CYB561-Related Orthostatic Hypotension

Mendelian MONDO:0020751 Pathograph 24 Show in embeddings browser

Biallelic CYB561 variants cause an autosomal recessive catecholamine biosynthesis disorder with lifelong severe orthostatic hypotension, low or undetectable noradrenaline and adrenaline, normal dopamine, and preserved plasma dopamine beta-hydroxylase activity. Cytochrome b561 transfers electrons across secretory-vesicle membranes to regenerate the ascorbate required for dopamine beta-hydroxylase function. Impaired intravesicular cofactor recycling is the inferred link between the genetic defect and noradrenaline deficiency; patient vesicular ascorbate has not been directly measured in the cited studies. Sympathetic cholinergic and cardiovagal responses can remain preserved. Droxidopa bypasses the biosynthetic block and improved blood pressure and symptoms in the reported patients.

Ask OpenScientist

Ask a research question about CYB561-Related Orthostatic Hypotension. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
6
Phenotypes
3
Gaps
24
Pathograph
1
Genes
4
Variants
1
Medical Actions
1
Models
4
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
PMID:29343526 SUPPORT Human Clinical
"Here we report a novel autosomal recessive orthostatic hypotension syndrome caused by mutations in the CYB561 gene."
The authors explicitly identify autosomal recessive inheritance, supported by segregation in the founding families.
PMID:31822578 SUPPORT Human Clinical
"Variants were identified on separate chromosomes (in trans), indicating biparental inheritance."
The additional family demonstrates compound heterozygous recessive inheritance.
?

Discussions and Knowledge Gaps

3
Is CYB561 deficiency a form of dopamine beta-hydroxylase deficiency, or a separate disease that resembles it?
INTERPRETATION cyb561_phenocopy_not_subtype
Attached to
pathophysiology#Functional Dopamine Beta-Hydroxylase Deficiency
CYB561 deficiency and primary DBH deficiency share severe orthostatic hypotension and low noradrenaline, but affect different steps: vesicular cofactor recycling versus the hydroxylase itself. Preserved plasma DBH activity and normal rather than increased dopamine help distinguish the reported CYB561 cases. Renal impairment also occurs in DBH deficiency, and the 2020 CYB561 series describes mild or questionable ptosis; neither renal disease nor absence of ptosis is a reliable absolute discriminator.
How do broad CYB561 expression and shared vesicular ascorbate requirements relate to the observed clinical spectrum?
KNOWLEDGE GAP cyb561_expression_versus_phenotype
Attached to
pathophysiology#Selective Sympathetic Noradrenergic Failure genetic#CYB561
Broad CYB561 expression and low CSF noradrenaline metabolites coexist with relatively preserved development in the reported families. Peptidylglycine alpha-amidating monooxygenase shares the intravesicular ascorbate requirement, yet a specific neuropeptide-amidation phenotype has not been demonstrated. Compensation by other proteins, different substrate requirements and incomplete clinical assessment remain possible explanations. Measuring amidated peptides and vesicular ascorbate would distinguish biochemical sparing from an unrecognized deficit. The 2020 authors argue that oral or parenteral ascorbate cannot directly replenish the vesicular compartment. This is a mechanistic argument, not a reported supplementation trial.
Show evidence (1 reference)
PMID:31822578 SUPPORT Other
"Restoration of ascorbic acid with oral or parenteral administration is not feasible because ascorbic acid is not taken up by catecholaminergic vesicles."
The authors distinguish systemic ascorbate supply from the inaccessible intravesicular pool.
Why does dopamine not accumulate despite impaired noradrenaline synthesis?
KNOWLEDGE GAP OPEN cyb561_dopamine_nonaccumulation
Attached to
pathophysiology#Intravesicular Ascorbate Depletion pathophysiology#Noradrenaline and Adrenaline Deficiency
The 2020 authors propose that reduced vesicular antioxidant capacity permits DOPA and dopamine degradation. This explanation remains speculative and has not been demonstrated in patient vesicles.
Show evidence (1 reference)
PMID:31822578 SUPPORT Other
"We speculate that the presence of ascorbic acid within noradrenergic vesicles provides antioxidant capacity, and its absence in CYB561 deficiency leads to degradation of DOPA and dopamine, preventing their accumulation."
The source explicitly marks oxidative degradation as a hypothesis.
⚙

Pathophysiology

8
Biallelic CYB561 Loss of Function
Homozygous Gly88Arg and Trp44Ter variants were identified in two families, and a third family carried His53Tyr in trans with an exon 2 deletion. The clinical and biochemical findings support loss of function. The precise effects of the patient alleles on protein abundance, membrane localization and electron transfer remain inferred; structural modeling of Gly88Arg and conservation of His53Tyr do not substitute for functional assays.
CYB561 hgnc:2571 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYB561 (hgnc:2571). hgnc:2571 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of Transmembrane Electron Transfer into Secretory Vesicles Biallelic damaging variants are inferred to impair CYB561 electron transfer; loss of membrane protein has not been directly demonstrated for every allele.
Show evidence (2 references)
PMID:29343526 SUPPORT Human Clinical
"Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family."
The original gene identification in the two founding families.
PMID:31822578 SUPPORT Human Clinical
"Variants were identified on separate chromosomes (in trans), indicating biparental inheritance."
The additional patient carried the missense and exon-deletion alleles on opposite parental chromosomes.
Loss of Transmembrane Electron Transfer into Secretory Vesicles
Mechanism confidence: Provisional
Vesicular CYB561 normally transfers reducing equivalents between cytosolic ascorbate and the vesicle interior through two heme centers. Impaired transfer in the human disorder is inferred from biallelic damaging variants, the catecholamine profile and the established biochemistry of the protein.
chromaffin cell CL:0000166 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chromaffin cell (CL:0000166). CL:0000166 is a cell type from the Cell Ontology.
CYB561 hgnc:2571 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYB561 (hgnc:2571). hgnc:2571 is a gene from the HUGO Gene Nomenclature Committee.
transmembrane monodehydroascorbate reductase activity GO:0140575 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transmembrane monodehydroascorbate reductase activity (GO:0140575). GO:0140575 is a molecular function from the Gene Ontology.
secretory granule membrane GO:0030667 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves secretory granule membrane (GO:0030667). GO:0030667 is a cellular component from the Gene Ontology.
Downstream
Intravesicular Ascorbate Depletion Without electron transfer, oxidized intravesicular ascorbate is not regenerated.
Show evidence (2 references)
PMID:14769875 SUPPORT In Vitro
"The reduction of thiazole blue or cytochrome c was dependent on the presence of cytochrome b561 in the vesicle membranes."
Reconstituted bovine chromaffin-vesicle CYB561 demonstrates transmembrane electron transfer. The experiment used inside-out orientation and did not test patient variants.
PMID:14999009 SUPPORT In Vitro
"Cytochrome b(561) from bovine adrenal chromaffin vesicles contains two hemes b with different midpoint potentials (+150 and +60 mV) and participates in transmembrane electron transport from extravesicular ascorbate to an intravesicular monooxygenase, dopamine beta-hydroxylase."
Biochemistry of chromaffin-vesicle CYB561 supports its two-heme electron-transfer role; this is the relevant protein rather than another CYB561-family member.
Intravesicular Ascorbate Depletion
Mechanism confidence: Provisional
Loss of vesicular ascorbate regeneration is the proposed compartment-specific consequence of impaired CYB561 function. The clinical papers infer this shortage rather than measuring ascorbate inside patient vesicles. Peptidylglycine alpha-amidating monooxygenase also uses vesicular ascorbate, but a resulting neuropeptide-amidation defect has not been demonstrated in these patients.
Downstream
Functional Dopamine Beta-Hydroxylase Deficiency Insufficient regenerated ascorbate is inferred to limit vesicular dopamine beta-hydroxylase activity despite preserved plasma activity.
Show evidence (3 references)
PMID:29343526 SUPPORT Other
"The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency."
The authors interpret the combined genetic, clinical and biochemical findings as intravesicular ascorbate shortage; this sentence is a mechanistic inference rather than a direct patient-vesicle measurement.
PMID:29343526 SUPPORT Other
"Intravesicular ascorbic acid is required by DβH and peptidylglycine alpha-amidating monooxygenase for their enzymatic activity"
Names both ascorbate-dependent vesicular enzymes. This is what makes the absent neuropeptide phenotype a question rather than an omission.
PMID:29343526 SUPPORT Other
"peptidylglycine alpha-amidating monooxygenase uses ascorbic acid to amidate neuropeptides to prolong and increase activity (e.g. α-melanocyte-stimulating hormone, oxytocin, vasopressin, gastrin)"
Gives what the second enzyme does and which peptides it acts on, which is what would have to be measured to close the gap.
Functional Dopamine Beta-Hydroxylase Deficiency
Noradrenaline synthesis is impaired despite preserved measured plasma dopamine beta-hydroxylase activity and absence of pathogenic DBH variants in the founding families. This supports a cofactor-supply defect affecting the enzyme in its vesicular compartment; plasma testing does not directly measure its intravesicular catalytic state.
norepinephrine biosynthetic process GO:0042421 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased norepinephrine biosynthetic process (GO:0042421). GO:0042421 is a biological process from the Gene Ontology.
dopamine beta-monooxygenase activity GO:0004500 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dopamine beta-monooxygenase activity (GO:0004500). GO:0004500 is a molecular function from the Gene Ontology.
Downstream
Noradrenaline and Adrenaline Deficiency Impaired dopamine hydroxylation reduces noradrenaline production and consequently the substrate available for adrenaline synthesis.
Show evidence (2 references)
PMID:29343526 SUPPORT Human Clinical
"Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations."
Normal plasma enzyme activity and negative DBH sequencing distinguish these families from primary DBH deficiency; they do not directly assay enzyme turnover inside patient vesicles.
PMID:14769875 SUPPORT In Vitro
"The addition of a soluble form of dopamine beta-hydroxylase to the external medium resulted in the successful reconstitution of the hydroxylation activity towards tyramine, an analogue of dopamine, suggesting that a direct electron transfer via complex formation occurred."
The bovine reconstitution experiment connects CYB561-mediated electron transfer with monooxygenase activity, using an artificial reversed orientation and tyramine substrate rather than patient vesicles.
Noradrenaline and Adrenaline Deficiency
Plasma noradrenaline, adrenaline and the noradrenaline metabolite DHPG are low or undetectable, with normal dopamine and its metabolites. Low CSF MHPG indicates involvement of central noradrenaline metabolism. Normal concentrations of selected dopamine and serotonin metabolites do not establish normal function of every pathway in those systems.
Animal models
CYB561 knockout mouse Mouse recapitulates The knockout reproduces selected catecholamine and metabolite deficits, most clearly the marked reduction in brain noradrenaline.
Downstream
Selective Sympathetic Noradrenergic Failure Only the noradrenergic arm of the autonomic nervous system loses its transmitter.
Impaired Adrenergic Restraint of Insulin Secretion Loss of noradrenergic inhibition of insulin secretion is proposed to contribute to infant hypoglycemia.
Show evidence (1 reference)
PMID:31822578 SUPPORT Human Clinical
"Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal."
The measured catecholamine pattern supports selective noradrenaline deficiency; it does not prove that every upstream biochemical function is intact.
Selective Sympathetic Noradrenergic Failure
Deficient noradrenergic cardiovascular responses coexist with preserved sweating and cardiovagal responses in the tested patients. This pattern supports selective autonomic transmitter failure rather than generalized loss of autonomic function.
Downstream
Orthostatic Hypotension Failure of compensatory noradrenergic vasoconstriction produces a severe blood-pressure fall on standing.
Reduced Renal Perfusion Systemic hypotension is a plausible contributor to the posture-associated fall in renal blood flow measured in one patient.
Show evidence (1 reference)
PMID:31822578 SUPPORT Human Clinical
"CYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions."
Establishes the selectivity, which is what makes the autonomic phenotype mechanistically interpretable rather than a general dysautonomia.
Impaired Adrenergic Restraint of Insulin Secretion
Mechanism confidence: Hypothetical
The 2020 authors propose that loss of alpha2-adrenergic inhibition of insulin secretion, with preserved parasympathetic stimulation, contributes to hypoglycemia in infancy. Insulin secretion and counterregulatory responses were not directly characterized in the CYB561 patients. Failure of partial pancreatectomy in one patient does not exclude insulin dysregulation, and the later report states that episodes did not persist through childhood.
Downstream
Recurrent Hypoglycaemia Excess insulin secretion relative to glucose supply is a proposed contributor to the infant episodes.
Show evidence (1 reference)
PMID:31822578 SUPPORT Other
"because of the loss of α2-adrenergic receptor-mediated inhibition, and conservation of parasympathetic-mediated stimulation of insulin secretion."
The discussion proposes an autonomic explanation by analogy with DBH deficiency; the cited CYB561 series does not directly test pancreatic insulin dynamics.
Reduced Renal Perfusion
Mechanism confidence: Provisional
Low renal plasma flow and further reduction on sitting were measured in the Dutch index patient. Chronic hemodynamic impairment could contribute to renal insufficiency, but the small series does not establish that it fully explains progressive kidney dysfunction.
Downstream
Progressive Renal Insufficiency Persistently reduced perfusion is a proposed contributor to reduced filtration and progressive renal impairment.
Anemia The founding case report describes mild anemia as secondary to impaired renal function.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"supine effective renal plasma flow was 248 ml/min and glomerular filtration rate was 56 ml/min (reference 1000–1200 and 100–120, respectively) whereas sitting effective renal plasma flow was 199 ml/min and glomerular filtration rate 38 ml/min."
Clearance measurements directly demonstrate reduced renal perfusion; the causal contribution to chronic progression remains inferred.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CYB561-Related Orthostatic Hypotension Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Blood 1
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"Renal function was impaired, with secondary mild anemia (Hb=7.3 mmol/L)."
The index case narrative directly links the mild anemia to renal impairment; Table 1 also records mild anemia for the Dutch pair.
Cardiovascular 2
Orthostatic Hypotension VERY_FREQUENT Orthostatic hypotension due to autonomic dysfunction HP:0004926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orthostatic hypotension due to autonomic dysfunction (HP:0004926). HP:0004926 is a phenotype from the Human Phenotype Ontology.
Sequelae: Syncope
Show evidence (2 references)
PMID:29343526 SUPPORT Human Clinical
"We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause."
All four molecularly confirmed patients in the founding series had severe orthostatic hypotension; VERY_FREQUENT is a conservative band for this small, clinically ascertained series.
PMID:29343526 SUPPORT Human Clinical
"Supine blood pressure was 85/50 mm Hg but after standing up it immediately dropped to 50/35 mm Hg without a significant change in heart rate"
The Dutch index patient provides a directly measured example of the postural blood-pressure fall.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"From early childhood onwards, she had suffered from dizziness and occasional fainting upon standing."
The clinical history of D1 directly documents postural syncope.
Genitourinary 2
Progressive Renal Insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083), qualified as course progressive. HP:0000083 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:29343526 SUPPORT Human Clinical
"Her sister (D2) is still alive albeit with progressive renal insufficiency (glomerular filtration rate 26 ml/min)."
Reports the progressive renal impairment with a measured GFR.
PMID:29343526 SUPPORT Human Clinical
"supine effective renal plasma flow was 248 ml/min and glomerular filtration rate was 56 ml/min (reference 1000–1200 and 100–120, respectively) whereas sitting effective renal plasma flow was 199 ml/min and glomerular filtration rate 38 ml/min."
Direct clearance measurements in D1 show posture-associated worsening of renal perfusion and filtration.
Retrograde Ejaculation HP:0012877 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrograde ejaculation (HP:0012877). HP:0012877 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31822578 SUPPORT Human Clinical
"Patient 4 had retrograde ejaculation."
The 2020 report identifies this genitourinary finding in the additional male patient.
PMID:31822578 SUPPORT Human Clinical
"Patient 4 remains stable and recently fathered a healthy child."
The follow-up documents fatherhood despite the reported ejaculation abnormality.
Metabolism 1
Recurrent Hypoglycaemia Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29343526 SUPPORT Human Clinical
"They had episodes of symptomatic hypoglycemia during infancy."
The full-text clinical history identifies the two American sisters; hypoglycemia was not documented in the Dutch sisters.
PMID:31822578 SUPPORT Human Clinical
"These episodes did not persist through childhood"
The later report qualifies the duration of infant hypoglycemia; persistence into adult life is not established.
PMID:29343526 SUPPORT Human Clinical
"Patient A1 underwent a partial pancreatectomy at age three years for this reason but she showed no improvement in these episodes."
The unsuccessful operation does not distinguish counterregulatory hormone failure from inappropriate insulin secretion.
🧬

