Hereditary spastic paraplegia 39

Summary

Hereditary spastic paraplegia 39 (MONDO:0012787) is a disease caused by PNPLA6 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PNPLA6 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,259
• 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:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006827	Atrophy of the spinal cord	Frequent (30-79%)
HP:0007002	Motor axonal neuropathy	Frequent (30-79%)
HP:0009055	Generalized limb muscle atrophy	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002066	Gait ataxia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 39
Mondo ID	MONDO:0012787
MeSH	C567433
OMIM	612020
Orphanet	139480
DOID	DOID:0110790
SNOMED CT	719103009
UMLS	C2677586
MedGen	383142
GARD	0004924
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 39 · hereditary spastic paraplegia caused by mutation in PNPLA6 · hereditary spastic paraplegia type 39 · NTE related motor neuron disorder · NTE-related motor neuron disorder · NTEMND · PNPLA6 hereditary spastic paraplegia · spastic paraplegia 39 · spastic paraplegia 39, autosomal recessive · spastic paraplegia due to neuropathy target esterase mutation · spastic paraplegia due to NTE mutation · SPG39

Data availability: 1,259 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 39

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 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, 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

Subtypes (1): PNPLA6-related spastic paraplegia with or without ataxia

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

600 retrieved; paginated sample, class counts are floors:

311 likely benign, 224 uncertain significance, 21 benign, 19 pathogenic, 11 conflicting classifications of pathogenicity, 8 likely pathogenic, 4 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
101039	NM_001166114.2(PNPLA6):c.3143C>T (p.Thr1048Ile)	PNPLA6	Pathogenic	criteria provided, single submitter
101041	NM_001166114.2(PNPLA6):c.3298G>A (p.Val1100Met)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101044	NM_001166114.2(PNPLA6):c.2489G>A (p.Gly830Glu)	PNPLA6	Pathogenic/Likely pathogenic	no assertion criteria provided
1027474	NM_001166114.2(PNPLA6):c.4051C>T (p.Arg1351Ter)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071668	NM_001166114.2(PNPLA6):c.2285_2286dup (p.Ser763fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1074568	NC_000019.9:g.(?7604804)(7607970_?)del	PNPLA6	Pathogenic	criteria provided, single submitter
1075623	NM_001166114.2(PNPLA6):c.2185-1G>T	PNPLA6	Pathogenic	criteria provided, single submitter
1195875	NM_001166114.2(PNPLA6):c.3104C>T (p.Ser1035Leu)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353395	NM_001166114.2(PNPLA6):c.1229dup (p.Ser411fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1375988	NM_001166114.2(PNPLA6):c.2839_2840dup (p.Arg949fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1377033	NM_001166114.2(PNPLA6):c.3296A>G (p.Tyr1099Cys)	PNPLA6	Pathogenic	criteria provided, single submitter
1381532	NM_001166114.2(PNPLA6):c.1692dup (p.Val565fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1383806	NM_001166114.2(PNPLA6):c.1684_1685del (p.Cys562fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1390532	NM_001166114.2(PNPLA6):c.897C>A (p.Tyr299Ter)	PNPLA6	Pathogenic	criteria provided, single submitter
1402204	NM_001166114.2(PNPLA6):c.2046C>A (p.Tyr682Ter)	PNPLA6	Pathogenic	criteria provided, single submitter
1421744	NM_001166114.2(PNPLA6):c.699_700del (p.Cys234fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1440677	NC_000019.10:g.7555609dup	PNPLA6	Pathogenic	criteria provided, single submitter
1452950	NM_001166114.2(PNPLA6):c.1606C>T (p.Gln536Ter)	PNPLA6	Pathogenic	criteria provided, single submitter
1455277	NM_001166114.2(PNPLA6):c.3361del (p.Leu1121fs)	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
183693	NM_001166114.2(PNPLA6):c.3266G>A (p.Arg1089Gln)	PNPLA6	Pathogenic	criteria provided, multiple submitters, no conflicts
1913453	NM_001166114.2(PNPLA6):c.1751del (p.Ile584fs)	PNPLA6	Pathogenic	criteria provided, single submitter
1975411	NM_001166114.2(PNPLA6):c.3851T>A (p.Leu1284Ter)	PNPLA6	Pathogenic	criteria provided, single submitter
2064887	NM_001166114.2(PNPLA6):c.1968C>A (p.Cys656Ter)	PNPLA6	Pathogenic	criteria provided, single submitter
1047508	NM_001166114.2(PNPLA6):c.913C>T (p.Arg305Trp)	PNPLA6	Likely pathogenic	criteria provided, single submitter
1493871	NM_001166114.2(PNPLA6):c.1005+1G>T	PNPLA6	Likely pathogenic	criteria provided, single submitter
1496092	NM_001166114.2(PNPLA6):c.3355G>C (p.Gly1119Arg)	PNPLA6	Likely pathogenic	criteria provided, single submitter
156539	NM_001166114.2(PNPLA6):c.3409C>T (p.Arg1137Cys)	PNPLA6	Likely pathogenic	criteria provided, single submitter
1705437	NM_001166114.2(PNPLA6):c.2575C>T (p.Arg859Ter)	PNPLA6	Likely pathogenic	criteria provided, single submitter
183692	NM_001166114.2(PNPLA6):c.3496G>A (p.Gly1166Ser)	PNPLA6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1956913	NM_001166114.2(PNPLA6):c.413+1G>A	PNPLA6	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 6 · 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
PNPLA6	Strong	Autosomal recessive	hereditary spastic paraplegia 39	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNPLA6	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
PNPLA6	Orphanet:1180	Ataxia-hypogonadism-choroidal dystrophy syndrome
PNPLA6	Orphanet:139480	Autosomal recessive spastic paraplegia type 39
PNPLA6	Orphanet:2377	Laurence-Moon syndrome
PNPLA6	Orphanet:3363	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome
MCOLN1	Orphanet:578	Mucolipidosis type IV

