⚙

Pathophysiology

4

Mitochondrial NADP(H) deficiency due to NADK2 loss

Biallelic loss-of-function variants in NADK2 (mitochondrial NAD kinase) abolish the mitochondrial NAD kinase activity required for NADP biosynthesis. This causes a profound deficiency of mitochondrial NADP(H), the cofactor pool that supplies reducing equivalents to multiple NADP(H)-dependent mitochondrial oxidoreductases. NADPH acts not only as a cosubstrate but also as a molecular chaperone that activates and stabilizes these enzymes, so its loss produces a combined, secondary enzyme deficiency state.

Neuron CL:0000540

NADP+ biosynthetic process GO:0006741 ↓ DECREASED

Mitochondrion GO:0005739

Downstream

Impaired DECR-mediated polyunsaturated fatty acid beta-oxidation Loss of mitochondrial NADP(H) deprives DECR of its required cofactor, causing secondary DECR deficiency.

Impaired lysine degradation causing hyperlysinemia The NADP(H)-dependent first step of lysine degradation is impaired by loss of mitochondrial NADP(H), causing hyperlysinemia.

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts."

Establishes that a causal NADK2 mutation produces decreased mitochondrial NADP(H), the upstream lesion of the disease.

PMID:24847004 SUPPORT Human Clinical

"Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes."

Explains the mechanism by which mitochondrial NADP(H) deficiency disables multiple downstream NADP(H)-dependent enzymes.

Impaired DECR-mediated polyunsaturated fatty acid beta-oxidation

Mitochondrial 2,4-dienoyl-CoA reductase (DECR) is an NADP(H)-dependent auxiliary enzyme of the mitochondrial beta-oxidation system that reduces the 2,4-dienoyl-CoA intermediates generated during oxidation of polyunsaturated fatty acids. With mitochondrial NADP(H) depleted, DECR activity is deficient (residual fibroblast activity ~10%), beta-oxidation of unsaturated fatty acids stalls at the dienoyl-CoA step, and PUFA-derived intermediates accumulate and appear in blood as the diagnostic C10:2 (decadienoyl) acylcarnitine. This impairs energy production from fatty acids under catabolic stress.

Hepatocyte CL:0000182

Fatty acid beta-oxidation GO:0006635 ↓ DECREASED Unsaturated fatty acid metabolic process GO:0033559 ↓ DECREASED

Downstream

Energy deficit and progressive neurodegeneration Impaired fatty acid energy production contributes to the cumulative energy deficit driving neurodegeneration.

Decreased circulating carnitine concentration

Organic aciduria

Show evidence (3 references)

PMID:24847004 SUPPORT Human Clinical

"DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2."

Demonstrates that DECR enzyme activity is deficient secondary to NADK2 loss and is restored by functional NADK2, confirming the causal chain.

PMID:19578400 SUPPORT Model Organism

"In Decr(-/-) mice, the mitochondrial beta-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates."

The Decr knockout mouse confirms that loss of DECR halts PUFA beta-oxidation at the dienoyl-CoA step.

PMID:19578400 SUPPORT Model Organism

"fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2))"

Identifies decadienoylcarnitine (C10:2) as the biomarker of incomplete PUFA oxidation arising from DECR deficiency.

Impaired lysine degradation causing hyperlysinemia

The first step of mitochondrial lysine degradation is catalyzed by the bifunctional aminoadipic semialdehyde synthase (AASS), whose lysine-ketoglutarate reductase activity is NADP(H)-dependent. With mitochondrial NADP(H) deficient, lysine catabolism is impaired in vivo, producing hyperlysinemia. The co-occurrence of elevated C10:2 acylcarnitine and hyperlysinemia is the distinctive combined biochemical signature of NADK2-related DECR deficiency.

L-lysine catabolic process GO:0019477 ↓ DECREASED

Downstream

Energy deficit and progressive neurodegeneration Disrupted amino acid metabolism contributes to the broader metabolic and energetic dysfunction.

Show evidence (1 reference)

PMID:24847004 SUPPORT Human Clinical

"DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency."

Establishes that the first step of lysine degradation is NADP-dependent and therefore impaired by mitochondrial NADP(H) deficiency, causing hyperlysinemia.

Energy deficit and progressive neurodegeneration

Beyond PUFA oxidation and lysine degradation, mitochondrial NADP(H) supports numerous other mitochondrial processes. NADK2-deficient patient fibroblasts show decreased oxygen consumption and increased extracellular acidification, consistent with a broad bioenergetic defect that meets clinical criteria for a mitochondrial disorder. The cumulative energy deficit and redox imbalance underlie the progressive encephalopathy, leukodystrophy, intermittent lactic acidosis, and multisystem decline (including renal tubular involvement).

Oligodendrocyte CL:0000128 Neuron CL:0000540 Kidney epithelial cell CL:0002518

Nervous system UBERON:0001016 Liver UBERON:0002107 Kidney UBERON:0002113

Downstream

Progressive encephalopathy

Leukodystrophy

Neonatal hypotonia

Failure to thrive

Developmental delay

Stress-induced lactic acidosis

Microcephaly

Seizures

Dystonia

Cerebellar atrophy

Spastic quadriplegia

Renal tubular acidosis

Ventriculomegaly

Corpus callosum hypoplasia

Cerebellar ataxia

Cerebral visual impairment

Nystagmus

Choreoathetosis

Abnormal basal ganglia MRI signal intensity

Show evidence (1 reference)

PMID:24847004 SUPPORT In Vitro

"We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder."

Bioenergetic measurements in patient fibroblasts support a broad mitochondrial dysfunction driving the progressive encephalopathy.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

22

Eye 1

Nystagmus FREQUENT Nystagmus HP:0000639

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0000639 | Nystagmus | Frequent (79-30%)"

Orphanet annotates nystagmus as a frequent feature.

Genitourinary 1

Organic aciduria FREQUENT Organic aciduria HP:0001992

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001992 | Organic aciduria | Frequent (79-30%)"

Orphanet annotates organic aciduria as a frequent feature.

Head and Neck 1

Microcephaly FREQUENT Microcephaly HP:0000252

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0000252 | Microcephaly | Frequent (79-30%)"

Orphanet annotates microcephaly as a frequent feature.

Musculoskeletal 1

Neonatal hypotonia FREQUENT Neonatal hypotonia HP:0001319

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001319 | Neonatal hypotonia | Frequent (79-30%)"

Orphanet annotates neonatal hypotonia as a frequent feature.

Nervous System 9

Leukodystrophy FREQUENT Leukodystrophy HP:0002415

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0002415 | Leukodystrophy | Frequent (79-30%)"

Orphanet annotates leukodystrophy as a frequent feature of this disease.

Developmental delay FREQUENT Global developmental delay HP:0001263

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"

Developmental delay reported in the index NADK2 case.

ORPHA:431361 SUPPORT

"HP:0001263 | Global developmental delay | Frequent (79-30%)"

Orphanet annotates global developmental delay as a frequent feature.

Seizures FREQUENT Seizure HP:0001250

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001250 | Seizure | Frequent (79-30%)"

Orphanet annotates seizures as a frequent feature.

Dystonia FREQUENT Dystonia HP:0001332

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001332 | Dystonia | Frequent (79-30%)"

Orphanet annotates dystonia as a frequent feature.

Cerebellar atrophy FREQUENT Cerebellar atrophy HP:0001272

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001272 | Cerebellar atrophy | Frequent (79-30%)"

Orphanet annotates cerebellar atrophy as a frequent feature.

Ventriculomegaly FREQUENT Ventriculomegaly HP:0002119

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0002119 | Ventriculomegaly | Frequent (79-30%)"

Orphanet annotates ventriculomegaly as a frequent feature.

Corpus callosum hypoplasia FREQUENT Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0002079 | Hypoplasia of the corpus callosum | Frequent (79-30%)"

Orphanet annotates corpus callosum hypoplasia as a frequent feature.

Cerebellar ataxia FREQUENT Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0002470 | Nonprogressive cerebellar ataxia | Frequent (79-30%)"

Orphanet annotates cerebellar ataxia (HP:0002470, Nonprogressive cerebellar ataxia) as a frequent feature. Because this disease has a progressive course, mapped here to HP:0002073 (Progressive cerebellar ataxia) rather than the Orphanet nonprogressive term.

Choreoathetosis FREQUENT Choreoathetosis HP:0001266

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001266 | Choreoathetosis | Frequent (79-30%)"

Orphanet annotates choreoathetosis as a frequent feature.

