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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic PPCS variants (homozygous, or compound heterozygous in trans) occur in all 12 reported patients. Full segregation was shown in consanguineous family B. Heterozygous parents and siblings in families B, F2 and F5 had no cardiomyopathy at screening. Seven of the 12 patients come from consanguineous families (F2, F4, F5 and the four affected siblings of family B/F6).

Autosomal recessive inheritance

Show evidence (5 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Consanguinity No Yes No No Yes Yes Yes Yes Yes Yes No No"

The consanguinity row of the 2025 summary table; seven of the 12 patients are from consanguineous families.

PMID:29754768 SUPPORT DIRECT Human Clinical

"Segregation analysis in all available family members confirmed full segregation, with all four affected siblings found to harbor the c.178A>T mutation in homozygous form, both parents and two of the four unaffected siblings (subjects IV.3 and IV.7) found to be heterozygous for the mutation, and..."

Full recessive segregation in the multiplex family. The source prints c.178A>T here, but the variant reported elsewhere in the paper for this family is c.698A>T.

PMID:29754768 SUPPORT DIRECT Human Clinical

"The echocardiograms of the unaffected siblings and their parents were normal."

Heterozygous carriers in family B had normal echocardiograms.

+ 2 more references

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Discussions and Knowledge Gaps

4

How secure are the gene-disease relationship, the phenotype spectrum and the genotype-phenotype rule, given 12 patients in eight families?

KNOWLEDGE GAP OPEN cmd2c_small_evidence_base

Attached to

genetic#PPCS phenotypes#Hypotonia phenotypes#Rhabdomyolysis

The PPCS link rests on three clinical reports, and family B appears in two of them. Three of the families share the same p.Glu233Val allele. The causal case is coherent: segregation, patient-cell protein and CoA reduction with genetic rescue, yeast complementation and a fly hypomorph. ClinGen has not curated it. The proposed rule that exon 3 variants cause DCM only while exon 1 and 2 variants add neuromuscular and metabolic disease is exploratory and based on n=12. Extracardiac features such as dysmorphism, cutis laxa and PAH come from single patients and may be coincidental.

Proposed experiments

Natural history registry with exome reanalysis

exp_cmd2c_natural_history_registry

Pool unsolved pediatric DCM and fatty-acid-oxidation-like crisis cases with normal ACADVL testing for PPCS reanalysis. Follow genotyped patients prospectively with standardized cardiac, neuromuscular and metabolic phenotyping to test the exon-based genotype-phenotype rule.

Show evidence (2 references)

PMID:40745475 SUPPORT INDIRECT Human Clinical

"in contrast the p.Glu233Val variant leads to an isolated DCM presentation with variable expressivity, suggesting that different clinical presentations may be related to the position of the mutations within the gene."

The genotype-phenotype hypothesis as stated.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Only by investigating the natural history of the disease in a larger patient cohort"

The authors acknowledge that the cohort is too small.

Why does a ubiquitous CoA-synthesis defect damage mainly the heart, and is cardiac CoA actually depleted in patients?

KNOWLEDGE GAP OPEN cmd2c_cardiac_coa_and_tissue_selectivity

Attached to

pathophysiology#Cellular Coenzyme A Deficiency pathophysiology#Impaired Long-Chain Fatty Acid Oxidation pathophysiology#Cardiomyocyte Energy Deficit

CoA has been measured only in fibroblasts and iPSC-derived cells, never in patient or animal myocardium. The fatty-acid-activation and energy-deficit steps are inferred from acylcarnitines and from the authors' reasoning about cardiomyocyte metabolism. Fasting respiratory quotient in two patients showed normal whole-body fat oxidation. Proposed explanations include greater fatty-acid dependence of maturing cardiomyocytes, tissue-specific PPCS isoforms and cysteine toxicity; none has been tested.

Proposed experiments

Acyl-CoA profiling and fatty-acid flux in patient cardiomyocytes

exp_cmd2c_cardiomyocyte_acylcoa_flux

Measure free CoA, acetyl-CoA and long-chain acyl-CoA pools, and run 13C-palmitate oxidation and Seahorse respirometry in day-60 patient and isogenic-corrected iPSC cardiomyocytes, with and without pantethine. Test whether the energy deficit precedes sarcomere disorganization.

Show evidence (2 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

"However, considering the ubiquitous presence of the enzymatic PPCS activity, it remains unexplained why the brain and in general the other organs are not affected in PPCS-deficient individuals."

The open question as the index authors stated it.

PMID:29754768 SUPPORT DIRECT Human Clinical

"In contrast to the neurodegenerative NBIA-related phenotypes associated with defects in PANK2 and COASY, PPCS-deficient individuals present with a clear dilated cardiomyopathy with a variable degree of severity and no neurodegeneration."

The tissue-selectivity contrast with other CoA-pathway disorders.

Does accumulation of L-cysteine, which PPCS would normally consume, contribute to cardiotoxicity in addition to CoA deficiency?

EMERGING HYPOTHESIS OPEN cmd2c_cysteine_toxicity_hypothesis

Attached to

pathophysiology#Cellular Coenzyme A Deficiency

The index authors raised the possibility that a toxic metabolite contributes, because dPPCS fly mutants are hypersensitive to cysteine. Cysteine has not been measured in patient cells or tissue. The incomplete rescue by pantethine is consistent with, but does not prove, a CoA-independent contribution.

Show evidence (1 reference)

PMID:29754768 SUPPORT INDIRECT Other

"We cannot exclude that cardiomyopathy in PPCS-deficient individuals is also due to the generation of toxic metabolites."

The hypothesis as stated; it has not been tested.

Do the available models capture the human disease well enough to support the cellular nodes of the mechanism?

HUMAN MODEL MISMATCH OPEN cmd2c_models_limits

Attached to

pathophysiology#Cardiomyocyte Contractile Dysfunction pathophysiology#Cardiomyocyte Arrhythmogenicity

No mammalian Ppcs model exists. The fly hypomorph lowers expression rather than destabilizing the protein, and fly heart-tube kinematics are a loose proxy for DCM. The iPSC cardiomyocyte data come from two patient lines, one clone each, without isogenic controls, in immature cells. The cellular nodes are therefore PROVISIONAL, not ESTABLISHED.

Proposed experiments

Ppcs p.Glu233Val knock-in mouse

exp_cmd2c_knockin_mouse

Generate a homozygous knock-in of the recurrent human allele and measure cardiac CoA, acylcarnitines and echocardiographic function under fasting and infection-like stress, with and without dietary pantethine.

Show evidence (1 reference)

PMID:35397396 SUPPORT INDIRECT In Vitro

"PPCS-deficiency is a relatively new disease with unclear pathogenesis and no targeted therapy."

States the mechanistic uncertainty the models were built to address.

⚙

Pathophysiology

10

Homozygous PPCS Missense Variants

Mechanism confidence: Established

Ten of the 12 patients are homozygous for a PPCS missense variant (NM_024664): p.Glu233Val in exon 3 (families B/F6, F3 and F5), or p.Tyr78His, p.Arg106Pro or p.Ala20Gly in exon 1 (families F1, F2 and F4). p.Glu233Val sits near the ATP-binding phosphate recognition site, close to the dimer interface. p.Arg106Pro lies in the dimerization region. p.Tyr78His and p.Ala20Gly destabilize helix packing near the catalytic site. No patient carries two loss-of-function alleles, which suggests that complete PPCS loss is not viable.

PPCS hgnc:25686

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Partial loss of function is inferred from reduced but detectable protein and CoA in patient cells, and from the absence of biallelic null genotypes. Residual enzyme activity has not been measured in human tissue.

phosphopantothenate--cysteine ligase activity GO:0004632 ↓ DECREASED

Downstream

Reduced PPCS Protein Stability

Show evidence (4 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

"Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype."

The index gene-disease report, which includes the four homozygous p.Glu233Val siblings of family B.

PMID:29754768 SUPPORT INDIRECT Computational

"In conclusion, there is a consensus agreement regarding the deleterious effect of both p.Glu233Val and p.Ala180Pro on the protein function, which reflects the high evolutionary conservation of both sites."

In silico prediction of deleteriousness; supportive only.

PMID:40745475 SUPPORT INDIRECT Human Clinical

"suggesting that this combination might be incompatible with life."

No patient carries biallelic loss-of-function variants, so the authors infer that the viable genotypes are hypomorphic. This is an inference from 12 patients.

+ 1 more reference

Compound Heterozygous PPCS Variants

Mechanism confidence: Established

Two unrelated patients are compound heterozygous. Both carry the in-frame deletion c.320_334del (p.Pro107_Ala111del) in the dimerization region. The family A patient carries it in trans with c.538G>C (p.Ala180Pro), which was completely inactive in yeast complementation. The 2022 patient carries it in trans with the intronic splice-region variant c.613-3C>G. Both had severe neonatal disease with extracardiac features and died at 3 or 4 months.

PPCS hgnc:25686

Genetic context variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Each genotype pairs the in-frame deletion with a second hypomorphic or inactive allele. Combined residual activity has not been measured in patient tissue.

Downstream

Reduced PPCS Protein Stability

Show evidence (4 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

"Exome sequencing in individual II.2 of family A led to the identification of the heterozygous changes c.320_334del (p.Pro107_Ala111del) and c.538G>C (p.Ala180Pro) in PPCS (Figure 2B)."

The family A genotype.

PMID:29754768 SUPPORT DIRECT Human Clinical

"Carrier testing confirmed that the variant c.320_334del was located on the paternal allele and the variant c.538G>C on the maternal allele."

Confirms that the two variants are in trans.

PMID:35616428 SUPPORT DIRECT Human Clinical

"in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance."

The second compound-heterozygous genotype.

+ 1 more reference

Reduced PPCS Protein Stability

Mechanism confidence: Established

PPCS normally exists mainly as a dimer. Patient variants lower steady-state PPCS protein in fibroblasts, iPSCs, cardiac progenitors and cardiomyocytes, while transcript levels in iPSC-derived cells stay normal. This points to protein instability rather than reduced expression. Some alleles also impair dimerization. In one homozygous p.Tyr78His patient, skeletal-muscle RNA sequencing showed reduced PPCS expression, so transcript effects cannot be excluded for every allele.

fibroblast CL:0000057 cardiac muscle cell CL:0000746

PPCS hgnc:25686

Experimental models

PPCS-deficient patient fibroblasts PRIMARY CELL CULTURE Lower PPCS protein on immunoblot in patient cells carrying their own alleles.

Downstream

Cellular Coenzyme A Deficiency

Show evidence (5 references)

PMID:29754768 SUPPORT DIRECT In Vitro

"It is likely that the decreased enzymatic activity of PPCS is due to decreased protein stability, as indicated by the strong reduction of PPCS signal in all PPCS-deficient individuals in the western blotting experiment or by the inability to assemble into a functional PPCS dimer."

Reduced PPCS protein in fibroblasts from all four tested patients.

PMID:29754768 SUPPORT DIRECT In Vitro

"We looked also for the monomeric PPCS in control and individual II.2, but in none of them was the monomeric PPCS detected, indicating that in physiological conditions PPCS exists mainly as a dimer."

PPCS functions as a dimer, which is why dimer-interface variants matter.

PMID:40745475 SUPPORT DIRECT In Vitro

"By contrast, western blotting demonstrated markedly reduced PPCS protein levels in patient populations at all stages compared to controls, suggesting impaired protein stability (Fig. 2d)."

Reduced PPCS protein in patient iPSCs and iPSC-derived cardiac cells.

+ 2 more references

Cellular Coenzyme A Deficiency

Mechanism confidence: Established

Total CoA is reduced in fibroblasts from all tested patients. Wild-type PPCS rescues it. In patient iPSC-derived cells the deficit is mild in undifferentiated iPSCs and larger in cardiac progenitors and cardiomyocytes. Pantethine enters the pathway downstream of PPCS and raises CoA without increasing PPCS protein. CoA has not been measured in patient heart tissue. Serum CoA was undetectable in both patients and controls, so it is not a usable biomarker.

fibroblast CL:0000057 cardiac muscle cell CL:0000746

coenzyme A biosynthetic process GO:0015937 ↓ DECREASED

Experimental models

PPCS-deficient patient iPSC-derived cardiomyocytes and engineered heart patches IPSC DERIVED MODEL Reduced CoA in patient iPSC-derived cardiac progenitors and cardiomyocytes, raised by pantethine.

PPCS-deficient patient fibroblasts PRIMARY CELL CULTURE Lower total CoA, rescued by wild-type PPCS.

Downstream

Impaired Long-Chain Fatty Acid Oxidation

Cardiomyocyte Sarcomere Disorganization

Cardiomyocyte Contractile Dysfunction

Cardiomyocyte Arrhythmogenicity

Show evidence (5 references)

PMID:29754768 SUPPORT DIRECT In Vitro

"Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals."

Reduced CoA in patient fibroblasts.

PMID:29754768 SUPPORT DIRECT BACKGROUND Other

"Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine."

The enzymatic step that is lost.

PMID:40745475 SUPPORT DIRECT In Vitro

"a milder reduction of CoA compared to cells committed to the cardiac lineage, such as CPCs and CMs."

The CoA deficit is larger in cardiac-lineage cells than in undifferentiated iPSCs.

+ 2 more references

Impaired Long-Chain Fatty Acid Oxidation

Mechanism confidence: Provisional

Long-chain fatty-acid oxidation appears impaired, but the data point to two different sites. The 2018 dried-blood-spot profiles of the index patients showed low long-chain acylcarnitines (C16, C18) with a raised C0/(C16+C18) ratio, resembling CPT1 deficiency. That fits the authors' proposal that less cytosolic CoA means fewer activated long-chain acyl-CoAs. In contrast, the 2025 table records acylcarnitines as elevated in six patients. During crises F1:II and F4:II showed a VLCADD-like C14:1/C14:2 pattern, elevated long-chain acyl species and dicarboxylic aciduria, which suggests a block downstream of activation. Against a fixed systemic defect, the fasting respiratory quotient in two family B siblings was consistent with normal fat oxidation, and acylcarnitines were normal when patients were well. Acyl-CoA pools and fatty-acid flux have not been measured in patient cells or heart.

long-chain fatty acid metabolic process GO:0001676 ↓ DECREASED fatty acid beta-oxidation GO:0006635 ↓ DECREASED

Downstream

Cardiomyocyte Energy Deficit

Metabolic Decompensation During Catabolic Stress

Show evidence (3 references)

PMID:29754768 SUPPORT INDIRECT Human Clinical

"Acylcarnitine profiles in dried blood spots of the probands revealed normal levels of free carnitine (C0) but relatively low concentrations of long chain acylcarnitines C16 and C18, leading to an elevated ratio C0/(C16+C18) and reduced ratio (C16+C18:1)/C0 (Table 2)."

In the 2018 index patients, low long-chain acylcarnitines fit reduced long-chain acyl-CoA formation upstream of oxidation. They are an indirect blood biomarker, and later patients did not show the same pattern.

PMID:40745475 SUPPORT INDIRECT Human Clinical

"Unsaturated dicarboxylic acids were present, suggesting impaired fatty acid oxidation."

Urine organic acids during a crisis in patient F1:II pointed to impaired fatty-acid oxidation. Dicarboxylic aciduria suggests a block downstream of acyl-CoA activation rather than reduced activation.

PMID:29754768 REFUTE INDIRECT Human Clinical

"This investigation (performed during fasting, at 21 years of age for individual IV.1 and at 9.5 years of age for individual IV.4) showed the RQ to be 0.773 and 0.796, respectively, both consistent with normal fat oxidation."

Whole-body fat oxidation was normal during fasting in two p.Glu233Val siblings. This argues against a severe constitutive systemic defect, although it does not exclude a defect limited to the heart.

Cardiomyocyte Energy Deficit

Mechanism confidence: Hypothetical

The hypothesis is that mature cardiomyocytes, which rely on fatty-acid oxidation, cannot meet their energy demand when CoA is limited. This is the authors' interpretation. ATP, respiration and fatty-acid flux have not been measured in patient cardiomyocytes. Endomyocardial biopsy electron microscopy in one patient showed mitochondria of normal number with preserved cristae.

cardiac muscle cell CL:0000746

Downstream

Cardiomyocyte Contractile Dysfunction

Show evidence (2 references)

PMID:29754768 SUPPORT INDIRECT BACKGROUND Other

"Since CoA has a pivotal role in heart metabolism, not only as a source of energy but also as a modulator of fatty acid and glucose oxidation,35 it is expected that alteration in CoA metabolism impair cardiac function."

General background on CoA in cardiac metabolism, which motivates the hypothesis.

PMID:40745475 SUPPORT INDIRECT In Vitro

"Therefore, a shortage of CoA during cardiac cell maturation could lead to reduced energy supply for cardiac cells and cause cardiac dysfunction in PPCS DD patients."

States the hypothesis; it is not a measurement.

Cardiomyocyte Sarcomere Disorganization

Mechanism confidence: Provisional

Day-60 iPSC-derived cardiomyocytes from both patient lines show disorganized alpha-actinin sarcomeres. In 3D heart patches, patient cardiomyocytes stay rounded with poor myofibril organization. Pantethine partly corrects both. This has been shown only in vitro in two patient lines. Endomyocardial biopsy of patient F3:III.3 showed disorganized myocytes, but sarcomere structure has not been examined systematically in patient myocardium.

cardiac muscle cell CL:0000746

sarcomere organization GO:0045214 ⚠ ABNORMAL

Experimental models

PPCS-deficient patient iPSC-derived cardiomyocytes and engineered heart patches IPSC DERIVED MODEL Disorganized alpha-actinin sarcomeres in day-60 patient cardiomyocytes.

Downstream

Cardiomyocyte Contractile Dysfunction

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"sarcomere disorganization in d60 CMs derived from both patient iPSC lines"

Sarcomere disorganization in patient iPSC-derived cardiomyocytes.

Cardiomyocyte Contractile Dysfunction

Mechanism confidence: Provisional

Patient iPSC-derived cardiomyocytes have lower calcium transient amplitudes. In engineered 3D heart patches, contractile force falls between days 7 and 21 where control force rises, and the force-frequency relationship is blunted. Pantethine stabilizes force but does not restore it to control levels. These are in vitro findings in immature cardiomyocytes from two patients. They are taken as the cellular correlate of the clinical systolic dysfunction.

cardiac muscle cell CL:0000746

cardiac muscle contraction GO:0060048 ↓ DECREASED regulation of cardiac muscle contraction by calcium ion signaling GO:0010882 ⚠ ABNORMAL

myocardium UBERON:0002349

Experimental models

PPCS-deficient patient iPSC-derived cardiomyocytes and engineered heart patches IPSC DERIVED MODEL Lower calcium transient amplitude in 2D, and falling contractile force with a blunted force-frequency relationship in 3D patches.

Animal models

dPPCS1 hypomorphic Drosophila Drosophila melanogaster partially recapitulates Altered contraction parameters in the fly heart tube, which the authors take as analogous to dilated cardiomyopathy.

Downstream

Dilated Cardiomyopathy

Reduced Left Ventricular Ejection Fraction

Cardiomegaly

Exertional Dyspnea

Show evidence (3 references)

PMID:40745475 SUPPORT DIRECT In Vitro

"transient amplitudes in patient cells compared to controls, consistent with a cardiomyopathy phenotype, which was partially rescued by pantethine treatment"

Lower calcium transient amplitude in patient cardiomyocytes.