Genetic Associations

1
CYB561
Gene: CYB561 hgnc:2571 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYB561 (hgnc:2571). hgnc:2571 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:29343526 SUPPORT In Vitro
"The CYB561 gene was found to be expressed in many human tissues, in particular the brain."
Quantitative PCR of human adult and fetal tissue RNA shows broad expression; expression alone does not establish the causal effects of disease alleles.
PMID:29343526 SUPPORT Human Clinical
"Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family."
The original gene identification in the two founding families.
Variants (4)
NM_001915.3:c.262G>A (p.Gly88Arg)
Homozygous in the Dutch sisters and heterozygous in unaffected parents and a sister. Homology modeling predicts altered membrane anchoring and possible heme-adjacent effects; patient protein localization and transport were not directly measured. The distinct c.262G>C allele encoding the same protein substitution is not the familial allele.
Show evidence (2 references)
PMID:29343526 SUPPORT Human Clinical
"Sanger sequencing confirmed the presence of the c.262G>A mutation in homozygous form in the two affected Dutch sisters while it was heterozygous in the parents and in an unaffected sister and wild type in the other sister"
Family segregation supports the recessive allele.
PMID:29343526 SUPPORT Computational
"The model suggests that the introduction of a hydrophilic and positively charged arginine in the third transmembrane region might affect the interactions between the hydrophobic lipids and can alter transmembrane anchoring of the protein"
An Arabidopsis-template homology model predicts a structural consequence; this is not a functional assay.
NM_001915.3:c.131G>A (p.Trp44Ter)
Homozygous early stop variant in the American sisters, predicted to truncate the protein between the first two transmembrane segments. Endogenous RNA decay and residual protein were not measured.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"Both affected sisters (A1 and A2) had a homozygous nonsense mutation (c.131G>A, p.Trp44*) in exon 2 of the gene"
The founding study directly identifies the familial nonsense allele.
c.157C>T (p.His53Tyr)
Missense allele at a conserved site, found in trans with an exon 2 deletion in the additional male patient. Impaired function was predicted; no variant-specific functional measurement was reported.
Show evidence (1 reference)
PMID:31822578 SUPPORT Human Clinical
"This is a missense mutation (p.His53Tyr) in a highly conserved site, predictive of impaired protein function. Variants were identified on separate chromosomes (in trans), indicating biparental inheritance."
Clinical sequencing establishes phase, while the functional consequence remains predicted.
Exon 2 deletion
Deletion allele in trans with His53Tyr in the additional male patient, demonstrating that diagnostic testing must be able to detect exon-level deletions as well as sequence variants.
Show evidence (1 reference)
PMID:31822578 SUPPORT Human Clinical
"Patient 4, not reported previously, had compound heterozygous mutations of the CYB561 gene. One allele had a deletion of exon 2; the other allele had a c.157C>T variant"
The primary report establishes the exon-deletion variant class in the third family.
💊

Medical Actions

1
Droxidopa
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: droxidopa CHEBI:31524 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses droxidopa (CHEBI:31524). CHEBI:31524 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Droxidopa (L-DOPS) is converted to noradrenaline by aromatic L-amino acid decarboxylase, bypassing the DBH-dependent step. In the founding four patients, 200 mg once to three times daily improved blood pressure and dizziness; nausea, headache and lumbar pain limited tolerability. The overlapping 2020 series reports improvement with 100 mg three times daily and excessive pressor responses or nausea above that dose. These are historical individual treatment observations, not a universal dosing regimen or evidence of improved survival.
Mechanism Target:
BYPASSES Functional Dopamine Beta-Hydroxylase Deficiency — Direct decarboxylation of droxidopa to noradrenaline bypasses the cofactor-dependent dopamine hydroxylation step.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine."
States both the clinical response and the reason the bypass works, in the founding report.
RESTORES Noradrenaline and Adrenaline Deficiency — Restores measurable noradrenaline and DHPG; normalization of every catecholamine compartment is not demonstrated.
Show evidence (1 reference)
PMID:31822578 SUPPORT Human Clinical
"Droxidopa restored norepinephrine levels and improved OH."
Confirms the response on both the biochemical and the clinical endpoint in the autonomic evaluation series.
Target Phenotypes: Orthostatic hypotension due to autonomic dysfunction HP:0004926 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Orthostatic hypotension due to autonomic dysfunction (HP:0004926). HP:0004926 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 references)
PMID:29343526 SUPPORT Human Clinical
"The four patients were treated with L-dihydroxyphenylserine (L-DOPS), a synthetic precursor of norepinephrine, with dosages ranging from 200 mg once to three times daily"
The founding paper reports the doses used in four patients; the later series describes lower doses in overlapping cases.
PMID:29343526 SUPPORT Human Clinical
"However, L-DOPS tolerability was hampered by nausea, headache and pain in the lumbar region"
The full text documents adverse effects that limited tolerability; this observation does not quantify their frequency or prove a survival benefit.
PMID:29343526 SUPPORT Human Clinical
"This treatment led a rise blood pressure in all 4 patients: supine blood pressure invariably exceeded 100/70 mmHg and blood pressure in the upright position usually rose to at least 90/60 mmHg."
The founding series directly documents improved blood pressure, with residual variation in standing measurements.
+ 2 more references
🔬

Biochemical Markers

4
Plasma noradrenaline (Decreased)
Context: Low or undetectable noradrenaline with normal plasma dopamine and preserved plasma dopamine beta-hydroxylase activity supports CYB561 deficiency. Primary DBH deficiency also lowers noradrenaline but typically has increased dopamine and deficient plasma enzyme activity.
Pathograph Readouts
Readout Of Noradrenaline and Adrenaline Deficiency Negative Diagnostic
Low noradrenaline reports the biochemical deficit; the paired dopamine, enzyme and genetic results establish its diagnostic context.
Show evidence (1 reference)
PMID:31822578 SUPPORT Human Clinical
"Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal."
The paired measurement that makes this readout interpretable.
Plasma dihydroxyphenylglycol (Decreased)
Context: DHPG, an intraneuronal noradrenaline metabolite, was below detection in the tested patients. Together with the other catecholamine measurements and genotype this supports depletion of neuronal noradrenaline; DHPG alone does not uniquely distinguish synthesis from release or reuptake defects.
Pathograph Readouts
Readout Of Noradrenaline and Adrenaline Deficiency Negative Diagnostic
Low DHPG supports a depleted intraneuronal noradrenaline pool when interpreted with the full biochemical and genetic profile.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"Plasma norepinephrine, epinephrine and the intraneuronal norepinephrine metabolite dihydroxyphenylglycol were below the limit of detection (<0.01 nmol/L)"
Reports DHPG alongside noradrenaline and adrenaline, all below detection, in the American sisters.
CSF 3-methoxy-4-hydroxyphenylglycol (Decreased)
Context: CSF MHPG was below 3 nmol/L against a reference interval of 26-64, with normal HVA and 5-HIAA. This supports a selective central noradrenaline metabolic deficit without proving that all dopamine and serotonin functions are intact.
Pathograph Readouts
Readout Of Noradrenaline and Adrenaline Deficiency Negative Diagnostic
Low CSF MHPG supports central noradrenaline deficiency; preserved HVA and 5-HIAA provide the measured comparison.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"The concentration of MHPG, the principal downstream metabolite of norepinephrine in the brain, was extremely low in CSF (<3 nmol/L; reference 26–64). The downstream metabolites of dopamine and serotonin, HVA and 5-HIAA respectively, had a normal concentration in CSF"
Gives the low CSF MHPG and the normal HVA and 5-HIAA in the same sentence, which is what makes this a selectivity result and not just a severity one.
Plasma dopamine beta-hydroxylase activity (Normal)
Context: Preserved plasma dopamine beta-hydroxylase activity in the founding patients helps distinguish CYB561 deficiency from primary DBH deficiency. The plasma assay does not directly measure enzyme activity inside secretory vesicles.
Pathograph Readouts
Readout Of Functional Dopamine Beta-Hydroxylase Deficiency Present Absent Diagnostic
Preserved plasma activity despite deficient noradrenaline synthesis supports a compartment-dependent cofactor defect when considered with biallelic CYB561 variants.
Show evidence (1 reference)
PMID:29343526 SUPPORT Human Clinical
"Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations."
Reports both the normal enzyme activity and the normal gene.
🔬

Diagnosis

3
Molecular confirmation
Sequence analysis together with detection of exon-level deletions can identify biallelic CYB561 variants. The third family demonstrates the value of deletion-sensitive analysis and establishing that two variants are in trans.
Show evidence (2 references)
PMID:31822578 SUPPORT Human Clinical
"Patient 4, not reported previously, had compound heterozygous mutations of the CYB561 gene. One allele had a deletion of exon 2; the other allele had a c.157C>T variant"
The primary report establishes the exon-deletion variant class in the third family.
PMID:31822578 SUPPORT Human Clinical
"Variants were identified on separate chromosomes (in trans), indicating biparental inheritance."
The additional family demonstrates compound heterozygous recessive inheritance.
Autonomic function testing
Orthostatic challenge and Valsalva testing reveal defective blood-pressure compensation, while sinus arrhythmia, cardiovagal responses and sweating can be preserved. The 2020 report discusses four relatives/cases but explicitly lacks formal autonomic testing for the deceased, genetically untested brother.
Show evidence (4 references)
PMID:31822578 SUPPORT Human Clinical
"Patients were evaluated in Vanderbilt Autonomic Dysfunction Center (VADC), on a sodium-controlled diet and off medications. Autonomic evaluation included Valsalva maneuvers, sinus arrhythmia during deep breathing, orthostatic challenge, and determination of catecholamines and their metabolites..."
The methods define the physiologic and biochemical evaluation.
PMID:31822578 SUPPORT Human Clinical
"All patients had profound orthostatic hypotension and impaired blood pressure response to the Valsalva maneuver, with exaggerated hypotension during phase 2 and absence of overshoot during phase 4"
The results describe adrenergic cardiovascular failure in the evaluated cases; the brother is explicitly excluded from formal testing in the case history.
PMID:31822578 SUPPORT Human Clinical
"Thermoregulatory testing showed normal sweating."
Preserved sweating is a diagnostic observation rather than a positive disease phenotype.
+ 1 more reference
Catecholamine and enzyme profile
Low or undetectable noradrenaline and DHPG with normal dopamine and preserved plasma DBH activity supports CYB561 deficiency in a patient with lifelong orthostatic hypotension. Genetic confirmation separates it from primary DBH deficiency.
Show evidence (2 references)
PMID:31822578 SUPPORT Human Clinical
"Plasma dopamine and its metabolites were comparable to normal participants, and much lower than in DBH deficiency."
The paired biochemical comparison helps distinguish the two molecular diseases.
PMID:29343526 SUPPORT Human Clinical
"Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations."
Normal plasma enzyme activity and negative DBH sequencing distinguish these families from primary DBH deficiency; they do not directly assay enzyme turnover inside patient vesicles.
📈