Cellular 1

Decreased circulating carnitine concentration FREQUENT Decreased circulating carnitine concentration HP:0003234

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0003234 | Decreased circulating carnitine concentration | Frequent (79-30%)"

Orphanet annotates decreased circulating carnitine as a frequent feature.

Growth 1

Failure to thrive FREQUENT Failure to thrive HP:0001508

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"

Failure to thrive reported in the index NADK2 case.

ORPHA:431361 SUPPORT

"HP:0001508 | Failure to thrive | Frequent (79-30%)"

Orphanet annotates failure to thrive as a frequent feature.

Other 7

Progressive encephalopathy FREQUENT Progressive encephalopathy HP:0002448

Course: PROGRESSIVE

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder."

Severe encephalopathy is reported in the index NADK2 case.

ORPHA:431361 SUPPORT

"HP:0002448 | Progressive encephalopathy | Frequent (79-30%)"

Orphanet annotates progressive encephalopathy as a frequent feature.

Stress-induced lactic acidosis FREQUENT Stress/infection-induced lactic acidosis HP:0004897

Temporal: RECURRENT

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"

Lactic acidosis reported in the index NADK2 case.

ORPHA:431361 SUPPORT

"HP:0004897 | Stress/infection-induced lactic acidosis | Frequent (79-30%)"

Orphanet annotates stress/infection-induced lactic acidosis as a frequent feature.

Spastic quadriplegia FREQUENT Progressive spastic quadriplegia HP:0002478

Course: PROGRESSIVE

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0002478 | Progressive spastic quadriplegia | Frequent (79-30%)"

Orphanet annotates progressive spastic quadriplegia as a frequent feature.

Renal tubular acidosis FREQUENT Renal tubular acidosis HP:0001947

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0001947 | Renal tubular acidosis | Frequent (79-30%)"

Orphanet annotates renal tubular acidosis as a frequent feature.

Cerebral visual impairment FREQUENT Cerebral visual impairment HP:0100704

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0100704 | Cerebral visual impairment | Frequent (79-30%)"

Orphanet annotates cerebral visual impairment as a frequent feature.

Abnormal basal ganglia MRI signal intensity FREQUENT Abnormal basal ganglia MRI signal intensity HP:0012751

Show evidence (1 reference)

ORPHA:431361 SUPPORT

"HP:0012751 | Abnormal basal ganglia MRI signal intensity | Frequent (79-30%)"

Orphanet annotates abnormal basal ganglia MRI signal intensity as a frequent feature.

Hyperlysinemia FREQUENT Hyperlysinemia HP:0002161

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine."

Hyperlysinemia is part of the defining biochemical phenotype.

ORPHA:431361 SUPPORT

"HP:0002161 | Hyperlysinemia | Frequent (79-30%)"

Orphanet annotates hyperlysinemia as a frequent feature.

🧬

Genetic Associations

1

NADK2 variants

Gene: NADK2 hgnc:26404 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:24847004 SUPPORT Human Clinical

"Exome sequencing revealed a causal mutation in NADK2."

Exome sequencing identified NADK2 as the causal gene.

ORPHA:431361 SUPPORT

"NADK2 | NAD kinase 2, mitochondrial | hgnc:26404 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet attributes the disease to loss-of-function germline mutations in NADK2.

💊

Medical Actions

3

Dietary management and metabolic support

Action: dietary intervention MAXO:0000088

Management is supportive and metabolic. Reported attempts in the literature include dietary lysine restriction, caloric/nutritional support to limit catabolism, and avoidance of fasting and catabolic stress. These are management attempts rather than established disease-modifying therapy.

Show evidence (1 reference)

PMID:24847004 PARTIAL Human Clinical

"Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine."

The disorder affecting lysine and PUFA metabolism provides the rationale for dietary lysine restriction and avoidance of catabolic stress; no proven disease-modifying therapy is established.

Supportive care

Action: Supportive Care NCIT:C15747

Multidisciplinary supportive care for the progressive neurometabolic disease, including management of seizures, feeding, and intercurrent metabolic decompensation during illness.

Show evidence (1 reference)

PMID:24847004 PARTIAL Human Clinical

"the disease course is consistent with clinical criteria for a mitochondrial disorder"

The mitochondrial, multisystem, progressive nature of the disease justifies supportive, symptom-directed care.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Given autosomal recessive inheritance, genetic counseling and carrier/cascade testing are the most actionable preventive strategies once a familial NADK2 variant is known.

Show evidence (1 reference)

PMID:24847004 PARTIAL Human Clinical

"We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2."

Identification of NADK2 as the causal gene enables genetic counseling and carrier testing for autosomal recessive disease.

🔬

Biochemical Markers

3

Elevated C10:2 (decadienoyl) acylcarnitine (INCREASED)

Show evidence (1 reference)

PMID:19578400 SUPPORT Model Organism

"fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2))"

Decadienoylcarnitine (C10:2) accumulates as a product of incomplete PUFA oxidation when DECR is deficient.

Hyperlysinemia (INCREASED)

Show evidence (1 reference)

PMID:24847004 SUPPORT Human Clinical

"DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency."

The NADP(H)-dependent first step of lysine degradation is impaired, raising lysine levels.

Elevated lactate (INCREASED)

Show evidence (1 reference)

PMID:24847004 SUPPORT Human Clinical

"We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"

Lactic acidosis indicates elevated lactate.

{ }

Source YAML

click to show

name: DECR Deficiency
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
  Progressive encephalopathy with leukodystrophy due to DECR deficiency
  (MONDO:0014464; OMIM:616034; also called 2,4-dienoyl-CoA reductase deficiency
  with hyperlysinemia) is an extremely rare autosomal recessive mitochondrial
  disorder. It is caused by biallelic loss-of-function variants in NADK2, the
  gene encoding mitochondrial NAD kinase. NADK2 deficiency causes a deficiency
  of mitochondrial NADP(H), which in turn disables NADP(H)-dependent
  mitochondrial enzymes — most prominently 2,4-dienoyl-CoA reductase (DECR),
  required for beta-oxidation of polyunsaturated fatty acids, and the lysine
  degradation pathway. The result is a characteristic combined biochemical
  signature of elevated C10:2 (decadienoyl) acylcarnitine plus hyperlysinemia,
  together with broader mitochondrial dysfunction. Clinically the disorder
  presents in the neonatal period or early infancy with hypotonia, failure to
  thrive, acquired microcephaly, developmental delay, leukodystrophy and other
  CNS malformations, intermittent lactic acidosis provoked by catabolic stress,
  and a progressive encephalopathy that may evolve to epilepsy, dystonia,
  cerebellar ataxia, cerebral visual impairment, renal tubular acidosis and
  spastic quadriplegia, with death in childhood in severe cases.
disease_term:
  preferred_term: DECR Deficiency
  term:
    id: MONDO:0014464
    label: progressive encephalopathy with leukodystrophy due to DECR deficiency
parents:
- leukodystrophy
- mitochondrial disease
- inborn error of metabolism

references:
- reference: PMID:24847004
  title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
- reference: PMID:19578400
  title: "Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis."
- reference: ORPHA:431361
  title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"

pathophysiology:
- name: Mitochondrial NADP(H) deficiency due to NADK2 loss
  description: >
    Biallelic loss-of-function variants in NADK2 (mitochondrial NAD kinase)
    abolish the mitochondrial NAD kinase activity required for NADP biosynthesis.
    This causes a profound deficiency of mitochondrial NADP(H), the cofactor pool
    that supplies reducing equivalents to multiple NADP(H)-dependent mitochondrial
    oxidoreductases. NADPH acts not only as a cosubstrate but also as a molecular
    chaperone that activates and stabilizes these enzymes, so its loss produces a
    combined, secondary enzyme deficiency state.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: NADP+ biosynthetic process
    term:
      id: GO:0006741
      label: NADP+ biosynthetic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: Mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts."
    explanation: >
      Establishes that a causal NADK2 mutation produces decreased mitochondrial
      NADP(H), the upstream lesion of the disease.
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes."
    explanation: >
      Explains the mechanism by which mitochondrial NADP(H) deficiency disables
      multiple downstream NADP(H)-dependent enzymes.
  downstream:
  - target: Impaired DECR-mediated polyunsaturated fatty acid beta-oxidation
    causal_link_type: DIRECT
    description: >
      Loss of mitochondrial NADP(H) deprives DECR of its required cofactor,
      causing secondary DECR deficiency.
  - target: Impaired lysine degradation causing hyperlysinemia
    causal_link_type: DIRECT
    description: >
      The NADP(H)-dependent first step of lysine degradation is impaired by loss
      of mitochondrial NADP(H), causing hyperlysinemia.