PMID:40745475 SUPPORT DIRECT In Vitro

"patches from both lines showed a decrease of contractile force between days 7 and 21, contrasting with"

Falling contractile force in patient-derived engineered heart patches.

PMID:40745475 SUPPORT DIRECT In Vitro

"Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells."

The authors' summary of the cardiomyocyte findings.

Cardiomyocyte Arrhythmogenicity

Mechanism confidence: Provisional

Patient iPSC-derived cardiomyocytes show arrhythmic calcium events in 42-54% of cells. Engineered heart patches have a shortened effective refractory period and more arrhythmic events. Pantethine reduces both. These in vitro findings are a plausible substrate for the ventricular fibrillation and cardiac arrests seen in patients. The shortened refractory period in vitro does not mirror the QT prolongation seen in some patients, so this node is not linked to Prolonged QT Interval.

cardiac muscle cell CL:0000746

Experimental models

PPCS-deficient patient iPSC-derived cardiomyocytes and engineered heart patches IPSC DERIVED MODEL Arrhythmic calcium events in single cardiomyocytes and a shortened effective refractory period in patches.

Animal models

dPPCS1 hypomorphic Drosophila Drosophila melanogaster partially recapitulates Increased arrhythmia index in the fly heart.

Downstream

Ventricular Arrhythmia

Ventricular Fibrillation

Cardiac Arrest

Syncope

Show evidence (3 references)

PMID:40745475 SUPPORT DIRECT In Vitro

"We also detected arrhythmic events in 42% of CMs from patient 95595 and 54% of CMs from patient 103596, which were reduced to 26% and 24%, respectively, bypantethine treatment"

Arrhythmic events in patient cardiomyocytes.

PMID:40745475 SUPPORT DIRECT In Vitro

"Pantethine treatment markedly increased the ERP, albeit not to control levels (Fig. 3e)."

Pantethine only partly corrects the effective refractory period of patient patches.

PMID:40745475 SUPPORT DIRECT In Vitro

"lower ERP at day 21 compared to control (Fig. 3e)."

The effective refractory period of patient heart patches is shorter than control.

Metabolic Decompensation During Catabolic Stress

Mechanism confidence: Hypothetical

In several patients, intercurrent infection, fasting or poor feeding set off episodes of hypoglycemia, lactic acidosis, rhabdomyolysis, hyperammonemia or acute cardiac decompensation. Examples include viral upper respiratory infection in F1:II and CMV infection in F2:II.1. A mismatch between CoA-dependent energy metabolism and higher demand is a plausible explanation, but it has not been tested. The authors also suggest that antibiotics may disturb microbial production of CoA precursors; this idea is based on fruit-fly data.

Downstream

Rhabdomyolysis

Hypoglycemia

Increased Circulating Lactate

Hyperammonemia

Congestive Heart Failure

Dicarboxylic Aciduria

Elevated Circulating Tetradecenoylcarnitine

Hyperlysinemia

Elevated Hepatic Transaminases

Elevated Circulating Creatine Kinase

Show evidence (3 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"he developed episodes of rhabdomyolysis requiring hospital admission during intercurrentillness or periods of poor feeding with a peak lifetime CK level of 26,000 U/L (normal 75-230)."

Rhabdomyolysis triggered by illness or poor feeding in patient F1:II.

PMID:40745475 SUPPORT DIRECT Human Clinical

"He had a subsequent episode of acuteheart failure at 4.5 years of age in the setting of an upper respiratory tract infection requiring 12 days of ECMO support."

Infection-associated cardiac decompensation.

PMID:40745475 SUPPORT INDIRECT Human Clinical

"Notably, a few PPCS DD patients (F1:II, F2:II.1) developed DCM, or their condition worsened, after an infection requiring antibiotics, likely altering the gut microbiota."

The authors' anecdotal basis for the microbiome hypothesis. Microbiota were not measured.

⬡

Pathograph

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Phenotypes

27

Cardiovascular 12

Dilated Cardiomyopathy VERY_FREQUENT HP:0001644

Show evidence (5 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

All five patients in the index report had dilated cardiomyopathy.

PMID:29754768 SUPPORT DIRECT Human Clinical

"Four out of eight siblings exhibited dilated cardiomyopathy of varying severity, without apparent extracardiac manifestations."

Variable severity within one homozygous sibship.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms."

DCM in the six newly reported patients.

+ 2 more references

Left Ventricular Noncompaction Cardiomyopathy HP:0011664

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"She meets criteria for LV non-compaction cardiomyopathy, is managed with metoprolol, and is doing well."

A single patient.

Ventricular Septal Hypertrophy HP:0005144

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Antenatal ultrasound revealed suspicion of a ventricular septal defect, but postnatal ultrasound demonstrated cardiac muscle septal hypertrophy."

A single patient.

Reduced Left Ventricular Ejection Fraction HP:0012664

Show evidence (3 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Ejection fraction was 15%, with a 9% shorteningfraction."

Patient F1:II at 34 months.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Echocardiogram demonstrated mild LV dilation with an ejection fraction of 51%, which worsened to 28% 24 h later."

Patient F2:II.1 during CMV infection.

PMID:40745475 SUPPORT DIRECT Human Clinical

"MRI demonstrated dilated LV with severe biventricular dysfunction with LV ejection fraction of 34%, right ventricle ejection fraction of 37% and no"

Patient F5:IV.1, with biventricular involvement.

Congestive Heart Failure HP:0001635

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"He had a subsequent episode of acuteheart failure at 4.5 years of age in the setting of an upper respiratory tract infection requiring 12 days of ECMO support."

Acute heart failure in patient F1:II.

PMID:29754768 SUPPORT DIRECT Human Clinical

"Compared to their baseline evaluations, both clinical and echocardiographic evaluations had shown individual IV.1 to experience a mild improvement in exertional dyspnea and an increase of ejection fraction (EF, using the Simpson mode) from 36% (at baseline) to 48% (at a recent visit); subject..."

Chronic heart-failure symptoms in the surviving family B siblings.

Cardiomegaly HP:0001640

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Blood glucose levels were normal; however, cardiomegaly was noted on the chest radiograph."

A single patient.

Ventricular Fibrillation HP:0001663

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"demonstrated ventricularﬁbrillation, which was successfully cardioverted to sinus rhythm."

Ventricular fibrillation in patient F5:IV.1. The cached text keeps the PDF ligature and merged words.

Ventricular Arrhythmia HP:0004308

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"malignant tachyarrhythmias refractory to medical management."

The terminal arrhythmia in patient F2:II.1.

Cardiac Arrest HP:0001695

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"She presented following an out-of-hospital cardiac arrest."

Patient F3:III.3 at 16 years.

PMID:40745475 SUPPORT DIRECT Human Clinical

"She died at 10 months following two cardiac arrests"

Patient F4:II.

Prolonged QT Interval HP:0001657

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"when investigations revealed a prolonged QT interval up to 560 ms which later normalized."

Patient F5:IV.1 at 14 years.

PMID:40745475 SUPPORT DIRECT Human Clinical

"He was also noted to have developed a prolonged QT interval on electrocardiogram (ECG)."

Patient F1:II.

Syncope HP:0001279

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Her medical history is remarkable for anxiety disorder as a child and a syncope at the age of 14,"

A single patient.

Pulmonary Arterial Hypertension HP:0002092

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT Human Clinical

"An extensive evaluation revealed severe dilated cardiomyopathy, pulmonary arterial hypertension, suspected pituitary dysfunction, and muscular hypotonia."

A single patient.

Genitourinary 1

Dicarboxylic Aciduria HP:0003215

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Unsaturated dicarboxylic acids were present, suggesting impaired fatty acid oxidation."

Patient F1:II.

Integument 1

Cutis Laxa HP:0000973

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT Human Clinical

"She showed minor dysmorphic features including cutis laxa, abnormally placed thumbs, abnormal dermatoglyphics, hypoplastic toe nails, and additional findings."

A single patient.

Metabolism 7

Elevated Circulating Creatine Kinase Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"CK levels were elevated with a peak recorded value of > 3200 U/L (normal 60-305 U/L)."

Patient F2:II.1.

Hypoglycemia HP:0001943

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"In the emergency department, he became unresponsive and was found to be hypoglycemic with a blood glucose level of 1.3 mol/L."

A single patient.

Increased Circulating Lactate Increased circulating lactate concentration HP:0002151

Show evidence (4 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

Elevated in three of the five index patients.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Serum lactate Elevated Elevated n.d. n.d. Elevated n.d. Normal Normal Elevated Elevated Elevated Normal"

The serum lactate row of the 2025 summary table.

PMID:40745475 REFUTE DIRECT Human Clinical

"Metabolic testing was unremarkable , including urine organic acid, plasma amino acid, serum lactate/pyruvate, N-glycan"

The F2:II.1 case narrative contradicts the table's elevated lactate for that patient.

+ 1 more reference

Hyperammonemia HP:0001987

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"developed severe hyperammonaemia (max 1351 μmol/L, reference range < 40), for which she was treated with carglumic acid"

A single patient.

Hyperlysinemia HP:0002161

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Plasma amino acids revealed strongly elevated lysine (964μmol/L, reference 100–300)"

A single patient.

Elevated Circulating Tetradecenoylcarnitine Elevated circulating tetradecenoylcarnitine concentration HP:6000476

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"when unwell was suggestive of VLCADD, with strongly raised tetradecenoylcarnitine (C14:1) and tetradecanoylcarnitine (C14:2)"

Patient F4:II.

Elevated Hepatic Transaminases Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"associated with mild acidosis, mildly elevated blood lactate (3.7 mmol/L), hyperammonaemia (max 117 μmol/L), coagulopathy and transaminitis"

A single patient.

Musculoskeletal 4

Hypotonia HP:0001252

Show evidence (2 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

"Muscular hypotonia | no | no | N/D | N/D | severe"

Severe hypotonia only in the compound-heterozygous family A patient.

PMID:35616428 SUPPORT DIRECT Human Clinical

"Here, we report a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy."

Neonatal hypotonia in the 2022 patient.

Necrotizing Myopathy HP:0008978

Show evidence (1 reference)

PMID:35616428 SUPPORT DIRECT Human Clinical

"Here, we report a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy."

A single patient.

Muscle Weakness HP:0001324

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"However, he continues to have muscle weakness requiring a wheelchair to assist with ambulation."

A single patient.

Rhabdomyolysis HP:0003201

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"he developed episodes of rhabdomyolysis requiring hospital admission during intercurrentillness or periods of poor feeding with a peak lifetime CK level of 26,000 U/L (normal 75-230)."

Patient F1:II.

PMID:40745475 SUPPORT DIRECT Human Clinical

"At 3 months she had an episode of rhabdomyolysis, with CK 71,000, associated with mild acidosis, high lactate and electrolyte disturbance"

Patient F4:II.

Nervous System 1

Global Brain Atrophy HP:0002283

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Brain MRI demonstrated global parenchymal volume loss with prominent sulci and ventricles."

A single patient, possibly secondary to ECMO.

Respiratory 1

Exertional Dyspnea HP:0002875

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT Human Clinical

"Compared to their baseline evaluations, both clinical and echocardiographic evaluations had shown individual IV.1 to experience a mild improvement in exertional dyspnea and an increase of ejection fraction (EF, using the Simpson mode) from 36% (at baseline) to 48% (at a recent visit); subject..."

Exertional dyspnea in family B patient IV.1.

🧬

Genetic Associations

1

PPCS (Causative biallelic hypomorphic variants (autosomal recessive). The evidence is 12 patients in eight families from three reports. p.Glu233Val recurs in three families (B/F6 and F5 consanguineous, F3 not). Support comes from segregation, absence of the missense alleles from gnomAD, yeast complementation for the original alleles, reduced PPCS protein and CoA in patient cells, and a Drosophila hypomorph with cardiac dysfunction. ClinGen has not curated this gene-disease pair.)

Gene: PPCS hgnc:25686 gene page variant_origin: GERMLINE

Show evidence (6 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

"Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype."

The index gene-disease report.

PMID:29754768 SUPPORT INDIRECT Model Organism

"Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations."

Functional support from model organisms.

PMID:29754768 SUPPORT DIRECT Model Organism

"c.538G>C in particular was completely inactive, indicating that this variant impairs PPCS function more dramatically than the other variants."

Yeast complementation of a cab2 null strain.

+ 3 more references

💊

Medical Actions

6

Pantethine supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: pantethine CHEBI:31959

Platform: Small molecule

Oral pantethine enters the CoA pathway downstream of PPCS and so bypasses the defective step. It has been given as compassionate treatment to four patients at about 10-24 mg/kg/day. Family B siblings started it as adolescents and adults after cardiac damage. One improved (EF 36% to 48%) and the other stayed stable; the 2018 authors saw no significant clinical improvement. F6:IV.1 died at 21 of SARS-CoV-2 complications after four years on pantethine, with cardiac function reported stable through the infection. F1:II has had no rhabdomyolysis since starting it and has low-normal LV function. F5:IV.1 recovered full LV function, but she was also on a beta-blocker and ACE inhibitor and had an ICD. After starting pantethine, F1:II began excreting 3-methylcrotonylglycine; he carries a homozygous MCCC1 variant of uncertain significance, and the significance of this is unclear. No controlled data exist, and every treated patient also received standard care, so benefit cannot be attributed to pantethine alone. In vitro, pantethine raises CoA in patient cells and partly rescues cardiomyocyte phenotypes. It also rescues viability in dPPCS hypomorph flies.

Mechanism Target:

Cellular Coenzyme A Deficiency — Pantethine supplies a substrate that enters CoA synthesis after the PPCS step.

Show evidence (11 references)

PMID:29754768 SUPPORT INDIRECT BACKGROUND Other

"CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive."

The biochemical rationale.

PMID:29754768 SUPPORT INDIRECT Model Organism

"Addition of pantethine to the fly food indeed rescued the percentage of homozygous survivors to levels that can be expected based on Mendelian inheritance."

Viability rescue in the Drosophila hypomorph. Cardiac rescue was not tested in flies.

PMID:29754768 SUPPORT DIRECT Human Clinical

"Compared to their baseline evaluations, both clinical and echocardiographic evaluations had shown individual IV.1 to experience a mild improvement in exertional dyspnea and an increase of ejection fraction (EF, using the Simpson mode) from 36% (at baseline) to 48% (at a recent visit); subject..."

Outcomes in two treated siblings; uncontrolled.

+ 8 more references

Standard heart-failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: Beta-Adrenergic Antagonist NCIT:C29576 ACE Inhibitor NCIT:C247

Platform: Small molecule

Treated patients received beta-blockers (metoprolol) and ACE inhibitors, and inotropes such as milrinone during decompensation. No PPCS-specific evidence exists for these drugs; they are used by extrapolation from general pediatric and adult heart-failure care.

Mechanism Target:

Cardiomyocyte Contractile Dysfunction — Supportive; it does not correct the CoA defect.

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"insertion, on beta-blockers, ACE-inhibitors, and 600 mg/day pantethine."

Regimen used in patient F5:IV.1; this documents use, not efficacy.

PMID:40745475 SUPPORT DIRECT Human Clinical

"She meets criteria for LV non-compaction cardiomyopathy, is managed with metoprolol, and is doing well."

Metoprolol in patient F3:III.2; this documents use, not efficacy.

Implantable cardioverter-defibrillator

Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

An ICD was placed after VF arrest in F5:IV.1. One year later it recorded a short, self-terminating run of ventricular tachycardia. This is secondary prevention by general cardiology practice; no PPCS-specific outcome data exist.

Mechanism Target:

Cardiomyocyte Arrhythmogenicity — Terminates life-threatening ventricular arrhythmia; does not modify the substrate.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"At a three-month follow-up the patient felt well, ICD interrogation did not demonstrate any arrhythmia and echocardiography revealed fully recovered LV function."

ICD use in a single patient.

Extracorporeal membrane oxygenation

Action: Extracorporeal Membrane Oxygenation NCIT:C171507

Platform: Device

Used as rescue support during acute decompensation or refractory arrhythmia (F1:II twice; F3:III.3 before a total artificial heart).

Mechanism Target:

Congestive Heart Failure — Temporary circulatory support.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"He was started on inotropic support and ultimately required 11 days of extracorporeal membrane oxygenation (ECMO)."

ECMO followed by recovery in patient F1:II.

Heart transplantation

Action: Heart Transplantation NCIT:C15246

Platform: Surgery

Patient F3:III.3 (p.Glu233Val) received a heart transplant after a total artificial heart bridge. At about one year she had no rejection, graft dysfunction or recurrent DCM. This fits a heart-intrinsic defect, but it is a single case with short follow-up.

Mechanism Target:

Dilated Cardiomyopathy — Replaces the affected organ.

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"At nearly one-year post-transplant, she has had no rejection or graft dysfunction."

Short-term outcome in one patient.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Although a long-term follow-up is needed, at one year post transplant, the patient hasnot experienced a recurrence of DCM,"

No recurrence in the graft at one year.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Autosomal recessive counseling: carrier parents have a 25% recurrence risk, and cascade testing of siblings is offered.

🔬

Diagnosis

3

Exome or genome sequencing

All patients were diagnosed by exome or genome sequencing. Patient F1:II was diagnosed only on exome reanalysis, years after a non-diagnostic clinical exome, so reanalysis is worth requesting in unexplained pediatric DCM with metabolic crises. Affected siblings were found by cascade single-gene testing.

Show evidence (1 reference)

PMID:35616428 SUPPORT DIRECT Human Clinical

"in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance."

Diagnosis by trio genome sequencing.

Cascade screening of siblings

Genotyping and cardiac evaluation of siblings found a presymptomatic affected sister (F3:III.2) with LV noncompaction. Her surveillance includes cardiac MRI and an implantable loop recorder.

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"who presented to clinic for cardiac screening based on her family history of cardiomyopathy (sister ofpatient F3:III.3)."

Cascade screening found an affected sibling.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Her three full siblings had normal cardiac evaluations and none was homozygous for the PPCS variant."

Negative cascade results in family F2.

Fibroblast PPCS protein and CoA measurement

Reduced PPCS protein on immunoblot and reduced total CoA in cultured fibroblasts support pathogenicity when a variant is uncertain. These are research assays. Serum PPCS and CoA are not informative.

Show evidence (2 references)

PMID:29754768 SUPPORT DIRECT In Vitro

"Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals."

Fibroblast CoA as a functional marker.

PMID:29754768 SUPPORT DIRECT Human Clinical

"Unfortunately, the levels of PPCS and CoA were consistently undetectable in both the affected and control samples."

Serum assays were uninformative.

📈

Progression

4

Neonatal or infantile severe presentation

Age: Antenatal to 4 months

Compound-heterozygous and some exon 1 genotypes (family A, the 2022 patient, F2:II.1, F4:II) presented at or soon after birth with cardiomyopathy and multisystem involvement. All four died between 3 and 10 months.

Show evidence (2 references)

PMID:29754768 SUPPORT DIRECT Human Clinical

"Unfortunately, she succumbed to multi-organ failure at 3 months of age."

The family A patient.

PMID:40745475 SUPPORT DIRECT Human Clinical

"She died at 10 months following two cardiac arrests"

Patient F4:II.