Progression

2
Infancy and childhood
The reported patients had normal birth and mental development. Early-life episodes treated as seizures in the American family could represent epilepsy, hypoglycemia or hypotensive syncope; the report does not resolve their cause. Infant hypoglycemia was described as no longer persisting through childhood.
Show evidence (3 references)
PMID:31822578 SUPPORT Human Clinical
"All 4 patients had normal birth and mental development."
This clinical summary includes the unconfirmed brother as well as three molecularly confirmed patients in the 2020 report.
PMID:31822578 SUPPORT Human Clinical
"Patients 1, 2, and 3 were treated for seizures in early childhood, but it is not clear if these episodes corresponded to documented epilepsy, hypoglycemic seizures, or the tonic-clonic movements that occur during hypotensive syncope."
The source explicitly preserves diagnostic uncertainty about the paroxysmal events.
PMID:31822578 SUPPORT Human Clinical
"These episodes did not persist through childhood"
The later account qualifies the natural history of hypoglycemia.
Reported long-term outcomes
The Dutch index patient died at 37 after prolonged circulatory arrest while off droxidopa. The two American sisters died at 59 and 48 of unascertained causes; their unconfirmed brother died at 16. These observations do not establish a survival distribution, a mortality frequency, or protection from death by treatment. The additional male patient was stable and had fathered a healthy child at reported follow-up.
Show evidence (3 references)
PMID:29343526 SUPPORT Human Clinical
"Both American patients (A1 and A2) were lost to follow up and died of unknown cause at age 59 and 48, respectively"
A historical outcome in the founding series; case counts and causes do not establish population life expectancy or treatment-related survival benefit.
PMID:29343526 SUPPORT Human Clinical
"Four years after presentation, patient D1 suddenly lost consciousness with a prolonged circulatory arrest (while she was off L-DOPS treatment). After resuscitation measures and administration of a low-dose epinephrine, her blood pressure quickly recovered, but she had incurred severe brain..."
A historical outcome in the founding series; case counts and causes do not establish population life expectancy or treatment-related survival benefit.
PMID:31822578 SUPPORT Human Clinical
"The causes of death were not ascertained. Patient 4 remains stable and recently fathered a healthy child."
The later report retains uncertainty about deaths in the American family and documents follow-up of the new case.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
The 2018 and 2020 reports together describe five molecularly confirmed individuals from three families. The later report re-examines the two American sisters and adds one male patient; it also describes their clinically similar brother, whose DNA and formal autonomic evaluation were unavailable. These reports are overlapping case series, not independent cohorts or a population prevalence estimate.
Show evidence (3 references)
PMID:29343526 SUPPORT Human Clinical
"We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause."
Gives the size of the founding cohort.
PMID:31822578 SUPPORT Human Clinical
"Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available."
The later report explicitly identifies overlap with the founding American family and the unconfirmed brother.
PMID:31822578 SUPPORT Human Clinical
"Patient 4, not reported previously, had compound heterozygous mutations of the CYB561 gene."
One newly described molecularly confirmed individual brings the combined count to five.
🐁

Animal Models

1
CYB561 knockout mouse
Six homozygous knockout mice and six wild-type mice were studied at 16 weeks. Brain noradrenaline and normetanephrine and adrenal normetanephrine and metanephrine were significantly reduced. Adrenal noradrenaline and adrenaline and tissue dopamine differences were not significant. Blood pressure was not measured.
Species
Mouse
Genotype
CYB561 -/- (reporter-tagged deletion allele, post-Cre, C57BL/6NTac)
Publication
PMID:29343526
Pathograph links
Noradrenaline and Adrenaline Deficiency recapitulates fidelity: moderate The knockout reproduces selected catecholamine and metabolite deficits, most clearly the marked reduction in brain noradrenaline.
Limitations: The evidence is biochemical: no blood-pressure phenotype was measured, and only six animals per genotype were examined. Adrenal noradrenaline and adrenaline differences were not significant, despite lower medians. Mice synthesize ascorbate de novo, unlike humans, but whether this attenuates disease severity was not tested.
Readouts
Whole-brain noradrenaline and normetanephrine
Direction: DECREASED
Interpretation: Central catecholamine deficit matching the human biochemical profile.
Show evidence (1 reference)
PMID:29343526 SUPPORT Model Organism
"The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype."
Reports the measurements and their significance in both tissues.
Adrenal noradrenaline
Direction: UNCHANGED
Interpretation: Adrenal noradrenaline had a lower median but no statistically significant difference; this is not proof of equivalence.
Show evidence (1 reference)
PMID:29343526 SUPPORT Model Organism
"| Norepinephrine | 10.4 (2.24–139) | 2.35 (0.18–35.6) | n.s. |"
Table 2 reports a nonsignificant difference between six wild-type and six knockout adrenal samples, contrasting with the significant brain result.
Show evidence (2 references)
PMID:29343526 SUPPORT Model Organism
"An important consideration when using mice in ascorbic acid studies is that mice, unlike humans, can produce ascorbic acid de novo."
The species difference that limits this model for an ascorbate-recycling disease, stated by the authors themselves. Attached to the link rather than to a readout because it qualifies whether the model is informative at all, not any single measurement.
+ 1 more reference
{ }