- name: Impaired DECR-mediated polyunsaturated fatty acid beta-oxidation
  description: >
    Mitochondrial 2,4-dienoyl-CoA reductase (DECR) is an NADP(H)-dependent
    auxiliary enzyme of the mitochondrial beta-oxidation system that reduces the
    2,4-dienoyl-CoA intermediates generated during oxidation of polyunsaturated
    fatty acids. With mitochondrial NADP(H) depleted, DECR activity is deficient
    (residual fibroblast activity ~10%), beta-oxidation of unsaturated fatty acids
    stalls at the dienoyl-CoA step, and PUFA-derived intermediates accumulate and
    appear in blood as the diagnostic C10:2 (decadienoyl) acylcarnitine. This
    impairs energy production from fatty acids under catabolic stress.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: Unsaturated fatty acid metabolic process
    term:
      id: GO:0033559
      label: unsaturated fatty acid metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2."
    explanation: >
      Demonstrates that DECR enzyme activity is deficient secondary to NADK2 loss
      and is restored by functional NADK2, confirming the causal chain.
  - reference: PMID:19578400
    reference_title: "Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Decr(-/-) mice, the mitochondrial beta-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates."
    explanation: >
      The Decr knockout mouse confirms that loss of DECR halts PUFA
      beta-oxidation at the dienoyl-CoA step.
  - reference: PMID:19578400
    reference_title: "Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2))"
    explanation: >
      Identifies decadienoylcarnitine (C10:2) as the biomarker of incomplete PUFA
      oxidation arising from DECR deficiency.
  downstream:
  - target: Energy deficit and progressive neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Impaired fatty acid energy production contributes to the cumulative energy
      deficit driving neurodegeneration.
  - target: Decreased circulating carnitine concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Organic aciduria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Impaired lysine degradation causing hyperlysinemia
  description: >
    The first step of mitochondrial lysine degradation is catalyzed by the
    bifunctional aminoadipic semialdehyde synthase (AASS), whose lysine-ketoglutarate
    reductase activity is NADP(H)-dependent. With mitochondrial NADP(H) deficient,
    lysine catabolism is impaired in vivo, producing hyperlysinemia. The
    co-occurrence of elevated C10:2 acylcarnitine and hyperlysinemia is the
    distinctive combined biochemical signature of NADK2-related DECR deficiency.
  biological_processes:
  - preferred_term: L-lysine catabolic process
    term:
      id: GO:0019477
      label: L-lysine catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency."
    explanation: >
      Establishes that the first step of lysine degradation is NADP-dependent and
      therefore impaired by mitochondrial NADP(H) deficiency, causing
      hyperlysinemia.
  downstream:
  - target: Energy deficit and progressive neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Disrupted amino acid metabolism contributes to the broader metabolic and
      energetic dysfunction.

- name: Energy deficit and progressive neurodegeneration
  description: >
    Beyond PUFA oxidation and lysine degradation, mitochondrial NADP(H) supports
    numerous other mitochondrial processes. NADK2-deficient patient fibroblasts
    show decreased oxygen consumption and increased extracellular acidification,
    consistent with a broad bioenergetic defect that meets clinical criteria for a
    mitochondrial disorder. The cumulative energy deficit and redox imbalance
    underlie the progressive encephalopathy, leukodystrophy, intermittent lactic
    acidosis, and multisystem decline (including renal tubular involvement).
  cell_types:
  - preferred_term: Oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: Kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  locations:
  - preferred_term: Nervous system
    term:
      id: UBERON:0001016
      label: nervous system
  - preferred_term: Liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder."
    explanation: >
      Bioenergetic measurements in patient fibroblasts support a broad
      mitochondrial dysfunction driving the progressive encephalopathy.
  downstream:
  - target: Progressive encephalopathy
    causal_link_type: DIRECT
  - target: Leukodystrophy
    causal_link_type: DIRECT
  - target: Neonatal hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Stress-induced lactic acidosis
    causal_link_type: DIRECT
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar atrophy
    causal_link_type: DIRECT
  - target: Spastic quadriplegia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Renal tubular acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Corpus callosum hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebral visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Choreoathetosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal basal ganglia MRI signal intensity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

phenotypes:
- category: Phenotypic
  name: Progressive encephalopathy
  description: >
    Severe, progressive encephalopathy suggestive of a mitochondrial disorder,
    a defining clinical feature of the disease.
  phenotype_term:
    preferred_term: Progressive encephalopathy
    term:
      id: HP:0002448
      label: Progressive encephalopathy
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder."
    explanation: Severe encephalopathy is reported in the index NADK2 case.
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002448 | Progressive encephalopathy | Frequent (79-30%)"
    explanation: Orphanet annotates progressive encephalopathy as a frequent feature.

- category: Phenotypic
  name: Leukodystrophy
  description: >
    White matter disease / leukodystrophy is part of the disease name and
    progressive CNS pathology.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002415 | Leukodystrophy | Frequent (79-30%)"
    explanation: Orphanet annotates leukodystrophy as a frequent feature of this disease.

- category: Phenotypic
  name: Neonatal hypotonia
  description: Neonatal hypotonia is a presenting feature.
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001319 | Neonatal hypotonia | Frequent (79-30%)"
    explanation: Orphanet annotates neonatal hypotonia as a frequent feature.

- category: Phenotypic
  name: Failure to thrive
  description: Failure to thrive is a presenting feature.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: FREQUENT
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"
    explanation: Failure to thrive reported in the index NADK2 case.
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001508 | Failure to thrive | Frequent (79-30%)"
    explanation: Orphanet annotates failure to thrive as a frequent feature.

- category: Phenotypic
  name: Developmental delay
  description: Global developmental delay is a presenting feature.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"
    explanation: Developmental delay reported in the index NADK2 case.
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001263 | Global developmental delay | Frequent (79-30%)"
    explanation: Orphanet annotates global developmental delay as a frequent feature.

- category: Phenotypic
  name: Stress-induced lactic acidosis
  description: >
    Intermittent lactic acidosis, often provoked by catabolic stress
    (e.g., infection), reflecting mitochondrial dysfunction.
  phenotype_term:
    preferred_term: Stress/infection-induced lactic acidosis
    term:
      id: HP:0004897
      label: Stress/infection-induced lactic acidosis
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"
    explanation: Lactic acidosis reported in the index NADK2 case.
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0004897 | Stress/infection-induced lactic acidosis | Frequent (79-30%)"
    explanation: Orphanet annotates stress/infection-induced lactic acidosis as a frequent feature.

- category: Phenotypic
  name: Microcephaly
  description: Acquired microcephaly develops over the disease course.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0000252 | Microcephaly | Frequent (79-30%)"
    explanation: Orphanet annotates microcephaly as a frequent feature.

- category: Phenotypic
  name: Seizures
  description: Epilepsy/seizures develop later in the disease course.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001250 | Seizure | Frequent (79-30%)"
    explanation: Orphanet annotates seizures as a frequent feature.

- category: Phenotypic
  name: Dystonia
  description: Dystonia is among the later neurological complications.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001332 | Dystonia | Frequent (79-30%)"
    explanation: Orphanet annotates dystonia as a frequent feature.

- category: Phenotypic
  name: Cerebellar atrophy
  description: Cerebellar atrophy is among the CNS abnormalities.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001272 | Cerebellar atrophy | Frequent (79-30%)"
    explanation: Orphanet annotates cerebellar atrophy as a frequent feature.

- category: Phenotypic
  name: Spastic quadriplegia
  description: Progressive spastic quadriplegia is among the severe later complications.
  phenotype_term:
    preferred_term: Progressive spastic quadriplegia
    term:
      id: HP:0002478
      label: Progressive spastic quadriplegia
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002478 | Progressive spastic quadriplegia | Frequent (79-30%)"
    explanation: Orphanet annotates progressive spastic quadriplegia as a frequent feature.

- category: Phenotypic
  name: Renal tubular acidosis
  description: Renal tubular acidosis reflects multisystem mitochondrial involvement.
  phenotype_term:
    preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001947 | Renal tubular acidosis | Frequent (79-30%)"
    explanation: Orphanet annotates renal tubular acidosis as a frequent feature.

- category: Phenotypic
  name: Ventriculomegaly
  description: Ventriculomegaly is among the central nervous system abnormalities.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002119 | Ventriculomegaly | Frequent (79-30%)"
    explanation: Orphanet annotates ventriculomegaly as a frequent feature.