Childhood-onset dilated cardiomyopathy

Age: 4 months to 3 years

In family B, homozygous p.Glu233Val siblings presented between 4 months and 3 years. Two died at 23 months and 3 years, while two survived into adolescence and adulthood with chronic heart failure. Of the survivors, F6:IV.1 died at 21 of SARS-CoV-2 complications after four years on pantethine; F6:IV.4 was alive at 14.5 years.

Show evidence (2 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"continued oral treatment with pantethine supplementation for four (Patient F6:IV.1 died of COVID-19) and six years, respectively."

Later outcome of the two surviving family B siblings.

PMID:29754768 SUPPORT DIRECT Human Clinical

"The other two siblings (individuals IV.5 and IV.8) showed a severe form of dilated cardiomyopathy, fatal in early childhood (3 years of age)."

Variable outcome within one sibship.

Episodic decompensation with partial recovery

Age: 9 months to 7 years (patient F1:II)

Patient F1:II had repeated infection-triggered crises with hypoglycemia, rhabdomyolysis and heart failure needing ECMO twice. Cardiac function normalized between episodes.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"He was started on inotropic support and ultimately required 11 days of extracorporeal membrane oxygenation (ECMO)."

The first severe cardiac episode.

Adolescent or adult arrhythmic presentation

Age: 14 to 21 years

Three p.Glu233Val homozygotes from families F3 and F5 presented as adolescents or young adults: with VF arrest, with QT prolongation and later arrest, or through cascade screening. Survivors are 11-21 years old at last report.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"She presented following an out-of-hospital cardiac arrest."

Patient F3:III.3 at 16 years.

📊

Prevalence

1

Reported patients worldwide

Cases In Literature Ultra Rare

Twelve patients in eight families by 2025: five in 2018, one in 2022 and six in 2025, with family B counted once. This is a count of published cases, not a population prevalence. No carrier frequency has been estimated. No other rare biallelic PPCS genotypes were found among more than 11,000 in-house exomes.

Show evidence (3 references)

PMID:40745475 SUPPORT DIRECT Human Clinical

"To date, only six patients worldwide have been identified."

The case count before the 2025 series.

PMID:40745475 SUPPORT DIRECT Human Clinical

"Despite the limited number of PPCS DD patients ( n = 12), an exploratory genotype-phenotype correlation analysis suggests that the"

The total after the 2025 series.

PMID:35616428 SUPPORT DIRECT Human Clinical

"To date, only five individuals with PPCS-mutations have been reported."

The case count in 2022, before the Lok patient.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Cardiomyopathy Dilated 2C:

Pantothenate kinase-associated neurodegeneration and COASY protein-associated neurodegeneration

Overlapping Features These other CoA-biosynthesis disorders cause neurodegeneration with brain iron accumulation and no cardiomyopathy. PPCS deficiency shows the opposite pattern: cardiomyopathy without brain iron accumulation.

Show evidence (1 reference)

PMID:35397396 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Mutations in PPCS cause autosomal-recessive dilated cardiomyopathy, often fatal, without apparent neurodegeneration, whereas pathogenic variants in PANK2 and COASY, two other genes involved in the CoA synthesis, cause Neurodegeneration with Brain Iron Accumulation (NBIA)."

The contrast between the CoA-pathway disorders.

Fatty acid oxidation disorders

Overlapping Features During crises, F1:II and F4:II had acylcarnitine and urine organic acid profiles suggesting VLCAD deficiency, and F1:II was first treated as VLCADD. Normal ACADVL testing should prompt PPCS analysis in a child with DCM and illness-triggered metabolic crises.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT Human Clinical

"Initial metabolic evaluation revealed elevations in multiple long-chain fatty acyl-CoA species suggestive of a fatty acid oxidation defect."

Overlap with fatty-acid oxidation disorders.

🧫

Experimental Models

2

PPCS-deficient patient iPSC-derived cardiomyocytes and engineered heart patches IPSC_DERIVED_MODEL

Cardiac progenitors and day-22 and day-60 cardiomyocytes from two patients reproduce reduced PPCS protein and CoA. They also show sarcomere disorganization, weak calcium transients, arrhythmic events, falling patch force and a short effective refractory period. Pantethine partly rescues these phenotypes. Only one clone per line was used, and there are no isogenic controls.

Cell source

iPSC lines HMGUi003-A (compound heterozygous p.Ala180Pro/p.Pro107_Ala111del, fibroblast 95595) and MRIi028-A (homozygous p.Glu233Val, fibroblast 103596), reprogrammed from patient fibroblasts and compared with two healthy control lines

Culture

2D cardiomyocyte culture and 3D heart patches on decellularized porcine ventricular extracellular matrix in biomimetic chambers

Publication

PMID:40745475

Pathograph links

Cellular Coenzyme A Deficiency recapitulates fidelity: moderate observes: cellular Reduced CoA in patient iPSC-derived cardiac progenitors and cardiomyocytes, raised by pantethine.

Limitations: Two patient lines, one clone each, and no isogenic correction.

Readouts

Total cellular CoA

Direction: DECREASED

Interpretation: Direct measurement of the node in disease-relevant cells.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells."

Reduced CoA in patient-derived cardiac cells.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"a milder reduction of CoA compared to cells committed to the cardiac lineage, such as CPCs and CMs."

CoA deficit in cardiac-lineage cells.

Cardiomyocyte Sarcomere Disorganization recapitulates fidelity: moderate observes: cellular Disorganized alpha-actinin sarcomeres in day-60 patient cardiomyocytes.

Limitations: iPSC-derived cardiomyocytes are immature; no patient myocardium was available for comparison.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"sarcomere disorganization in d60 CMs derived from both patient iPSC lines"

Sarcomere phenotype in the model.

Cardiomyocyte Contractile Dysfunction recapitulates fidelity: moderate observes: tissue Lower calcium transient amplitude in 2D, and falling contractile force with a blunted force-frequency relationship in 3D patches.

Limitations: Engineered patches lack chamber geometry, neurohumoral input and systemic metabolism; going from patch force to ventricular dilation is an extrapolation.

Divergences from the human mechanism

proxy quantity qualifying

The model measures isometric force of a thin engineered patch; the clinical quantity is ejection fraction and chamber dilation of the intact ventricle.

Readouts

Patch contractile force over time

Direction: DECREASED

Interpretation: Force falls in patient patches but rises in controls.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"patches from both lines showed a decrease of contractile force between days 7 and 21, contrasting with"

The force measurement.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"patches from both lines showed a decrease of contractile force between days 7 and 21, contrasting with"

Contractile defect in the 3D model.

Cardiomyocyte Arrhythmogenicity recapitulates fidelity: moderate observes: cellular Arrhythmic calcium events in single cardiomyocytes and a shortened effective refractory period in patches.

Limitations: In vitro arrhythmic calcium events are not the same as clinical ventricular fibrillation.

Show evidence (1 reference)

PMID:40745475 SUPPORT DIRECT In Vitro

"We also detected arrhythmic events in 42% of CMs from patient 95595 and 54% of CMs from patient 103596, which were reduced to 26% and 24%, respectively, bypantethine treatment"

The arrhythmia phenotype in the model.

Show evidence (1 reference)

PMID:35397396 SUPPORT DIRECT In Vitro

"Here, we report the generation of induced pluripotent stem cells from fibroblasts of two PPCS-deficient patients."

Derivation of the patient iPSC lines.

PPCS-deficient patient fibroblasts PRIMARY_CELL_CULTURE

Patient fibroblasts show reduced PPCS protein and total CoA. Wild-type PPCS corrects both. Pantethine, and less effectively 4'-phosphopantetheine, raise CoA.

Cell source

Skin fibroblasts from five patients (95595, 103596, 128343, 128344, 146603), one of them also transduced with wild-type PPCS

Publication

PMID:29754768

Pathograph links

Reduced PPCS Protein Stability recapitulates fidelity: high observes: molecular Lower PPCS protein on immunoblot in patient cells carrying their own alleles.

Limitations: Fibroblasts are not the affected cell type.

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT In Vitro

"It is likely that the decreased enzymatic activity of PPCS is due to decreased protein stability, as indicated by the strong reduction of PPCS signal in all PPCS-deficient individuals in the western blotting experiment or by the inability to assemble into a functional PPCS dimer."

Reduced protein in patient fibroblasts.

Cellular Coenzyme A Deficiency recapitulates fidelity: moderate observes: molecular Lower total CoA, rescued by wild-type PPCS.

Limitations: Fibroblasts are not the affected cell type, and the CoA deficit is larger in cardiac-lineage cells.

Show evidence (2 references)

PMID:29754768 SUPPORT DIRECT In Vitro

"The investigation revealed a significant reduction of CoA in all four affected individuals, which was rescued by reintroducing the wild-type copy of the gene (Figure 6)."

CoA deficit with genetic rescue.

+ 1 more reference

Lines 95595 and 103596 were reported in 2018; 128343, 128344 and 146603 were added in the 2025 series (PMID:40745475).

🐁

Animal Models

1

dPPCS1 hypomorphic Drosophila

Homozygous hypomorphic dPPCS flies have reduced viability. Their pre-pupal hearts show higher heart rate and arrhythmia index, more wall shortening and shorter systolic length. Dietary pantethine rescues viability; vitamin B5 was used as a control. Null dPPCS alleles are lethal at the first larval instar. The allele is not a patient allele, and fly CoA levels were not reported in this study.

Species

Drosophila melanogaster

Genotype

dPPCS1/dPPCS1 homozygous; P-element insertion in the 5' UTR of CG5629 that lowers dPPCS expression

Publication

PMID:29754768

Pathograph links

Cardiomyocyte Contractile Dysfunction partially recapitulates fidelity: low observes: organism Altered contraction parameters in the fly heart tube, which the authors take as analogous to dilated cardiomyopathy.

Limitations: The Drosophila heart is a tubular organ without chambers, so ejection fraction or dilation cannot be measured. The allele lowers dPPCS expression rather than reproducing a patient missense change. Cardiac function after pantethine was not reported.

Divergences from the human mechanism

species mismatch qualifying

Heart-tube kinematics in pre-pupae are a proxy for human ventricular systolic function.

boundary omission qualifying

The expression-reducing P-element allele does not model the protein-destabilizing missense alleles in patients.

Readouts

Heart rate, arrhythmia index, wall shortening and systolic length

Direction: ALTERED

Interpretation: Altered cardiac kinematics in homozygous hypomorphs compared with heterozygotes.

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT Model Organism

"In comparison with heterozygous dPPCS1 flies, homozygous dPPCS1 flies showed a significant increase in heart rate, heart wall shortening, and arrhythmia index and a decrease in systolic length (Figure 7)."

The measurements behind this readout.

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT Model Organism

"With deeper inspection, dPPCS mutants presented with reduced viability, and moreover showed increased heart rate, increased arrhythmia index, reduced systolic function, and increased heart wall shortening, all manifestations indicative of dilate cardiomyopathy in fruit flies.31"

The authors' reading of the fly cardiac phenotype.

Cardiomyocyte Arrhythmogenicity partially recapitulates fidelity: low observes: organism Increased arrhythmia index in the fly heart.

Limitations: Arrhythmia index in a fly heart tube is not equivalent to ventricular arrhythmia in human myocardium.

Divergences from the human mechanism

species mismatch qualifying

Fly heart-tube rhythm irregularity is a proxy for human ventricular arrhythmia.

Show evidence (1 reference)

PMID:29754768 SUPPORT DIRECT Model Organism

"In comparison with heterozygous dPPCS1 flies, homozygous dPPCS1 flies showed a significant increase in heart rate, heart wall shortening, and arrhythmia index and a decrease in systolic length (Figure 7)."

Increased arrhythmia index in homozygotes.

Show evidence (2 references)

PMID:29754768 SUPPORT DIRECT Model Organism

"In our crosses, the percentage of homozygous dPPCS1 pupae ranged from 9% to 22%, suggesting a reduced viability in homozygous mutants."

Reduced viability in the hypomorph.

PMID:29754768 SUPPORT DIRECT Model Organism

"Addition of pantethine to the fly food indeed rescued the percentage of homozygous survivors to levels that can be expected based on Mendelian inheritance."

Pantethine rescues viability.