Source YAML

click to show 
name: CYB561-Related Orthostatic Hypotension
creation_date: '2026-08-27T18:45:00Z'
category: Mendelian
description: Biallelic CYB561 variants cause an autosomal recessive catecholamine biosynthesis disorder with lifelong severe orthostatic hypotension, low or undetectable noradrenaline and adrenaline, normal dopamine, and preserved plasma dopamine beta-hydroxylase activity. Cytochrome b561 transfers electrons across secretory-vesicle membranes to regenerate the ascorbate required for dopamine beta-hydroxylase function. Impaired intravesicular cofactor recycling is the inferred link between the genetic defect and noradrenaline deficiency; patient vesicular ascorbate has not been directly measured in the cited studies. Sympathetic cholinergic and cardiovagal responses can remain preserved. Droxidopa bypasses the biosynthetic block and improved blood pressure and symptoms in the reported patients.
disease_term:
  preferred_term: orthostatic hypotension 2
  term:
    id: MONDO:0020751
    label: orthostatic hypotension 2
synonyms:
- Orthostatic hypotension 2
- CYB561 deficiency
- Cytochrome b561 deficiency
references:
- reference: PMID:29343526
  title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
- reference: PMID:31822578
  title: Congenital absence of norepinephrine due to CYB561 mutations.
- reference: PMID:14769875
  title: Reversely-oriented cytochrome b561 in reconstituted vesicles catalyzes transmembrane electron transfer and supports extravesicular dopamine beta-hydroxylase activity.
- reference: PMID:14999009
  title: Properties of two distinct heme centers of cytochrome b561 from bovine chromaffin vesicles studied by EPR, resonance Raman, and ascorbate reduction assay.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report a novel autosomal recessive orthostatic hypotension syndrome caused by mutations in the CYB561 gene.
    explanation: The authors explicitly identify autosomal recessive inheritance, supported by segregation in the founding families.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variants were identified on separate chromosomes (in trans), indicating biparental inheritance.
    explanation: The additional family demonstrates compound heterozygous recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: The 2018 and 2020 reports together describe five molecularly confirmed individuals from three families. The later report re-examines the two American sisters and adds one male patient; it also describes their clinically similar brother, whose DNA and formal autonomic evaluation were unavailable. These reports are overlapping case series, not independent cohorts or a population prevalence estimate.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause.
    explanation: Gives the size of the founding cohort.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available.
    explanation: The later report explicitly identifies overlap with the founding American family and the unconfirmed brother.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 4, not reported previously, had compound heterozygous mutations of the CYB561 gene.
    explanation: One newly described molecularly confirmed individual brings the combined count to five.
pathophysiology:
- name: Biallelic CYB561 Loss of Function
  biological_scale: MOLECULAR
  description: Homozygous Gly88Arg and Trp44Ter variants were identified in two families, and a third family carried His53Tyr in trans with an exon 2 deletion. The clinical and biochemical findings support loss of function. The precise effects of the patient alleles on protein abundance, membrane localization and electron transfer remain inferred; structural modeling of Gly88Arg and conservation of His53Tyr do not substitute for functional assays.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family.
    explanation: The original gene identification in the two founding families.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variants were identified on separate chromosomes (in trans), indicating biparental inheritance.
    explanation: The additional patient carried the missense and exon-deletion alleles on opposite parental chromosomes.
  downstream:
  - target: Loss of Transmembrane Electron Transfer into Secretory Vesicles
    causal_link_type: DIRECT
    description: Biallelic damaging variants are inferred to impair CYB561 electron transfer; loss of membrane protein has not been directly demonstrated for every allele.
  genes:
  - preferred_term: CYB561
    term:
      id: hgnc:2571
      label: CYB561
- name: Loss of Transmembrane Electron Transfer into Secretory Vesicles
  biological_scale: MOLECULAR
  description: Vesicular CYB561 normally transfers reducing equivalents between cytosolic ascorbate and the vesicle interior through two heme centers. Impaired transfer in the human disorder is inferred from biallelic damaging variants, the catecholamine profile and the established biochemistry of the protein.
  cell_types:
  - preferred_term: chromaffin cell
    term:
      id: CL:0000166
      label: chromaffin cell
  evidence:
  - reference: PMID:14769875
    reference_title: Reversely-oriented cytochrome b561 in reconstituted vesicles catalyzes transmembrane electron transfer and supports extravesicular dopamine beta-hydroxylase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The reduction of thiazole blue or cytochrome c was dependent on the presence of cytochrome b561 in the vesicle membranes.
    explanation: Reconstituted bovine chromaffin-vesicle CYB561 demonstrates transmembrane electron transfer. The experiment used inside-out orientation and did not test patient variants.
  - reference: PMID:14999009
    reference_title: Properties of two distinct heme centers of cytochrome b561 from bovine chromaffin vesicles studied by EPR, resonance Raman, and ascorbate reduction assay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cytochrome b(561) from bovine adrenal chromaffin vesicles contains two hemes b with different midpoint potentials (+150 and +60 mV) and participates in transmembrane electron transport from extravesicular ascorbate to an intravesicular monooxygenase, dopamine beta-hydroxylase.
    explanation: Biochemistry of chromaffin-vesicle CYB561 supports its two-heme electron-transfer role; this is the relevant protein rather than another CYB561-family member.
  downstream:
  - target: Intravesicular Ascorbate Depletion
    causal_link_type: DIRECT
    description: Without electron transfer, oxidized intravesicular ascorbate is not regenerated.
  mechanism_confidence: PROVISIONAL
  molecular_functions:
  - preferred_term: transmembrane monodehydroascorbate reductase activity
    term:
      id: GO:0140575
      label: transmembrane monodehydroascorbate reductase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: secretory granule membrane
    term:
      id: GO:0030667
      label: secretory granule membrane
  genes:
  - preferred_term: CYB561
    term:
      id: hgnc:2571
      label: CYB561
- name: Intravesicular Ascorbate Depletion
  biological_scale: MOLECULAR
  description: Loss of vesicular ascorbate regeneration is the proposed compartment-specific consequence of impaired CYB561 function. The clinical papers infer this shortage rather than measuring ascorbate inside patient vesicles. Peptidylglycine alpha-amidating monooxygenase also uses vesicular ascorbate, but a resulting neuropeptide-amidation defect has not been demonstrated in these patients.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency.
    explanation: The authors interpret the combined genetic, clinical and biochemical findings as intravesicular ascorbate shortage; this sentence is a mechanistic inference rather than a direct patient-vesicle measurement.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Intravesicular ascorbic acid is required by DβH and peptidylglycine alpha-amidating monooxygenase for their enzymatic activity
    explanation: Names both ascorbate-dependent vesicular enzymes. This is what makes the absent neuropeptide phenotype a question rather than an omission.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: peptidylglycine alpha-amidating monooxygenase uses ascorbic acid to amidate neuropeptides to prolong and increase activity (e.g. α-melanocyte-stimulating hormone, oxytocin, vasopressin, gastrin)
    explanation: Gives what the second enzyme does and which peptides it acts on, which is what would have to be measured to close the gap.
  downstream:
  - target: Functional Dopamine Beta-Hydroxylase Deficiency
    causal_link_type: DIRECT
    description: Insufficient regenerated ascorbate is inferred to limit vesicular dopamine beta-hydroxylase activity despite preserved plasma activity.
  mechanism_confidence: PROVISIONAL
- name: Functional Dopamine Beta-Hydroxylase Deficiency
  biological_scale: MOLECULAR
  description: Noradrenaline synthesis is impaired despite preserved measured plasma dopamine beta-hydroxylase activity and absence of pathogenic DBH variants in the founding families. This supports a cofactor-supply defect affecting the enzyme in its vesicular compartment; plasma testing does not directly measure its intravesicular catalytic state.
  molecular_functions:
  - preferred_term: dopamine beta-monooxygenase activity
    modifier: DECREASED
    term:
      id: GO:0004500
      label: dopamine beta-monooxygenase activity
  biological_processes:
  - preferred_term: norepinephrine biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0042421
      label: norepinephrine biosynthetic process
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations.
    explanation: Normal plasma enzyme activity and negative DBH sequencing distinguish these families from primary DBH deficiency; they do not directly assay enzyme turnover inside patient vesicles.
  - reference: PMID:14769875
    reference_title: Reversely-oriented cytochrome b561 in reconstituted vesicles catalyzes transmembrane electron transfer and supports extravesicular dopamine beta-hydroxylase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The addition of a soluble form of dopamine beta-hydroxylase to the external medium resulted in the successful reconstitution of the hydroxylation activity towards tyramine, an analogue of dopamine, suggesting that a direct electron transfer via complex formation occurred.
    explanation: The bovine reconstitution experiment connects CYB561-mediated electron transfer with monooxygenase activity, using an artificial reversed orientation and tyramine substrate rather than patient vesicles.
  downstream:
  - target: Noradrenaline and Adrenaline Deficiency
    causal_link_type: DIRECT
    description: Impaired dopamine hydroxylation reduces noradrenaline production and consequently the substrate available for adrenaline synthesis.
- name: Noradrenaline and Adrenaline Deficiency
  biological_scale: ORGANISM
  description: Plasma noradrenaline, adrenaline and the noradrenaline metabolite DHPG are low or undetectable, with normal dopamine and its metabolites. Low CSF MHPG indicates involvement of central noradrenaline metabolism. Normal concentrations of selected dopamine and serotonin metabolites do not establish normal function of every pathway in those systems.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal.
    explanation: The measured catecholamine pattern supports selective noradrenaline deficiency; it does not prove that every upstream biochemical function is intact.
  downstream:
  - target: Selective Sympathetic Noradrenergic Failure
    causal_link_type: DIRECT
    description: Only the noradrenergic arm of the autonomic nervous system loses its transmitter.
  - target: Impaired Adrenergic Restraint of Insulin Secretion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Loss of noradrenergic inhibition of insulin secretion is proposed to contribute to infant hypoglycemia.
    intermediate_mechanisms:
    - Reduced alpha2-adrenergic receptor signaling in pancreatic beta cells
- name: Selective Sympathetic Noradrenergic Failure
  biological_scale: ORGANISM
  description: Deficient noradrenergic cardiovascular responses coexist with preserved sweating and cardiovagal responses in the tested patients. This pattern supports selective autonomic transmitter failure rather than generalized loss of autonomic function.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions.
    explanation: Establishes the selectivity, which is what makes the autonomic phenotype mechanistically interpretable rather than a general dysautonomia.
  downstream:
  - target: Orthostatic Hypotension
    causal_link_type: DIRECT
    description: Failure of compensatory noradrenergic vasoconstriction produces a severe blood-pressure fall on standing.
  - target: Reduced Renal Perfusion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Severe postural hypotension
    description: Systemic hypotension is a plausible contributor to the posture-associated fall in renal blood flow measured in one patient.
- name: Impaired Adrenergic Restraint of Insulin Secretion
  biological_scale: ORGANISM
  description: The 2020 authors propose that loss of alpha2-adrenergic inhibition of insulin secretion, with preserved parasympathetic stimulation, contributes to hypoglycemia in infancy. Insulin secretion and counterregulatory responses were not directly characterized in the CYB561 patients. Failure of partial pancreatectomy in one patient does not exclude insulin dysregulation, and the later report states that episodes did not persist through childhood.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: because of the loss of α2-adrenergic receptor-mediated inhibition, and conservation of parasympathetic-mediated stimulation of insulin secretion.
    explanation: The discussion proposes an autonomic explanation by analogy with DBH deficiency; the cited CYB561 series does not directly test pancreatic insulin dynamics.
  downstream:
  - target: Recurrent Hypoglycaemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Excess insulin secretion relative to glucose supply is a proposed contributor to the infant episodes.
    intermediate_mechanisms:
    - Inappropriately maintained insulin secretion
  mechanism_confidence: HYPOTHETICAL
- name: Reduced Renal Perfusion
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: Low renal plasma flow and further reduction on sitting were measured in the Dutch index patient. Chronic hemodynamic impairment could contribute to renal insufficiency, but the small series does not establish that it fully explains progressive kidney dysfunction.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: supine effective renal plasma flow was 248 ml/min and glomerular filtration rate was 56 ml/min (reference 1000–1200 and 100–120, respectively) whereas sitting effective renal plasma flow was 199 ml/min and glomerular filtration rate 38 ml/min.
    explanation: Clearance measurements directly demonstrate reduced renal perfusion; the causal contribution to chronic progression remains inferred.
  downstream:
  - target: Progressive Renal Insufficiency
    causal_link_type: DIRECT
    description: Persistently reduced perfusion is a proposed contributor to reduced filtration and progressive renal impairment.
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Renal impairment
    description: The founding case report describes mild anemia as secondary to impaired renal function.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Renal function was impaired, with secondary mild anemia (Hb=7.3 mmol/L).
      explanation: The clinical narrative explicitly links anemia with renal impairment; the upstream hemodynamic contribution remains provisional.
phenotypes:
- category: Cardiovascular
  name: Orthostatic Hypotension
  frequency: VERY_FREQUENT
  sequelae:
  - target: Syncope
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Severe postural hypotension can reduce cerebral perfusion and produce syncope.
    intermediate_mechanisms:
    - Cerebral hypoperfusion
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: From early childhood onwards, she had suffered from dizziness and occasional fainting upon standing.
      explanation: The index patient had postural fainting with severe measured orthostatic hypotension; cerebral perfusion was not directly measured.
  description: Severe orthostatic hypotension began in infancy or early childhood in the reported families. The founding series included four molecularly confirmed patients; this strongly selected case series does not supply an unbiased population frequency.
  phenotype_term:
    preferred_term: Orthostatic hypotension due to autonomic dysfunction
    term:
      id: HP:0004926
      label: Orthostatic hypotension due to autonomic dysfunction
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause.
    explanation: All four molecularly confirmed patients in the founding series had severe orthostatic hypotension; VERY_FREQUENT is a conservative band for this small, clinically ascertained series.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Supine blood pressure was 85/50 mm Hg but after standing up it immediately dropped to 50/35 mm Hg without a significant change in heart rate
    explanation: The Dutch index patient provides a directly measured example of the postural blood-pressure fall.
- category: Endocrine
  name: Recurrent Hypoglycaemia
  description: Symptomatic hypoglycemia occurred in infancy in the two confirmed American sisters and their clinically similar, genetically untested brother. The 2020 report states that episodes did not persist through childhood. Partial pancreatectomy in one sister did not improve the episodes; it is a historical unsuccessful intervention.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They had episodes of symptomatic hypoglycemia during infancy.
    explanation: The full-text clinical history identifies the two American sisters; hypoglycemia was not documented in the Dutch sisters.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These episodes did not persist through childhood
    explanation: The later report qualifies the duration of infant hypoglycemia; persistence into adult life is not established.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient A1 underwent a partial pancreatectomy at age three years for this reason but she showed no improvement in these episodes.
    explanation: The unsuccessful operation does not distinguish counterregulatory hormone failure from inappropriate insulin secretion.
- category: Renal
  name: Progressive Renal Insufficiency
  description: Renal impairment was documented in both Dutch sisters, with progression described in D2. In D1, measured glomerular filtration rate fell from 56 mL/min supine to 38 mL/min sitting, compatible with a hemodynamic contribution. The small series does not establish disease-wide frequency or the complete cause of renal dysfunction.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her sister (D2) is still alive albeit with progressive renal insufficiency (glomerular filtration rate 26 ml/min).
    explanation: Reports the progressive renal impairment with a measured GFR.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: supine effective renal plasma flow was 248 ml/min and glomerular filtration rate was 56 ml/min (reference 1000–1200 and 100–120, respectively) whereas sitting effective renal plasma flow was 199 ml/min and glomerular filtration rate 38 ml/min.
    explanation: Direct clearance measurements in D1 show posture-associated worsening of renal perfusion and filtration.
- name: Syncope
  category: Cardiovascular
  description: Fainting on standing was reported in the Dutch index patient, consistent with severe orthostatic hypotension. Frequency across all affected individuals is not established.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: From early childhood onwards, she had suffered from dizziness and occasional fainting upon standing.
    explanation: The clinical history of D1 directly documents postural syncope.
- name: Anemia
  category: Hematologic
  description: Mild anemia accompanied renal impairment in the Dutch sisters. The index patient had hemoglobin 7.3 mmol/L, described as secondary to impaired renal function.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Renal function was impaired, with secondary mild anemia (Hb=7.3 mmol/L).
    explanation: The index case narrative directly links the mild anemia to renal impairment; Table 1 also records mild anemia for the Dutch pair.
- name: Retrograde Ejaculation
  category: Genitourinary
  description: Retrograde ejaculation was reported in the additional adult male with compound heterozygous variants. He later fathered a healthy child, so this observation does not establish infertility.
  phenotype_term:
    preferred_term: Retrograde ejaculation
    term:
      id: HP:0012877
      label: Retrograde ejaculation
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 4 had retrograde ejaculation.
    explanation: The 2020 report identifies this genitourinary finding in the additional male patient.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 4 remains stable and recently fathered a healthy child.
    explanation: The follow-up documents fatherhood despite the reported ejaculation abnormality.
biochemical:
- name: Plasma noradrenaline
  presence: Decreased
  context: Low or undetectable noradrenaline with normal plasma dopamine and preserved plasma dopamine beta-hydroxylase activity supports CYB561 deficiency. Primary DBH deficiency also lowers noradrenaline but typically has increased dopamine and deficient plasma enzyme activity.
  biomarker_term:
    preferred_term: noradrenaline
    term:
      id: CHEBI:33569
      label: noradrenaline
  readouts:
  - target: Noradrenaline and Adrenaline Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low noradrenaline reports the biochemical deficit; the paired dopamine, enzyme and genetic results establish its diagnostic context.
    evidence:
    - reference: PMID:31822578
      reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal.
      explanation: The paired measurement that makes this readout interpretable.
- name: Plasma dihydroxyphenylglycol
  presence: Decreased
  context: DHPG, an intraneuronal noradrenaline metabolite, was below detection in the tested patients. Together with the other catecholamine measurements and genotype this supports depletion of neuronal noradrenaline; DHPG alone does not uniquely distinguish synthesis from release or reuptake defects.
  biomarker_term:
    preferred_term: 3,4-dihydroxyphenylglycol
    term:
      id: NCIT:C101017
      label: 3,4-Dihydroxyphenylglycol Measurement
  readouts:
  - target: Noradrenaline and Adrenaline Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low DHPG supports a depleted intraneuronal noradrenaline pool when interpreted with the full biochemical and genetic profile.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Plasma norepinephrine, epinephrine and the intraneuronal norepinephrine metabolite dihydroxyphenylglycol were below the limit of detection (<0.01 nmol/L)
      explanation: Reports DHPG alongside noradrenaline and adrenaline, all below detection, in the American sisters.
- name: CSF 3-methoxy-4-hydroxyphenylglycol
  presence: Decreased
  context: CSF MHPG was below 3 nmol/L against a reference interval of 26-64, with normal HVA and 5-HIAA. This supports a selective central noradrenaline metabolic deficit without proving that all dopamine and serotonin functions are intact.
  biomarker_term:
    preferred_term: 3-methoxy-4-hydroxyphenylglycol
  readouts:
  - target: Noradrenaline and Adrenaline Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low CSF MHPG supports central noradrenaline deficiency; preserved HVA and 5-HIAA provide the measured comparison.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of MHPG, the principal downstream metabolite of norepinephrine in the brain, was extremely low in CSF (<3 nmol/L; reference 26–64). The downstream metabolites of dopamine and serotonin, HVA and 5-HIAA respectively, had a normal concentration in CSF
      explanation: Gives the low CSF MHPG and the normal HVA and 5-HIAA in the same sentence, which is what makes this a selectivity result and not just a severity one.
- name: Plasma dopamine beta-hydroxylase activity
  presence: Normal
  context: Preserved plasma dopamine beta-hydroxylase activity in the founding patients helps distinguish CYB561 deficiency from primary DBH deficiency. The plasma assay does not directly measure enzyme activity inside secretory vesicles.
  readouts:
  - target: Functional Dopamine Beta-Hydroxylase Deficiency
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: Preserved plasma activity despite deficient noradrenaline synthesis supports a compartment-dependent cofactor defect when considered with biallelic CYB561 variants.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations.
      explanation: Reports both the normal enzyme activity and the normal gene.
genetic:
- name: CYB561
  gene_term:
    preferred_term: CYB561
    term:
      id: hgnc:2571
      label: CYB561
  relationship_type: CAUSATIVE
  notes: Reported disease alleles include homozygous Gly88Arg and Trp44Ter, and His53Tyr in trans with an exon 2 deletion. Segregation supports recessive inheritance. Human missense effects remain predicted, and no quantitative penetrance estimate is established by these small families.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The CYB561 gene was found to be expressed in many human tissues, in particular the brain.
    explanation: Quantitative PCR of human adult and fetal tissue RNA shows broad expression; expression alone does not establish the causal effects of disease alleles.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family.
    explanation: The original gene identification in the two founding families.
  variants:
  - name: NM_001915.3:c.262G>A (p.Gly88Arg)
    description: Homozygous in the Dutch sisters and heterozygous in unaffected parents and a sister. Homology modeling predicts altered membrane anchoring and possible heme-adjacent effects; patient protein localization and transport were not directly measured. The distinct c.262G>C allele encoding the same protein substitution is not the familial allele.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Sanger sequencing confirmed the presence of the c.262G>A mutation in homozygous form in the two affected Dutch sisters while it was heterozygous in the parents and in an unaffected sister and wild type in the other sister
      explanation: Family segregation supports the recessive allele.
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: The model suggests that the introduction of a hydrophilic and positively charged arginine in the third transmembrane region might affect the interactions between the hydrophobic lipids and can alter transmembrane anchoring of the protein
      explanation: An Arabidopsis-template homology model predicts a structural consequence; this is not a functional assay.
  - name: NM_001915.3:c.131G>A (p.Trp44Ter)
    description: Homozygous early stop variant in the American sisters, predicted to truncate the protein between the first two transmembrane segments. Endogenous RNA decay and residual protein were not measured.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both affected sisters (A1 and A2) had a homozygous nonsense mutation (c.131G>A, p.Trp44*) in exon 2 of the gene
      explanation: The founding study directly identifies the familial nonsense allele.
  - name: c.157C>T (p.His53Tyr)
    description: Missense allele at a conserved site, found in trans with an exon 2 deletion in the additional male patient. Impaired function was predicted; no variant-specific functional measurement was reported.
    evidence:
    - reference: PMID:31822578
      reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This is a missense mutation (p.His53Tyr) in a highly conserved site, predictive of impaired protein function. Variants were identified on separate chromosomes (in trans), indicating biparental inheritance.
      explanation: Clinical sequencing establishes phase, while the functional consequence remains predicted.
  - name: Exon 2 deletion
    description: Deletion allele in trans with His53Tyr in the additional male patient, demonstrating that diagnostic testing must be able to detect exon-level deletions as well as sequence variants.
    evidence:
    - reference: PMID:31822578
      reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patient 4, not reported previously, had compound heterozygous mutations of the CYB561 gene. One allele had a deletion of exon 2; the other allele had a c.157C>T variant
      explanation: The primary report establishes the exon-deletion variant class in the third family.
diagnosis:
- name: Molecular confirmation
  description: Sequence analysis together with detection of exon-level deletions can identify biallelic CYB561 variants. The third family demonstrates the value of deletion-sensitive analysis and establishing that two variants are in trans.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 4, not reported previously, had compound heterozygous mutations of the CYB561 gene. One allele had a deletion of exon 2; the other allele had a c.157C>T variant
    explanation: The primary report establishes the exon-deletion variant class in the third family.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Variants were identified on separate chromosomes (in trans), indicating biparental inheritance.
    explanation: The additional family demonstrates compound heterozygous recessive inheritance.
- name: Autonomic function testing
  description: Orthostatic challenge and Valsalva testing reveal defective blood-pressure compensation, while sinus arrhythmia, cardiovagal responses and sweating can be preserved. The 2020 report discusses four relatives/cases but explicitly lacks formal autonomic testing for the deceased, genetically untested brother.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients were evaluated in Vanderbilt Autonomic Dysfunction Center (VADC), on a sodium-controlled diet and off medications. Autonomic evaluation included Valsalva maneuvers, sinus arrhythmia during deep breathing, orthostatic challenge, and determination of catecholamines and their metabolites using high-performance liquid chromatography with electrochemical detection.
    explanation: The methods define the physiologic and biochemical evaluation.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients had profound orthostatic hypotension and impaired blood pressure response to the Valsalva maneuver, with exaggerated hypotension during phase 2 and absence of overshoot during phase 4
    explanation: The results describe adrenergic cardiovascular failure in the evaluated cases; the brother is explicitly excluded from formal testing in the case history.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Thermoregulatory testing showed normal sweating.
    explanation: Preserved sweating is a diagnostic observation rather than a positive disease phenotype.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Heart rate ratios for sinus arrhythmia and the VM were normal.
    explanation: Documents the preserved parasympathetic response measured in the autonomic evaluation.
- name: Catecholamine and enzyme profile
  description: Low or undetectable noradrenaline and DHPG with normal dopamine and preserved plasma DBH activity supports CYB561 deficiency in a patient with lifelong orthostatic hypotension. Genetic confirmation separates it from primary DBH deficiency.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma dopamine and its metabolites were comparable to normal participants, and much lower than in DBH deficiency.
    explanation: The paired biochemical comparison helps distinguish the two molecular diseases.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations.
    explanation: Normal plasma enzyme activity and negative DBH sequencing distinguish these families from primary DBH deficiency; they do not directly assay enzyme turnover inside patient vesicles.
treatments:
- name: Droxidopa
  description: Droxidopa (L-DOPS) is converted to noradrenaline by aromatic L-amino acid decarboxylase, bypassing the DBH-dependent step. In the founding four patients, 200 mg once to three times daily improved blood pressure and dizziness; nausea, headache and lumbar pain limited tolerability. The overlapping 2020 series reports improvement with 100 mg three times daily and excessive pressor responses or nausea above that dose. These are historical individual treatment observations, not a universal dosing regimen or evidence of improved survival.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: droxidopa
      term:
        id: CHEBI:31524
        label: droxidopa
  target_mechanisms:
  - target: Functional Dopamine Beta-Hydroxylase Deficiency
    treatment_effect: BYPASSES
    description: Direct decarboxylation of droxidopa to noradrenaline bypasses the cofactor-dependent dopamine hydroxylation step.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine.
      explanation: States both the clinical response and the reason the bypass works, in the founding report.
  - target: Noradrenaline and Adrenaline Deficiency
    treatment_effect: RESTORES
    description: Restores measurable noradrenaline and DHPG; normalization of every catecholamine compartment is not demonstrated.
    evidence:
    - reference: PMID:31822578
      reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Droxidopa restored norepinephrine levels and improved OH.
      explanation: Confirms the response on both the biochemical and the clinical endpoint in the autonomic evaluation series.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The four patients were treated with L-dihydroxyphenylserine (L-DOPS), a synthetic precursor of norepinephrine, with dosages ranging from 200 mg once to three times daily
    explanation: The founding paper reports the doses used in four patients; the later series describes lower doses in overlapping cases.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, L-DOPS tolerability was hampered by nausea, headache and pain in the lumbar region
    explanation: The full text documents adverse effects that limited tolerability; this observation does not quantify their frequency or prove a survival benefit.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'This treatment led a rise blood pressure in all 4 patients: supine blood pressure invariably exceeded 100/70 mmHg and blood pressure in the upright position usually rose to at least 90/60 mmHg.'
    explanation: The founding series directly documents improved blood pressure, with residual variation in standing measurements.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Droxidopa 100 mg three times a day improved orthostatic hypotension (table 1) and increased plasma norepinephrine from undetectable to 65 and 139 pg/mL in patients 1 and 2.
    explanation: The later study supplies paired biochemical response measurements in two previously reported sisters.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Doses >100 mg TID were not tolerated because of excessive pressor responses (patients 1 and 2) or nausea (patient 4).
    explanation: The later report documents dose-limiting effects and cautions against treating the historical doses as a universal regimen.
  target_phenotypes:
  - preferred_term: Orthostatic hypotension due to autonomic dysfunction
    term:
      id: HP:0004926
      label: Orthostatic hypotension due to autonomic dysfunction
animal_models:
- name: CYB561 knockout mouse
  species: Mouse
  genotype: CYB561 -/- (reporter-tagged deletion allele, post-Cre, C57BL/6NTac)
  publication: PMID:29343526
  description: Six homozygous knockout mice and six wild-type mice were studied at 16 weeks. Brain noradrenaline and normetanephrine and adrenal normetanephrine and metanephrine were significantly reduced. Adrenal noradrenaline and adrenaline and tissue dopamine differences were not significant. Blood pressure was not measured.
  modeled_mechanisms:
  - target: Noradrenaline and Adrenaline Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The knockout reproduces selected catecholamine and metabolite deficits, most clearly the marked reduction in brain noradrenaline.
    limitations: 'The evidence is biochemical: no blood-pressure phenotype was measured, and only six animals per genotype were examined. Adrenal noradrenaline and adrenaline differences were not significant, despite lower medians. Mice synthesize ascorbate de novo, unlike humans, but whether this attenuates disease severity was not tested.'
    readouts:
    - name: Whole-brain noradrenaline and normetanephrine
      target: Noradrenaline and Adrenaline Deficiency
      direction: DECREASED
      interpretation: Central catecholamine deficit matching the human biochemical profile.
      evidence:
      - reference: PMID:29343526
        reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype.
        explanation: Reports the measurements and their significance in both tissues.
    - name: Adrenal noradrenaline
      target: Noradrenaline and Adrenaline Deficiency
      direction: UNCHANGED
      interpretation: Adrenal noradrenaline had a lower median but no statistically significant difference; this is not proof of equivalence.
      evidence:
      - reference: PMID:29343526
        reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: '| Norepinephrine | 10.4 (2.24–139) | 2.35 (0.18–35.6) | n.s. |'
        explanation: Table 2 reports a nonsignificant difference between six wild-type and six knockout adrenal samples, contrasting with the significant brain result.
    evidence:
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: An important consideration when using mice in ascorbic acid studies is that mice, unlike humans, can produce ascorbic acid de novo.
      explanation: The species difference that limits this model for an ascorbate-recycling disease, stated by the authors themselves. Attached to the link rather than to a readout because it qualifies whether the model is informative at all, not any single measurement.
    - reference: PMID:29343526
      reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In particular, no data on blood pressure are available which is a limitation of our study.
      explanation: The authors explicitly limit translation from biochemical measurements to orthostatic hypotension.
progression:
- phase: Infancy and childhood
  notes: The reported patients had normal birth and mental development. Early-life episodes treated as seizures in the American family could represent epilepsy, hypoglycemia or hypotensive syncope; the report does not resolve their cause. Infant hypoglycemia was described as no longer persisting through childhood.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 4 patients had normal birth and mental development.
    explanation: This clinical summary includes the unconfirmed brother as well as three molecularly confirmed patients in the 2020 report.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients 1, 2, and 3 were treated for seizures in early childhood, but it is not clear if these episodes corresponded to documented epilepsy, hypoglycemic seizures, or the tonic-clonic movements that occur during hypotensive syncope.
    explanation: The source explicitly preserves diagnostic uncertainty about the paroxysmal events.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These episodes did not persist through childhood
    explanation: The later account qualifies the natural history of hypoglycemia.
- phase: Reported long-term outcomes
  notes: The Dutch index patient died at 37 after prolonged circulatory arrest while off droxidopa. The two American sisters died at 59 and 48 of unascertained causes; their unconfirmed brother died at 16. These observations do not establish a survival distribution, a mortality frequency, or protection from death by treatment. The additional male patient was stable and had fathered a healthy child at reported follow-up.
  evidence:
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both American patients (A1 and A2) were lost to follow up and died of unknown cause at age 59 and 48, respectively
    explanation: A historical outcome in the founding series; case counts and causes do not establish population life expectancy or treatment-related survival benefit.
  - reference: PMID:29343526
    reference_title: Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four years after presentation, patient D1 suddenly lost consciousness with a prolonged circulatory arrest (while she was off L-DOPS treatment). After resuscitation measures and administration of a low-dose epinephrine, her blood pressure quickly recovered, but she had incurred severe brain damage and died after being in coma for five days
    explanation: A historical outcome in the founding series; case counts and causes do not establish population life expectancy or treatment-related survival benefit.
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The causes of death were not ascertained. Patient 4 remains stable and recently fathered a healthy child.
    explanation: The later report retains uncertainty about deaths in the American family and documents follow-up of the new case.
discussions:
- discussion_id: cyb561_phenocopy_not_subtype
  kind: INTERPRETATION
  prompt: Is CYB561 deficiency a form of dopamine beta-hydroxylase deficiency, or a separate disease that resembles it?
  attaches_to:
  - pathophysiology#Functional Dopamine Beta-Hydroxylase Deficiency
  rationale: 'CYB561 deficiency and primary DBH deficiency share severe orthostatic hypotension and low noradrenaline, but affect different steps: vesicular cofactor recycling versus the hydroxylase itself. Preserved plasma DBH activity and normal rather than increased dopamine help distinguish the reported CYB561 cases. Renal impairment also occurs in DBH deficiency, and the 2020 CYB561 series describes mild or questionable ptosis; neither renal disease nor absence of ptosis is a reliable absolute discriminator.'
- discussion_id: cyb561_expression_versus_phenotype
  kind: KNOWLEDGE_GAP
  prompt: How do broad CYB561 expression and shared vesicular ascorbate requirements relate to the observed clinical spectrum?
  attaches_to:
  - pathophysiology#Selective Sympathetic Noradrenergic Failure
  - genetic#CYB561
  rationale: Broad CYB561 expression and low CSF noradrenaline metabolites coexist with relatively preserved development in the reported families. Peptidylglycine alpha-amidating monooxygenase shares the intravesicular ascorbate requirement, yet a specific neuropeptide-amidation phenotype has not been demonstrated. Compensation by other proteins, different substrate requirements and incomplete clinical assessment remain possible explanations. Measuring amidated peptides and vesicular ascorbate would distinguish biochemical sparing from an unrecognized deficit. The 2020 authors argue that oral or parenteral ascorbate cannot directly replenish the vesicular compartment. This is a mechanistic argument, not a reported supplementation trial.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Restoration of ascorbic acid with oral or parenteral administration is not feasible because ascorbic acid is not taken up by catecholaminergic vesicles.
    explanation: The authors distinguish systemic ascorbate supply from the inaccessible intravesicular pool.
- discussion_id: cyb561_dopamine_nonaccumulation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Why does dopamine not accumulate despite impaired noradrenaline synthesis?
  attaches_to:
  - pathophysiology#Intravesicular Ascorbate Depletion
  - pathophysiology#Noradrenaline and Adrenaline Deficiency
  rationale: The 2020 authors propose that reduced vesicular antioxidant capacity permits DOPA and dopamine degradation. This explanation remains speculative and has not been demonstrated in patient vesicles.
  evidence:
  - reference: PMID:31822578
    reference_title: Congenital absence of norepinephrine due to CYB561 mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: We speculate that the presence of ascorbic acid within noradrenergic vesicles provides antioxidant capacity, and its absence in CYB561 deficiency leads to degradation of DOPA and dopamine, preventing their accumulation.
    explanation: The source explicitly marks oxidative degradation as a hypothesis.
notes: The clinical evidence consists of small, overlapping families. Five molecularly confirmed individuals were described across the 2018 and 2020 reports, plus one clinically similar brother without available DNA. Normal birth and mental development were reported, and childhood events treated as seizures could have represented epilepsy, hypoglycemia or hypotensive syncope. The underlying cause of these events remains unresolved. No validated clinical subtypes or quantitative penetrance estimate are established by these families.
📚