- category: Phenotypic
  name: Corpus callosum hypoplasia
  description: Hypoplasia of the corpus callosum is among the CNS abnormalities.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002079 | Hypoplasia of the corpus callosum | Frequent (79-30%)"
    explanation: Orphanet annotates corpus callosum hypoplasia as a frequent feature.

- category: Phenotypic
  name: Cerebellar ataxia
  description: Cerebellar ataxia develops later in the disease course.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002470 | Nonprogressive cerebellar ataxia | Frequent (79-30%)"
    explanation: >
      Orphanet annotates cerebellar ataxia (HP:0002470, Nonprogressive cerebellar
      ataxia) as a frequent feature. Because this disease has a progressive course,
      mapped here to HP:0002073 (Progressive cerebellar ataxia) rather than the
      Orphanet nonprogressive term.

- category: Phenotypic
  name: Cerebral visual impairment
  description: Cortical/cerebral visual impairment occurs in severe cases.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0100704 | Cerebral visual impairment | Frequent (79-30%)"
    explanation: Orphanet annotates cerebral visual impairment as a frequent feature.

- category: Phenotypic
  name: Nystagmus
  description: Involuntary oscillatory eye movements, a neurological sign in this leukodystrophy.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0000639 | Nystagmus | Frequent (79-30%)"
    explanation: Orphanet annotates nystagmus as a frequent feature.

- category: Phenotypic
  name: Choreoathetosis
  description: >
    A movement disorder combining chorea and athetosis, distinct from the dystonia
    also seen in this disease.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001266 | Choreoathetosis | Frequent (79-30%)"
    explanation: Orphanet annotates choreoathetosis as a frequent feature.

- category: Phenotypic
  name: Abnormal basal ganglia MRI signal intensity
  description: >
    Neuroimaging shows abnormal signal in the basal ganglia, reflecting the CNS
    pathology of this neurodegenerative disorder.
  phenotype_term:
    preferred_term: Abnormal basal ganglia MRI signal intensity
    term:
      id: HP:0012751
      label: Abnormal basal ganglia MRI signal intensity
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0012751 | Abnormal basal ganglia MRI signal intensity | Frequent (79-30%)"
    explanation: Orphanet annotates abnormal basal ganglia MRI signal intensity as a frequent feature.

- category: Laboratory
  name: Hyperlysinemia
  description: >
    Elevated plasma lysine resulting from NADP(H)-dependent impairment of the
    first step of lysine degradation; a hallmark of the NADK2-related phenotype.
  phenotype_term:
    preferred_term: Hyperlysinemia
    term:
      id: HP:0002161
      label: Hyperlysinemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine."
    explanation: Hyperlysinemia is part of the defining biochemical phenotype.
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0002161 | Hyperlysinemia | Frequent (79-30%)"
    explanation: Orphanet annotates hyperlysinemia as a frequent feature.

- category: Laboratory
  name: Decreased circulating carnitine concentration
  description: >
    Low free/total carnitine, a common secondary finding in fatty acid oxidation
    disorders including DECR deficiency.
  phenotype_term:
    preferred_term: Decreased circulating carnitine concentration
    term:
      id: HP:0003234
      label: Decreased circulating carnitine concentration
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0003234 | Decreased circulating carnitine concentration | Frequent (79-30%)"
    explanation: Orphanet annotates decreased circulating carnitine as a frequent feature.

- category: Laboratory
  name: Organic aciduria
  description: >
    Urinary excretion of non-amino organic acids, including unsaturated
    dicarboxylic acids reflecting the impaired polyunsaturated fatty acid
    beta-oxidation in DECR deficiency.
  phenotype_term:
    preferred_term: Organic aciduria
    term:
      id: HP:0001992
      label: Organic aciduria
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "HP:0001992 | Organic aciduria | Frequent (79-30%)"
    explanation: Orphanet annotates organic aciduria as a frequent feature.

genetic:
- name: NADK2 variants
  notes: >
    Biallelic loss-of-function variants in NADK2 (mitochondrial NAD kinase) cause
    the disease. A homozygous nonsense variant was identified by exome sequencing
    in the index case; rescue of the DECR defect by transfection of functional
    NADK2 confirmed causality.
  gene_term:
    preferred_term: NADK2
    term:
      id: hgnc:26404
      label: NADK2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:24847004
      reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2."
      explanation: >
        NADK2 is established as the causal gene; the disorder is autosomal
        recessive with a homozygous variant in the proband.
    - reference: ORPHA:431361
      reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
      supports: SUPPORT
      snippet: "Autosomal recessive"
      explanation: Orphanet reports autosomal recessive inheritance.
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed a causal mutation in NADK2."
    explanation: Exome sequencing identified NADK2 as the causal gene.
  - reference: ORPHA:431361
    reference_title: "Progressive encephalopathy with leukodystrophy due to DECR deficiency"
    supports: SUPPORT
    snippet: "NADK2 | NAD kinase 2, mitochondrial | hgnc:26404 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: >
      Orphanet attributes the disease to loss-of-function germline mutations in
      NADK2.

biochemical:
- name: Elevated C10:2 (decadienoyl) acylcarnitine
  notes: >
    Elevation of the C10:2 (decadienoyl) acylcarnitine is the signature analyte of
    impaired polyunsaturated fatty acid beta-oxidation in DECR deficiency, derived
    from incomplete oxidation of linoleic acid (C18:2). It is detectable on the
    plasma acylcarnitine profile and has been used as a newborn-screening marker,
    though it is neither fully sensitive nor specific.
  biomarker_term:
    preferred_term: O-acylcarnitine
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
  presence: INCREASED
  evidence:
  - reference: PMID:19578400
    reference_title: "Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2))"
    explanation: >
      Decadienoylcarnitine (C10:2) accumulates as a product of incomplete PUFA
      oxidation when DECR is deficient.

- name: Hyperlysinemia
  notes: Elevated plasma/CSF/urine lysine due to impaired lysine degradation.
  biomarker_term:
    preferred_term: L-lysine
    term:
      id: CHEBI:18019
      label: L-lysine
  presence: INCREASED
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency."
    explanation: >
      The NADP(H)-dependent first step of lysine degradation is impaired, raising
      lysine levels.

- name: Elevated lactate
  notes: Elevated blood/CSF lactate reflecting mitochondrial dysfunction.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  presence: INCREASED
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy"
    explanation: Lactic acidosis indicates elevated lactate.

treatments:
- name: Dietary management and metabolic support
  description: >
    Management is supportive and metabolic. Reported attempts in the literature
    include dietary lysine restriction, caloric/nutritional support to limit
    catabolism, and avoidance of fasting and catabolic stress. These are
    management attempts rather than established disease-modifying therapy.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine."
    explanation: >
      The disorder affecting lysine and PUFA metabolism provides the rationale for
      dietary lysine restriction and avoidance of catabolic stress; no proven
      disease-modifying therapy is established.

- name: Supportive care
  description: >
    Multidisciplinary supportive care for the progressive neurometabolic disease,
    including management of seizures, feeding, and intercurrent metabolic
    decompensation during illness.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the disease course is consistent with clinical criteria for a mitochondrial disorder"
    explanation: >
      The mitochondrial, multisystem, progressive nature of the disease justifies
      supportive, symptom-directed care.

- name: Genetic counseling
  description: >
    Given autosomal recessive inheritance, genetic counseling and carrier/cascade
    testing are the most actionable preventive strategies once a familial NADK2
    variant is known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24847004
    reference_title: "Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2."
    explanation: >
      Identification of NADK2 as the causal gene enables genetic counseling and
      carrier testing for autosomal recessive disease.

datasets: []

📚

References & Deep Research

References

3

PMID:24847004

Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia.

No top-level findings curated for this source.

PMID:19578400

Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis.

No top-level findings curated for this source.

