Holocarboxylase Synthetase Deficiency

Mendelian MONDO:0009666 Pathograph 40 Organic Acidemia Inborn error of metabolism

Holocarboxylase synthetase deficiency is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in the HLCS gene. HLCS catalyzes the covalent attachment of biotin to the four biotin-dependent carboxylases: pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and acetyl-CoA carboxylase (ACC). Loss of HLCS activity produces multiple carboxylase deficiency, disrupting gluconeogenesis, amino acid catabolism, propionate metabolism, and fatty acid synthesis. Clinical manifestations include episodic or persistent metabolic acidosis, lactic acidosis, hyperammonemia, ketosis, seizures, skin rash, alopecia, and developmental delay. Onset is typically neonatal but late-onset forms occur. Pharmacologic biotin supplementation is the primary disease-modifying therapy, often producing dramatic biochemical and clinical improvement.

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Pathophysiology

HLCS molecular function deficiency

Biallelic HLCS pathogenic variants reduce holocarboxylase synthetase catalytic activity.

hepatocyte link

HLCS

biotin metabolic process link ↕ DYSREGULATED

biotin-protein ligase activity link ↓ DECREASED

mitochondrion link

Downstream

Impaired HLCS-mediated protein biotinylation Reduced HLCS function impairs biotinylation of carboxylase apoproteins.

Show evidence (1 reference)

PMID:39194177 SUPPORT Human Clinical

"Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle."

Supports HLCS molecular deficiency as the initiating event.

Impaired HLCS-mediated protein biotinylation

HLCS covalently links biotin to apocarboxylases to generate active holocarboxylases. Deficiency impairs this biotinylation step, reducing activation of biotin-dependent carboxylases.

biotin metabolic process link

Downstream

Multiple carboxylase deficiency Reduced biotinylation leaves multiple carboxylases in low-activity apo forms.

Cutaneous and hair involvement Defective biotin-dependent enzyme activation is associated with cutaneous and hair manifestations in HLCS deficiency.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

"After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up."

Clinical reversibility with biotin is consistent with a primary defect in biotin-dependent enzyme activation.

Multiple carboxylase deficiency

Impaired HLCS activity produces concurrent functional deficiency of pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and acetyl-CoA carboxylase (ACC), creating a multi-pathway metabolic block.

hepatocyte link

carboxylic acid metabolic process link ↕ DYSREGULATED fatty acid biosynthetic process link ↓ DECREASED

pyruvate carboxylase activity link ↓ DECREASED propionyl-CoA carboxylase activity link ↓ DECREASED methylcrotonoyl-CoA carboxylase activity link ↓ DECREASED acetyl-CoA carboxylase activity link ↓ DECREASED

Downstream

Disrupted gluconeogenesis and lactic acidosis PC dysfunction impairs pyruvate anaplerosis and glucose production.

Impaired leucine catabolism MCC dysfunction drives accumulation of leucine-pathway intermediates.

Impaired propionate metabolism PCC dysfunction drives accumulation of propionyl-derived metabolites.

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle."

Directly supports concurrent deficiency of multiple carboxylases in HLCS deficiency.

PMID:36890565 SUPPORT Human Clinical

"The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals."

Simultaneous elevation of multiple pathway metabolites supports a multi-carboxylase defect state.

Disrupted gluconeogenesis and lactic acidosis

Pyruvate carboxylase (PC) deficiency due to impaired biotinylation reduces conversion of pyruvate to oxaloacetate, impairing gluconeogenesis and TCA cycle anaplerosis. This contributes to lactic acidosis and hypoglycemia observed in affected patients.

hepatocyte link

gluconeogenesis link pyruvate metabolic process link

liver link

Downstream

Secondary organic acidemia and ketotic decompensation Impaired carbohydrate flux contributes to metabolic decompensation under catabolic stress.

Lactic acidosis Pyruvate carboxylase-related impairment manifests clinically as lactic acidosis.

Hypoglycemia Reduced gluconeogenic capacity can present as hypoglycemia during illness or poor intake.