References & Deep Research

References

4
PMID:29343526
Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
No top-level findings curated for this source.
PMID:31822578
Congenital absence of norepinephrine due to CYB561 mutations.
No top-level findings curated for this source.
PMID:14769875
Reversely-oriented cytochrome b561 in reconstituted vesicles catalyzes transmembrane electron transfer and supports extravesicular dopamine beta-hydroxylase activity.
No top-level findings curated for this source.
PMID:14999009
Properties of two distinct heme centers of cytochrome b561 from bovine chromaffin vesicles studied by EPR, resonance Raman, and ascorbate reduction assay.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review CYB561 deficiency against full-text clinical and biochemical evidence · 2026-10-04T00:20:14Z · View source

Reviewed the deep-research report and citations across all eight completeness dimensions, then read the recovered full texts of PMID:29343526 and PMID:31822578 including the founding clinical and mouse tables. Corrected overlapping case counts (five confirmed individuals in three families, plus one untested relative), hypoglycemia mechanism and duration, mortality interpretation, DBH differential, mouse limitations and dosing evidence. Added source-specific genetics, diagnostics, syncope, anemia and retrograde ejaculation; moved preserved function and outcomes into appropriate sections. Replaced CYB561D1 family-level evidence with primary bovine CYB561 biochemistry (PMID:14769875 and PMID:14999009; abstract-only after full-text attempts). Kept unmeasured vesicular and pancreatic mechanisms provisional or hypothetical. Verified hgnc:2571 and MONDO:0020751 through OAK; rejected incorrect report identifiers and gene-family substitutions. GeneReviews helper: NO_CHAPTER; generic StatPearls OH chapter is adjacent scope. ClinicalTrials.gov API CYB561 search returned zero studies on 2026-10-04. General OH supportive treatments and standard recessive counseling in research were extrapolations, not CYB561-specific trials or guidelines. No validated clinical subtypes or quantitative penetrance estimate established. Schema, term, reference and content checks run before PR.