ORPHA:431361

Progressive encephalopathy with leukodystrophy due to DECR deficiency

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

DECR Deficiency (mitochondrial 2,4-dienoyl‑CoA reductase deficiency): Disease Characteristics Research Report

Edison Scientific Literature 10 citations 2026-06-04T18:09:08.695898

DECR Deficiency (mitochondrial 2,4-dienoyl‑CoA reductase deficiency): Disease Characteristics Research Report

Executive summary

“Mitochondrial 2,4‑dienoyl‑CoA reductase (DECR) deficiency” is an extremely rare inborn error of metabolism classically defined biochemically by impaired oxidation of polyunsaturated fatty acids (PUFAs) with accumulation of the acylcarnitine C10:2 (decadienoylcarnitine) and low DECR enzymatic activity. In the best-characterized modern molecular cases, the apparent DECR defect was secondary to autosomal recessive NADK2 deficiency, which causes mitochondrial NADP(H) deficiency and thereby disables NADPH-dependent mitochondrial enzymes including DECR and AASS (lysine pathway), producing a combined signature of C10:2 elevation + hyperlysinemia and severe neurometabolic disease. (houten2014mitochondrialnadp(h)deficiency pages 9-10, houten2014mitochondrialnadp(h)deficiency pages 5-7, houten2014mitochondrialnadp(h)deficiency pages 1-2)

A primary, Mendelian DECR1 (DECR)-mutant human disorder is suggested by historical biochemistry-first reports and by strong mouse genetic evidence, but coding DECR1 mutations were excluded in the NADK2-related human cases described in the key Human Molecular Genetics report, leaving the extent of confirmed human DECR1‑biallelic disease incompletely resolved in the tool-accessible literature used here. (houten2014mitochondrialnadp(h)deficiency pages 4-5, houten2014mitochondrialnadp(h)deficiency pages 5-7)

1. Disease information

What is the disease?

DECR deficiency refers to deficient activity of mitochondrial 2,4‑dienoyl‑CoA reductase (DECR), an auxiliary enzyme required for complete mitochondrial β‑oxidation of polyunsaturated fatty acids by reducing 2,4‑dienoyl‑CoA intermediates. Loss of activity leads to accumulation of characteristic PUFA-derived intermediates (detected as C10:2 acylcarnitine) and clinical decompensation under metabolic stress. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

Key identifiers (OMIM/Orphanet/MeSH/MONDO)

Within the tool-accessible corpus for this run, I could not reliably retrieve OMIM/Orphanet/MONDO identifiers for “DECR deficiency/DECR1 deficiency.” Accordingly, identifier mapping should be validated directly in OMIM/Orphanet/MONDO during knowledge-base curation.

Common synonyms / alternative names

Mitochondrial 2,4‑dienoyl‑CoA reductase deficiency
DECR deficiency
(Biochemical signature) C10:2 (decadienoyl)carnitine elevation suggestive of impaired PUFA oxidation (wanders2019translationalmetabolisma pages 3-3, houten2014mitochondrialnadp(h)deficiency pages 4-5)

Evidence sources

Evidence is derived from: * Individual patient reports/series with deep biochemical phenotyping and genetics (notably NADK2-associated cases). (houten2014mitochondrialnadp(h)deficiency pages 4-5, houten2014mitochondrialnadp(h)deficiency pages 5-7, houten2014mitochondrialnadp(h)deficiency pages 1-2) * Aggregated biochemical screening considerations (newborn screening marker interpretation) discussed within primary case literature. (houten2014mitochondrialnadp(h)deficiency pages 10-12) * A mechanistic Decr knockout mouse model that supports pathway understanding and biomarker interpretation. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

2. Etiology

Disease causal factors

Genetic causes (current evidence)

1) Secondary DECR deficiency due to NADK2 deficiency (autosomal recessive) * A homozygous nonsense NADK2 variant (reported as c.1018C>T; p.R340X) caused mitochondrial NADP(H) deficiency, which in turn impaired NADPH-dependent mitochondrial enzymes including DECR and AASS (lysine pathway), explaining C10:2 elevation plus hyperlysinemia. (houten2014mitochondrialnadp(h)deficiency pages 5-7) * In this context, the DECR biochemical phenotype is downstream of NADK2 and reflects combined mitochondrial redox cofactor deficiency rather than a structural DECR1 defect. (houten2014mitochondrialnadp(h)deficiency pages 9-10, houten2014mitochondrialnadp(h)deficiency pages 10-12)

2) Primary DECR deficiency (putative DECR1-related) * Historical biochemical cases of “DECR deficiency” predate current sequencing and reported low enzyme activity in tissues. (houten2014mitochondrialnadp(h)deficiency pages 2-4) * A Decr knockout mouse strongly supports that loss of mitochondrial DECR activity is sufficient to cause the characteristic C10:2 biomarker and stress-intolerance phenotype. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2) * However, in the best-characterized modern human cases in the available evidence, targeted sequencing excluded DECR1 coding mutations. (houten2014mitochondrialnadp(h)deficiency pages 4-5, houten2014mitochondrialnadp(h)deficiency pages 5-7)

Risk factors

Fasting / metabolic stress is a key precipitant of hypoglycemia and decompensation in Decr−/− mice and is mechanistically plausible as a trigger in humans with FAO auxiliary enzyme deficiency. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

Protective factors

No DECR- or NADK2-specific protective factors were identified in the available evidence.

Gene–environment interactions

A plausible interaction is genetic impairment of PUFA β‑oxidation (DECR pathway defect) with environmental/physiologic stressors (fasting, illness, cold exposure), which increases energy demand and reliance on fatty acid oxidation and may precipitate decompensation. In Decr−/− mice, acute cold stress and fasting precipitated severe phenotypes. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

3. Phenotypes

Core phenotype spectrum (humans; NADK2-associated secondary DECR deficiency)

Clinical presentation can be severe, early-onset, and progressive: * Failure to thrive (HP:0001508), microcephaly (HP:0000252), hypotonia (HP:0001252) (houten2014mitochondrialnadp(h)deficiency pages 2-4) * Developmental delay (HP:0001263) and progressive neurologic decline (houten2014mitochondrialnadp(h)deficiency pages 1-2) * Movement disorder including choreoathetosis/dystonia (HP:0001266/HP:0001332) (houten2014mitochondrialnadp(h)deficiency pages 4-5) * Epilepsy (HP:0001250), cortical blindness/visual loss (HP:0000608/HP:0000505) in severe cases (houten2014mitochondrialnadp(h)deficiency pages 4-5) * Lactic acidosis (HP:0003128) and renal tubular acidosis (HP:0001947) consistent with multisystem mitochondrial dysfunction (houten2014mitochondrialnadp(h)deficiency pages 4-5) * Neuroimaging: progressive leukodystrophy / white matter disease (HP:0002415), cerebral atrophy (HP:0002059), basal ganglia lesions (HP:0002134) (houten2014mitochondrialnadp(h)deficiency pages 4-5)

Age of onset: reported as early infancy (e.g., presentation at 8 weeks) (houten2014mitochondrialnadp(h)deficiency pages 2-4).

Severity/progression: severe, progressive encephalopathy with death in childhood reported in the detailed NADK2-associated cases. (houten2014mitochondrialnadp(h)deficiency pages 4-5)

Phenotypes (mouse model; primary Decr deficiency)

Decr−/− mice demonstrate: * Severe fasting/stress intolerance with profound hypoglycemia and “unimpaired ketogenesis” (consistent with preserved ketone production despite impaired PUFA oxidation) (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2) * Hepatic steatosis (fatty liver) and accumulation of unsaturated fatty acids in hepatic lipids (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2) * Cold intolerance / fatal hypothermia with impaired thermogenesis under acute cold challenge (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

Quality of life impact

Human cases described are consistent with severe neurodevelopmental disability and progressive neurologic impairment, implying major quality-of-life impact; disease-specific QoL instruments were not identified in the accessible evidence. (houten2014mitochondrialnadp(h)deficiency pages 4-5)

4. Genetic / molecular information

Causal genes

NADK2 (mitochondrial NAD kinase): confirmed cause of mitochondrial NADP(H) deficiency leading to secondary DECR deficiency with hyperlysinemia. (houten2014mitochondrialnadp(h)deficiency pages 5-7, houten2014mitochondrialnadp(h)deficiency pages 1-2)
DECR1 (mitochondrial 2,4‑dienoyl‑CoA reductase): strongly supported by mouse knockout as essential for PUFA β‑oxidation and the C10:2 biomarker, but definitive human DECR1-biallelic disease was not established in the key human case series available here. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2, houten2014mitochondrialnadp(h)deficiency pages 5-7)

Pathogenic variants (reported in accessible evidence)

NADK2 c.1018C>T (p.R340X), homozygous in the proband and heterozygous in parents; associated with absent NADK2 protein and low mitochondrial NADP(H). (houten2014mitochondrialnadp(h)deficiency pages 5-7)

Functional consequences

NADK2 deficiency reduces mitochondrial NADP(H) and thereby disables NADPH-dependent mitochondrial enzymes; the paper emphasizes NADPH as both a cosubstrate and a stabilizing/chaperoning factor for enzymes like DECR and AASS, explaining combined biochemical signatures (C10:2 elevation + hyperlysinemia). (houten2014mitochondrialnadp(h)deficiency pages 1-2)

