Severe neurodegenerative syndrome with lipodystrophy

Summary

Severe neurodegenerative syndrome with lipodystrophy (MONDO:0014402) is a disease caused by BSCL2 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BSCL2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 106
• Phenotypes (HPO): 37
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	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:0002448	Progressive encephalopathy	Obligate (100%)
HP:0000842	Hyperinsulinemia	Very frequent (80-99%)
HP:0000855	Insulin resistance	Very frequent (80-99%)
HP:0003758	Reduced subcutaneous adipose tissue	Very frequent (80-99%)
HP:0007272	Progressive psychomotor deterioration	Very frequent (80-99%)
HP:0009064	Generalized lipodystrophy	Very frequent (80-99%)
HP:0025128	Reduced intraabdominal adipose tissue	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002275	Poor motor coordination	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002066	Gait ataxia	Occasional (5-29%)
HP:0002230	Generalized hirsutism	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002273	Tetraparesis	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0002451	Limb dystonia	Occasional (5-29%)
HP:0002529	Neuronal loss in central nervous system	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0002133	Status epilepticus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe neurodegenerative syndrome with lipodystrophy
Mondo ID	MONDO:0014402
OMIM	615924
Orphanet	363400
UMLS	C4014700
MedGen	863137
GARD	0017552
Is cancer (heuristic)	no

Also known as: encephalopathy, progressive, with or without lipodystrophy · PELD · severe neurodegenerative syndrome due to BSCL2 deficiency

Data availability: 106 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › severe neurodegenerative syndrome with lipodystrophy

Related subtypes (10): congenital generalized lipodystrophy, lipodystrophy due to peptidic growth factors deficiency, Wiedemann-Rautenstrauch syndrome, SHORT syndrome, lipodystrophy-intellectual disability-deafness syndrome, Keppen-Lubinsky syndrome, lipoatrophy with diabetes, leukomelanodermic papules, liver steatosis, and hypertrophic cardiomyopathy, mandibuloacral dysplasia, Berardinelli-Seip congenital lipodystrophy, familial partial lipodystrophy

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

106 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 15 conflicting classifications of pathogenicity, 6 likely benign, 6 pathogenic, 6 likely pathogenic, 4 benign, 4 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
143858	NM_001122955.4(BSCL2):c.985C>T (p.Arg329Ter)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
372120	NM_001122955.4(BSCL2):c.974dup (p.Ile326fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
393432	NM_001122955.4(BSCL2):c.631-1G>C	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4535	NM_001122955.4(BSCL2):c.509_513del (p.Tyr170fs)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4536	NM_001122955.4(BSCL2):c.517dup (p.Thr173fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4540	NM_001122955.4(BSCL2):c.828del (p.Tyr277fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
844412	NM_001122955.4(BSCL2):c.486+1G>A	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
947075	NM_001122955.4(BSCL2):c.1361_1386del (p.Arg454fs)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372119	NM_001122955.4(BSCL2):c.864-2A>G	HNRNPUL2-BSCL2	Pathogenic	criteria provided, single submitter
4539	NM_001122955.4(BSCL2):c.826G>C (p.Ala276Pro)	HNRNPUL2-BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
1802590	NM_001122955.4(BSCL2):c.1076dup (p.Pro359_Glu360insTer)	BSCL2	Likely pathogenic	criteria provided, single submitter
3383977	NM_001122955.4(BSCL2):c.825dup (p.Ala276fs)	BSCL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599919	NM_001122955.4(BSCL2):c.1048C>T (p.Arg350Ter)	BSCL2	Likely pathogenic	criteria provided, single submitter
3599928	NM_001122955.4(BSCL2):c.766-1G>A	BSCL2	Likely pathogenic	criteria provided, single submitter
3599931	NM_001122955.4(BSCL2):c.512_519del (p.Arg171fs)	BSCL2	Likely pathogenic	criteria provided, single submitter
930514	NM_001122955.4(BSCL2):c.974del (p.Gly325fs)	BSCL2	Likely pathogenic	criteria provided, single submitter
1032980	NM_001122955.4(BSCL2):c.1360C>T (p.Arg454Ter)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
143859	NM_001122955.4(BSCL2):c.538G>T (p.Glu180Ter)	BSCL2	Conflicting classifications of pathogenicity	no assertion criteria provided
210545	NM_001122955.4(BSCL2):c.1031C>T (p.Ser344Phe)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246509	NM_001122955.4(BSCL2):c.299G>T (p.Cys100Phe)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3599921	NM_001122955.4(BSCL2):c.894C>T (p.Cys298=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3599923	NM_001122955.4(BSCL2):c.864A>G (p.Arg288=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
393431	NM_001122955.4(BSCL2):c.1299TTCTGC[1] (p.434SA[1])	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411581	NM_001122955.4(BSCL2):c.1145C>T (p.Ser382Leu)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
543290	NM_001122955.4(BSCL2):c.1101G>A (p.Pro367=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569480	NM_001122955.4(BSCL2):c.359A>G (p.Tyr120Cys)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
617998	NM_001122955.4(BSCL2):c.934G>A (p.Val312Ile)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
700938	NM_001122955.4(BSCL2):c.532C>G (p.Leu178Val)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952140	NM_001122955.4(BSCL2):c.1004A>C (p.Gln335Pro)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
955662	NM_001122955.4(BSCL2):c.466A>G (p.Thr156Ala)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 4 · 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
BSCL2	Definitive	Autosomal recessive	congenital generalized lipodystrophy type 2	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	gencc,clinvar
HNRNPUL2-BSCL2	HGNC:49189	ENSG00000234857		HNRNPUL2-BSCL2 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BSCL2	Other/Unknown	no		Seipin
HNRNPUL2-BSCL2	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pituitary gland	1
primary visual cortex	1
superior frontal gyrus	1
islet of Langerhans	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
HNRNPUL2-BSCL2	134		yes	stromal cell of endometrium, ventricular zone, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BSCL2	1,503
HNRNPUL2-BSCL2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BSCL2	Q96G97	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
lipid droplet formation	1	991.3×	0.003	BSCL2
lipid droplet organization	1	936.2×	0.003	BSCL2
negative regulation of lipid catabolic process	1	842.6×	0.003	BSCL2
lipid storage	1	543.6×	0.003	BSCL2
lipid catabolic process	1	244.2×	0.006	BSCL2
fat cell differentiation	1	181.2×	0.006	BSCL2
positive regulation of cold-induced thermogenesis	1	163.6×	0.006	BSCL2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BSCL2	0	0
HNRNPUL2-BSCL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	2	BSCL2, HNRNPUL2-BSCL2

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)
BSCL2	0	—
HNRNPUL2-BSCL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04113317	PHASE3	COMPLETED	Granulocyte-Colony Stimulating Factor (G-CSF) as Optimizing Therapy for Pediatric Liver Transplantation