	NM_001368809.2(AMPD2):c.1325del (p.Pro442fs)	AMPD2	Likely pathogenic	criteria provided, single submitter
4791019	NM_001368809.2(AMPD2):c.1080+2T>G	AMPD2	Likely pathogenic	criteria provided, single submitter
1332816	NM_001368809.2(AMPD2):c.970C>T (p.Arg324Trp)	AMPD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1613636	NM_001368809.2(AMPD2):c.223-5C>A	AMPD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183289	NM_001368809.2(AMPD2):c.1457G>A (p.Arg486Gln)	AMPD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
AMPD2	Supportive	Autosomal recessive	hereditary spastic paraplegia 63	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMPD2	Orphanet:369920	Pontocerebellar hypoplasia type 9
AMPD2	Orphanet:401805	Autosomal recessive spastic paraplegia type 63
EPS8L3	Orphanet:444	Marie Unna hereditary hypotrichosis

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
AMPD2	HGNC:469	ENSG00000116337	Q01433	AMP deaminase 2	gencc,clinvar
EPS8L3	HGNC:21297	ENSG00000198758	Q8TE67	Epidermal growth factor receptor kinase substrate 8-like protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMPD2	AMP deaminase 2	AMP deaminase plays a critical role in energy metabolism.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMPD2	Enzyme (other)	yes	3.5.4.6	AMPD, A/AMP_deam_AS, Metal_Hydrolase
EPS8L3	Scaffold/PPI	no		SH3_domain, PH-like_dom_sf, PTB

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
adenohypophysis	1
granulocyte	1
pituitary gland	1
ileal mucosa	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMPD2	262	ubiquitous	marker	adenohypophysis, pituitary gland, granulocyte
EPS8L3	161	tissue_specific	marker	mucosa of transverse colon, rectum, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMPD2	2,024
EPS8L3	632

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMPD2	Q01433	4
EPS8L3	Q8TE67	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Nucleotide salvage	1	1142.0×	0.002	AMPD2
Purine salvage	1	878.5×	0.002	AMPD2
Metabolism of nucleotides	1	300.5×	0.004	AMPD2
Metabolism	1	11.6×	0.086	AMPD2

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
cyclic purine nucleotide metabolic process	1	8426.0×	0.002	AMPD2
IMP biosynthetic process	1	2808.7×	0.002	AMPD2
IMP salvage	1	1685.2×	0.002	AMPD2
GMP salvage	1	1404.3×	0.002	AMPD2
regulation of hair cycle	1	1203.7×	0.002	EPS8L3
AMP metabolic process	1	936.2×	0.002	AMPD2
podocyte development	1	766.0×	0.003	AMPD2
GTP metabolic process	1	561.7×	0.003	AMPD2
positive regulation of ruffle assembly	1	495.6×	0.003	EPS8L3
regulation of Rho protein signal transduction	1	255.3×	0.005	EPS8L3
ATP metabolic process	1	234.1×	0.005	AMPD2
energy homeostasis	1	135.9×	0.009	AMPD2
Rho protein signal transduction	1	123.9×	0.009	EPS8L3
cholesterol homeostasis	1	78.0×	0.013	AMPD2

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
AMPD2	0	0
EPS8L3	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
AMPD2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMPD2	3.5.4.6	AMP deaminase

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	1	AMPD2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EPS8L3

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)
AMPD2	4	—
EPS8L3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.