progressive encephalopathy with leukodystrophy due to DECR deficiency

Summary

progressive encephalopathy with leukodystrophy due to DECR deficiency (MONDO:0014464) is a disease caused by NADK2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NADK2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 226
• Phenotypes (HPO): 28

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)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001733	Pancreatitis	Frequent (30-79%)
HP:0001947	Renal tubular acidosis	Frequent (30-79%)
HP:0001992	Organic aciduria	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002161	Hyperlysinemia	Frequent (30-79%)
HP:0002415	Leukodystrophy	Frequent (30-79%)
HP:0002448	Progressive encephalopathy	Frequent (30-79%)
HP:0002470	Nonprogressive cerebellar ataxia	Frequent (30-79%)
HP:0002478	Progressive spastic quadriplegia	Frequent (30-79%)
HP:0003206	Decreased activity of NADPH oxidase	Frequent (30-79%)
HP:0003234	Decreased circulating carnitine concentration	Frequent (30-79%)
HP:0004897	Stress/infection-induced lactic acidosis	Frequent (30-79%)
HP:0010536	Central sleep apnea	Frequent (30-79%)
HP:0010967	Abnormal circulating carnitine concentration	Frequent (30-79%)
HP:0011951	Aspiration pneumonia	Frequent (30-79%)
HP:0012547	Abnormal involuntary eye movements	Frequent (30-79%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Frequent (30-79%)
HP:0100704	Cerebral visual impairment	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive encephalopathy with leukodystrophy due to DECR deficiency
Mondo ID	MONDO:0014464
MeSH	C565624
OMIM	616034
Orphanet	431361
UMLS	C1857252
MedGen	346552
GARD	0010327
Is cancer (heuristic)	no

Also known as: 2,4-alpha dienoyl-CoA reductase deficiency · 2,4-dienoyl-CoA reductase deficiency · DECR deficiency with hyperlysinemia · DECRD · dienoyl-CoA reductase deficiency · progressive encephalopathy with leukodystrophy due to DECR deficiency

Data availability: 226 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › disorder of phospholipids, sphingolipids and fatty acids biosynthesis › progressive encephalopathy with leukodystrophy due to DECR deficiency

Related subtypes (16): Sengers syndrome, Sjogren-Larsson syndrome, Barth syndrome, megaconial type congenital muscular dystrophy, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, spinocerebellar ataxia type 38, progressive myoclonic epilepsy type 8, neutral lipid storage disease, fatty acid hydroxylase-associated neurodegeneration, hereditary sensory and autonomic neuropathy type 1, GM3 synthase deficiency, nephrotic syndrome 14, 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

226 retrieved; paginated sample, class counts are floors:

108 uncertain significance, 96 likely benign, 14 benign, 5 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
830231	NM_001085411.3(NADK2):c.956+6T>C	NADK2	Pathogenic	no assertion criteria provided
156239	NM_001085411.3(NADK2):c.1018C>T (p.Arg340Ter)	NADK2	Likely pathogenic	criteria provided, single submitter
1878982	NM_001085411.3(NADK2):c.161_186dup (p.Asp63fs)	LOC129993801	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2727557	NM_001085411.3(NADK2):c.1013-13_1013-9del	NADK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
515746	NM_001085411.3(NADK2):c.389+6T>C	NADK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
715274	NM_001085411.3(NADK2):c.349A>G (p.Ile117Val)	NADK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
798229	NM_001085411.3(NADK2):c.1225A>G (p.Met409Val)	NADK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1409057	NM_001359.2(DECR1):c.619G>T (p.Val207Leu)	DECR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1498201	NM_001359.2(DECR1):c.58G>A (p.Ala20Thr)	DECR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
638468	NM_001359.2(DECR1):c.202G>A (p.Gly68Ser)	DECR1	Uncertain significance	criteria provided, single submitter
1011392	NM_001085411.3(NADK2):c.283G>T (p.Glu95Ter)	LOC129993801	Uncertain significance	criteria provided, single submitter
1053414	NM_001085411.3(NADK2):c.5C>T (p.Thr2Ile)	LOC129993801	Uncertain significance	criteria provided, single submitter
1395871	NM_001085411.3(NADK2):c.130_136dup (p.His46fs)	LOC129993801	Uncertain significance	criteria provided, single submitter
1419239	NM_001085411.3(NADK2):c.95_107del (p.Ala32fs)	LOC129993801	Uncertain significance	criteria provided, single submitter
1437781	NM_001085411.3(NADK2):c.185C>G (p.Ala62Gly)	LOC129993801	Uncertain significance	criteria provided, single submitter
1481741	NM_001085411.3(NADK2):c.77C>T (p.Pro26Leu)	LOC129993801	Uncertain significance	criteria provided, single submitter
1498255	NM_001085411.3(NADK2):c.264T>G (p.Arg88=)	LOC129993801	Uncertain significance	criteria provided, single submitter
1951837	NM_001085411.3(NADK2):c.184G>C (p.Ala62Pro)	LOC129993801	Uncertain significance	criteria provided, single submitter
1983016	NM_001085411.3(NADK2):c.158G>A (p.Arg53His)	LOC129993801	Uncertain significance	criteria provided, single submitter
2054036	NM_001085411.3(NADK2):c.212TGG[3] (p.Val74del)	LOC129993801	Uncertain significance	criteria provided, single submitter
2078715	NM_001085411.3(NADK2):c.166G>A (p.Ala56Thr)	LOC129993801	Uncertain significance	criteria provided, single submitter
2084959	NM_001085411.3(NADK2):c.239A>G (p.Tyr80Cys)	LOC129993801	Uncertain significance	criteria provided, multiple submitters, no conflicts
2120517	NM_001085411.3(NADK2):c.136C>T (p.His46Tyr)	LOC129993801	Uncertain significance	criteria provided, single submitter
2140971	NM_001085411.3(NADK2):c.77C>G (p.Pro26Arg)	LOC129993801	Uncertain significance	criteria provided, multiple submitters, no conflicts
2721521	NM_001085411.3(NADK2):c.300+3G>A	LOC129993801	Uncertain significance	criteria provided, single submitter
2762031	NM_001085411.3(NADK2):c.107G>A (p.Arg36Gln)	LOC129993801	Uncertain significance	criteria provided, single submitter
2843973	NM_001085411.3(NADK2):c.71G>A (p.Arg24Gln)	LOC129993801	Uncertain significance	criteria provided, single submitter
2915781	NM_001085411.3(NADK2):c.62C>T (p.Ala21Val)	LOC129993801	Uncertain significance	criteria provided, single submitter
2999115	NM_001085411.3(NADK2):c.40C>T (p.Arg14Cys)	LOC129993801	Uncertain significance	criteria provided, multiple submitters, no conflicts
3659050	NM_001085411.3(NADK2):c.242A>T (p.Glu81Val)	LOC129993801	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
NADK2	Strong	Autosomal recessive	progressive encephalopathy with leukodystrophy due to DECR deficiency	4
DECR1	Limited	Unknown	progressive encephalopathy with leukodystrophy due to DECR deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NADK2	Orphanet:431361	Progressive encephalopathy with leukodystrophy due to DECR deficiency

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
NADK2	HGNC:26404	ENSG00000152620	Q4G0N4	NAD kinase 2, mitochondrial	gencc,clinvar
DECR1	HGNC:2753	ENSG00000104325	Q16698	2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NADK2	NAD kinase 2, mitochondrial	Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+).
DECR1	2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial	Auxiliary enzyme of beta-oxidation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NADK2	Kinase	yes	2.7.1.23	NADK, NADK2_mit, NAD/diacylglycerol_kinase_sf
DECR1	Enzyme (other)	yes	1.3.1.124	SDR_fam, NAD(P)-bd_dom_sf

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
epithelial cell of pancreas	1
liver	1
right lobe of liver	1
heart right ventricle	1
left ventricle myocardium	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NADK2	258	ubiquitous	marker	liver, right lobe of liver, epithelial cell of pancreas
DECR1	296	ubiquitous	marker	left ventricle myocardium, heart right ventricle, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DECR1	4,079
NADK2	778

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NADK2	Q4G0N4	5
DECR1	Q16698	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	951.7×	0.007	DECR1
Nicotinate metabolism	1	196.9×	0.018	NADK2
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.024	NADK2
Metabolism of vitamins and cofactors	1	58.3×	0.024	NADK2
Mitochondrial protein degradation	1	57.1×	0.024	NADK2
Metabolism of proteins	1	6.2×	0.165	NADK2
Metabolism	1	5.8×	0.165	NADK2

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
NADP+ biosynthetic process	1	1203.7×	0.002	NADK2
NAD+ metabolic process	1	936.2×	0.002	NADK2
fatty acid beta-oxidation	1	187.2×	0.007	DECR1
positive regulation of cold-induced thermogenesis	1	81.8×	0.012	DECR1

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
NADK2	0	0
DECR1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
DECR1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NADK2	2.7.1.23	NAD+ kinase
DECR1	1.3.1.124	2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing]

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	2	NADK2, DECR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
NADK2	0	—
DECR1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.