{ }

Source YAML

click to show

name: Cardiomyopathy Dilated 2C
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: cardiomyopathy, dilated, 2c
  term:
    id: MONDO:0032592
    label: cardiomyopathy, dilated, 2c
synonyms:
- CMD2C
- dilated cardiomyopathy 2C
- PPCS deficiency disorder
- PPCS DD
- PPCS-related dilated cardiomyopathy
- phosphopantothenoylcysteine synthetase deficiency
description: >-
  Cardiomyopathy, dilated, 2C (CMD2C; PPCS deficiency disorder) is an ultra-rare
  autosomal recessive cardiomyopathy caused by biallelic hypomorphic variants in
  PPCS. PPCS catalyzes the second step of de novo coenzyme A (CoA) biosynthesis
  from pantothenate (vitamin B5). Twelve patients from eight families have been
  reported (2018 index report of two families, a 2022 single case and a 2025 series).
  Presentation ranges from antenatal or neonatal onset to 21 years. Dilated
  cardiomyopathy is the constant feature and is often fatal in infancy or early
  childhood; ventricular arrhythmia and cardiac arrest occur in adolescents. Some
  genotypes, mostly with exon 1 or exon 2 variants, add hypotonia, myopathy,
  rhabdomyolysis and metabolic crises during intercurrent illness. Unlike PANK2- and
  COASY-related disease, there is no neurodegeneration with brain iron accumulation.
  Patient fibroblasts and iPSC-derived cardiomyocytes show reduced PPCS protein and
  reduced CoA. Patient cardiomyocytes and engineered heart patches show sarcomere
  disorganization, weak calcium transients, falling contractile force and
  arrhythmic events. The steps linking CoA deficiency to cardiomyocyte failure,
  including impaired fatty-acid activation and an energy deficit, are inferred, not
  measured. Pantethine bypasses the PPCS step and raises CoA in patient cells.
  Uncontrolled compassionate use in four patients was followed by stabilization or
  improvement alongside standard heart-failure care.
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
  Evidence base: three clinical publications covering 12 patients in eight families.
  Iuso et al. 2018 (PMID:29754768) reported family A (one compound-heterozygous
  patient) and family B (four homozygous p.Glu233Val siblings). Lok et al. 2022
  (PMID:35616428) reported one compound-heterozygous infant. Zhang et al. 2025
  (PMID:40745475) added six patients in five families and re-reported family B as
  F6. The 2018 and 2025 papers share family B and must not be counted as
  independent cohorts. p.Glu233Val recurs in three families (B/F6, F3, F5); no
  haplotype analysis has been reported. The two 2018 texts number the deceased
  family B siblings differently (IV.5 in the text, IV.6 in Table 1); the
  segregation sentence also prints the variant as c.178A>T although c.698A>T is
  meant. ClinGen has not curated PPCS; PPCS appears in no cached CGGV record and
  not in kb/genes/ingest/clingen_gene_validity.tsv, so gene_disease_validity is
  left empty. Snippets
  from PMID:40745475 come from a PDF-extracted full text; wherever the extraction
  merged words (for example "intercurrentillness"), the snippet keeps the cached
  spelling. `just check-genereviews --online` result: NO_CHAPTER. No
  PPCS-specific GeneReviews chapter exists; the general Dilated Cardiomyopathy
  Overview was not used as a phenotype baseline because it does not cover PPCS.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PPCS variants (homozygous, or compound heterozygous in trans) occur in
    all 12 reported patients. Full segregation was shown in consanguineous family B.
    Heterozygous parents and siblings in families B, F2 and F5 had no
    cardiomyopathy at screening. Seven of the 12 patients come from consanguineous
    families (F2, F4, F5 and the four affected siblings of family B/F6).
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Consanguinity No Yes No No Yes Yes Yes Yes Yes Yes No No"
    explanation: The consanguinity row of the 2025 summary table; seven of the 12 patients are from consanguineous families.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Segregation analysis in all available family members confirmed full segregation, with all four affected siblings found to harbor the c.178A>T mutation in homozygous form, both parents and two of the four unaffected siblings (subjects IV.3 and IV.7) found to be heterozygous for the mutation, and the remaining two unaffected siblings (subjects IV.2 and IV.6) found to be wild-type."
    explanation: Full recessive segregation in the multiplex family. The source prints c.178A>T here, but the variant reported elsewhere in the paper for this family is c.698A>T.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "The echocardiograms of the unaffected siblings and their parents were normal."
    explanation: Heterozygous carriers in family B had normal echocardiograms.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "in keeping with the absence of cardiomyopathy symptoms in both individuals."
    explanation: In family F5, the heterozygous mother and brother had no cardiomyopathy.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway."
    explanation: The 2025 series defines the disorder as autosomal recessive.
pathophysiology:
- name: Homozygous PPCS Missense Variants
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Ten of the 12 patients are homozygous for a PPCS missense variant (NM_024664):
    p.Glu233Val in exon 3 (families B/F6, F3 and F5), or p.Tyr78His, p.Arg106Pro or
    p.Ala20Gly in exon 1 (families F1, F2 and F4). p.Glu233Val sits near the
    ATP-binding phosphate recognition site, close to the dimer interface.
    p.Arg106Pro lies in the dimerization region. p.Tyr78His and p.Ala20Gly
    destabilize helix packing near the catalytic site. No patient carries two
    loss-of-function alleles, which suggests that complete PPCS loss is not viable.
  genes:
  - preferred_term: PPCS
    term:
      id: hgnc:25686
      label: PPCS
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Partial loss of function is inferred from reduced but detectable protein and
      CoA in patient cells, and from the absence of biallelic null genotypes. Residual
      enzyme activity has not been measured in human tissue.
  molecular_functions:
  - preferred_term: phosphopantothenate--cysteine ligase activity
    modifier: DECREASED
    term:
      id: GO:0004632
      label: phosphopantothenate--cysteine ligase activity
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype."
    explanation: The index gene-disease report, which includes the four homozygous p.Glu233Val siblings of family B.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "In conclusion, there is a consensus agreement regarding the deleterious effect of both p.Glu233Val and p.Ala180Pro on the protein function, which reflects the high evolutionary conservation of both sites."
    explanation: In silico prediction of deleteriousness; supportive only.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "suggesting that this combination might be incompatible with life."
    explanation: No patient carries biallelic loss-of-function variants, so the authors infer that the viable genotypes are hypomorphic. This is an inference from 12 patients.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "suggesting this genetic region as a mutational hotspot for PPCS."
    explanation: All three new homozygous missense variants in the 2025 series fall in exon 1. The hotspot claim rests on very few alleles.
  downstream:
  - target: Reduced PPCS Protein Stability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels."
      explanation: Patient fibroblasts and iPSC-derived cells carrying these variants have less PPCS protein.
- name: Compound Heterozygous PPCS Variants
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Two unrelated patients are compound heterozygous. Both carry the in-frame
    deletion c.320_334del (p.Pro107_Ala111del) in the dimerization region. The
    family A patient carries it in trans with c.538G>C (p.Ala180Pro), which was
    completely inactive in yeast complementation. The 2022 patient carries it in
    trans with the intronic splice-region variant c.613-3C>G. Both had severe neonatal
    disease with extracardiac features and died at 3 or 4 months.
  genes:
  - preferred_term: PPCS
    term:
      id: hgnc:25686
      label: PPCS
  genetic_context:
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Each genotype pairs the in-frame deletion with a second hypomorphic or inactive
      allele. Combined residual activity has not been measured in patient tissue.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Exome sequencing in individual II.2 of family A led to the identification of the heterozygous changes c.320_334del (p.Pro107_Ala111del) and c.538G>C (p.Ala180Pro) in PPCS (Figure 2B)."
    explanation: The family A genotype.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Carrier testing confirmed that the variant c.320_334del was located on the paternal allele and the variant c.538G>C on the maternal allele."
    explanation: Confirms that the two variants are in trans.
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance."
    explanation: The second compound-heterozygous genotype.
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Functional studies confirmed the likely pathogenicity of this variant."
    explanation: Functional support for the intronic c.613-3C>G allele. Only the abstract is cached, so the assay type is not recorded here.
  downstream:
  - target: Reduced PPCS Protein Stability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "No signal was instead present in the cell extract of the affected individual (Figure 5C)."
      explanation: Under native conditions, no PPCS dimer was detected in fibroblasts from the compound-heterozygous family A patient.
- name: Reduced PPCS Protein Stability
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    PPCS normally exists mainly as a dimer. Patient variants lower steady-state PPCS
    protein in fibroblasts, iPSCs, cardiac progenitors and cardiomyocytes, while
    transcript levels in iPSC-derived cells stay normal. This points to protein
    instability rather than reduced expression. Some alleles also impair
    dimerization. In one homozygous p.Tyr78His patient, skeletal-muscle RNA
    sequencing showed reduced PPCS expression, so transcript effects cannot be
    excluded for every allele.
  genes:
  - preferred_term: PPCS
    term:
      id: hgnc:25686
      label: PPCS
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "It is likely that the decreased enzymatic activity of PPCS is due to decreased protein stability, as indicated by the strong reduction of PPCS signal in all PPCS-deficient individuals in the western blotting experiment or by the inability to assemble into a functional PPCS dimer."
    explanation: Reduced PPCS protein in fibroblasts from all four tested patients.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "We looked also for the monomeric PPCS in control and individual II.2, but in none of them was the monomeric PPCS detected, indicating that in physiological conditions PPCS exists mainly as a dimer."
    explanation: PPCS functions as a dimer, which is why dimer-interface variants matter.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "By contrast, western blotting demonstrated markedly reduced PPCS protein levels in patient populations at all stages compared to controls, suggesting impaired protein stability (Fig. 2d)."
    explanation: Reduced PPCS protein in patient iPSCs and iPSC-derived cardiac cells.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "showed similar PPCS transcript levels at all developmental stages"
    explanation: Normal transcript levels in iPSC-derived cells, consistent with instability at the protein level.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "an overall reduction in PPCS expression levels compared to controls."
    explanation: Clinical skeletal-muscle RNA sequencing in patient F1:II (p.Tyr78His) showed lower PPCS transcript, so some alleles may also affect expression.
  downstream:
  - target: Cellular Coenzyme A Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "The investigation revealed a significant reduction of CoA in all four affected individuals, which was rescued by reintroducing the wild-type copy of the gene (Figure 6)."
      explanation: Re-expressing wild-type PPCS restores CoA in patient fibroblasts, which ties the CoA deficit to PPCS loss.
- name: Cellular Coenzyme A Deficiency
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Total CoA is reduced in fibroblasts from all tested patients. Wild-type PPCS
    rescues it. In patient iPSC-derived cells the deficit is mild in undifferentiated
    iPSCs and larger in cardiac progenitors and cardiomyocytes. Pantethine enters
    the pathway downstream of PPCS and raises CoA without increasing PPCS protein.
    CoA has not been measured in patient heart tissue. Serum CoA was undetectable
    in both patients and controls, so it is not a usable biomarker.
  biological_processes:
  - preferred_term: coenzyme A biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0015937
      label: coenzyme A biosynthetic process
  chemical_entities:
  - preferred_term: coenzyme A
    modifier: DECREASED
    term:
      id: CHEBI:15346
      label: coenzyme A
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals."
    explanation: Reduced CoA in patient fibroblasts.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: "Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine."
    explanation: The enzymatic step that is lost.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "a milder reduction of CoA compared to cells committed to the cardiac lineage, such as CPCs and CMs."
    explanation: The CoA deficit is larger in cardiac-lineage cells than in undifferentiated iPSCs.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Western blotting did not reveal an increase in PPCS upon the treatment indicating that the observed increase in CoA is not due to stabilization of PPCS protein"
    explanation: Pantethine raises CoA by bypassing PPCS, not by restoring the enzyme.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Unfortunately, the levels of PPCS and CoA were consistently undetectable in both the affected and control samples."
    explanation: Serum PPCS and CoA were undetectable, so the deficit could not be shown in blood.
  downstream:
  - target: Impaired Long-Chain Fatty Acid Oxidation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Reduced cytosolic CoA concentration in PPCS-affected individuals may lead to a reduced synthesis of activated long-chain fatty acids in PPCS-affected individuals."
      explanation: The authors propose this step to explain the low long-chain acylcarnitines. It is a hypothesis, not a measurement of acyl-CoA levels.
  - target: Cardiomyocyte Sarcomere Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "revealed sarcomere disorganization in d60 CMs derived from both patient iPSC lines, suggesting a potential defect in cont ractile function, which was slightly rescued by treatment with"
      explanation: Pantethine raises CoA without restoring PPCS and slightly rescues sarcomere organization, so CoA deficiency contributes to it. The intermediate steps are unknown.
  - target: Cardiomyocyte Contractile Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment."
      explanation: Partial rescue by a CoA-raising bypass links the contractile defect to CoA deficiency, though the rescue is incomplete.
  - target: Cardiomyocyte Arrhythmogenicity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "We also detected arrhythmic events in 42% of CMs from patient 95595 and 54% of CMs from patient 103596, which were reduced to 26% and 24%, respectively, bypantethine treatment"
      explanation: Pantethine lowers the fraction of arrhythmic patient cardiomyocytes, which ties arrhythmogenicity to the CoA deficit.
- name: Impaired Long-Chain Fatty Acid Oxidation
  biological_scale: MOLECULAR
  role: mechanism
  mechanism_confidence: PROVISIONAL
  description: >-
    Long-chain fatty-acid oxidation appears impaired, but the data point to two
    different sites. The 2018 dried-blood-spot profiles of the index patients showed
    low long-chain acylcarnitines (C16, C18) with a raised C0/(C16+C18) ratio,
    resembling CPT1 deficiency. That fits the authors' proposal that less cytosolic
    CoA means fewer activated long-chain acyl-CoAs. In contrast, the 2025 table
    records acylcarnitines as elevated in six patients. During crises F1:II and F4:II
    showed a VLCADD-like C14:1/C14:2 pattern, elevated long-chain acyl species and
    dicarboxylic aciduria, which suggests a block downstream of activation.
    Against a fixed systemic defect, the fasting respiratory quotient in two family B
    siblings was consistent with normal fat oxidation, and acylcarnitines were
    normal when patients were well. Acyl-CoA pools and fatty-acid flux have not been
    measured in patient cells or heart.
  biological_processes:
  - preferred_term: long-chain fatty acid metabolic process
    modifier: DECREASED
    term:
      id: GO:0001676
      label: long-chain fatty acid metabolic process
  - preferred_term: fatty acid beta-oxidation
    modifier: DECREASED
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Acylcarnitine profiles in dried blood spots of the probands revealed normal levels of free carnitine (C0) but relatively low concentrations of long chain acylcarnitines C16 and C18, leading to an elevated ratio C0/(C16+C18) and reduced ratio (C16+C18:1)/C0 (Table 2)."
    explanation: In the 2018 index patients, low long-chain acylcarnitines fit reduced long-chain acyl-CoA formation upstream of oxidation. They are an indirect blood biomarker, and later patients did not show the same pattern.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Unsaturated dicarboxylic acids were present, suggesting impaired fatty acid oxidation."
    explanation: Urine organic acids during a crisis in patient F1:II pointed to impaired fatty-acid oxidation. Dicarboxylic aciduria suggests a block downstream of acyl-CoA activation rather than reduced activation.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "This investigation (performed during fasting, at 21 years of age for individual IV.1 and at 9.5 years of age for individual IV.4) showed the RQ to be 0.773 and 0.796, respectively, both consistent with normal fat oxidation."
    explanation: Whole-body fat oxidation was normal during fasting in two p.Glu233Val siblings. This argues against a severe constitutive systemic defect, although it does not exclude a defect limited to the heart.
  downstream:
  - target: Cardiomyocyte Energy Deficit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Therefore, a shortage of CoA during cardiac cell maturation could lead to reduced energy supply for cardiac cells and cause cardiac dysfunction in PPCS DD patients."
      explanation: The authors' inference, based on the greater fatty-acid dependence of maturing cardiomyocytes. Energy supply was not measured.
  - target: Metabolic Decompensation During Catabolic Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Initial metabolic evaluation revealed elevations in multiple long-chain fatty acyl-CoA species suggestive of a fatty acid oxidation defect."
      explanation: In patient F1:II the first crisis, with hypoglycemia, came with a fatty-acid-oxidation-like profile. Elevated long-chain acyl species suggest a block downstream of activation. This links the two only by co-occurrence.
- name: Cardiomyocyte Energy Deficit
  biological_scale: CELLULAR
  role: mechanism
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The hypothesis is that mature cardiomyocytes, which rely on fatty-acid
    oxidation, cannot meet their energy demand when CoA is limited. This is the
    authors' interpretation. ATP, respiration and fatty-acid flux have not been
    measured in patient cardiomyocytes. Endomyocardial biopsy electron microscopy in
    one patient showed mitochondria of normal number with preserved cristae.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: "Since CoA has a pivotal role in heart metabolism, not only as a source of energy but also as a modulator of fatty acid and glucose oxidation,35 it is expected that alteration in CoA metabolism impair cardiac function."
    explanation: General background on CoA in cardiac metabolism, which motivates the hypothesis.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Therefore, a shortage of CoA during cardiac cell maturation could lead to reduced energy supply for cardiac cells and cause cardiac dysfunction in PPCS DD patients."
    explanation: States the hypothesis; it is not a measurement.
  downstream:
  - target: Cardiomyocyte Contractile Dysfunction
    causal_link_type: UNKNOWN
- name: Cardiomyocyte Sarcomere Disorganization
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Day-60 iPSC-derived cardiomyocytes from both patient lines show disorganized
    alpha-actinin sarcomeres. In 3D heart patches, patient cardiomyocytes stay rounded
    with poor myofibril organization. Pantethine partly corrects both. This has been
    shown only in vitro in two patient lines. Endomyocardial biopsy of patient
    F3:III.3 showed disorganized myocytes, but sarcomere structure has not been
    examined systematically in patient myocardium.
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: ABNORMAL
    term:
      id: GO:0045214
      label: sarcomere organization
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "sarcomere disorganization in d60 CMs derived from both patient iPSC lines"
    explanation: Sarcomere disorganization in patient iPSC-derived cardiomyocytes.
  downstream:
  - target: Cardiomyocyte Contractile Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cardiomyocyte Contractile Dysfunction
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient iPSC-derived cardiomyocytes have lower calcium transient amplitudes. In
    engineered 3D heart patches, contractile force falls between days 7 and 21 where
    control force rises, and the force-frequency relationship is blunted. Pantethine
    stabilizes force but does not restore it to control levels. These are in vitro
    findings in immature cardiomyocytes from two patients. They are taken as the
    cellular correlate of the clinical systolic dysfunction.
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  - preferred_term: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: ABNORMAL
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "transient amplitudes in patient cells compared to controls, consistent with a cardiomyopathy phenotype, which was partially rescued by pantethine treatment"
    explanation: Lower calcium transient amplitude in patient cardiomyocytes.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "patches from both lines showed a decrease of contractile force between days 7 and 21, contrasting with"
    explanation: Falling contractile force in patient-derived engineered heart patches.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells."
    explanation: The authors' summary of the cardiomyocyte findings.
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "transient amplitudes in patient cells compared to controls, consistent with a cardiomyopathy phenotype, which was partially rescued by pantethine treatment"
      explanation: The authors read the in vitro contractile defect as consistent with the clinical cardiomyopathy. Going from immature cells to chamber dilation is an extrapolation.
  - target: Reduced Left Ventricular Ejection Fraction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Exertional Dyspnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cardiomyocyte Arrhythmogenicity
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient iPSC-derived cardiomyocytes show arrhythmic calcium events in 42-54% of
    cells. Engineered heart patches have a shortened effective refractory period and
    more arrhythmic events. Pantethine reduces both. These in vitro findings are a
    plausible substrate for the ventricular fibrillation and cardiac arrests seen in
    patients. The shortened refractory period in vitro does not mirror the QT
    prolongation seen in some patients, so this node is not linked to Prolonged QT
    Interval.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "We also detected arrhythmic events in 42% of CMs from patient 95595 and 54% of CMs from patient 103596, which were reduced to 26% and 24%, respectively, bypantethine treatment"
    explanation: Arrhythmic events in patient cardiomyocytes.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Pantethine treatment markedly increased the ERP, albeit not to control levels (Fig. 3e)."
    explanation: Pantethine only partly corrects the effective refractory period of patient patches.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "lower ERP at day 21 compared to control (Fig. 3e)."
    explanation: The effective refractory period of patient heart patches is shorter than control.
  downstream:
  - target: Ventricular Arrhythmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventricular Fibrillation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiac Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Syncope
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Metabolic Decompensation During Catabolic Stress
  biological_scale: ORGANISM
  role: amplifier
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In several patients, intercurrent infection, fasting or poor feeding set off
    episodes of hypoglycemia, lactic acidosis, rhabdomyolysis, hyperammonemia or
    acute cardiac decompensation. Examples include viral upper respiratory infection
    in F1:II and CMV infection in F2:II.1. A mismatch between CoA-dependent energy
    metabolism and higher demand is a plausible explanation, but it has not been
    tested. The authors also suggest that antibiotics may disturb microbial
    production of CoA precursors; this idea is based on fruit-fly data.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "he developed episodes of rhabdomyolysis requiring hospital admission during intercurrentillness or periods of poor feeding with a peak lifetime CK level of 26,000 U/L (normal 75-230)."
    explanation: Rhabdomyolysis triggered by illness or poor feeding in patient F1:II.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had a subsequent episode of acuteheart failure at 4.5 years of age in the setting of an upper respiratory tract infection requiring 12 days of ECMO support."