Create: CYB561-Related Orthostatic Hypotension · 2026-08-27T19:35:13Z · View source

Curated CYB561-related orthostatic hypotension (MONDO:0020751) from a claude_code deep-research report. Seven pathophysiology nodes, one connected component. The mechanism is a compartment-specific redox-recycling defect: cytochrome b561 regenerates ascorbate inside the catecholamine secretory vesicle, so its loss starves dopamine beta-hydroxylase of cofactor while leaving the enzyme structurally intact and catalytically normal on plasma assay. That dissociation is curated as both a pathophysiology node and a biochemical readout because it is the diagnostic discriminator against DBH deficiency. Droxidopa is modeled as BYPASSES on the functional-deficiency node, since it reaches noradrenaline without the cofactor-dependent step. The preflight WARN (DBH at 63 percent of CYB561 mentions) was genuine and is addressed: DBH content was used only for the differential, an INTERPRETATION discussion curates the relationship explicitly as a phenocopy rather than a subtype, and no DBH-deficiency observation is cited as a CYB561 finding. A second entity risk the preflight did not flag was found and handled: PMID:36903505 concerns CYB561D1, a different family member in a cancer context, and is cited only for the family-level biochemical property with the explanation saying so; two further search hits on other family members were excluded entirely. A KNOWLEDGE_GAP records the unexplained mismatch between broad CYB561 expression and the narrowly noradrenergic phenotype. Prevalence is CASES_IN_LITERATURE against five characterized patients. One schema fix: readout direction NO_CHANGE is not permitted, replaced with PRESENT_ABSENT and the interpretation reworded to match. Validation: 17/17 snippets verified plus an independent raw-substring re-check; schema, terms, entity-refs, duplicate-keys and reference titles pass.

Claude Code ▸
CYB561-Related Orthostatic Hypotension: Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 20 citations 2026-08-27T18:58:14.092246

CYB561-Related Orthostatic Hypotension: Comprehensive Research Report

1. Disease Information

Overview. CYB561-related orthostatic hypotension (clinically designated Orthostatic Hypotension 2, ORTHYP2; OMIM #618182) is an ultra-rare, autosomal recessive monogenic disorder of catecholamine biosynthesis. It causes severe, lifelong, disabling neurogenic orthostatic hypotension due to a selective, isolated failure to synthesize norepinephrine (noradrenaline) and epinephrine (adrenaline) from dopamine, while sympathetic cholinergic (sweating) and parasympathetic function remain intact. It is biochemically and clinically a phenocopy of dopamine β-hydroxylase (DBH) deficiency but is caused by a different gene — CYB561 — that encodes an essential redox cofactor-recycling protein rather than the catecholamine-synthesizing enzyme itself (van den Berg et al., Circ Res 2018; Shibao et al., Neurology 2020).

Key identifiers: - OMIM phenotype: #618182 — Orthostatic Hypotension 2 (ORTHYP2) - OMIM gene: 600019 — Cytochrome b561; CYB561 (aliases: CYB561A1, FRRS2, CGCytb) - Gene location: Chromosome 17q23.3 (GRCh38: chr17:63,432,304–63,446,639); NCBI Gene ID 1534; HGNC:2576 - Protein: Transmembrane ascorbate-dependent reductase CYB561 (UniProt P49447), 251 amino acids, ~27.6 kDa - Related/parent MONDO concept: MONDO:0005469 (orthostatic hypotension) — a disease-specific MONDO term for the CYB561 subtype specifically has not been confirmed as separately minted at time of writing; ORTHYP2/OMIM:618182 is the authoritative cross-reference to use - Note: This is distinct from Orthostatic Hypotension 1 (ORTHYP1, OMIM #223360), which is dopamine β-hydroxylase (DBH) deficiency itself (chromosome 9q34, DBH* gene)

Synonyms/alternative names: Orthostatic hypotension 2; ORTHYP2; CYB561 deficiency; congenital absence of norepinephrine due to CYB561 mutations; cytochrome b561 deficiency

Evidence basis: All clinical knowledge derives from two published families comprising a total of 4–5 documented patients worldwide (as of the most recent literature identified) — this is one of the rarest monogenic disorders in the medical literature, described in only two primary papers (2018, 2020). Information is therefore aggregated, case-series-level clinical/biochemical/genetic data plus a knockout mouse model, not large-cohort or EHR-derived data.

2. Etiology

Disease causal factor: Purely genetic — biallelic (homozygous or compound heterozygous) loss-of-function pathogenic variants in CYB561. There is no known environmental, infectious, or acquired trigger; the mechanism is a congenital, constitutive metabolic block.

Genetic risk factors (causal variants identified to date): | Variant (HGVS) | Protein change | Type | Family/patients | Zygosity | |---|---|---|---|---| | c.262G>A | p.Gly88Arg (G88R) | Missense, exon 3, highly conserved residue in 3rd transmembrane domain | Dutch family (2 sisters) | Homozygous | | c.131G>A | p.Trp44* (W44X) | Nonsense, exon 2 | American family, sisters (patients 1 & 2) | Homozygous | | Exon 2 deletion | — | Large deletion (null allele) | American family, patient 4 (Indian-origin) | Compound heterozygous (in trans with below) | | c.157C>T | p.His53Tyr (H53Y) | Missense, previously unreported, highly conserved site | Same patient 4 | Compound heterozygous |

(van den Berg MP, et al. Circ Res. 2018;122(6):846–854, doi:10.1161/CIRCRESAHA.117.311949; Shibao CA, Garland EM, Black BK, Mathias CJ, Grant MB, Root AW, Robertson D, Biaggioni I. "Congenital absence of norepinephrine due to CYB561 mutations." Neurology. 2020;94(2):e200–e204, PMID: 31822578, PMCID: PMC6988982)

Population variant frequency (heterozygous carrier data from gnomAD, cited in OMIM #618182): - The G88R-equivalent change (c.262G>C) was found heterozygous in 2 of 126,628 non-Finnish European alleles in gnomAD. - The W44X nonsense variant was found once in 110,060 non-Finnish European control alleles. - These very low population frequencies are consistent with an ultra-rare autosomal recessive disorder and argue against significant population stratification of carrier frequency, though systematic gnomAD constraint metrics (pLI, missense Z-score) for CYB561 were not identified in available sources.

Environmental risk factors: None identified — this is a fully penetrant congenital enzymatic/cofactor defect, not modulated by lifestyle, toxins, or occupational exposure. (Volume depletion, heat, prolonged standing, and vasodilating drugs are expected to exacerbate symptoms mechanically, as with any severe orthostatic hypotension, but do not cause the underlying molecular lesion.)

Protective factors: None specific to genotype have been reported (too few patients for a genotype-modifier analysis). No protective variants or gene-environment interaction studies exist for this ultra-rare condition.

Mechanistic link (etiology → pathophysiology bridge): CYB561 encodes a six-transmembrane-helix, two-heme-b cytochrome resident in catecholamine secretory vesicle membranes. It transfers electrons from cytoplasmic ascorbate across the vesicle membrane to regenerate ascorbate (from its oxidized semidehydroascorbate/monodehydroascorbate radical form) inside the vesicle lumen. Intravesicular ascorbate is the essential electron-donating cofactor for dopamine β-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, and also serves peptidylglycine α-amidating monooxygenase (PAM). Loss-of-function CYB561 variants abolish intravesicular ascorbate recycling, producing a functional (secondary) DBH deficiency despite structurally and enzymatically normal DBH protein and a wild-type DBH gene.

3. Phenotypes

Phenotype data are drawn from the 4 fully characterized patients (2 sibling pairs) in van den Berg 2018 and Shibao 2020.

Phenotype Type Frequency in reported cohort Onset Course HPO suggestion
Severe orthostatic hypotension Clinical sign 4/4 (100%) Infancy/early childhood, lifelong Chronic, disabling, non-progressive but persistent HP:0001278 (Orthostatic hypotension)
Syncope/near-syncope on standing Symptom Frequent, reported in all patients Infancy–childhood onward Episodic, provoked by upright posture HP:0001279 (Syncope)
Lack of compensatory tachycardia on standing Clinical/physiologic sign Present (heart rate ratios for sinus arrhythmia and Valsalva normal, but no adequate BP-driven tachycardic compensation) — Chronic HP:0031637 (Impaired ability to increase heart rate with exercise) — closest match; consider free text
Impaired Valsalva blood pressure response Physiologic/laboratory abnormality 4/4 — Chronic No precise HP term; describe via Autonomic function test abnormality HP:0012332
Episodic/recurrent hypoglycemia Laboratory/clinical 3/4 (patients 1, 2, 3) — severe enough that patient 2 underwent partial pancreatectomy Childhood Episodic HP:0001943 (Hypoglycemia)
Seizures (childhood) Clinical sign Reported in at least 3 patients, etiology unclear (possibly hypoglycemia- or hypotension-related) Childhood Episodic HP:0001250 (Seizure)
Impaired renal function / decreased GFR Laboratory abnormality Reported in OMIM clinical synopsis for a subset of patients Variable, later-onset Can be progressive HP:0012622 (Chronic kidney disease) / HP:0012213 (Abnormal renal physiology)
Normal sweating (thermoregulatory/sudomotor function) Preserved function (negative finding) 4/4 normal — Stable Relevant as a distinguishing negative — HP:0000970 (Hyperhidrosis)/absence noted
Preserved parasympathetic (cardiovagal) function Preserved function 4/4 normal (neck suction, phenylephrine responses intact) — Stable —
Normal birth and mental/cognitive development Negative finding 4/4 — — Explicitly documented as normal — important for distinguishing from syndromic mitochondrial/neurodevelopmental disorders
Reduced life expectancy / early mortality Outcome One patient (patient 3, brother of patients 1–2) died at age 16 Childhood/adolescence — HP:0034396 (or free text mortality note)

Quality of life impact: Patients describe the orthostatic hypotension as profoundly disabling — near-continuous presyncope/syncope risk on standing severely limits activities of daily living, education, and employment; no formal EQ-5D/SF-36 data have been published for this specific cohort, but qualitative descriptions in both primary papers characterize impact as severe and lifelong until droxidopa treatment. Recurrent, severe hypoglycemia requiring surgical intervention (pancreatectomy) in childhood represents an additional major QoL and safety burden.

Suggested HPO terms: HP:0001278 (Orthostatic hypotension), HP:0001943 (Hypoglycemia), HP:0001250 (Seizure), HP:0012622 (Chronic kidney disease), HP:0001279 (Syncope), HP:0012332 (Abnormal autonomic nervous system physiology).

4. Genetic/Molecular Information

Causal gene: CYB561 (HGNC:2576; NCBI Gene 1534; OMIM *600019); no other gene has been implicated in ORTHYP2.

Pathogenic variant summary (see Section 2 table for full HGVS detail): - Variant classification: All four reported alleles are consistent with pathogenic/loss-of-function under ACMG/AMP-type reasoning — nonsense (W44X), a large exonic deletion (exon 2), and two missense changes (G88R, H53Y) at residues that are highly evolutionarily conserved and lie within/near transmembrane or heme-coordinating regions critical to redox function. Formal ClinVar submission status for each variant was not independently confirmed in the sources reviewed here; curators should verify current ClinVar classification before citing a specific ACMG category. - Variant type spectrum: missense (2), nonsense (1), whole-exon deletion (1) — i.e., a mix of null and likely hypomorphic/null missense alleles, consistent with a fully recessive loss-of-function mechanism. - Allele frequency: Both missense/nonsense changes are present at very low frequency in gnomAD non-Finnish European controls (2/126,628 and 1/110,060 alleles respectively; see Section 2), consistent with pathogenicity and rarity. - Origin: All variants reported are germline; no somatic CYB561 variants are relevant to this disease phenotype (somatic CYB561 alterations have been studied in an entirely unrelated context — oncology, see below). - Functional consequence: Loss of CYB561 transmembrane electron-transfer/ascorbate-recycling activity → failure to regenerate intravesicular ascorbate → functional/secondary loss of DBH catalytic activity (DBH protein itself and its gene are normal) → failure of dopamine-to-norepinephrine conversion.

Modifier genes: None have been identified or proposed; the cohort is far too small (single-digit patients) to support modifier-gene analysis.

Epigenetic information: No epigenetic (DNA methylation, histone modification) studies of CYB561 or ORTHYP2 have been published.

Chromosomal abnormalities: None reported beyond the intragenic exon-2 deletion described above; no aneuploidy, translocation, or large structural rearrangement has been implicated.

Protein structure context: CYB561 belongs to the cytochrome b561 family of transmembrane ascorbate-dependent reductases, characterized by six transmembrane α-helices with the central four coordinating two b-type heme groups via four conserved histidine residues, enabling trans-bilayer electron transfer from cytoplasmic ascorbate to luminal semidehydroascorbate radical. This structural framework explains why missense substitutions at conserved transmembrane/heme-adjacent residues (G88R, H53Y) are functionally disruptive.

Suggested ontology terms: hgnc:2576 (CYB561 gene), GO terms for molecular function: monodehydroascorbate reductase (NAD(P)H) activity / transmembrane electron transporter activity; GO cellular component: secretory vesicle membrane.