Suggested GO / pathway terms (for curation; not exhaustive)

GO:0006635 fatty acid beta-oxidation
GO:0006636 unsaturated fatty acid metabolic process
GO:0055114 oxidation-reduction process
Reactome/KEGG concept: PUFA β‑oxidation auxiliary enzymes requiring DECR for 2,4‑dienoyl‑CoA intermediates (supported by pathway schematic evidence). (miinalainen2009mitochondrial24dienoylcoareductase media db369249)

Suggested cell types (CL terms) and tissues

Based on energy-demand and reported pathology: * Hepatocyte (CL:0000182) / liver involvement (steatosis; biochemical FAO organ) (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2) * Neuron (CL:0000540) and oligodendrocyte (CL:0000128) as plausible cell types in progressive leukodystrophy/encephalopathy (houten2014mitochondrialnadp(h)deficiency pages 4-5) * Renal tubular epithelial cell (CL:0000066) (renal tubular acidosis) (houten2014mitochondrialnadp(h)deficiency pages 4-5)

5. Environmental information

No specific toxins/lifestyle infectious triggers were identified. The main non-genetic precipitants described are metabolic stressors (fasting, cold exposure) in the mouse model. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

6. Mechanism / pathophysiology

Molecular pathway and causal chain

Upstream trigger: Loss of DECR activity (primary Decr knockout) or loss of mitochondrial NADP(H) (NADK2 deficiency) → reduced ability to reduce 2,4‑dienoyl‑CoA intermediates during mitochondrial PUFA β‑oxidation. (houten2014mitochondrialnadp(h)deficiency pages 1-2, miinalainen2009mitochondrial24dienoylcoareductase media db369249)

Biochemical block: Incomplete PUFA β‑oxidation → accumulation of PUFA-derived intermediates that appear in blood as C10:2 (decadienoyl)carnitine; mouse fasting acylcarnitine profiles show marked C10:2 accumulation in Decr−/− mice. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2, miinalainen2009mitochondrial24dienoylcoareductase media f7dcc2b0)

Downstream metabolic effects: Energy stress response impairment under fasting/cold challenge → severe hypoglycemia and stress intolerance; liver lipid accumulation/steatosis; compensatory upregulation of peroxisomal β‑oxidation/ω‑oxidation in mice. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

Multisystem mitochondrial dysfunction (NADK2 cases): Mitochondrial redox cofactor deficiency also affects additional NADPH-dependent enzymes and is associated with reduced maximal oxygen consumption and increased extracellular acidification in fibroblasts, consistent with broader mitochondrial disease and severe neurodegeneration. (houten2014mitochondrialnadp(h)deficiency pages 9-10)

Key biochemical abnormalities (with suggested CHEBI entities)

C10:2 acylcarnitine / decadienoylcarnitine (CHEBI mapping to be validated; key diagnostic analyte) (houten2014mitochondrialnadp(h)deficiency pages 4-5, miinalainen2009mitochondrial24dienoylcoareductase media f7dcc2b0)
Lysine (CHEBI:18019) elevated in NADK2-associated phenotype (hyperlysinemia) (houten2014mitochondrialnadp(h)deficiency pages 4-5)
Lactate (CHEBI:24996) elevated (lactic acidosis) (houten2014mitochondrialnadp(h)deficiency pages 4-5)

Authoritative expert framing (abstract quote)

A translational metabolism review described the diagnostic clue as: “a very unusual C10:2 acylcarnitine… most likely derived from linoleic acid (C18:2) oxidation.” (wanders2019translationalmetabolisma pages 3-3)

7. Anatomical structures affected

Organs/systems (supported by evidence)

Central nervous system (UBERON:0001016): progressive encephalopathy/leukodystrophy and basal ganglia lesions in severe human cases. (houten2014mitochondrialnadp(h)deficiency pages 4-5)
Liver (UBERON:0002107): steatosis and lipid accumulation in Decr−/− mice; clinically relevant FAO organ. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)
Kidney (UBERON:0002113): renal tubular acidosis in human NADK2-associated cases. (houten2014mitochondrialnadp(h)deficiency pages 4-5)

Subcellular localization

Mitochondrion (GO:0005739): DECR function is mitochondrial; NADK2 generates mitochondrial NADP(H). (houten2014mitochondrialnadp(h)deficiency pages 1-2)

8. Temporal development

Onset: infancy (e.g., 8 weeks in a reported case) (houten2014mitochondrialnadp(h)deficiency pages 2-4)
Course: progressive neurologic decline with episodic metabolic derangements (intermittent lactic acidosis described) and early mortality in severe cases. (houten2014mitochondrialnadp(h)deficiency pages 4-5)

9. Inheritance and population

Inheritance

NADK2-associated secondary DECR deficiency is autosomal recessive, supported by homozygous variant in the proband and heterozygosity in parents. (houten2014mitochondrialnadp(h)deficiency pages 5-7)

Epidemiology

The disorder is described as very rare: the key report notes only a historical single case (1990) and a second, newly characterized case, underscoring paucity of epidemiologic data. (houten2014mitochondrialnadp(h)deficiency pages 2-4)
In the broader context of sudden unexpected death (SUD) in infancy/childhood, metabolic disorders are estimated to account for ~3–5% of cases (not specific to DECR). (hung2024driedbloodspot pages 1-2)

10. Diagnostics

Clinical laboratory tests and biomarkers

Front-line biochemical screening * Acylcarnitine profile (tandem MS): elevation of C10:2 (decadienoyl)carnitine is the signature marker discussed for DECR deficiency and was retrospectively present at low levels on newborn blood spot in a NADK2 case. (houten2014mitochondrialnadp(h)deficiency pages 10-12, houten2014mitochondrialnadp(h)deficiency pages 2-4) * Plasma/CSF amino acids: hyperlysinemia can co-occur in NADK2-associated cases. (houten2014mitochondrialnadp(h)deficiency pages 4-5, houten2014mitochondrialnadp(h)deficiency pages 5-7) * Lactate: elevated in blood/CSF in severe neurometabolic presentations. (houten2014mitochondrialnadp(h)deficiency pages 4-5) * Urine organic acids: persistent abnormalities reported (e.g., lactic/pyruvic and other acids), consistent with mitochondrial dysfunction. (houten2014mitochondrialnadp(h)deficiency pages 4-5)

Functional/confirmatory testing * DECR enzyme activity assay in fibroblasts/tissues (reported residual ~10% using sorboyl‑CoA substrate). (houten2014mitochondrialnadp(h)deficiency pages 4-5) * Cellular bioenergetics (oxygen consumption / extracellular acidification) consistent with mitochondrial disorder. (houten2014mitochondrialnadp(h)deficiency pages 9-10)

Genetic testing

In NADK2-associated cases, exome sequencing identified the causal NADK2 variant after targeted gene testing excluded DECR1/related genes; rescue experiments via wild-type NADK2 expression restored biochemical defects, strengthening causal inference. (houten2014mitochondrialnadp(h)deficiency pages 5-7, houten2014mitochondrialnadp(h)deficiency pages 1-2)

Newborn screening and screening limitations

Newborn screening programs have used C10:2‑carnitine as the primary marker; the key report emphasizes that slight C10:2 elevations are neither fully specific nor sensitive, since other FAO disorders can also elevate C10:2. (houten2014mitochondrialnadp(h)deficiency pages 10-12)
The authors suggested that adding lysine could improve screening specificity for the NADK2-associated combined phenotype (C10:2 + hyperlysinemia). (houten2014mitochondrialnadp(h)deficiency pages 10-12)

Differential diagnosis (examples)

Other fatty acid oxidation disorders (FAODs) with overlapping acylcarnitine patterns and stress-induced hypoglycemia; in NADK2-associated disease, broader mitochondrial dysfunction is also present. (houten2014mitochondrialnadp(h)deficiency pages 10-12, houten2014mitochondrialnadp(h)deficiency pages 9-10)
Primary hyperlysinemia due to lysine pathway defects (contextualized in the NADK2 paper as a confounder). (houten2014mitochondrialnadp(h)deficiency pages 2-4)

11. Outcome / prognosis

Severe NADK2-associated secondary DECR deficiency can be progressive and fatal in childhood, with progressive leukodystrophy/encephalopathy and multisystem involvement. (houten2014mitochondrialnadp(h)deficiency pages 4-5)
Prognosis for putative primary DECR1-related human disease cannot be estimated from the limited accessible evidence; in mice, baseline compensation exists but metabolic stress causes severe hypoglycemia and intolerance. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)

12. Treatment

Reported management attempts (human cases)

In the detailed NADK2-associated report, interventions attempted included: * Dietary lysine restriction (MAXO suggestion: dietary amino acid restriction) * Caloric support (MAXO: nutritional support therapy) * Medium-chain fatty acids (often used in FAO disorders to bypass some β‑oxidation steps) * Carnitine supplementation These are described as management attempts rather than established effective therapy. (houten2014mitochondrialnadp(h)deficiency pages 4-5)

Clinical trials

No DECR/NADK2-specific interventional clinical trials were identified in this run’s clinical trial retrieval.