Lactic acid Lactate elevation is the biochemical counterpart of lactic acidosis.

Show evidence (2 references)

PMID:32841162 SUPPORT Human Clinical

"Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia."

Confirms lactic acidosis as a typical manifestation of HLCS deficiency, consistent with impaired PC-dependent gluconeogenesis.

PMID:39194177 SUPPORT Human Clinical

"An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation."

Illustrates severe lactic acidosis in neonatal HLCS deficiency from impaired gluconeogenesis.

Impaired leucine catabolism

Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) disrupts leucine catabolism, leading to accumulation of C5-hydroxylated leucine-pathway metabolites and 3-methylcrotonylglycine.

hepatocyte link

leucine catabolic process link

mitochondrion link

Downstream

Secondary organic acidemia and ketotic decompensation Leucine-pathway metabolite accumulation contributes to acute metabolic crisis.

3-Hydroxyisovalerylcarnitine (C5-OH) MCC pathway impairment increases the C5-OH acylcarnitine marker.

3-Hydroxyisovaleric acid MCC pathway impairment increases urinary hydroxyisovalerate-class metabolites.

3-Methylcrotonylglycine MCC pathway impairment increases urinary 3-methylcrotonylglycine.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

Documents increased MCC-related metabolites in HLCS deficiency.

Impaired propionate metabolism

Deficiency of propionyl-CoA carboxylase (PCC) impairs propionate catabolism, contributing to elevations of methylcitric acid and 3-hydroxypropionate.

hepatocyte link

propionate catabolic process link

mitochondrion link

Downstream

Secondary organic acidemia and ketotic decompensation Propionyl-derived metabolite accumulation contributes to decompensation.

3-Hydroxypropionate PCC pathway impairment increases urinary 3-hydroxypropionate.

Methylcitric acid PCC pathway impairment increases urinary methylcitric acid.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

Documents increased PCC-related metabolites in HLCS deficiency.

Secondary organic acidemia and ketotic decompensation

Combined pathway dysfunction causes recurrent high-anion-gap metabolic acidosis and ketotic decompensation, particularly during catabolic stress.

Downstream

Secondary hyperammonemia Acute metabolic stress can secondarily impair nitrogen handling.

Glucose dysregulation and hyperglycemic ketoacidosis Stress-state management can unmask insulin secretion abnormalities.

Neurologic metabolic decompensation Acidotic decompensation, organic acid accumulation, hypoglycemia, and hyperammonemia can produce acute neurologic dysfunction.

Systemic feeding and growth involvement Multisystem decompensation and chronic illness can include feeding difficulty and impaired growth.

Metabolic acidosis Organic acid accumulation manifests clinically as metabolic acidosis.

Vomiting Acute metabolic decompensation commonly presents with vomiting.

Tachypnea Severe acidosis can drive rapid breathing as respiratory compensation.

Show evidence (2 references)

PMID:38550975 SUPPORT Human Clinical

"An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency."

Documents severe metabolic decompensation in HLCS deficiency.

PMID:39391064 SUPPORT Human Clinical

"The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration."

Confirms that acute acidotic decompensation can also occur in late-onset HLCS deficiency.

Secondary hyperammonemia

Hyperammonemia can emerge during acute decompensation, likely from catabolic stress and secondary disturbance of nitrogen disposal.

urea cycle link

Downstream

Hyperammonemia The secondary nitrogen-disposal disturbance manifests as elevated circulating ammonia.

Show evidence (2 references)

PMID:32841162 SUPPORT Human Clinical

"Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia."

Directly lists hyperammonemia as a typical manifestation.

PMID:38550975 SUPPORT Human Clinical

"She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed."

Documents hyperammonemia during acute HLCS decompensation.

Glucose dysregulation and hyperglycemic ketoacidosis

In some patients, secondary Krebs cycle disturbances may impair pancreatic beta-cell insulin secretion, leading to hyperglycemic ketoacidosis during glucose infusion therapy.

tricarboxylic acid cycle link

Downstream

Hyperglycemia Impaired glucose-stimulated insulin secretion can cause hyperglycemia during glucose infusion.