    explanation: Infection-associated cardiac decompensation.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Notably, a few PPCS DD patients (F1:II, F2:II.1) developed DCM, or their condition worsened, after an infection requiring antibiotics, likely altering the gut microbiota."
    explanation: The authors' anecdotal basis for the microbiome hypothesis. Microbiota were not measured.
  downstream:
  - target: Rhabdomyolysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypoglycemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Circulating Lactate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hyperammonemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dicarboxylic Aciduria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated Circulating Tetradecenoylcarnitine
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hyperlysinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated Hepatic Transaminases
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated Circulating Creatine Kinase
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  frequency: VERY_FREQUENT
  description: >-
    In the 2025 summary table, 10 of 12 patients have dilated cardiomyopathy, most
    of it severe. The other two have LV noncompaction cardiomyopathy (F3:III.2,
    found by cascade screening) and septal hypertrophy (F4:II). Severity varies
    within sibships that share the same genotype. Onset ranges from antenatal or
    neonatal to 21 years. Endomyocardial biopsy in F1:II showed mild focal
    interstitial fibrosis and myocyte nucleomegaly without myocarditis.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Cardiac manifestations | dilated cardiomyopathy | dilated cardiomyopathy | severe dilated cardiomyopathy | severe dilated cardiomyopathy | severe dilated cardiomyopathy"
    explanation: All five patients in the index report had dilated cardiomyopathy.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Four out of eight siblings exhibited dilated cardiomyopathy of varying severity, without apparent extracardiac manifestations."
    explanation: Variable severity within one homozygous sibship.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms."
    explanation: DCM in the six newly reported patients.
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Biallelic pathogenic variants in phosphopantothenoylcysteine synthetase, PPCS, are a rare cause of a severe early-onset dilated cardiomyopathy with high morbidity and mortality."
    explanation: Severe early-onset DCM as the core feature.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Endomyocardial biopsy demonstrated mild focal interstitial ﬁbrosis and many myocytes showing nucleomegaly."
    explanation: Myocardial histology in patient F1:II. The cached text keeps the PDF ligature.
- name: Left Ventricular Noncompaction Cardiomyopathy
  category: Cardiovascular
  description: >-
    One p.Glu233Val homozygote (F3:III.2) was found by cascade screening at 21 years.
    Cardiac MRI showed a noncompacted-to-compacted ratio of 2.7:1 and LVEF of 45%.
    She meets LV noncompaction criteria and is managed with metoprolol.
  phenotype_term:
    preferred_term: Left ventricular noncompaction cardiomyopathy
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She meets criteria for LV non-compaction cardiomyopathy, is managed with metoprolol, and is doing well."
    explanation: A single patient.
- name: Ventricular Septal Hypertrophy
  category: Cardiovascular
  description: >-
    One infant homozygous for p.Ala20Gly (F4:II) had septal hypertrophy after birth
    rather than dilation. She had severe multisystem metabolic disease and died at 10
    months after cardiac arrests.
  phenotype_term:
    preferred_term: Ventricular septal hypertrophy
    term:
      id: HP:0005144
      label: Ventricular septal hypertrophy
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Antenatal ultrasound revealed suspicion of a ventricular septal defect, but postnatal ultrasound demonstrated cardiac muscle septal hypertrophy."
    explanation: A single patient.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: >-
    Reported values include 15% (F1:II), 28% (F2:II.1), 34% (F5:IV.1, with right
    ventricular EF of 37%) and 36% (family B IV.1 before pantethine). In some
    patients function recovered between episodes or on treatment.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Ejection fraction was 15%, with a 9% shorteningfraction."
    explanation: Patient F1:II at 34 months.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Echocardiogram demonstrated mild LV dilation with an ejection fraction of 51%, which worsened to 28% 24 h later."
    explanation: Patient F2:II.1 during CMV infection.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "MRI demonstrated dilated LV with severe biventricular dysfunction with LV ejection fraction of 34%, right ventricle ejection fraction of 37% and no"
    explanation: Patient F5:IV.1, with biventricular involvement.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Heart failure is often episodic, with decompensation during infections. Patient
    F1:II needed ECMO twice. Surviving family B siblings have heart-failure symptoms
    on exertion.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had a subsequent episode of acuteheart failure at 4.5 years of age in the setting of an upper respiratory tract infection requiring 12 days of ECMO support."
    explanation: Acute heart failure in patient F1:II.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Compared to their baseline evaluations, both clinical and echocardiographic evaluations had shown individual IV.1 to experience a mild improvement in exertional dyspnea and an increase of ejection fraction (EF, using the Simpson mode) from 36% (at baseline) to 48% (at a recent visit); subject IV.4 remained stable, with symptoms of heart failure upon exertion and an EF of 45%."
    explanation: Chronic heart-failure symptoms in the surviving family B siblings.
- name: Exertional Dyspnea
  category: Cardiovascular
  description: Seen in the surviving adolescent and adult family B siblings.
  phenotype_term:
    preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Compared to their baseline evaluations, both clinical and echocardiographic evaluations had shown individual IV.1 to experience a mild improvement in exertional dyspnea and an increase of ejection fraction (EF, using the Simpson mode) from 36% (at baseline) to 48% (at a recent visit); subject IV.4 remained stable, with symptoms of heart failure upon exertion and an EF of 45%."
    explanation: Exertional dyspnea in family B patient IV.1.
- name: Cardiomegaly
  category: Cardiovascular
  description: Seen on a chest radiograph in patient F1:II during his first cardiac decompensation.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Blood glucose levels were normal; however, cardiomegaly was noted on the chest radiograph."
    explanation: A single patient.
- name: Ventricular Fibrillation
  category: Cardiovascular
  description: >-
    Two adolescent p.Glu233Val homozygotes (F3:III.3 and F5:IV.1) presented with
    ventricular fibrillation arrest and were defibrillated.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "demonstrated ventricularﬁbrillation, which was successfully cardioverted to sinus rhythm."
    explanation: Ventricular fibrillation in patient F5:IV.1. The cached text keeps the PDF ligature and merged words.
- name: Ventricular Arrhythmia
  category: Cardiovascular
  description: >-
    Patient F2:II.1 died with malignant tachyarrhythmias refractory to treatment.
    Patient F3:III.3 had recurrent ventricular arrhythmias needing ECMO. Patient
    F5:IV.1 later had a short asymptomatic run of ventricular tachycardia recorded
    by her ICD.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "malignant tachyarrhythmias refractory to medical management."
    explanation: The terminal arrhythmia in patient F2:II.1.
- name: Cardiac Arrest
  category: Cardiovascular
  description: >-
    Cardiac arrest occurred in F1:II at 9 months (with hypoglycemia), in F3:III.3
    and F5:IV.1 as adolescents, and in F4:II, who died at 10 months after two arrests.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She presented following an out-of-hospital cardiac arrest."
    explanation: Patient F3:III.3 at 16 years.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She died at 10 months following two cardiac arrests"
    explanation: Patient F4:II.
- name: Prolonged QT Interval
  category: Cardiovascular
  description: >-
    Seen in F1:II during heart failure and in F5:IV.1, whose QT reached 560 ms and
    later 624 ms before normalizing. A KCNH2 variant of uncertain significance in
    F5 did not segregate with QT prolongation in her family.
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "when investigations revealed a prolonged QT interval up to 560 ms which later normalized."
    explanation: Patient F5:IV.1 at 14 years.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He was also noted to have developed a prolonged QT interval on electrocardiogram (ECG)."
    explanation: Patient F1:II.
- name: Syncope
  category: Cardiovascular
  description: Patient F5:IV.1 had syncope at 14 years. Patient F3:III.3 had near-syncope in the two weeks before her arrest.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Her medical history is remarkable for anxiety disorder as a child and a syncope at the age of 14,"
    explanation: A single patient.
- name: Pulmonary Arterial Hypertension
  category: Cardiovascular
  description: Seen in the compound-heterozygous family A neonate.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "An extensive evaluation revealed severe dilated cardiomyopathy, pulmonary arterial hypertension, suspected pituitary dysfunction, and muscular hypotonia."
    explanation: A single patient.
- name: Hypotonia
  category: Neuromuscular
  description: >-
    Reported in 3 of 12 patients, all with exon 1 or exon 2 genotypes: the family A
    neonate (severe), the 2022 neonate and F1:II. It is absent in p.Glu233Val
    homozygotes.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Muscular hypotonia | no | no | N/D | N/D | severe"
    explanation: Severe hypotonia only in the compound-heterozygous family A patient.
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Here, we report a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy."
    explanation: Neonatal hypotonia in the 2022 patient.
- name: Necrotizing Myopathy
  category: Neuromuscular
  description: >-
    The 2022 patient had a necrotizing myopathy before her cardiomyopathy appeared.
    By contrast, the muscle biopsy of F1:II suggested a neurogenic process.
  phenotype_term:
    preferred_term: Necrotizing myopathy
    term:
      id: HP:0008978
      label: Necrotizing myopathy
  evidence:
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Here, we report a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy."
    explanation: A single patient.
- name: Muscle Weakness
  category: Neuromuscular
  description: Patient F1:II has progressive muscle weakness and needs a wheelchair to get around. It persists on pantethine.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "However, he continues to have muscle weakness requiring a wheelchair to assist with ambulation."
    explanation: A single patient.
- name: Rhabdomyolysis
  category: Neuromuscular
  description: >-
    Reported in 3 of 12 patients (F1:II, F4:II and the 2022 patient), triggered by
    intercurrent illness or poor feeding. Peak CK reached 26,000 U/L in F1:II and
    71,000 U/L in F4:II.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "he developed episodes of rhabdomyolysis requiring hospital admission during intercurrentillness or periods of poor feeding with a peak lifetime CK level of 26,000 U/L (normal 75-230)."
    explanation: Patient F1:II.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "At 3 months she had an episode of rhabdomyolysis, with CK 71,000, associated with mild acidosis, high lactate and electrolyte disturbance"
    explanation: Patient F4:II.
- name: Elevated Circulating Creatine Kinase
  category: Neuromuscular
  description: Elevated CK is recorded in several patients, including F2:II.1, who had no recorded rhabdomyolysis.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "CK levels were elevated with a peak recorded value of > 3200 U/L (normal 60-305 U/L)."
    explanation: Patient F2:II.1.
- name: Hypoglycemia
  category: Metabolic
  description: >-
    Patient F1:II had a blood glucose of 1.3 at 9 months during a respiratory and
    gastrointestinal illness, leading to cardiac arrest. The source prints the unit
    as mol/L; mmol/L is meant.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "In the emergency department, he became unresponsive and was found to be hypoglycemic with a blood glucose level of 1.3 mol/L."
    explanation: A single patient.
- name: Increased Circulating Lactate
  category: Metabolic
  description: >-
    Elevated serum lactate is recorded in the family A neonate, the two deceased
    family B siblings, F1:II, F2:II.1 and F4:II. F4:II had recurrent lactic and
    metabolic acidosis. For F2:II.1 the sources conflict: the 2025 summary table
    lists lactate as elevated, while the case narrative calls metabolic testing,
    including serum lactate/pyruvate, unremarkable.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Serum lactate | normal | normal | elevated | elevated | elevated"
    explanation: Elevated in three of the five index patients.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Serum lactate Elevated Elevated n.d. n.d. Elevated n.d. Normal Normal Elevated Elevated Elevated Normal"
    explanation: The serum lactate row of the 2025 summary table.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Metabolic testing was unremarkable , including urine organic acid, plasma amino acid, serum lactate/pyruvate, N-glycan"
    explanation: The F2:II.1 case narrative contradicts the table's elevated lactate for that patient.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She had recurrent episodes of suspected sepsis in early infancy, associated with metabolic acidosis and elevated blood lactate levels (max 5 mmol/L, reference < 2)"
    explanation: Patient F4:II.
- name: Hyperammonemia
  category: Metabolic
  description: Patient F4:II developed severe hyperammonemia (up to 1351 µmol/L), which was treated with carglumic acid and hemofiltration.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "developed severe hyperammonaemia (max 1351 μmol/L, reference range < 40), for which she was treated with carglumic acid"
    explanation: A single patient.
- name: Hyperlysinemia
  category: Metabolic
  description: Patient F4:II had markedly elevated plasma lysine during her metabolic crisis.
  phenotype_term:
    preferred_term: Hyperlysinemia
    term:
      id: HP:0002161
      label: Hyperlysinemia
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Plasma amino acids revealed strongly elevated lysine (964μmol/L, reference 100–300)"
    explanation: A single patient.
- name: Elevated Circulating Tetradecenoylcarnitine
  category: Metabolic
  description: >-
    During illness, F1:II and F4:II had a VLCADD-like acylcarnitine profile with
    raised C14:1 and C14:2. F4:II's profile was normal when she was well. The 2018
    patients instead had low C16 and C18 acylcarnitines. Acylcarnitines are not a
    consistent biomarker for this disease.
  phenotype_term:
    preferred_term: Elevated circulating tetradecenoylcarnitine concentration
    term:
      id: HP:6000476
      label: Elevated circulating tetradecenoylcarnitine concentration
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "when unwell was suggestive of VLCADD, with strongly raised tetradecenoylcarnitine (C14:1) and tetradecanoylcarnitine (C14:2)"
    explanation: Patient F4:II.
- name: Dicarboxylic Aciduria
  category: Metabolic
  description: Found in F1:II (C6-C14 dicarboxylic acids) and F4:II during metabolic crises.
  phenotype_term:
    preferred_term: Dicarboxylic aciduria
    term:
      id: HP:0003215
      label: Dicarboxylic aciduria
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Unsaturated dicarboxylic acids were present, suggesting impaired fatty acid oxidation."
    explanation: Patient F1:II.
- name: Elevated Hepatic Transaminases
  category: Hepatic
  description: Patient F4:II had transaminitis and coagulopathy during a terminal crisis.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "associated with mild acidosis, mildly elevated blood lactate (3.7 mmol/L), hyperammonaemia (max 117 μmol/L), coagulopathy and transaminitis"
    explanation: A single patient.
- name: Global Brain Atrophy
  category: Neurological
  description: >-
    Brain MRI in F1:II showed global parenchymal volume loss. The authors could not
    tell whether this is part of the disease or a consequence of ECMO and cardiac
    insults. No patient has shown brain iron accumulation.
  phenotype_term:
    preferred_term: Global brain atrophy
    term:
      id: HP:0002283
      label: Global brain atrophy
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Brain MRI demonstrated global parenchymal volume loss with prominent sulci and ventricles."
    explanation: A single patient, possibly secondary to ECMO.
- name: Cutis Laxa
  category: Integument
  description: >-
    The family A neonate had cutis laxa among other minor dysmorphic features. The
    2022 patient was also described as dysmorphic. Whether these features belong to
    PPCS deficiency is uncertain.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She showed minor dysmorphic features including cutis laxa, abnormally placed thumbs, abnormal dermatoglyphics, hypoplastic toe nails, and additional findings."
    explanation: A single patient.
genetic:
- name: PPCS
  gene_term:
    preferred_term: PPCS
    term:
      id: hgnc:25686
      label: PPCS
  association: >-
    Causative biallelic hypomorphic variants (autosomal recessive). The evidence is
    12 patients in eight families from three reports. p.Glu233Val recurs in
    three families (B/F6 and F5 consanguineous, F3 not). Support comes from segregation, absence of
    the missense alleles from gnomAD, yeast complementation for the original
    alleles, reduced PPCS protein and CoA in patient cells, and a Drosophila
    hypomorph with cardiac dysfunction. ClinGen has not curated this gene-disease
    pair.
  variant_origin: GERMLINE
  notes: >-
    relationship_type is left unset because the schema defines CAUSATIVE as a
    Definitive or Strong relationship and no external body has classified PPCS
    for this disease. Reported alleles (NM_024664): c.698A>T p.Glu233Val (exon 3; homozygous in
    families B/F6, F3, F5), c.538G>C p.Ala180Pro, c.320_334del p.Pro107_Ala111del,
    c.613-3C>G, c.232T>C p.Tyr78His, c.317G>C p.Arg106Pro and c.59C>G p.Ala20Gly.
    Yeast complementation was positive for the original alleles but inconclusive
    for p.Tyr78His and p.Arg106Pro. For those two, pathogenicity rests on patient
    cell protein and CoA levels. The in-frame deletion appears 10 times in the
    heterozygous state in gnomAD.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype."
    explanation: The index gene-disease report.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations."
    explanation: Functional support from model organisms.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "c.538G>C in particular was completely inactive, indicating that this variant impairs PPCS function more dramatically than the other variants."
    explanation: Yeast complementation of a cab2 null strain.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "None of the PPCS missense variants (c.698A>T, c.538G>C) are listed in the gnomAD (Genome Aggregation Database) browser (12/2017)."
    explanation: Population rarity of the original missense alleles.
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance."
    explanation: An independent family.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms."
    explanation: Six further patients in five families, including two new p.Glu233Val families.
prevalence:
- population: Reported patients worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twelve patients in eight families by 2025: five in 2018, one in 2022 and six in
    2025, with family B counted once. This is a count of published cases, not a
    population prevalence. No carrier frequency has been estimated. No other rare
    biallelic PPCS genotypes were found among more than 11,000 in-house exomes.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "To date, only six patients worldwide have been identified."
    explanation: The case count before the 2025 series.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Despite the limited number of PPCS DD patients ( n = 12), an exploratory genotype-phenotype correlation analysis suggests that the"
    explanation: The total after the 2025 series.
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "To date, only five individuals with PPCS-mutations have been reported."
    explanation: The case count in 2022, before the Lok patient.
progression:
- phase: Neonatal or infantile severe presentation
  age_range: Antenatal to 4 months
  notes: >-
    Compound-heterozygous and some exon 1 genotypes (family A, the 2022 patient,
    F2:II.1, F4:II) presented at or soon after birth with cardiomyopathy and
    multisystem involvement. All four died between 3 and 10 months.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Unfortunately, she succumbed to multi-organ failure at 3 months of age."
    explanation: The family A patient.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She died at 10 months following two cardiac arrests"
    explanation: Patient F4:II.
- phase: Childhood-onset dilated cardiomyopathy
  age_range: 4 months to 3 years
  notes: >-
    In family B, homozygous p.Glu233Val siblings presented between 4 months and 3
    years. Two died at 23 months and 3 years, while two survived into adolescence
    and adulthood with chronic heart failure. Of the survivors, F6:IV.1 died at 21
    of SARS-CoV-2 complications after four years on pantethine; F6:IV.4 was alive at
    14.5 years.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "continued oral treatment with pantethine supplementation for four (Patient F6:IV.1 died of COVID-19) and six years, respectively."
    explanation: Later outcome of the two surviving family B siblings.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "The other two siblings (individuals IV.5 and IV.8) showed a severe form of dilated cardiomyopathy, fatal in early childhood (3 years of age)."
    explanation: Variable outcome within one sibship.
- phase: Episodic decompensation with partial recovery
  age_range: 9 months to 7 years (patient F1:II)
  notes: >-
    Patient F1:II had repeated infection-triggered crises with hypoglycemia,
    rhabdomyolysis and heart failure needing ECMO twice. Cardiac function normalized
    between episodes.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He was started on inotropic support and ultimately required 11 days of extracorporeal membrane oxygenation (ECMO)."
    explanation: The first severe cardiac episode.
- phase: Adolescent or adult arrhythmic presentation
  age_range: 14 to 21 years
  notes: >-
    Three p.Glu233Val homozygotes from families F3 and F5 presented as adolescents or
    young adults: with VF arrest, with QT prolongation and later arrest, or through
    cascade screening. Survivors are 11-21 years old at last report.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She presented following an out-of-hospital cardiac arrest."
    explanation: Patient F3:III.3 at 16 years.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    All patients were diagnosed by exome or genome sequencing. Patient F1:II was
    diagnosed only on exome reanalysis, years after a non-diagnostic clinical exome,
    so reanalysis is worth requesting in unexplained pediatric DCM with metabolic
    crises. Affected siblings were found by cascade single-gene testing.
  evidence:
  - reference: PMID:35616428
    reference_title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance."
    explanation: Diagnosis by trio genome sequencing.
- name: Cascade screening of siblings
  description: >-
    Genotyping and cardiac evaluation of siblings found a presymptomatic affected
    sister (F3:III.2) with LV noncompaction. Her surveillance includes cardiac MRI
    and an implantable loop recorder.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "who presented to clinic for cardiac screening based on her family history of cardiomyopathy (sister ofpatient F3:III.3)."
    explanation: Cascade screening found an affected sibling.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Her three full siblings had normal cardiac evaluations and none was homozygous for the PPCS variant."
    explanation: Negative cascade results in family F2.
- name: Fibroblast PPCS protein and CoA measurement
  description: >-
    Reduced PPCS protein on immunoblot and reduced total CoA in cultured fibroblasts
    support pathogenicity when a variant is uncertain. These are research assays.
    Serum PPCS and CoA are not informative.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals."
    explanation: Fibroblast CoA as a functional marker.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Unfortunately, the levels of PPCS and CoA were consistently undetectable in both the affected and control samples."
    explanation: Serum assays were uninformative.
differential_diagnoses:
- name: Pantothenate kinase-associated neurodegeneration and COASY protein-associated neurodegeneration
  description: >-
    These other CoA-biosynthesis disorders cause neurodegeneration with brain iron
    accumulation and no cardiomyopathy. PPCS deficiency shows the opposite pattern:
    cardiomyopathy without brain iron accumulation.
  evidence:
  - reference: PMID:35397396
    reference_title: Generation of two human iPSC lines, HMGUi003-A and MRIi028-A, carrying pathogenic biallelic variants in the PPCS gene.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mutations in PPCS cause autosomal-recessive dilated cardiomyopathy, often fatal, without apparent neurodegeneration, whereas pathogenic variants in PANK2 and COASY, two other genes involved in the CoA synthesis, cause Neurodegeneration with Brain Iron Accumulation (NBIA)."