5. Environmental Information

  • Environmental factors: None are causal. As with all forms of severe autonomic/neurogenic orthostatic hypotension, non-causal exacerbating factors likely include heat exposure, large meals (postprandial hypotension), dehydration, and vasoactive/vasodilating medications — these are inferred from general orthostatic hypotension physiology rather than reported specifically for CYB561 patients in the literature reviewed.
  • Lifestyle factors: Not specifically studied in this cohort; general orthostatic hypotension management principles (fluid/salt intake, compression garments, avoidance of prolonged standing) apply by extension from DBH-deficiency and general neurogenic-OH literature, but are not disease-specific findings.
  • Infectious agents: Not applicable — no infectious trigger or association has been described.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Molecular trigger: Biallelic loss-of-function CYB561 variants → absent/non-functional CYB561 transmembrane ascorbate-dependent reductase in catecholamine secretory vesicle membranes (chromaffin cells of adrenal medulla and sympathetic noradrenergic neurons).
  2. Biochemical consequence: Failure to regenerate reduced ascorbate within the vesicle lumen (via trans-membrane electron transfer from cytosolic ascorbate) → progressive depletion of intravesicular ascorbate.
  3. Enzymatic consequence: Dopamine β-hydroxylase (DBH), the vesicular enzyme that hydroxylates dopamine to norepinephrine, requires ascorbate as an electron-donating cofactor at each catalytic cycle; without regenerated ascorbate, DBH is catalytically starved — producing a functional DBH deficiency despite normal DBH protein, normal plasma DBH enzyme activity, and a wild-type DBH gene.
  4. Cellular/systems consequence: Norepinephrine (and downstream epinephrine, synthesized from norepinephrine in the adrenal medulla) synthesis fails almost completely — plasma norepinephrine and its intraneuronal metabolite DHPG are undetectable, while dopamine and its metabolites remain normal (notably, in contrast to primary DBH deficiency where dopamine accumulates to markedly elevated levels — the authors hypothesize that the loss of ascorbate's local antioxidant capacity within the vesicle instead promotes degradation of DOPA/dopamine rather than their accumulation).
  5. Organ/systemic consequence: Loss of sympathetic noradrenergic vasoconstrictor tone → inability to maintain blood pressure on standing → severe orthostatic hypotension, syncope, and (in childhood) episodic hypoglycemia (loss of catecholamine-driven counter-regulation) and possible renal hypoperfusion contributing to chronic kidney impairment in some patients.
  6. Selectively spared systems: Sympathetic cholinergic (sudomotor/sweating) and parasympathetic (cardiovagal, e.g., heart-rate responses to Valsalva/neck suction/phenylephrine) pathways are intact, because these do not depend on DBH-catalyzed norepinephrine synthesis in the same secretory-vesicle compartment — this selective sparing is a key diagnostic and mechanistic signature of the disease.

Molecular pathway/players: Dopamine → (DBH, ascorbate-cofactor-dependent) → norepinephrine → (in adrenal medulla, phenylethanolamine N-methyltransferase, PNMT) → epinephrine. CYB561 operates upstream of DBH as a cofactor-regeneration (ascorbate-recycling) protein, not as part of the catecholamine biosynthetic pathway itself. CYB561 also supports peptidylglycine α-amidating monooxygenase (PAM), another ascorbate-dependent secretory-vesicle enzyme, though a clinical phenotype attributable to PAM dysfunction has not been specifically documented in these patients.

Cellular processes involved: Catecholamine biosynthesis and vesicular storage/secretion in chromaffin cells (adrenal medulla) and postganglionic sympathetic noradrenergic neurons; transmembrane electron transport; ascorbate redox cycling.

Protein dysfunction: Loss-of-function of a transmembrane electron-transfer protein (not misfolding/aggregation-type pathology as documented; missense variants likely destabilize the heme-coordinating transmembrane architecture).

Biochemical abnormalities (documented, with values from Shibao et al. 2020): - Plasma norepinephrine: undetectable (pre-treatment) - Plasma DHPG (intraneuronal norepinephrine metabolite): undetectable (pre-treatment) - Plasma dopamine and dopamine metabolites: normal - Plasma DBH enzymatic activity: normal (tested in patients 1 and 2) — confirming the defect is upstream/cofactor-related, not in the DBH enzyme itself - Post-droxidopa treatment: Patient 1 norepinephrine rose to 65 pg/mL, DHPG to 771 pg/mL; Patient 2 norepinephrine rose to 139 pg/mL, DHPG to 1,220 pg/mL — demonstrating that exogenous L-DOPS bypasses the defect and restores measurable norepinephrine synthesis via DOPA-decarboxylase.

Tissue damage mechanisms: Chronic hypotension/hypoperfusion is proposed (though not formally proven mechanistically in the literature) as a contributor to the renal dysfunction/reduced GFR noted in some patients; this remains an area of uncertainty rather than an established causal chain.

Molecular profiling / omics: No transcriptomic, proteomic, metabolomic, single-cell, or spatial-omics datasets specific to human CYB561-deficient tissue have been published (patient tissue for such studies is essentially unobtainable given the extreme rarity and the non-lethal, non-biopsied nature of the primary affected tissue — sympathetic neurons/adrenal medulla). The main molecular data available are targeted plasma catecholamine/metabolite panels (above) and the knockout mouse brain/adrenal catecholamine profiling described in Section 15.

Suggested GO terms: GO:0140905 (or nearest current term for monodehydroascorbate reductase / transmembrane ascorbate-ferrireductase activity), GO:0042423 (catecholamine biosynthetic process), GO:0006584 (catecholamine metabolic process). Suggested CL terms: CL:0002673 (adrenal medulla chromaffin cell), CL:0011103 or nearest sympathetic noradrenergic neuron term.

7. Anatomical Structures Affected

  • Organ level:
  • Primary: Adrenal medulla (chromaffin cells) and postganglionic sympathetic noradrenergic neurons (the norepinephrine-synthesizing tissues where CYB561 is highly expressed in catecholamine secretory vesicles).
  • Secondary: Cardiovascular system (functional consequence — inability to maintain blood pressure); kidney (reported impaired GFR/renal dysfunction in a subset of patients, presumed secondary to chronic hypoperfusion, though the pathomechanism is not definitively established); pancreas (implicated only indirectly — partial pancreatectomy was performed in one patient for severe recurrent hypoglycemia, but the pancreas is not a primary site of CYB561 pathology; the hypoglycemia is attributed to loss of catecholamine-mediated glucose counter-regulation).

  • Body systems: Cardiovascular (autonomic/neurogenic hypotension), endocrine/metabolic (hypoglycemia), renal, and — via seizures of unclear etiology — potentially neurologic (secondary to hypoglycemia/hypotension rather than primary CNS pathology).

  • Tissue and cell level: Chromaffin cells of the adrenal medulla; sympathetic noradrenergic (postganglionic) neurons. Suggested UBERON: UBERON:0002001 (adrenal medulla); suggested CL: adrenal medulla chromaffin cell, sympathetic neuron.

  • Subcellular level: Catecholamine (chromaffin/large dense-core) secretory vesicles — specifically the vesicle membrane, where CYB561 resides as an integral transmembrane protein performing trans-bilayer electron transfer. Suggested GO Cellular Component: GO:0034774 (secretory granule lumen) / GO:0030667 (secretory granule membrane).

  • Localization/lateralization: Systemic/bilateral — this is a generalized sympathetic noradrenergic defect (adrenal medulla is typically bilateral; sympathetic neurons are distributed throughout the body), not a focal or lateralized process.

8. Temporal Development

  • Onset: Infancy or early childhood (explicitly stated in OMIM #618182 clinical description); orthostatic hypotension has been lifelong/present since early life in every reported patient.
  • Onset pattern: Congenital/insidious — present from earliest life rather than acute onset in adulthood, distinguishing it from acquired autonomic failure syndromes (e.g., pure autonomic failure, multiple system atrophy) that typically present in mid-to-late adulthood.
  • Progression/stages: No formal staging system exists. The orthostatic hypotension itself appears to be a stable, chronic, lifelong deficit (not neurodegenerative/progressive in the way synucleinopathies are), but individual complications (renal dysfunction, hypoglycemic episodes) can evolve over the patient's lifetime. Patients have been characterized/followed into adulthood (oldest reported patients evaluated at ages 38–39), indicating survival well into adulthood is possible with recognition and treatment, though one sibling (patient 3) died at age 16, indicating the disease carries significant premature-mortality risk if unrecognized/untreated.
  • Course pattern: Chronic and disabling but not classically "progressive" in a neurodegenerative sense; hypoglycemic and (childhood) seizure episodes are episodic superimposed events rather than a steadily worsening baseline.
  • Duration: Lifelong/chronic — no spontaneous resolution has been described.
  • Remission patterns: No spontaneous remission reported; treatment-induced improvement (droxidopa) is substantial and sustained for the orthostatic hypotension component specifically (see Section 12).
  • Critical periods: Childhood is a particularly high-risk window given the reported severe hypoglycemic episodes (one requiring partial pancreatectomy) and childhood-onset seizures — early diagnosis in infancy/childhood, before catastrophic hypoglycemic or hypotensive events occur, appears to be an important unmet clinical need highlighted implicitly by the case histories.

9. Inheritance and Population

  • Epidemiology: No formal prevalence or incidence estimate exists — this is one of the rarest described monogenic disorders, with only 2 families (4–5 patients) reported in the peer-reviewed literature to date (2018 and 2020 publications). It should be considered "ultra-rare" / essentially unquantifiable epidemiologically at this time; extrapolation from gnomAD carrier frequencies (see Section 2) would suggest a theoretical population prevalence far below 1 in 1,000,000, consistent with the observed case count, but no formal birth-prevalence study has been performed.
  • Inheritance pattern: Autosomal recessive (biallelic pathogenic CYB561 variants required; heterozygous carriers are unaffected).
  • Penetrance: Appears to be complete/fully penetrant in the biallelic state based on all reported cases, though the total number of genotyped individuals is far too small for a formal penetrance estimate.
  • Expressivity: Some variability is noted — e.g., not all patients had documented seizures or renal dysfunction, and severity of hypoglycemia varied (only one patient required pancreatectomy) — but core features (severe orthostatic hypotension, undetectable norepinephrine, preserved cholinergic/parasympathetic function) were consistent across all reported patients.
  • Genetic anticipation: Not applicable/not reported (no repeat-expansion mechanism involved).
  • Germline mosaicism: Not reported.
  • Founder effects: No specific founder mutation/population has been identified; reported families are of Dutch, American (non-Hispanic Caucasian), and Indian ancestry respectively — i.e., globally distributed rather than confined to a single founder population, though the extremely small number of families precludes any definitive geographic/ethnic epidemiology.
  • Consanguinity: Not explicitly reported as a factor in the published pedigrees (the Dutch sisters were homozygous for G88R and the American sisters homozygous for W44X, which could reflect either consanguinity or a more common regional allele, but this was not specifically discussed in available source summaries).
  • Carrier frequency: Estimated indirectly from gnomAD data (see Section 2): approximately 1.6–0.9 per 100,000 non-Finnish European alleles for the two specific reported variants — true carrier frequency across all possible pathogenic CYB561 alleles and populations is unknown.
  • Population demographics: Reported patients are of Dutch, American (Caucasian non-Hispanic), and Indian ancestry — no clear ethnic predisposition has been established given the small sample.
  • Sex ratio: Notably, reported adult patients described in detail (patients 1, 2, 4) are female; one male sibling (patient 3) was also affected and died at age 16 — with such a small cohort, no meaningful sex-ratio conclusion can be drawn (autosomal recessive inheritance predicts equal sex distribution).
  • Age distribution: Patients evaluated ranged from age 13 (deceased at 16) to age 39 at time of clinical description, indicating both childhood and adult survival are possible.

10. Diagnostics

Clinical/laboratory tests: - Plasma catecholamine panel (the key diagnostic test): Undetectable plasma norepinephrine and DHPG with normal plasma dopamine and dopamine metabolites is the biochemical hallmark. This pattern differs subtly but importantly from classic DBH deficiency, where plasma dopamine is typically markedly elevated (accumulated upstream of the enzymatic block) rather than normal — a potentially useful biochemical discriminator, per the mechanistic hypothesis discussed in Shibao et al. 2020. - Plasma DBH enzyme activity assay: Normal in CYB561-deficient patients (tested in 2 patients) — this is the critical test that distinguishes CYB561 deficiency (functional/secondary DBH deficiency) from primary DBH deficiency (ORTHYP1), where plasma DBH activity is absent/markedly reduced. - Autonomic function testing: - Valsalva maneuver: exaggerated hypotension during phase 2, absent blood pressure overshoot during phase 4 — abnormal, consistent with sympathetic noradrenergic failure. - Heart rate ratios (sinus arrhythmia, Valsalva ratio): normal — indicating intact parasympathetic/cardiovagal function. - Cardiovagal baroreflex testing (neck suction, phenylephrine pressor challenge): normal responses. - Thermoregulatory sweat testing: normal — indicating intact sympathetic cholinergic function. - Tilt-table/orthostatic vital signs: profound blood-pressure drop on standing without compensatory tachycardia.

Genetic testing: - Recommended approach: Given the extreme rarity and the specificity of the biochemical phenotype (undetectable norepinephrine/DHPG with normal dopamine and normal plasma DBH activity), targeted Sanger sequencing or a small autonomic-failure/catecholamine gene panel including CYB561 and DBH is reasonable once the biochemical pattern is established; whole-exome sequencing (as was used in the discovery of both reported families) is appropriate when the biochemical pattern is atypical or a panel is unrevealing. - Single-gene testing: CYB561 sequencing plus deletion/duplication analysis (given that one reported allele was a whole-exon deletion, copy-number-sensitive methods such as MLPA or exome-based CNV calling are important, not sequencing alone). - Gene panels: No dedicated commercial "CYB561 panel" is documented in the sources reviewed; it would logically be included in autonomic-failure/dysautonomia or catecholamine-biosynthesis gene panels alongside DBH, TH (tyrosine hydroxylase), and DDC (aromatic L-amino acid decarboxylase). - WES/WGS utility: Both discovery families were solved by exome/genomic sequencing approaches — this remains the most practical diagnostic route for an ultra-rare, non-panel-covered condition. - Chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not indicated — this is a single-gene autosomal recessive disorder with no chromosomal or mitochondrial component identified.

Omics-based diagnostics: Not part of the standard/reported diagnostic workflow — plasma catecholamine biochemistry plus targeted/exome genetic sequencing are the established diagnostic route; no transcriptomic, proteomic, or liquid-biopsy diagnostic approach is described for this condition.

Clinical criteria: No formal consensus diagnostic-criteria statement (e.g., society guideline) exists for CYB561-related orthostatic hypotension specifically, given its recent discovery (2018) and extreme rarity. Diagnosis is currently case-based, built on the combination of (1) lifelong severe orthostatic hypotension, (2) undetectable plasma norepinephrine/DHPG with normal dopamine, (3) normal plasma DBH activity, and (4) biallelic CYB561 variants.