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
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	gencc,clinvar
MCOLN1	HGNC:13356	ENSG00000090674	Q9GZU1	Mucolipin-1	clinvar
ZNF358	HGNC:16838	ENSG00000198816	Q9NW07	Zinc finger protein 358	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
MCOLN1	Mucolipin-1	Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis.
ZNF358	Zinc finger protein 358	May be involved in transcriptional regulation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
MCOLN1	Other/Unknown	no		PKD1_2_channel, Mucolipin, ML1_ELD
ZNF358	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, C2H2-ZF_Transcription_Reg

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
granulocyte	1
metanephros cortex	1
upper lobe of left lung	1
right adrenal gland	1
right adrenal gland cortex	1
spleen	1
apex of heart	1
lower esophagus muscularis layer	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPLA6	276	ubiquitous	marker	granulocyte, metanephros cortex, upper lobe of left lung
MCOLN1	255	ubiquitous	marker	spleen, right adrenal gland cortex, right adrenal gland
ZNF358	234	ubiquitous	marker	apex of heart, right frontal lobe, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPLA6	2,676
MCOLN1	1,412
ZNF358	783

Intra-cohort edges

A	B	Sources
MCOLN1	PNPLA6	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCOLN1	Q9GZU1	25

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA6	Q8IY17	69.75
ZNF358	Q9NW07	64.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Glycerophospholipid catabolism	1	815.7×	0.009	PNPLA6
TRP channels	1	203.9×	0.010	MCOLN1
Transferrin endocytosis and recycling	1	184.2×	0.010	MCOLN1
Iron uptake and transport	1	173.0×	0.010	MCOLN1
Stimuli-sensing channels	1	68.0×	0.021	MCOLN1
Ion channel transport	1	48.0×	0.024	MCOLN1
Transport of small molecules	1	12.6×	0.078	MCOLN1

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
calcium ion export	1	1404.3×	0.007	MCOLN1
positive regulation of lysosome organization	1	1404.3×	0.007	MCOLN1
iron ion transmembrane transport	1	802.5×	0.007	MCOLN1
cellular response to pH	1	702.2×	0.007	MCOLN1
transferrin transport	1	510.7×	0.008	MCOLN1
phagosome maturation	1	401.2×	0.008	MCOLN1
glycerophospholipid catabolic process	1	351.1×	0.008	PNPLA6
phosphatidylcholine metabolic process	1	267.5×	0.009	PNPLA6
monoatomic cation transport	1	255.3×	0.009	MCOLN1
neural tube development	1	175.5×	0.010	ZNF358
embryonic forelimb morphogenesis	1	165.2×	0.010	ZNF358
intracellular zinc ion homeostasis	1	160.5×	0.010	MCOLN1
stem cell population maintenance	1	140.4×	0.011	ZNF358
autophagosome maturation	1	117.0×	0.012	MCOLN1
release of sequestered calcium ion into cytosol	1	114.6×	0.012	MCOLN1
protein homotetramerization	1	79.1×	0.016	MCOLN1
calcium ion transmembrane transport	1	70.2×	0.017	MCOLN1
cellular response to calcium ion	1	66.9×	0.017	MCOLN1
adaptive immune response	1	28.1×	0.037	MCOLN1
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZNF358

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PNPLA6	0	0
MCOLN1	0	0
ZNF358	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MCOLN1	9	Binding:9
PNPLA6	1	Binding:1

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

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	0
E	Difficult family or no structure, no drug	3	PNPLA6, MCOLN1, ZNF358

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PNPLA6	1	—
MCOLN1	9	—
ZNF358	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.