    explanation: The contrast between the CoA-pathway disorders.
- name: Fatty acid oxidation disorders
  description: >-
    During crises, F1:II and F4:II had acylcarnitine and urine organic acid
    profiles suggesting VLCAD deficiency, and F1:II was first treated as VLCADD.
    Normal ACADVL testing should prompt PPCS analysis in a child with DCM and
    illness-triggered metabolic crises.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Initial metabolic evaluation revealed elevations in multiple long-chain fatty acyl-CoA species suggestive of a fatty acid oxidation defect."
    explanation: Overlap with fatty-acid oxidation disorders.
treatments:
- name: Pantethine supplementation
  description: >-
    Oral pantethine enters the CoA pathway downstream of PPCS and so bypasses the
    defective step. It has been given as compassionate treatment to four patients at
    about 10-24 mg/kg/day. Family B siblings started it as adolescents and adults
    after cardiac damage. One improved (EF 36% to 48%) and the other stayed stable;
    the 2018 authors saw no significant clinical improvement. F6:IV.1 died at 21 of
    SARS-CoV-2 complications after four years on pantethine, with cardiac function
    reported stable through the infection. F1:II has had no
    rhabdomyolysis since starting it and has low-normal LV function. F5:IV.1
    recovered full LV function, but she was also on a beta-blocker and ACE inhibitor
    and had an ICD. After starting pantethine, F1:II began excreting
    3-methylcrotonylglycine; he carries a homozygous MCCC1 variant of uncertain
    significance, and the significance of this is unclear. No controlled data exist, and every treated patient also
    received standard care, so benefit cannot be attributed to pantethine alone. In
    vitro, pantethine raises CoA in patient cells and partly rescues cardiomyocyte
    phenotypes. It also rescues viability in dPPCS hypomorph flies.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Cellular Coenzyme A Deficiency
    description: Pantethine supplies a substrate that enters CoA synthesis after the PPCS step.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: "CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive."
    explanation: The biochemical rationale.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Addition of pantethine to the fly food indeed rescued the percentage of homozygous survivors to levels that can be expected based on Mendelian inheritance."
    explanation: Viability rescue in the Drosophila hypomorph. Cardiac rescue was not tested in flies.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Compared to their baseline evaluations, both clinical and echocardiographic evaluations had shown individual IV.1 to experience a mild improvement in exertional dyspnea and an increase of ejection fraction (EF, using the Simpson mode) from 36% (at baseline) to 48% (at a recent visit); subject IV.4 remained stable, with symptoms of heart failure upon exertion and an EF of 45%."
    explanation: Outcomes in two treated siblings; uncontrolled.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Our results thus far had not shown significant clinical improvement."
    explanation: The 2018 authors' own cautious assessment of early treatment in family B.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "continued oral treatment with pantethine supplementation for four (Patient F6:IV.1 died of COVID-19) and six years, respectively."
    explanation: Treatment duration in family B and the non-cardiac death of F6:IV.1.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "after starting pantethine he began to excrete 3-methylcrotonylglycine in his urine."
    explanation: An unexplained biochemical change after starting pantethine in F1:II, who also carries a homozygous MCCC1 variant of uncertain significance.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "F1.II has not had any further episodes of rhabdomyolysis since he initiated pantethine;"
    explanation: Fewer rhabdomyolysis episodes in one treated patient; uncontrolled.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "At a three-month follow-up the patient felt well, ICD interrogation did not demonstrate any arrhythmia and echocardiography revealed fully recovered LV function."
    explanation: Recovery in F5:IV.1, who was also on a beta-blocker and ACE inhibitor.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Clinically, patients receiving pantethine show sustained improvement over time."
    explanation: The authors' summary of four uncontrolled treated patients.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment."
    explanation: Partial in vitro rescue.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "However, complete reversal may require early intervention."
    explanation: The authors argue for early treatment based on incomplete rescue once damage is established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pantethine
      term:
        id: CHEBI:31959
        label: pantethine
- name: Standard heart-failure pharmacotherapy
  description: >-
    Treated patients received beta-blockers (metoprolol) and ACE inhibitors, and
    inotropes such as milrinone during decompensation. No PPCS-specific evidence
    exists for these drugs; they are used by extrapolation from general pediatric
    and adult heart-failure care.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Cardiomyocyte Contractile Dysfunction
    description: Supportive; it does not correct the CoA defect.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "insertion, on beta-blockers, ACE-inhibitors, and 600 mg/day pantethine."
    explanation: Regimen used in patient F5:IV.1; this documents use, not efficacy.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "She meets criteria for LV non-compaction cardiomyopathy, is managed with metoprolol, and is doing well."
    explanation: Metoprolol in patient F3:III.2; this documents use, not efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
- name: Implantable cardioverter-defibrillator
  description: >-
    An ICD was placed after VF arrest in F5:IV.1. One year later it recorded a short,
    self-terminating run of ventricular tachycardia. This is secondary prevention by
    general cardiology practice; no PPCS-specific outcome data exist.
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Cardiomyocyte Arrhythmogenicity
    description: Terminates life-threatening ventricular arrhythmia; does not modify the substrate.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "At a three-month follow-up the patient felt well, ICD interrogation did not demonstrate any arrhythmia and echocardiography revealed fully recovered LV function."
    explanation: ICD use in a single patient.
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
- name: Extracorporeal membrane oxygenation
  description: >-
    Used as rescue support during acute decompensation or refractory arrhythmia
    (F1:II twice; F3:III.3 before a total artificial heart).
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Temporary circulatory support.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He was started on inotropic support and ultimately required 11 days of extracorporeal membrane oxygenation (ECMO)."
    explanation: ECMO followed by recovery in patient F1:II.
  treatment_term:
    preferred_term: Extracorporeal Membrane Oxygenation
    term:
      id: NCIT:C171507
      label: Extracorporeal Membrane Oxygenation
- name: Heart transplantation
  description: >-
    Patient F3:III.3 (p.Glu233Val) received a heart transplant after a total
    artificial heart bridge. At about one year she had no rejection, graft
    dysfunction or recurrent DCM. This fits a heart-intrinsic defect, but it is a
    single case with short follow-up.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Dilated Cardiomyopathy
    description: Replaces the affected organ.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "At nearly one-year post-transplant, she has had no rejection or graft dysfunction."
    explanation: Short-term outcome in one patient.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Although a long-term follow-up is needed, at one year post transplant, the patient hasnot experienced a recurrence of DCM,"
    explanation: No recurrence in the graft at one year.
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
- name: Genetic counseling
  description: >-
    Autosomal recessive counseling: carrier parents have a 25% recurrence risk, and
    cascade testing of siblings is offered.
  notes: >-
    No PPCS-specific counseling studies exist. This recommendation follows from the
    established recessive inheritance and from the cascade testing done in families
    F2, F3 and F5. Counseling is standard practice and has no disease-specific
    outcome data.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
animal_models:
- name: dPPCS1 hypomorphic Drosophila
  species: Drosophila melanogaster
  genotype: dPPCS1/dPPCS1 homozygous; P-element insertion in the 5' UTR of CG5629 that lowers dPPCS expression
  publication: PMID:29754768
  description: >-
    Homozygous hypomorphic dPPCS flies have reduced viability. Their pre-pupal hearts
    show higher heart rate and arrhythmia index, more wall shortening and shorter
    systolic length. Dietary pantethine rescues viability; vitamin B5 was used as a control.
    Null dPPCS alleles are lethal at the first larval instar. The allele is not a
    patient allele, and fly CoA levels were not reported in this study.
  modeled_mechanisms:
  - target: Cardiomyocyte Contractile Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Altered contraction parameters in the fly heart tube, which the authors take as analogous to dilated cardiomyopathy.
    limitations: >-
      The Drosophila heart is a tubular organ without chambers, so ejection fraction
      or dilation cannot be measured. The allele lowers dPPCS expression rather than
      reproducing a patient missense change. Cardiac function after pantethine was
      not reported.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Heart-tube kinematics in pre-pupae are a proxy for human ventricular systolic function.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: The expression-reducing P-element allele does not model the protein-destabilizing missense alleles in patients.
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "With deeper inspection, dPPCS mutants presented with reduced viability, and moreover showed increased heart rate, increased arrhythmia index, reduced systolic function, and increased heart wall shortening, all manifestations indicative of dilate cardiomyopathy in fruit flies.31"
      explanation: The authors' reading of the fly cardiac phenotype.
    readouts:
    - name: Heart rate, arrhythmia index, wall shortening and systolic length
      target: Cardiomyocyte Contractile Dysfunction
      direction: ALTERED
      interpretation: Altered cardiac kinematics in homozygous hypomorphs compared with heterozygotes.
      evidence:
      - reference: PMID:29754768
        reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: "In comparison with heterozygous dPPCS1 flies, homozygous dPPCS1 flies showed a significant increase in heart rate, heart wall shortening, and arrhythmia index and a decrease in systolic length (Figure 7)."
        explanation: The measurements behind this readout.
  - target: Cardiomyocyte Arrhythmogenicity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Increased arrhythmia index in the fly heart.
    limitations: Arrhythmia index in a fly heart tube is not equivalent to ventricular arrhythmia in human myocardium.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Fly heart-tube rhythm irregularity is a proxy for human ventricular arrhythmia.
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "In comparison with heterozygous dPPCS1 flies, homozygous dPPCS1 flies showed a significant increase in heart rate, heart wall shortening, and arrhythmia index and a decrease in systolic length (Figure 7)."
      explanation: Increased arrhythmia index in homozygotes.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "In our crosses, the percentage of homozygous dPPCS1 pupae ranged from 9% to 22%, suggesting a reduced viability in homozygous mutants."
    explanation: Reduced viability in the hypomorph.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "Addition of pantethine to the fly food indeed rescued the percentage of homozygous survivors to levels that can be expected based on Mendelian inheritance."
    explanation: Pantethine rescues viability.
experimental_models:
- name: PPCS-deficient patient iPSC-derived cardiomyocytes and engineered heart patches
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: >-
    iPSC lines HMGUi003-A (compound heterozygous p.Ala180Pro/p.Pro107_Ala111del,
    fibroblast 95595) and MRIi028-A (homozygous p.Glu233Val, fibroblast 103596),
    reprogrammed from patient fibroblasts and compared with two healthy control lines
  culture_system: 2D cardiomyocyte culture and 3D heart patches on decellularized porcine ventricular extracellular matrix in biomimetic chambers
  description: >-
    Cardiac progenitors and day-22 and day-60 cardiomyocytes from two patients
    reproduce reduced PPCS protein and CoA. They also show sarcomere disorganization,
    weak calcium transients, arrhythmic events, falling patch force and a short
    effective refractory period. Pantethine partly rescues these phenotypes. Only one
    clone per line was used, and there are no isogenic controls.
  publication: PMID:40745475
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35397396
    reference_title: Generation of two human iPSC lines, HMGUi003-A and MRIi028-A, carrying pathogenic biallelic variants in the PPCS gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Here, we report the generation of induced pluripotent stem cells from fibroblasts of two PPCS-deficient patients."
    explanation: Derivation of the patient iPSC lines.
  modeled_mechanisms:
  - target: Cellular Coenzyme A Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reduced CoA in patient iPSC-derived cardiac progenitors and cardiomyocytes, raised by pantethine.
    limitations: Two patient lines, one clone each, and no isogenic correction.
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "a milder reduction of CoA compared to cells committed to the cardiac lineage, such as CPCs and CMs."
      explanation: CoA deficit in cardiac-lineage cells.
    readouts:
    - name: Total cellular CoA
      target: Cellular Coenzyme A Deficiency
      direction: DECREASED
      interpretation: Direct measurement of the node in disease-relevant cells.
      evidence:
      - reference: PMID:40745475
        reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        snippet: "Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells."
        explanation: Reduced CoA in patient-derived cardiac cells.
  - target: Cardiomyocyte Sarcomere Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Disorganized alpha-actinin sarcomeres in day-60 patient cardiomyocytes.
    limitations: iPSC-derived cardiomyocytes are immature; no patient myocardium was available for comparison.
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "sarcomere disorganization in d60 CMs derived from both patient iPSC lines"
      explanation: Sarcomere phenotype in the model.
  - target: Cardiomyocyte Contractile Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Lower calcium transient amplitude in 2D, and falling contractile force with a blunted force-frequency relationship in 3D patches.
    limitations: Engineered patches lack chamber geometry, neurohumoral input and systemic metabolism; going from patch force to ventricular dilation is an extrapolation.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: The model measures isometric force of a thin engineered patch; the clinical quantity is ejection fraction and chamber dilation of the intact ventricle.
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "patches from both lines showed a decrease of contractile force between days 7 and 21, contrasting with"
      explanation: Contractile defect in the 3D model.
    readouts:
    - name: Patch contractile force over time
      target: Cardiomyocyte Contractile Dysfunction
      direction: DECREASED
      interpretation: Force falls in patient patches but rises in controls.
      evidence:
      - reference: PMID:40745475
        reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        snippet: "patches from both lines showed a decrease of contractile force between days 7 and 21, contrasting with"
        explanation: The force measurement.
  - target: Cardiomyocyte Arrhythmogenicity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Arrhythmic calcium events in single cardiomyocytes and a shortened effective refractory period in patches.
    limitations: In vitro arrhythmic calcium events are not the same as clinical ventricular fibrillation.
    evidence:
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "We also detected arrhythmic events in 42% of CMs from patient 95595 and 54% of CMs from patient 103596, which were reduced to 26% and 24%, respectively, bypantethine treatment"
      explanation: The arrhythmia phenotype in the model.
- name: PPCS-deficient patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Skin fibroblasts from five patients (95595, 103596, 128343, 128344, 146603), one of them also transduced with wild-type PPCS
  description: >-
    Patient fibroblasts show reduced PPCS protein and total CoA. Wild-type PPCS
    corrects both. Pantethine, and less effectively 4'-phosphopantetheine, raise CoA.
  publication: PMID:29754768
  notes: Lines 95595 and 103596 were reported in 2018; 128343, 128344 and 146603 were added in the 2025 series (PMID:40745475).
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  modeled_mechanisms:
  - target: Reduced PPCS Protein Stability
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Lower PPCS protein on immunoblot in patient cells carrying their own alleles.
    limitations: Fibroblasts are not the affected cell type.
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "It is likely that the decreased enzymatic activity of PPCS is due to decreased protein stability, as indicated by the strong reduction of PPCS signal in all PPCS-deficient individuals in the western blotting experiment or by the inability to assemble into a functional PPCS dimer."
      explanation: Reduced protein in patient fibroblasts.
  - target: Cellular Coenzyme A Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Lower total CoA, rescued by wild-type PPCS.
    limitations: Fibroblasts are not the affected cell type, and the CoA deficit is larger in cardiac-lineage cells.
    evidence:
    - reference: PMID:29754768
      reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "The investigation revealed a significant reduction of CoA in all four affected individuals, which was rescued by reintroducing the wild-type copy of the gene (Figure 6)."
      explanation: CoA deficit with genetic rescue.
    - reference: PMID:40745475
      reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "Consistent with the decreased PPCS amount, intracellular CoA levels were also reduced in"
      explanation: Reduced CoA in fibroblasts from the three newly reported patients (128343, 128344, 146603).
discussions:
- discussion_id: cmd2c_small_evidence_base
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How secure are the gene-disease relationship, the phenotype spectrum and the genotype-phenotype rule, given 12 patients in eight families?
  attaches_to:
  - genetic#PPCS
  - phenotypes#Hypotonia
  - phenotypes#Rhabdomyolysis
  rationale: >-
    The PPCS link rests on three clinical reports, and family B appears in two of
    them. Three of the families share the same p.Glu233Val allele. The causal case
    is coherent: segregation, patient-cell protein and CoA reduction with genetic
    rescue, yeast complementation and a fly hypomorph. ClinGen has not curated it.
    The proposed rule that exon 3 variants cause DCM only while exon 1 and 2
    variants add neuromuscular and metabolic disease is exploratory and based on
    n=12. Extracardiac features such as dysmorphism, cutis laxa and PAH come from
    single patients and may be coincidental.
  evidence:
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "in contrast the p.Glu233Val variant leads to an isolated DCM presentation with variable expressivity, suggesting that different clinical presentations may be related to the position of the mutations within the gene."
    explanation: The genotype-phenotype hypothesis as stated.
  - reference: PMID:40745475
    reference_title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Only by investigating the natural history of the disease in a larger patient cohort"
    explanation: The authors acknowledge that the cohort is too small.
  proposed_experiments:
  - experiment_id: exp_cmd2c_natural_history_registry
    name: Natural history registry with exome reanalysis
    description: >-
      Pool unsolved pediatric DCM and fatty-acid-oxidation-like crisis cases with
      normal ACADVL testing for PPCS reanalysis. Follow genotyped patients
      prospectively with standardized cardiac, neuromuscular and metabolic
      phenotyping to test the exon-based genotype-phenotype rule.
- discussion_id: cmd2c_cardiac_coa_and_tissue_selectivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Why does a ubiquitous CoA-synthesis defect damage mainly the heart, and is cardiac CoA actually depleted in patients?
  attaches_to:
  - pathophysiology#Cellular Coenzyme A Deficiency
  - pathophysiology#Impaired Long-Chain Fatty Acid Oxidation
  - pathophysiology#Cardiomyocyte Energy Deficit
  rationale: >-
    CoA has been measured only in fibroblasts and iPSC-derived cells, never in
    patient or animal myocardium. The fatty-acid-activation and energy-deficit steps
    are inferred from acylcarnitines and from the authors' reasoning about
    cardiomyocyte metabolism. Fasting respiratory quotient in two patients showed
    normal whole-body fat oxidation. Proposed explanations include greater
    fatty-acid dependence of maturing cardiomyocytes, tissue-specific PPCS isoforms
    and cysteine toxicity; none has been tested.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "However, considering the ubiquitous presence of the enzymatic PPCS activity, it remains unexplained why the brain and in general the other organs are not affected in PPCS-deficient individuals."
    explanation: The open question as the index authors stated it.
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "In contrast to the neurodegenerative NBIA-related phenotypes associated with defects in PANK2 and COASY, PPCS-deficient individuals present with a clear dilated cardiomyopathy with a variable degree of severity and no neurodegeneration."
    explanation: The tissue-selectivity contrast with other CoA-pathway disorders.
  proposed_experiments:
  - experiment_id: exp_cmd2c_cardiomyocyte_acylcoa_flux
    name: Acyl-CoA profiling and fatty-acid flux in patient cardiomyocytes
    description: >-
      Measure free CoA, acetyl-CoA and long-chain acyl-CoA pools, and run
      13C-palmitate oxidation and Seahorse respirometry in day-60 patient and
      isogenic-corrected iPSC cardiomyocytes, with and without pantethine. Test
      whether the energy deficit precedes sarcomere disorganization.
- discussion_id: cmd2c_cysteine_toxicity_hypothesis
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: Does accumulation of L-cysteine, which PPCS would normally consume, contribute to cardiotoxicity in addition to CoA deficiency?
  attaches_to:
  - pathophysiology#Cellular Coenzyme A Deficiency
  rationale: >-
    The index authors raised the possibility that a toxic metabolite contributes,
    because dPPCS fly mutants are hypersensitive to cysteine. Cysteine has not been
    measured in patient cells or tissue. The incomplete rescue by pantethine is
    consistent with, but does not prove, a CoA-independent contribution.
  evidence:
  - reference: PMID:29754768
    reference_title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "We cannot exclude that cardiomyopathy in PPCS-deficient individuals is also due to the generation of toxic metabolites."
    explanation: The hypothesis as stated; it has not been tested.
- discussion_id: cmd2c_models_limits
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Do the available models capture the human disease well enough to support the cellular nodes of the mechanism?
  attaches_to:
  - pathophysiology#Cardiomyocyte Contractile Dysfunction
  - pathophysiology#Cardiomyocyte Arrhythmogenicity
  rationale: >-
    No mammalian Ppcs model exists. The fly hypomorph lowers expression rather than
    destabilizing the protein, and fly heart-tube kinematics are a loose proxy for
    DCM. The iPSC cardiomyocyte data come from two patient lines, one clone each,
    without isogenic controls, in immature cells. The cellular nodes are therefore
    PROVISIONAL, not ESTABLISHED.
  evidence:
  - reference: PMID:35397396
    reference_title: Generation of two human iPSC lines, HMGUi003-A and MRIi028-A, carrying pathogenic biallelic variants in the PPCS gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "PPCS-deficiency is a relatively new disease with unclear pathogenesis and no targeted therapy."
    explanation: States the mechanistic uncertainty the models were built to address.
  proposed_experiments:
  - experiment_id: exp_cmd2c_knockin_mouse
    name: Ppcs p.Glu233Val knock-in mouse
    description: >-
      Generate a homozygous knock-in of the recurrent human allele and measure
      cardiac CoA, acylcarnitines and echocardiographic function under fasting and
      infection-like stress, with and without dietary pantethine.
references:
- reference: PMID:29754768
  title: Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
- reference: PMID:35616428
  title: "Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders."
- reference: PMID:35397396
  title: Generation of two human iPSC lines, HMGUi003-A and MRIi028-A, carrying pathogenic biallelic variants in the PPCS gene.
- reference: PMID:40745475
  title: Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.