13. Prevention

Primary prevention is not established; given autosomal recessive inheritance for NADK2-associated disease, genetic counseling (MAXO: genetic counseling) and carrier testing/cascade testing are the most actionable preventive strategies once a familial variant is known. (houten2014mitochondrialnadp(h)deficiency pages 5-7)
Secondary prevention: early recognition of suggestive metabolic signatures (isolated or predominant C10:2 elevation; C10:2 + hyperlysinemia) and prompt genetic testing may reduce diagnostic delay, although evidence for improved outcomes is not available here. (houten2014mitochondrialnadp(h)deficiency pages 10-12)

14. Other species / natural disease

No naturally occurring veterinary DECR deficiency evidence was identified in the accessible corpus.

15. Model organisms

Mouse

A targeted Decr−/− knockout mouse is a key model demonstrating: * Accumulation of the diagnostic biomarker C10:2 (decadienoylcarnitine) during fasting * Stress-induced hypoglycemia with preserved ketogenesis * Hepatic steatosis and cold intolerance This model is directly relevant for biomarker interpretation and mechanistic studies of PUFA β‑oxidation auxiliary enzymes. (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2, miinalainen2009mitochondrial24dienoylcoareductase media f7dcc2b0)

Recent developments (prioritizing 2023–2024)

2024: Postmortem “metabolic autopsy” operationalization for IEMs (contextual, not DECR-specific)

A 2024 retrospective study from Hong Kong reinforces modern real-world implementation of IEM detection in sudden unexpected deaths via combined dried blood spot acylcarnitines/amino acids, urine organic acids when available, and NGS panels, and cites an estimated 3–5% contribution of metabolic disorders to SUD. This supports the utility of maintaining FAO/IEM competence in forensic/pediatric pathology workflows, even though DECR deficiency was not a highlighted diagnosis in the excerpted findings. (hung2024driedbloodspot pages 1-2)

Evidence gap

In this run, I did not retrieve 2023–2024 primary publications that add new confirmed human DECR1-biallelic cases, nor updated disease-specific consensus guidelines. The most disease-defining human molecular mechanism remained the 2014 NADK2 report, with the strongest mechanistic support from earlier mouse genetics.

Visual evidence (pathway + biomarker)

The following figure extractions show (i) the DECR-dependent PUFA β‑oxidation step and (ii) fasting-associated accumulation of C10:2 acylcarnitine in Decr−/− mice, supporting both mechanistic understanding and biomarker rationale. (miinalainen2009mitochondrial24dienoylcoareductase media db369249, miinalainen2009mitochondrial24dienoylcoareductase media f7dcc2b0)

Summary table

Entity	Causal gene/defect	Key biomarkers	Core clinical features	Notes on diagnosis/screening	Key citations
Human NADK2-related secondary DECR deficiency	Autosomal recessive NADK2 loss causing mitochondrial NADP(H) deficiency with secondary impairment of NADPH-dependent DECR activity; DECR1 coding mutations were excluded in the reported modern cases	Elevated C10:2 (decadienoyl)carnitine; hyperlysinemia in plasma/CSF/urine; elevated lactate; low free carnitine; abnormal urinary organic acids; residual fibroblast DECR activity ~10%	Early infancy onset; failure to thrive, developmental delay, hypotonia, progressive encephalopathy, movement disorder/choreoathetosis-dystonia, visual loss/cortical blindness, epilepsy, renal tubular acidosis; death in childhood in severe cases	Diagnosis integrated acylcarnitines, amino acids, fibroblast enzyme assay, and exome sequencing; mild newborn-screen C10:2 elevation may occur but is not fully sensitive/specific; authors suggested lysine might improve screening specificity	(houten2014mitochondrialnadp(h)deficiency pages 9-10, houten2014mitochondrialnadp(h)deficiency pages 4-5, houten2014mitochondrialnadp(h)deficiency pages 5-7, houten2014mitochondrialnadp(h)deficiency pages 10-12)
Historical 1990 DECR deficiency case	Biochemical mitochondrial 2,4-dienoyl-CoA reductase deficiency reported before modern molecular diagnosis; residual DECR activity 17% in muscle and 40% in liver; later literature indicates DECR1 mutations were not demonstrated in similar cases	Elevated plasma C10:2-carnitine; hyperlysinemia	Failure to thrive, persistent hypotonia, microcephaly; death at 4 months	Landmark historical case establishing the phenotype/biochemical signature; no definitive molecular cause reported in the available evidence	(houten2014mitochondrialnadp(h)deficiency pages 2-4)
Decr1 knockout mouse	Targeted Decr1/Decr disruption causing primary loss of mitochondrial 2,4-dienoyl-CoA reductase and defective PUFA β-oxidation	Increased serum decadienoylcarnitine (C10:2); urinary unsaturated dicarboxylic acids; hepatic steatosis with unsaturated fatty acid accumulation; hypoglycemia during fasting/stress	Usually compensated at baseline, but severe fasting/stress intolerance, profound hypoglycemia, impaired cold tolerance/thermogenesis, fatty liver; ketogenesis preserved	Strong mechanistic model for interpreting human C10:2 biomarker and PUFA β-oxidation block; supports causal role of DECR in metabolic adaptation rather than proving human DECR1-mutant cases	(miinalainen2009mitochondrial24dienoylcoareductase pages 1-2, wanders2019translationalmetabolisma pages 3-3, miinalainen2009mitochondrial24dienoylcoareductase media db369249)

Table: This table contrasts the historical human DECR phenotype, modern NADK2-related secondary DECR deficiency, and the Decr1 knockout mouse model. It highlights the key biomarker pattern, phenotype, and diagnostic implications useful for rare disease knowledge-base curation.

Curator notes / limitations

1) Ontology identifiers (OMIM/Orphanet/MONDO) were not retrievable with the available tools in this run; they must be filled via direct database lookup. 2) Human evidence in the accessible corpus most strongly supports NADK2-associated secondary DECR deficiency, while definitive DECR1-mutant human disease was not confirmed here. 3) Treatment evidence is limited to reported management attempts and general FAO-disorder logic; no proven disease-modifying therapy was identified in the retrieved evidence.

Key primary sources (with URLs and publication dates)

Miinalainen IJ et al. PLoS Genetics (2009-07). “Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis.” https://doi.org/10.1371/journal.pgen.1000543 (miinalainen2009mitochondrial24dienoylcoareductase pages 1-2)
Houten SM et al. Human Molecular Genetics (2014-09). “Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia.” https://doi.org/10.1093/hmg/ddu218 (houten2014mitochondrialnadp(h)deficiency pages 1-2)
Wanders RJA et al. Journal of Inherited Metabolic Disease (2019-02). “Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era.” https://doi.org/10.1002/jimd.12008 (wanders2019translationalmetabolisma pages 3-3)
Hung LY et al. Cureus (2024-06). “Dried Blood Spot Postmortem Metabolic Autopsy With Genotype Validation for Sudden Unexpected Deaths in Infancy and Childhood in Hong Kong.” https://doi.org/10.7759/cureus.62347 (hung2024driedbloodspot pages 1-2)