Differential diagnosis: - Dopamine β-hydroxylase (DBH) deficiency (ORTHYP1, OMIM #223360): The principal differential — nearly identical clinical/autonomic phenotype (severe lifelong orthostatic hypotension, ptosis, exercise intolerance, hypoglycemia in some cases) but distinguished biochemically by (a) markedly elevated plasma dopamine (vs. normal in CYB561 deficiency) and (b) absent/low plasma DBH enzyme activity (vs. normal in CYB561 deficiency), and genetically by pathogenic variants in DBH rather than CYB561. - Pure autonomic failure (PAF): Sporadic, adult-onset (not congenital), and no genetic cause has been established, unlike CYB561 deficiency's clear childhood onset and monogenic recessive basis. - Familial dysautonomia (hereditary sensory and autonomic neuropathy type III, ELP1/IKBKAP): Distinguished by prominent sensory neuropathy, absent overflow emotional tearing, hyperadrenergic vomiting crises, and optic neuropathy — features not present in isolated CYB561 deficiency, which spares sensory and cholinergic/parasympathetic pathways. - Multiple system atrophy / Parkinson disease with autonomic failure: Adult-onset synucleinopathies with additional motor/cognitive features, not congenital, and biochemically and genetically distinct.

Screening: No newborn screening, carrier screening, or population screening program exists for this condition, consistent with its ultra-rare status and recent (2018) discovery.

11. Outcome/Prognosis

  • Survival/mortality: No formal survival statistics exist given the tiny reported cohort. One reported patient (patient 3) died at age 16, indicating the disease can be life-threatening, particularly in childhood, likely related to severe hypoglycemic and/or hypotensive/syncopal episodes; other reported patients survived into their 30s. OMIM's clinical description notes that "some patients may also have renal dysfunction and reduced life expectancy," but this is a qualitative characterization rather than a quantified statistic.
  • Morbidity/function: Severe, lifelong disability from recurrent syncope/presyncope until treatment; recurrent hypoglycemia (one patient required partial pancreatectomy) represents an additional major source of morbidity, particularly in childhood.
  • Quality of life: Described qualitatively as severely impaired pre-treatment (disabling orthostatic hypotension); improved substantially with droxidopa in the cases reported, though no standardized QoL instrument (EQ-5D, SF-36) data have been published.
  • Complications: Recurrent hypoglycemia (occasionally requiring surgical intervention), childhood seizures (etiology not definitively established — plausibly hypoglycemia- and/or hypotension-related), and renal dysfunction/decreased GFR in a subset of patients.
  • Recovery potential/prognostic factors: With droxidopa treatment, plasma norepinephrine and its metabolite DHPG become measurable and orthostatic hypotension substantially improves — indicating that, unlike a neurodegenerative process, the underlying sympathetic neurons remain viable and capable of exocytotic norepinephrine release once the biosynthetic block is bypassed pharmacologically. This is a notably favorable prognostic feature relative to degenerative causes of autonomic failure.
  • Prognostic biomarkers: Plasma norepinephrine/DHPG levels serve as both diagnostic and treatment-response biomarkers (rising from undetectable to measurable levels with droxidopa, as quantified in Section 6).

12. Treatment

Pharmacotherapy (primary, disease-specific): - Droxidopa (L-threo-dihydroxyphenylserine, L-DOPS; brand name Northera®) is the cornerstone, mechanistically targeted treatment. It is a synthetic norepinephrine precursor that is converted directly to norepinephrine by the enzyme DOPA-decarboxylase (aromatic L-amino acid decarboxylase) — a step that is entirely independent of DBH and therefore bypasses the CYB561/DBH cofactor defect altogether. - Dosing (as reported): 100 mg three times daily was the effective and generally tolerated dose in the reported patients; higher doses caused excessive pressor responses in two patients and nausea in another, indicating a narrow therapeutic window requiring individualized titration. - Efficacy: Restored measurable plasma norepinephrine (rising from undetectable to 65–139 pg/mL) and DHPG (rising to 771–1,220 pg/mL), with corresponding improvement in orthostatic hypotension symptoms. - NCIT suggestion: NCIT:C15986 (Pharmacotherapy) as treatment_term, with therapeutic_agent bound to the specific compound (droxidopa; NCIT has a specific concept, "Droxidopa," commonly indexed as NCIT:C77244 — verify exact CURIE against the local NCIT adapter before curating) and therapeutic_modality: SMALL_MOLECULE. - Comparator/class context: Droxidopa is the same first-line agent used for classic DBH deficiency (ORTHYP1) and for neurogenic orthostatic hypotension broadly (e.g., in pure autonomic failure, multiple system atrophy, and diabetic autonomic neuropathy), where it is FDA-approved (Northera) for symptomatic neurogenic orthostatic hypotension.

Supportive/non-pharmacologic care (extrapolated from general severe-orthostatic-hypotension and DBH-deficiency management, not disease-specific trial data): - Increased fluid and salt intake, compression garments, physical countermaneuvers, and avoidance of triggers (heat, large meals, prolonged standing) are standard adjunctive measures for severe neurogenic orthostatic hypotension generally; specific trial data for the CYB561 population were not identified. - Management of hypoglycemia (dietary/monitoring measures; surgical partial pancreatectomy was used in one severe pediatric case, though this is not considered a standard/first-line intervention and reflects an individualized, severe presentation).

Advanced therapeutics (gene therapy, cell therapy, RNA-based, targeted/immunotherapy): None have been developed or trialed for this condition — given the extreme rarity (single-digit total reported patients worldwide), there is no commercial or research incentive/infrastructure for such advanced modalities at this time, and no ClinicalTrials.gov-registered interventional trial specific to CYB561-related orthostatic hypotension was identified in the sources reviewed.

Surgical/interventional: Partial pancreatectomy was performed in one patient specifically for management of severe, recurrent hypoglycemia — this addresses a complication, not the underlying molecular defect, and is not considered standard-of-care for the disease generally.

Experimental treatments: No disease-specific clinical trials (with NCT identifiers) were identified for CYB561-related orthostatic hypotension.

Treatment outcomes/adverse events: Dose-limiting adverse effects of droxidopa in this population were excessive pressor response (hypertension) at higher doses in two patients, and nausea in another — consistent with droxidopa's known adverse-event profile in the broader neurogenic-orthostatic-hypotension population (supine hypertension is a well-recognized, dose-related class effect).

Treatment strategy/algorithm: No formal published treatment algorithm exists specifically for this ultra-rare condition; management in the literature follows the same individualized dose-titration approach used for droxidopa in DBH deficiency and other neurogenic orthostatic hypotension syndromes — start low, titrate to symptomatic/hemodynamic effect while monitoring for supine hypertension.

Personalized medicine: The treatment is inherently mechanism-targeted/personalized in the sense that droxidopa specifically bypasses the identified enzymatic block (dopamine→norepinephrine via DOPA-decarboxylase rather than the defective ascorbate-dependent DBH pathway) — this represents a genotype-informed, mechanism-based therapeutic strategy, though it is empirically the same drug used for the phenotypically similar DBH deficiency rather than a CYB561-specific novel agent.

13. Prevention

  • Primary prevention: Not applicable in the traditional sense — this is a congenital, fully genetically determined disorder with no modifiable environmental cause to intervene upon before disease onset.
  • Secondary prevention (early detection): No population screening program exists. Given the severe childhood morbidity/mortality risk (hypoglycemia, seizures, and the reported death at age 16), early clinical recognition of the biochemical signature (undetectable norepinephrine/DHPG with normal dopamine and normal DBH activity) in a child with unexplained severe orthostatic hypotension and/or hypoglycemia could in principle allow earlier initiation of droxidopa and closer glycemic monitoring, but this is an inference from the case reports rather than a published screening recommendation.
  • Tertiary prevention: Droxidopa therapy and, where indicated, targeted management of hypoglycemia (dietary/monitoring strategies preferred over surgery where feasible) function as tertiary prevention against the disease's major complications (syncope-related injury, hypoglycemic seizures, and possibly progressive renal dysfunction from chronic hypoperfusion).
  • Immunization: Not applicable — non-infectious, non-immune-mediated disorder.
  • Genetic counseling: Because the disorder is autosomal recessive, genetic counseling for parents of an affected child (recurrence risk 25% per pregnancy) and, where relevant, carrier testing of at-risk family members / prenatal or preimplantation genetic testing in families with a known pathogenic CYB561 allele would follow standard autosomal-recessive counseling principles, though no disease-specific counseling guideline has been published given the extreme rarity.
  • Public health/environmental interventions: Not applicable.
  • Prophylaxis: No prophylactic pharmacologic strategy beyond ongoing droxidopa maintenance therapy has been described.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring CYB561-deficient disease has been reported in any non-human species (companion animals, livestock, or wildlife). No OMIA (Online Mendelian Inheritance in Animals) entry for a natural CYB561-associated disease was identified.
  • Orthologous gene: Mouse ortholog Cyb561 (MGI:103253), located on mouse chromosome 11; this ortholog is the basis of the engineered knockout model described in Section 15 (an induced/laboratory model, not a naturally occurring veterinary disease).
  • Comparative biology: The core biochemical machinery (CYB561–ascorbate–DBH axis) is evolutionarily conserved across vertebrates, and cytochrome b561-family ascorbate reductases are broadly conserved from insects to mammals (structural/functional comparative work exists on insect cytochrome b561 proteins as candidate ferric reductases), but no natural disease phenotype has been documented outside the engineered mouse knockout.
  • Zoonotic potential/cross-species transmission: Not applicable — this is a non-infectious, purely genetic/metabolic disorder.

15. Model Organisms

Mouse knockout model (the only reported animal model): - Model type: Genetic, constitutive knockout — Cyb561-null mice on a C57BL/6NTac genetic background, generated and characterized as part of the original human-disease-discovery study (van den Berg et al., Circ Res 2018). - Phenotype recapitulation: Catecholamine and downstream metabolite concentrations were measured in brain and adrenal tissue of 6 Cyb561 knockout mice. Findings included decreased norepinephrine and normetanephrine in whole-brain homogenates compared with wild-type mice, and decreased normetanephrine and metanephrine in adrenal glands — biochemically supporting the same norepinephrine-biosynthesis defect proposed for human patients, i.e., the model partially to substantially recapitulates the core biochemical lesion (reduced norepinephrine/downstream-metabolite synthesis). - Model limitations: An important caveat emphasized in the literature is that mice, unlike humans, can synthesize ascorbic acid de novo (via functional L-gulonolactone oxidase), whereas humans cannot. This is a fundamental species difference that likely blunts the severity of ascorbate depletion — and therefore of the downstream DBH/norepinephrine-synthesis defect — in the mouse model relative to the human disease, meaning the knockout mouse is expected to under-represent the severity of human CYB561 deficiency. Reported physiological/behavioral orthostatic-hypotension phenotyping (e.g., blood pressure telemetry, tilt response) in the knockout mice was not identified as having been performed/published in the sources reviewed here — the mouse data available are limited to tissue catecholamine/metabolite biochemistry rather than a full autonomic-physiology characterization. - Applications: The model supports study of the ascorbate-dependent catecholamine biosynthesis pathway and provides in vivo biochemical validation of the human genetic findings; it would be a candidate platform for testing pharmacologic bypass strategies (e.g., droxidopa) or future gene-replacement approaches, though no such intervention studies in the knockout model were identified in the literature reviewed. - Other model systems: No zebrafish, Drosophila, C. elegans, yeast, iPSC-derived, or organoid models of CYB561 deficiency were identified. No cell-line (e.g., PC12 chromaffin-like cell) CRISPR-knockout functional studies specific to the disease phenotype were found in the sources reviewed, though CYB561 has been studied via cell-line knockdown/overexpression in unrelated oncology contexts (see note below).

Note on an unrelated research literature: A substantial and growing body of recent literature (2023–2025) studies CYB561 in the context of cancer biology — e.g., as a prognostic biomarker and potential therapeutic target in breast cancer (via IRE1–XBP1–SREBF1 and FAK-ERK signaling, and via inhibition of H2AFY degradation), hepatocellular carcinoma, and prostate cancer neuroendocrine differentiation. This oncology literature is mechanistically and clinically distinct from CYB561-related orthostatic hypotension (it concerns CYB561 overexpression/dysregulation in tumor cells rather than germline loss-of-function causing autonomic failure) and should not be conflated with the disorder covered in this report, though curators should be aware of it when searching the literature to avoid Named-Entity-Confusion-type misattribution of evidence.

Summary Table of Key Ontology Term Suggestions

Category Term
Gene hgnc:2576 (CYB561)
OMIM gene 600019
OMIM phenotype 618182 (ORTHYP2)
Related MONDO MONDO:0005469 (orthostatic hypotension — generic; verify/curate subtype-specific term if one exists)
Phenotype (HP) HP:0001278 Orthostatic hypotension; HP:0001943 Hypoglycemia; HP:0001250 Seizure; HP:0012622 Chronic kidney disease; HP:0001279 Syncope
Anatomy (UBERON) UBERON:0002001 Adrenal medulla
Cell type (CL) Adrenal medulla chromaffin cell; sympathetic noradrenergic neuron
Chemical (CHEBI) Ascorbic acid; dopamine; noradrenaline (norepinephrine); droxidopa
Treatment (NCIT) NCIT:C15986 Pharmacotherapy (treatment_term) + therapeutic_agent: droxidopa
Inheritance Autosomal recessive (HP:0000007)

Sources

Limitations of this report: This is one of the rarest monogenic disorders in the medical literature, with the entire published human clinical evidence base consisting of two primary papers describing 4–5 total patients across 2 unrelated families. Several fields in the disease-characteristics template above (formal prevalence/incidence, QoL instrument scores, ACMG variant classifications, ClinVar status, gnomAD constraint metrics, autonomic-physiology data in the knockout mouse) could not be populated from the sources reviewed and should be flagged as "not available" rather than inferred when building the knowledge-base entry. Full-text access to the primary Circulation Research paper's tables/figures (patient-by-patient granular data, protein structural modeling) was not obtainable via the tools used here (paywalled/binary PDF); a curator with institutional journal access should verify granular table values directly against the primary source before final KB entry, per this repository's evidence-verification requirements.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 4
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMC:PMC10005133 (2 mentions) - Spectral and Redox Properties of a Recombinant Mouse Cytochrome b561 Protein Suggest Transmembrane Electron Transfer Function.
  • shared terms: cyb561

Weighed against this report's own most characteristic terms: hypotension, orthostatic, cyb561, patient, disease, severe, norepinephrine, dbh, clinical, gene, hypoglycemia, autonomic, dopamine, primary, disorder, exist, genetic, identified, phenotype, deficiency.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.