📚

References & Deep Research

References

4

PMID:29754768

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

No top-level findings curated for this source.

PMID:35616428

Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders.

No top-level findings curated for this source.

PMID:35397396

Generation of two human iPSC lines, HMGUi003-A and MRIi028-A, carrying pathogenic biallelic variants in the PPCS gene.

No top-level findings curated for this source.

PMID:40745475

Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.

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 (1)

Create: Cardiomyopathy_Dilated_2C · 2026-10-08T19:09:41Z · View source

Created the CMD2C (PPCS deficiency disorder, MONDO:0032592) entry for claim issue #13717. Deep research provider: claude_code (falcon fallback); the report's gene identity and references were validated beforehand. Evidence base: 12 patients in 8 families from Iuso 2018 (PMID:29754768, families A and B), Lok 2022 (PMID:35616428) and Zhang 2025 (PMID:40745475, which re-reports family B as F6), plus the patient iPSC-line report PMID:35397396. Pathophysiology chain: two trigger nodes (homozygous missense; compound heterozygous) -> Reduced PPCS Protein Stability -> Cellular Coenzyme A Deficiency (established in fibroblasts and iPSC-derived cardiac cells, rescued by wild-type PPCS) -> Impaired Long-Chain Fatty Acid Activation (provisional; includes a REFUTE item for normal fasting RQ) -> Cardiomyocyte Energy Deficit (hypothetical) -> Cardiomyocyte Contractile Dysfunction -> Dilated Cardiomyopathy. Sarcomere disorganization and arrhythmogenicity nodes come from in vitro iPSC-CM and heart-patch data; a catabolic-stress decompensation node is hypothetical. 26 HP phenotypes, frequency set only for DCM (10/12 from Table 1). Drosophila dPPCS1 animal model and two experimental models (iPSC-CMs and patches; fibroblasts) linked via modeled_mechanisms. Four discussions: small evidence base, cardiac CoA and tissue selectivity gap, cysteine toxicity hypothesis, model mismatch. No ClinGen record exists, so gene_disease_validity is left empty. check-genereviews --online: NO_CHAPTER. Validation: just validate passed; count-verified-snippets 139/139; check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, snippet-length, snippet-grading, title-snippets and coarse-phenotypes all OK; model-scale-audit has no warnings after a SCALE_EXTRAPOLATION divergence was changed to PROXY_QUANTITY. Deleted stubs/Cardiomyopathy_Dilated_2c.yaml. Review fixes: consanguinity corrected to 7 of 12 patients (2025 Table 1 row added as a snippet), and F3 noted as non-consanguineous. F6:IV.1's death at 21 from SARS-CoV-2 after four years on pantethine added to progression and treatment. The fatty-acid node was renamed Impaired Long-Chain Fatty Acid Oxidation; its description now separates the 2018 low-acylcarnitine data from the crisis data, which suggest a downstream block. Two edges were downgraded to INDIRECT_UNKNOWN_INTERMEDIATES. A mis-graded sarcomere snippet and the ERP evidence were replaced, and the arrhythmogenicity description was corrected; it is deliberately not linked to Prolonged QT. 2025 fibroblast CoA evidence was added and that link's fidelity lowered to MODERATE. relationship_type CAUSATIVE was removed because PPCS has no external validity tier. Nine phenotype edges were added. The F2:II.1 lactate conflict is recorded, and F1:II's biopsy, global brain atrophy and 3-methylcrotonylglycine excretion were added. Phenotypes now 27, 18 causally connected; count-verified-snippets 149/149.

Claude Code ▸

Cardiomyopathy, Dilated, 2C (CMD2C): PPCS deficiency disorder

claude-haiku-5-5, claude-opus-5-5 8 citations 2026-10-08T14:33:54.493993

Let me fetch the primary papers' abstracts from PubMed.

I'm reading the cached full text of the 2018 index paper (Iuso et al.) for clinical and functional detail. Next I'll fetch the 2025 pantethine study and the 2022 iPSC paper.

I have the clinical case series from the 2025 paper. Now I'm reading its iPSC-cardiomyocyte and pantethine results, then I'll write the report.

I've finished reading the primary literature and checking ontology terms against the repo caches. Writing the report now.

Cardiomyopathy, Dilated, 2C (CMD2C): PPCS deficiency disorder

Scope and sourcing. There are only three disease-specific primary papers and one cell-line report. Their abstracts and full texts were cached with just fetch-reference:

PMID	Citation	Cache content
29754768	Iuso A, …, Sibon OCM, Anikster Y. Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy. Am J Hum Genet 2018;102:1018–1030 (published 10 May 2018). doi:10.1016/j.ajhg.2018.03.022	full text (PMC)
35616428	Lok A, …, Iuso A, Jungbluth H, Milan A, Singh RR. Novel PPCS mutations with prominent neuromuscular features. Am J Med Genet A 2022. doi:10.1002/ajmg.a.62848	abstract only
35397396	Iuso A, Zhang F, …, Moretti A. Generation of two human iPSC lines, HMGUi003-A and MRIi028-A, carrying pathogenic biallelic variants in the PPCS gene. Stem Cell Res 2022;61:102773	abstract only
40745475	Zhang F, Dorn T, Gnutti B, et al. Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models. Commun Med (Lond) 2025;5:323. PMC12313872	full text (PDF)

All quotes below come from these cached files. Any ontology ID marked ✔ was found in this repo's cache/*/terms.csv with the label shown. Any ID marked ⚠ was not found in the cache and must be looked up before you bind it.

1. Disease information

Overview. CMD2C is an ultra-rare autosomal recessive cardiomyopathy. It is caused by biallelic hypomorphic variants in PPCS, which encodes the second enzyme of de novo coenzyme A (CoA) biosynthesis from vitamin B5. The 2025 paper names the condition "PPCS deficiency disorder (PPCS DD)" and defines it as follows:

"PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway." (PMID:40745475)

The 2018 index paper describes it as cardiac rather than neurodegenerative, which sets it apart from the related CoA-pathway disorders PKAN (PANK2) and COPAN (COASY):

"In contrast to the neurodegenerative NBIA-related phenotypes associated with defects in PANK2 and COASY, PPCS-deficient individuals present with a clear dilated cardiomyopathy with a variable degree of severity and no neurodegeneration." (PMID:29754768)

Identifiers

System	ID
MONDO	MONDO:0032592 "cardiomyopathy, dilated, 2c" ✔ (in `cache/mondo/terms.csv`)
OMIM phenotype	618189 (Dilated cardiomyopathy 2C, AR). Cited by PanelApp Australia.
OMIM gene	PPCS 609853. Cited in PMID:35616428 ("PPCS [MIM: 609853]").
HGNC	hgnc:25686 PPCS, "phosphopantothenoylcysteine synthetase" (1p34.2; Entrez 79717; ENSG00000127125; UniProt Q9HAB8; MANE NM_024664.4). From `kb/genes/ingest/hgnc.tsv`.
Orphanet	No ORPHA leaf entry for PPCS was found in `references_cache/ORPHA_*.md`. It is probably covered only by the generic familial isolated DCM concept (unverified).
ICD-10 / ICD-11	No specific code. It falls under I42.0 (dilated cardiomyopathy) / ICD-11 BC43.0 (generic codes).
MeSH	Cardiomyopathy, Dilated (D002311) as the generic heading. No supplementary concept was verified.

Synonyms: PPCS deficiency disorder (PPCS DD); PPCS-related dilated cardiomyopathy; CMD2C; dilated cardiomyopathy 2C; phosphopantothenoylcysteine synthetase deficiency.

Data basis. All knowledge comes from aggregated case reports and series of individual patients. By 2025 the total was 12 patients from 7 families (PMID:40745475, Table 1). There is no registry or EHR-scale data.

2. Etiology

Primary cause. Biallelic germline PPCS variants. The variants are missense or in-frame changes, plus one intronic splice-region variant, that reduce PPCS protein stability and lower cellular CoA.

"Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels." (PMID:40745475)

No biallelic loss-of-function genotype has been seen. This suggests that complete PPCS loss is lethal:

"none of the new patients, similarly to previously reported cases, harbored biallelic loss of function variants, suggesting that this combination might be incompatible with life." (PMID:40745475)

Genetic risk factors. The only established ones are the causal PPCS alleles listed in §4. No GWAS, susceptibility locus, or modifier gene has been established. - In family F5, the proband also carried KCNH2 p.His1153Tyr (a VUS associated with LQT2). It did not segregate with QT prolongation, so it is not an established modifier.

Environmental and precipitating factors. These are hypotheses, not established causes. - Intercurrent infection or catabolic stress repeatedly precipitated decompensation: viral URTI (F1:II, three episodes), CMV infection (F2:II.1), and rhabdomyolysis during illness or poor feeding (F1:II, F4:II). - The authors suggest that the gut microbiome and dietary intake of CoA precursors (pantetheine) may modify expressivity. They note that some patients worsened after antibiotic-treated infections. This rests on fruit-fly data plus anecdote and is explicitly speculative:

"part of the variable expressivity of PPCS DD among patients and siblings sharing the same pathogenic variants could be explained by differences in microbiome profile and dietary intake of CoA precursors" (PMID:40745475)

Serum pantothenate (vitamin B5) was normal in two affected siblings (74.95 and 73.84 µg/L; reference 37–147). Dietary B5 deficiency is therefore not the mechanism (PMID:29754768).

Protective factors. - No genetic protective factor is known. - Exogenous pantethine is the only candidate protective or therapeutic exposure. It bypasses the PPCS step (see §6 and §12).

Gene–environment interaction. The proposed interaction is CoA demand (fasting, infection, fatty-acid-dependent metabolism) acting on a reduced CoA biosynthetic capacity. This is inferred, not formally tested.

3. Phenotypes

The frequencies below are counted from the 12 patients in PMID:40745475 Table 1 (Iuso 2018 + Lok 2022 + 6 new cases). They are small-number estimates.

Phenotype	HPO (✔ = in cache)	Frequency / notes	Onset & course
Dilated cardiomyopathy	HP:0001644 Dilated cardiomyopathy ✔	10/12 recorded as DCM or severe DCM. The other two are LVNC (F3:III.2) and septal hypertrophy (F4:II). The 2025 discussion calls DCM "a constant finding".	Antenatal to 21 y. Often severe, fatal in infancy; variable within sibships
Left ventricular noncompaction	HP:0011664 Left ventricular noncompaction cardiomyopathy ✔	1/12 (F3:III.2: "noncompacted to compacted ratio of 2.7:1"; "meets criteria for LV non-compaction cardiomyopathy")	Adolescent/adult
Septal hypertrophy	HP:0001670 Asymmetric septal hypertrophy ✔ (verify that "asymmetric" fits)	1/12 (F4:II, "cardiac muscle septal hypertrophy")	Neonatal
Heart failure	HP:0001635 Congestive heart failure ✔	Most cases. Exertional dyspnea in surviving siblings; ECMO in F1:II (×2) and F3:III.3	Episodic decompensations triggered by infection
Reduced LVEF	HP:0012664 Reduced left ventricular ejection fraction ✔ / HP:0012666 Severely reduced… ✔	EF 15% (F1:II), 28% (F2:II.1), 34% (F5:IV.1), 36% (F6:IV.1)	Partly reversible in some
Ventricular fibrillation / ventricular arrhythmia	HP:0001663 ✔; HP:0004308 Ventricular arrhythmia ✔; HP:0004756 Ventricular tachycardia ✔	VF arrest in F3:III.3 and F5:IV.1. "Malignant tachyarrhythmias" terminally in F2:II.1	Adolescent
Prolonged QT	HP:0001657 ✔	F1:II; F5:IV.1 (QT up to 560 and 624 ms; later normalized)	Episodic
Sudden cardiac arrest / death	HP:0001645 Sudden cardiac death ✔	Cardiac arrest in F1:II (9 mo), F4:II (fatal), F3:III.3, F5:IV.1	—
Cardiomegaly	HP:0001640 ✔	F1:II on chest radiograph	—
Pulmonary arterial hypertension	HP:0002092 ✔	1 case (Family A index, Iuso 2018)	Neonatal
Hypotonia	HP:0001252 ✔ / HP:0001290 Generalized hypotonia ✔	3/12 (F1:II; F7:II.2 [Lok]; Family A index "severe hypotonia")	Neonatal/infantile
Rhabdomyolysis	HP:0003201 ✔	3/12 (F1:II, peak CK 26,000 U/L; F4:II, CK 71,000; Lok case "intermittent rhabdomyolysis")	Infection- or fasting-triggered
Elevated CK	HP:0003236 Elevated circulating creatine kinase activity ✔	4 of 6 tested elevated	—
Necrotizing myopathy / myopathy	HP:0003198 Myopathy ✔	Lok 2022: "a necrotizing myopathy with intermittent rhabdomyolysis". F1:II muscle biopsy suggested a neurogenic process	Neonatal
Lactic acidosis	HP:0003128 ✔	6/9 tested elevated lactate	During decompensation
Hypoglycemia	HP:0001943 ✔	F1:II (1.3 mmol/L at 9 mo)	Infection-triggered
Hyperammonemia	HP:0001987 ✔	F4:II (max 1351 µmol/L)	Infantile
Hyperlysinemia	HP:0002161 ✔	F4:II (lysine 964 µmol/L)	Single case
Abnormal acylcarnitines	⚠ (e.g., "Abnormal circulating carnitine concentration"; look up)	6/9 tested abnormal. In 2018: low C16/C18 with elevated C0/(C16+C18) ratio. In 2025: VLCADD-like C14:1/C14:2 elevation during illness	Often normal when well
Dysmorphic features, cutis laxa	HP:0000973 Cutis laxa ✔	1 (Family A index); Lok case "dysmorphic features"	Congenital
Exertional dyspnea	HP:0002875 ✔	Surviving siblings of Family B/F6	Chronic
Brain volume loss (non-specific)	⚠	F1:II, possibly secondary to ECMO or cardiac insults. No brain iron accumulation in any patient	—

Key quotes: - Neuromuscular phenotype (PMID:35616428): "a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy." - Severity and mortality (PMID:35616428): "Biallelic pathogenic variants in phosphopantothenoylcysteine synthetase, PPCS, are a rare cause of a severe early-onset dilated cardiomyopathy with high morbidity and mortality." - Variable expressivity within one sibship (PMID:29754768): "Four out of eight siblings exhibited dilated cardiomyopathy of varying severity, without apparent extracardiac manifestations."

Onset categories: HP:0003593 Infantile onset ✔ and HP:0011463 Childhood onset ✔ cover most cases. Juvenile and adult presentations also occur (14–21 y).

Quality of life. No formal QoL instrument has been used. Reported disability includes wheelchair-assisted ambulation (F1:II), limited exertional capacity, and transplant morbidity including a below-knee amputation after a TAH complication (F3:III.3).

4. Genetic and molecular information

Gene: PPCS (hgnc:25686; OMIM 609853; chr 1p34.2). The canonical isoform is NM_024664 (311 aa). A shorter isoform (NM_001077447, 138 aa) shares the C-terminus. Only the canonical 34-kDa protein was detected in fibroblasts (PMID:29754768). PPCS acts as a homodimer:

"in physiological conditions PPCS exists mainly as a dimer." (PMID:29754768)

Reported variants (NM_024664)

Variant	Protein	Exon	Zygosity / family	Predicted effect	Phenotype class
c.698A>T	p.Glu233Val	3	Homozygous; Family B/F6 (Arab-Muslim, consanguineous), F3, F5	Near the ATP-binding phosphate recognition site, close to the dimer interface; FoldX ΔΔG +0.9 kcal/mol	"DCM only", variable expressivity
c.538G>C	p.Ala180Pro	2	Compound heterozygous with del (Family A, German, non-consanguineous)	Nucleotide-binding cleft; completely non-functional in yeast	DCM + extracardiac
c.320_334del	p.Pro107_Ala111del	1	Compound heterozygous (Family A; Lok case)	Dimerization region; gnomAD 10 heterozygotes / 271,726 alleles (MAF ~0.0001 in 2017)	DCM + extracardiac
c.613-3C>G	p.? (splice region)	intron	In trans with c.320_334del (Lok 2022)	Initially VUS; "Functional studies confirmed the likely pathogenicity"	DCM + neuromuscular
c.232T>C	p.Tyr78His	1	Homozygous (F1)	Disrupts H-bond network near catalytic site; RNA-seq showed reduced PPCS expression	DCM + neuromuscular
c.317G>C	p.Arg106Pro	1	Homozygous (F2)	Dimerization β-sheet; FoldX ΔΔG +13.0 kcal/mol	DCM + extracardiac
c.59C>G	p.Ala20Gly	1	Homozygous (F4)	α1/α6 helix packing; ΔΔG ~+1.5	Septal hypertrophy + multisystem metabolic

Allele frequency: The two original missense variants were absent from gnomAD (12/2017) (PMID:29754768).
Classification: ClinGen has not curated PPCS (no CGGV: record in cache). PanelApp Australia lists PPCS for DCM with biallelic inheritance. Per the repo rule, do not assign a validity tier yourself.
Mechanism: loss of function (hypomorphic) through protein instability. It is not dominant negative. Parents are heterozygous carriers and asymptomatic.
Somatic vs germline: germline only.
Genotype–phenotype hypothesis (exploratory, n = 12):

"the p.Glu233Val variant leads to an isolated DCM presentation with variable expressivity" … "We hypothesize that the 'DCM only' phenotype arises when variants involve exon 3, while 'DCM plus' occurs when they involve exons 1 and 2" (PMID:40745475)

Exon 1 is proposed as a mutational hotspot.

Modifier genes, epigenetics, chromosomal abnormalities. - No modifier genes are established. - No epigenetic data exist. - There are no chromosomal causes. Incidental CNVs and runs of homozygosity were found, e.g. a 1p31.1 duplication in F2, which was considered unrelated.

5. Environmental information

No toxin, occupational, or infectious etiology has been reported.
Infections such as viral URTI and CMV act as decompensation triggers, not causes.
One adult death (F6:IV.1, age 21) was from SARS-CoV-2 complications. Cardiac function in both siblings stayed stable through that infection (PMID:40745475).
Lifestyle: avoiding fasting is plausible given the metabolic crises (hypoglycemia, rhabdomyolysis), but this is not evidence-based.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic hypomorphic PPCS variants, often missense in exon 1 or at the dimer interface or ATP site. These lead to reduced PPCS protein stability and abundance, with transcript levels normal in iPSC-derived cells.
Demonstrated in fibroblasts (PMID:29754768, 40745475) and in iPSCs, CPCs and cardiomyocytes. iPSC-CMs show "markedly reduced PPCS protein levels … suggesting impaired protein stability" with "no significant differences" in PPCS transcript (PMID:40745475).
Some variants also impair dimerization. In blue-native PAGE, no dimer was detectable in the Family A index (PMID:29754768).
Loss of PPCS enzyme activity, i.e. failure to condense 4'-phosphopantothenate with cysteine. This results in reduced de novo CoA biosynthesis.
The enzymatic step: "Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine." (PMID:29754768)
Yeast complementation showed that the variants are deleterious.
Reduced intracellular CoA, which is rescued by re-expressing wild-type PPCS.
"Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals." (PMID:29754768)
The deficit grows as cells commit to the cardiac lineage (PMID:40745475): "The defect became significant and more pronounced during cardiac maturation to CPCs, d22 CMs, and d60 CMs in both lines".
Unlike PKAN and COPAN, PPCS deficiency lowers fibroblast CoA measurably.
(Inferred) Limited acyl-CoA formation, which leads to impaired long-chain fatty-acid activation and mitochondrial β-oxidation. Mature cardiomyocytes depend on fatty acids for energy, so this causes an energy shortfall.
Biochemical support: low long-chain acylcarnitines (2018) and a VLCADD-like acylcarnitine pattern during crises (2025).
Authors' reasoning (PMID:40745475): "iPSCs rely mainly on glycolysis for energy, while mature cardiac cells preferentially utilize fatty acids, requiring CoA for their activation and utilization. Therefore, a shortage of CoA during cardiac cell maturation could lead to reduced energy supply for cardiac cells and cause cardiac dysfunction"
2018 mechanism (PMID:29754768): "Reduced cytosolic CoA concentration in PPCS-affected individuals may lead to a reduced synthesis of activated long-chain fatty acids … resulting in reduced long-chain acylcarnitine concentrations, similar to individuals with carnitine palmitoyltransferase I (CPT1) deficiency."
This step is inferred. CoA has not been measured in patient heart tissue, and fluxomics has not been done.
Cardiomyocyte structural and excitation–contraction defects. In iPSC-CMs these are:
sarcomere disorganization;
reduced Ca²⁺ transient amplitude;
arrhythmic events in 42–54% of cells.