References

(houten2014mitochondrialnadp(h)deficiency pages 9-10): Sander M. Houten, Simone Denis, Heleen te Brinke, Aldo Jongejan, Antoine H.C. van Kampen, Edward J. Bradley, Frank Baas, Raoul C.M. Hennekam, David S. Millington, Sarah P. Young, Dianne M. Frazier, Muge Gucsavas-Calikoglu, and Ronald J.A. Wanders. Mitochondrial nadp(h) deficiency due to a mutation in nadk2 causes dienoyl-coa reductase deficiency with hyperlysinemia. Human molecular genetics, 23 18:5009-16, Sep 2014. URL: https://doi.org/10.1093/hmg/ddu218, doi:10.1093/hmg/ddu218. This article has 89 citations and is from a domain leading peer-reviewed journal.
(houten2014mitochondrialnadp(h)deficiency pages 5-7): Sander M. Houten, Simone Denis, Heleen te Brinke, Aldo Jongejan, Antoine H.C. van Kampen, Edward J. Bradley, Frank Baas, Raoul C.M. Hennekam, David S. Millington, Sarah P. Young, Dianne M. Frazier, Muge Gucsavas-Calikoglu, and Ronald J.A. Wanders. Mitochondrial nadp(h) deficiency due to a mutation in nadk2 causes dienoyl-coa reductase deficiency with hyperlysinemia. Human molecular genetics, 23 18:5009-16, Sep 2014. URL: https://doi.org/10.1093/hmg/ddu218, doi:10.1093/hmg/ddu218. This article has 89 citations and is from a domain leading peer-reviewed journal.
(houten2014mitochondrialnadp(h)deficiency pages 1-2): Sander M. Houten, Simone Denis, Heleen te Brinke, Aldo Jongejan, Antoine H.C. van Kampen, Edward J. Bradley, Frank Baas, Raoul C.M. Hennekam, David S. Millington, Sarah P. Young, Dianne M. Frazier, Muge Gucsavas-Calikoglu, and Ronald J.A. Wanders. Mitochondrial nadp(h) deficiency due to a mutation in nadk2 causes dienoyl-coa reductase deficiency with hyperlysinemia. Human molecular genetics, 23 18:5009-16, Sep 2014. URL: https://doi.org/10.1093/hmg/ddu218, doi:10.1093/hmg/ddu218. This article has 89 citations and is from a domain leading peer-reviewed journal.
(houten2014mitochondrialnadp(h)deficiency pages 4-5): Sander M. Houten, Simone Denis, Heleen te Brinke, Aldo Jongejan, Antoine H.C. van Kampen, Edward J. Bradley, Frank Baas, Raoul C.M. Hennekam, David S. Millington, Sarah P. Young, Dianne M. Frazier, Muge Gucsavas-Calikoglu, and Ronald J.A. Wanders. Mitochondrial nadp(h) deficiency due to a mutation in nadk2 causes dienoyl-coa reductase deficiency with hyperlysinemia. Human molecular genetics, 23 18:5009-16, Sep 2014. URL: https://doi.org/10.1093/hmg/ddu218, doi:10.1093/hmg/ddu218. This article has 89 citations and is from a domain leading peer-reviewed journal.
(miinalainen2009mitochondrial24dienoylcoareductase pages 1-2): Ilkka J. Miinalainen, Werner Schmitz, Anne Huotari, Kaija J. Autio, Raija Soininen, Emiel Ver Loren van Themaat, Myriam Baes, Karl-Heinz Herzig, Ernst Conzelmann, and J. Kalervo Hiltunen. Mitochondrial 2,4-dienoyl-coa reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis. Jul 2009. URL: https://doi.org/10.1371/journal.pgen.1000543, doi:10.1371/journal.pgen.1000543. This article has 78 citations and is from a domain leading peer-reviewed journal.
(wanders2019translationalmetabolisma pages 3-3): Ronald J. A. Wanders, Frederic M. Vaz, Sacha Ferdinandusse, André B. P. van Kuilenburg, Stephan Kemp, Clara D. van Karnebeek, Hans R. Waterham, and Riekelt H. Houtkooper. Translational metabolism: a multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era. Journal of Inherited Metabolic Disease, 42:197-208, Feb 2019. URL: https://doi.org/10.1002/jimd.12008, doi:10.1002/jimd.12008. This article has 29 citations and is from a peer-reviewed journal.
(houten2014mitochondrialnadp(h)deficiency pages 10-12): Sander M. Houten, Simone Denis, Heleen te Brinke, Aldo Jongejan, Antoine H.C. van Kampen, Edward J. Bradley, Frank Baas, Raoul C.M. Hennekam, David S. Millington, Sarah P. Young, Dianne M. Frazier, Muge Gucsavas-Calikoglu, and Ronald J.A. Wanders. Mitochondrial nadp(h) deficiency due to a mutation in nadk2 causes dienoyl-coa reductase deficiency with hyperlysinemia. Human molecular genetics, 23 18:5009-16, Sep 2014. URL: https://doi.org/10.1093/hmg/ddu218, doi:10.1093/hmg/ddu218. This article has 89 citations and is from a domain leading peer-reviewed journal.
(houten2014mitochondrialnadp(h)deficiency pages 2-4): Sander M. Houten, Simone Denis, Heleen te Brinke, Aldo Jongejan, Antoine H.C. van Kampen, Edward J. Bradley, Frank Baas, Raoul C.M. Hennekam, David S. Millington, Sarah P. Young, Dianne M. Frazier, Muge Gucsavas-Calikoglu, and Ronald J.A. Wanders. Mitochondrial nadp(h) deficiency due to a mutation in nadk2 causes dienoyl-coa reductase deficiency with hyperlysinemia. Human molecular genetics, 23 18:5009-16, Sep 2014. URL: https://doi.org/10.1093/hmg/ddu218, doi:10.1093/hmg/ddu218. This article has 89 citations and is from a domain leading peer-reviewed journal.
(miinalainen2009mitochondrial24dienoylcoareductase media db369249): Ilkka J. Miinalainen, Werner Schmitz, Anne Huotari, Kaija J. Autio, Raija Soininen, Emiel Ver Loren van Themaat, Myriam Baes, Karl-Heinz Herzig, Ernst Conzelmann, and J. Kalervo Hiltunen. Mitochondrial 2,4-dienoyl-coa reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis. Jul 2009. URL: https://doi.org/10.1371/journal.pgen.1000543, doi:10.1371/journal.pgen.1000543. This article has 78 citations and is from a domain leading peer-reviewed journal.
(miinalainen2009mitochondrial24dienoylcoareductase media f7dcc2b0): Ilkka J. Miinalainen, Werner Schmitz, Anne Huotari, Kaija J. Autio, Raija Soininen, Emiel Ver Loren van Themaat, Myriam Baes, Karl-Heinz Herzig, Ernst Conzelmann, and J. Kalervo Hiltunen. Mitochondrial 2,4-dienoyl-coa reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis. Jul 2009. URL: https://doi.org/10.1371/journal.pgen.1000543, doi:10.1371/journal.pgen.1000543. This article has 78 citations and is from a domain leading peer-reviewed journal.
(hung2024driedbloodspot pages 1-2): Ling Yin Hung, Chloe M Mak, Ka Chung Foo, Chun Hei Toby Chan, Hok-Fung Tong, Tsz Ki Wong, Hoi Shan Leung, Ka Chai Cheung, Han Chih Hencher Lee, and Chor Kwan Ching. Dried blood spot postmortem metabolic autopsy with genotype validation for sudden unexpected deaths in infancy and childhood in hong kong. Cureus, Jun 2024. URL: https://doi.org/10.7759/cureus.62347, doi:10.7759/cureus.62347. This article has 2 citations.

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Medical Actions

Biochemical Markers

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References & Deep Research

References

Deep Research

DECR Deficiency (mitochondrial 2,4-dienoyl‑CoA reductase deficiency): Disease Characteristics Research Report

Executive summary

1. Disease information

What is the disease?

Key identifiers (OMIM/Orphanet/MeSH/MONDO)

Common synonyms / alternative names

Evidence sources

2. Etiology

Disease causal factors

Genetic causes (current evidence)

Risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

Core phenotype spectrum (humans; NADK2-associated secondary DECR deficiency)

Phenotypes (mouse model; primary Decr deficiency)

Quality of life impact

4. Genetic / molecular information

Causal genes

Pathogenic variants (reported in accessible evidence)

Functional consequences

Suggested GO / pathway terms (for curation; not exhaustive)

Suggested cell types (CL terms) and tissues

5. Environmental information

6. Mechanism / pathophysiology

Molecular pathway and causal chain

Key biochemical abnormalities (with suggested CHEBI entities)

Authoritative expert framing (abstract quote)

7. Anatomical structures affected

Organs/systems (supported by evidence)

Subcellular localization

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology

10. Diagnostics

Clinical laboratory tests and biomarkers

Genetic testing

Newborn screening and screening limitations

Differential diagnosis (examples)

11. Outcome / prognosis

12. Treatment

Reported management attempts (human cases)

Clinical trials

13. Prevention

14. Other species / natural disease

15. Model organisms

Mouse

Recent developments (prioritizing 2023–2024)

2024: Postmortem “metabolic autopsy” operationalization for IEMs (contextual, not DECR-specific)

Evidence gap

Visual evidence (pathway + biomarker)

Summary table

Curator notes / limitations

Key primary sources (with URLs and publication dates)

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