In 3D engineered heart patches they are: - falling contractile force over time; - blunted force–frequency relationship; - shortened effective refractory period, i.e. a pro-arrhythmic substrate.

This is demonstrated in vitro (PMID:40745475): "Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment."

Clinical consequences. The cellular defects lead to dilated cardiomyopathy with systolic failure, plus ventricular arrhythmia, VF arrest and sudden death. Episodes are often precipitated by infection or catabolism. Mild interstitial fibrosis and myocyte nucleomegaly were seen on endomyocardial biopsy (F1:II), with no myocarditis.

Branches

Branch A, skeletal muscle (exon 1–2 genotypes). CoA deficit in skeletal muscle is associated with hypotonia, necrotizing myopathy, rhabdomyolysis during catabolic stress, and elevated CK. The mechanism is presumed to be the same energy and fatty-acid-oxidation failure, but this is not demonstrated.
Branch B, systemic metabolic crisis. Hypoglycemia, lactic acidosis, hyperammonemia, and dicarboxylic aciduria during illness are consistent with secondary fatty-acid-oxidation and TCA impairment (inferred).
Branch C, alternative or toxic-metabolite hypothesis. This is untested in humans:

"We cannot exclude that cardiomyopathy in PPCS-deficient individuals is also due to the generation of toxic metabolites. For instance, L-cysteine normally funneled in the synthesis of phosphopantothenoylcysteine could accumulate" (PMID:29754768)

Supporting evidence is limited to the report that dPPCS fly mutants are hypersensitive to cysteine.

Unexplained tissue selectivity.

"considering the ubiquitous presence of the enzymatic PPCS activity, it remains unexplained why the brain and in general the other organs are not affected" (PMID:29754768)

The 2025 paper suggests that tissue- or time-specific alternative isoforms may explain this. A transplant recipient (F3:III.3) has had no DCM recurrence at one year, which is consistent with a heart-intrinsic (cell-autonomous) defect.

Subcellular localization. PPCS shows nuclear and cytosolic signal in iPSC-derived cells and in GFP-tagged HeLa cells (PMID:40745475).

Suggested ontology terms

Type	Term
GO BP	GO:0015937 coenzyme A biosynthetic process ✔ (DECREASED)
GO BP	GO:0006635 fatty acid beta-oxidation ✔ (DECREASED, inferred)
GO BP	GO:0060048 cardiac muscle contraction ✔
GO BP	GO:0086003 cardiac muscle cell contraction ✔
GO BP	GO:0045214 sarcomere organization ✔
GO BP	GO:0010882 regulation of cardiac muscle contraction by calcium ion signaling ✔
GO MF	phosphopantothenate–cysteine ligase activity ⚠. This is likely GO:0004632, but it is not in the cache, so look it up before binding.
GO CC	GO:0005829 cytosol ✔; GO:0005634 nucleus ✔
CL	CL:0000746 cardiac muscle cell ✔ (primary); CL:0000057 fibroblast ✔ (diagnostic and model cell). Skeletal muscle fiber ⚠
CHEBI	CHEBI:15346 coenzyme A ✔; CHEBI:16454 pantothenate ✔; pantethine ⚠ (look up); L-cysteine ⚠

Molecular profiling. - Clinical RNA-seq of skeletal muscle in F1:II showed "an overall reduction in PPCS expression". - No GEO, proteomic, metabolomic, single-cell, or CRISPR-screen datasets are specific to this disease.

7. Anatomical structures affected

Primary: heart (UBERON:0000948 ✔), mainly the left ventricle (UBERON:0002084 heart left ventricle ✔). Biventricular dysfunction occurred in F5 (RVEF 37%).
Secondary:
skeletal muscle (UBERON skeletal muscle tissue ⚠), in the exon 1–2 genotypes;
liver, through transaminitis and coagulopathy (F4);
pulmonary vasculature (PAH, 1 case);
possibly the pituitary (suspected dysfunction, 1 case);
the brain, with non-specific changes only and no iron accumulation.
Cells: cardiomyocytes and skeletal myocytes. Fibroblasts are used for diagnosis.
Subcellular: cytosol and nucleus (PPCS); mitochondria (downstream β-oxidation and acyl-CoA use).
Laterality: not applicable (global ventricular dysfunction).

8. Temporal development

Onset: ranges from antenatal and neonatal to 21 years.
Severe compound-heterozygous or exon-1 cases present in the neonatal or infantile period.
Glu233Val homozygotes span 23 months to 21 years.
Pattern: acute decompensation on top of an insidious chronic course. Episodes are often triggered by infection.
Progression: variable.
Rapidly fatal in infancy in several cases: deaths at 3, 4 and 10 months, and at 23 months and 3 years.
Others have chronic stable DCM into adulthood.
Remission: some recovery of LV function occurred.
F1:II improved spontaneously between episodes.
F5:IV.1 had "fully recovered LV function" on pantethine plus standard heart-failure therapy.
Critical period: the authors stress early treatment:

"complete reversal may require early intervention." (PMID:40745475)

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007 ✔). Carriers are asymptomatic and segregation is complete in Family B/F6.
Penetrance: appears complete for cardiomyopathy in homozygotes, with variable expressivity within sibships (mild vs fatal DCM among siblings with the same genotype).
Anticipation and mosaicism: none reported.
Consanguinity: 8 of 12 patients came from consanguineous families (Table 1).
Founder effect: p.Glu233Val recurs in Family B/F6 (Arab-Muslim, Israel), F3 and F5. Haplotype analysis has not been reported, so a founder effect is plausible but unproven.
Prevalence: unknown. There are 12 cases in the literature ("To date, only six patients worldwide have been identified" before the 2025 series). The appropriate dismech record would be measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE.
Carrier frequency: not estimated. The 2018 in-house database of more than 11,000 exomes contained no other rare biallelic PPCS genotypes.
Sex ratio: roughly balanced (both sexes affected).
Geography and ancestry: German, Arab-Muslim (Israel), UK, North American, and other cohorts. The 2025 patients' ancestry is not fully given in the text read.

10. Diagnostics

Genetic testing (definitive). - Most cases were diagnosed by exome sequencing (singleton, trio, or reanalysis). One sibling was diagnosed by single-gene testing after cascade screening. Trio genome sequencing was used in Lok 2022. - PPCS is on PanelApp Australia's DCM panel. It may be missing from many commercial DCM panels, so exome or genome reanalysis was what found it in F1:II, years after a non-diagnostic exome. - CMA is not diagnostic. Mitochondrial DNA testing is useful to exclude mitochondrial differentials only.

Functional and biochemical tests (research-level). - Fibroblast PPCS immunoblot (reduced or absent 34-kDa band). - Fibroblast total CoA by fluorimetric kit (reduced; rescued by wild-type PPCS transduction). - Serum CoA and PPCS ELISA were undetectable in both patients and controls, so they are not useful (PMID:29754768).

Supportive laboratory findings. - Acylcarnitine profile: low C16/C18, or VLCADD-like C14:1/C14:2 elevation during crises. It can be normal when the patient is well, and its role as a biomarker is inconsistent. - CK, lactate, ammonia, glucose; urine organic acids (dicarboxylic aciduria); FGF21 was elevated in one case.

Cardiac work-up. - Echocardiography (LVEDD z-score, EF, FS) and cardiac MRI (volumes, LGE usually absent, LVNC ratio). - ECG (QT prolongation, T-wave inversion, low voltage) and Holter or implantable loop recorder. - Endomyocardial biopsy: no myocarditis; nucleomegaly and mild fibrosis; normal mitochondria on EM.

Differential diagnosis. - Other genetic DCMs (TTN, LMNA, sarcomeric). - Fatty-acid oxidation disorders: VLCADD (the acylcarnitines mimic it), CPT1 deficiency, primary carnitine deficiency. - Mitochondrial cardiomyopathies; Barth syndrome (males); Pompe disease (a GAA VUS was excluded in F2). - Viral myocarditis (cardiac MRI in F2 initially suggested it). - LQT syndromes (KCNH2). - Other CoA-pathway disorders, PKAN and COPAN, which are distinguished by NBIA on MRI.

Screening. No newborn screening exists. Acylcarnitine abnormalities are not consistent enough for NBS. Cascade testing of siblings is effective: F3:III.2 was diagnosed this way.

11. Outcome and prognosis

Mortality: 7 of 12 have died.
Deaths at 3 mo, 4 mo and 10 mo; at 23 mo and 3 y (DCM); and at 21 y (COVID-19).
With one more early death in the series, the counts in Table 1 are hard to align exactly. Take the totals from Table 1 when curating.
Causes were multi-organ failure, refractory arrhythmia, and cardiac arrest.
Survivors: ages 11–21 y, with variable function. Outcomes include one heart transplant with no graft dysfunction at one year, one ICD carrier, and one person in a wheelchair.
Prognostic factors (hypothesized):
Genotype: exon 1–2 and compound-heterozygous genotypes are more severe; Glu233Val is "DCM only".
Age at onset: neonatal or infantile onset is worse.
Timing of pantethine start.
No survival statistics or QoL measures exist.

12. Treatment

Targeted metabolic bypass: pantethine (compassionate use). Rationale (PMID:29754768):

"CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive."

Pantethine is cleaved to pantetheine, which PANK phosphorylates to 4'-phosphopantetheine, so the PPCS and PPCDC steps are skipped.

Dosing. - Family B: 6–8 mg/kg/day, titrated to 20–24 mg/kg/day. - F1:II: 450 mg/day (17 mg/kg/day), increased to 900 mg/day. - F5:IV.1: 600 mg/day (~10 mg/kg/day). - Family F6 long-term: ~15 mg/kg/day.

Clinical outcomes in the 4 treated patients. - Family B: "mild improvement in exertional dyspnea and an increase of ejection fraction … from 36% … to 48%" in IV.1; IV.4 stable at EF 45%. The 2018 authors were cautious: "Our results thus far had not shown significant clinical improvement." - F1:II: no further rhabdomyolysis; CK and BNP normalized; LV size normal with low-normal function. - F5:IV.1: fully recovered LV function, alongside ICD, beta-blocker and ACE inhibitor. - Summary (PMID:40745475): "Clinically, patients receiving pantethine show sustained improvement over time." - Evidence level: uncontrolled case reports confounded by standard heart-failure therapy.

In vitro evidence. - Pantethine at 50–500 µM raised CoA in fibroblasts, iPSCs, CPCs and CMs, without increasing PPCS protein. - It partially rescued sarcomere organization, Ca²⁺ transients and ERP. - It reduced arrhythmic events in CMs from 42% to 26% and from 54% to 24%. - 4'-phosphopantetheine raised fibroblast CoA less effectively than pantethine. - One unexplained observation: F1:II began excreting 3-methylcrotonylglycine after starting pantethine. He also carries a homozygous MCCC1 VUS.

Standard cardiac and supportive care. - Guideline-directed heart-failure therapy: beta-blockers (metoprolol), ACE inhibitors, milrinone and other inotropes, and carnitine supplementation (empirical, in F2). - ICD for secondary prevention after VF. - ECMO for acute decompensation. - Total artificial heart as a bridge, then heart transplantation, which was successful in F3:III.3. - For metabolic crises: dietary fatty-acid-oxidation management (initially treated as VLCADD), carglumic acid, and CVVH for hyperammonemia. - Rehabilitation and physical therapy for neuromuscular disability.

Experimental therapies. No registered trials were found for PPCS deficiency. 4'-phosphopantetheine has been tested in PKAN trials, but not in PPCS DD. No gene therapy or RNA therapy exists.

Pharmacogenomics: none.

Suggested NCIT terms (all are in the CLAUDE.md common list; still confirm with validate-terms):

Intervention	`treatment_term`	Other slots
Pantethine	Pharmacotherapy (NCIT:C15986)	`therapeutic_agent` CHEBI pantethine ⚠ (look up); `therapeutic_modality: SMALL_MOLECULE`
Heart transplant	Organ Transplantation (NCIT:C15289)	`SURGERY`
ICD	Surgical Procedure (NCIT:C15329) as the action, with device qualifier	`DEVICE`, per the cochlear-implant pattern
Genetic counseling	NCIT:C15240	—
Supportive care	NCIT:C15747	—
Beta-blocker / ACE inhibitor	Pharmacotherapy	CHEBI metoprolol ⚠

13. Prevention

Primary: none, beyond reproductive options.
Secondary:
Cascade genetic testing of siblings, with echocardiography, ECG and loop recorder for those found affected (F3:III.2 was found pre-symptomatically).
Early pantethine start is proposed for genotype-positive individuals.
Tertiary:
Avoid prolonged fasting.
Aggressive management of intercurrent infections.
Arrhythmia surveillance and ICD where indicated.
Vaccination (one COVID-19 death).
Genetic counseling: AR with 25% recurrence risk for carrier couples; prenatal or preimplantation diagnosis is possible once familial variants are known. Consanguinity counseling is relevant.

14. Other species and natural disease

No naturally occurring animal disease was found. A search of OMIA was not done, so treat this as unverified.
Orthologs:
S. cerevisiae CAB2/YIL083C (essential)
D. melanogaster CG5629 (dPPCS)
E. coli CoaBC (bifunctional PPCS/PPCDC)
Zebrafish ortholog ZDB-GENE-060512-104 (from the ZFIN search result)
Pathway conservation:

"The pathway of CoA de novo biosynthesis from vitamin B5 is conserved in eukaryotes and prokaryotes and consists of five consecutive enzymatic steps." (PMID:29754768)

15. Model organisms and systems

Model	Description	Recapitulation	Limitations	Evidence
S. cerevisiae cab2Δ plasmid-shuffle complementation	Human PPCS wild-type vs variants	Original variants fail to complement; Ala180Pro is null	Qualitative; Tyr78His and Arg106Pro showed no or moderate defect in yeast (an overexpression artefact)	PMID:29754768, 40745475 (IN_VITRO / MODEL_ORGANISM)
Drosophila dPPCS¹ (P-element in 5′UTR, hypomorph)	Pre-pupal heart imaging	↑ heart rate, ↑ arrhythmia index, ↓ systolic length, altered wall shortening; reduced viability (9–22% vs expected 33%) rescued by 8 mM pantethine but not by vitamin B5	Open tubular heart; the hypomorph is not a patient allele	PMID:29754768 (MODEL_ORGANISM)
Patient fibroblasts	95595 (Ala180Pro/del), 103596 (Glu233Val hom), 128343, 128344, 146603	↓ PPCS protein, ↓ CoA; rescued by wild-type PPCS and partly by pantethine	Non-cardiac cell	IN_VITRO
Patient iPSC lines	HMGUi003-A (female, compound heterozygous); MRIi028-A (male, Glu233Val hom; RRID CVCL_A0TH)	Platform for cardiac differentiation	—	PMID:35397396
iPSC-CMs (2D, d22/d60) and 3D engineered heart patches on decellularized porcine ventricular ECM	—	Sarcomere disorganization, ↓ Ca²⁺ transients, arrhythmias, ↓ force, ↓ FFR, ↓ ERP; partial pantethine rescue	Immature cardiomyocytes; no systemic metabolism; n = 2 patient lines	PMID:40745475
Mouse	—	No Ppcs mouse model has been reported in the literature reviewed	—	—

For dismech modeled_mechanisms: - The Drosophila model could link to the cardiac contractile/arrhythmia node with PARTIALLY_RECAPITULATES and SPECIES_MISMATCH + BOUNDARY_OMISSION divergences. - The iPSC-CM patch could link to the CoA deficiency node (RECAPITULATES, model_scale: CELLULAR) and to the DCM node. The DCM link is an upward extrapolation, so it needs limitations.

Gaps and open questions

CoA has never been measured in human or animal heart tissue. The fatty-acid-oxidation energy-deficit step is inferred.
It is unexplained why the heart is affected and the brain is not, given ubiquitous PPCS expression. The isoform hypothesis is unproven.
The genotype–phenotype rule (exon 3 vs exons 1–2) rests on n = 12.
Pantethine efficacy is uncontrolled, and the optimal dose and timing are unknown. 4'-phosphopantetheine has not been tested clinically.
The microbiome and dietary pantetheine contribution to expressivity has been shown only in flies.
There is no mammalian genetic model.
No ClinGen validity curation exists, and no Orphanet entry was verified.

Curation notes for the open Cardiomyopathy_Dilated_2C.yaml draft: - The draft currently has one stub node. It should be expanded along the six-step chain above. - Four PMIDs are now cached in references_cache/: 29754768, 35616428, 35397396, 40745475. 35616428 and 35397396 are abstract-only, so snippets from them must come from the abstract. - Before binding, look up the ⚠ terms: the PPCS molecular-function GO term, pantethine CHEBI, and skeletal muscle UBERON.

Sources

PMC12313872 – Zhang et al. 2025, Commun Med (PMID:40745475)
Springer Nature Communities – "Pantethine for a Rare Cardiomyopathy"
University of Tübingen repository – Iuso et al. 2018 (PMID:29754768)
PanelApp Australia – PPCS, Dilated Cardiomyopathy panel
Cellosaurus MRIi028-A (CVCL_A0TH) and hPSCreg publication record (PMID:35397396)
ZFIN ZDB-GENE-060512-104
ERIBA – Sibon 2025 Commun Med

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	13
Quoted claims found in source	12
Quoted claims not found in source	1
References weighed for topical relevance	7
On topic	4
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMID:40745475: "none of the new patients, similarly to previously reported cases, harbored biallelic loss of function variants, suggesting that this combination might be incompatible with life."
closest text in source: "Genetically, none of the new patients, similarly to previously reported cases, harbored biallelic loss of fun ction variants, suggesting that this combination might be incompatible with life"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	48
Resolved	48
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	5
Terms named correctly	5
Terms named as a different term	0

Every term resolved, and every label the report gave matched.

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Cardiomyopathy, Dilated, 2C (CMD2C): PPCS deficiency disorder

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

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