Ketoacidosis Insulinopenia during decompensation can produce ketoacidosis.

Show evidence (2 references)

PMID:38550975 SUPPORT Human Clinical

"Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved."

Documents hyperglycemic ketoacidosis during HLCS decompensation and proposes secondary Krebs cycle disturbance mechanism.

PMID:38550975 SUPPORT Human Clinical

"We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia."

Provides mechanistic hypothesis for glucose dysregulation in HLCS decompensation.

Neurologic metabolic decompensation

Severe acidotic crises, hypoglycemia, hyperammonemia, and organic acid accumulation can produce acute neurologic dysfunction, including lethargy, hypotonia, and seizures. Delayed or severe crises can also contribute to developmental delay.

brain link

Downstream

Seizures Severe metabolic decompensation can produce seizures.

Lethargy Severe metabolic decompensation can reduce alertness.

Muscular hypotonia Acute neurologic metabolic dysfunction can manifest as hypotonia.

Global developmental delay Severe or delayed metabolic control can contribute to developmental delay.

Show evidence (2 references)

PMID:39391064 SUPPORT Human Clinical

"Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures."

Lists acute neurologic manifestations in the typical severe acidotic presentation.

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death."

Supports neurologic involvement including hypotonia, developmental delay, and seizures.

Cutaneous and hair involvement

HLCS deficiency includes cutaneous and hair findings such as rash, alopecia, and sometimes generalized ichthyosis. The graph groups these findings as downstream consequences of impaired biotin-dependent enzyme activation while leaving the tissue-level intermediates unspecified.

skin link

Downstream

Skin rash The cutaneous involvement includes eczematous or erythematous rash.

Alopecia The hair involvement includes alopecia.

Ichthyosis Severe cutaneous involvement may include generalized ichthyosis.

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death."

Lists rash and alopecia among the clinical manifestations of HLCS deficiency.

PMID:39194177 SUPPORT Human Clinical

"Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis."

Documents generalized ichthyosis before biotin therapy in a neonatal case.

Systemic feeding and growth involvement

Infantile HLCS deficiency can involve feeding difficulties and growth retardation as part of the multisystem clinical state. These endpoints may reflect systemic illness, poor intake, and recurrent decompensation rather than a single defined molecular intermediate.

Downstream

Feeding difficulties Multisystem illness can present with feeding difficulties.

Growth delay Chronic feeding and systemic involvement can manifest as growth retardation.

Show evidence (1 reference)

PMID:39634276 SUPPORT Human Clinical

"Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation"

Directly supports feeding and growth involvement in HLCS deficiency.

⬡

Pathograph

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

●

Phenotypes

Digestive 2

Vomiting Vomiting (HP:0002013)

Show evidence (2 references)

PMID:36890565 SUPPORT Human Clinical

"Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness"

Documents vomiting as a common symptom in the 28-patient cohort.

PMID:39391064 SUPPORT Human Clinical

"Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures."

Lists vomiting among typical presenting features.

Feeding difficulties Feeding difficulties (HP:0011968)

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures"

Lists feeding problems among clinical manifestations.

PMID:39634276 SUPPORT Human Clinical

"Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation"

Confirms feeding difficulties as a common manifestation.

Immune 1

Skin rash Eczematoid dermatitis (HP:0000964)

Show evidence (2 references)

PMID:36890565 SUPPORT Human Clinical

"Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness"

Documents rash as a common symptom in the 28-patient cohort.

PMID:39634276 SUPPORT Human Clinical

"Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation"

Confirms rash among common clinical manifestations of HLCS deficiency.

Integument 2

Alopecia Alopecia (HP:0001596)

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death."

Lists alopecia among clinical manifestations of HLCS deficiency.

PMID:32841162 SUPPORT Human Clinical

"Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia."

Confirms alopecia as a typical manifestation.

Ichthyosis Ichthyosis (HP:0008064)

Show evidence (1 reference)

PMID:39194177 SUPPORT Human Clinical

"Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis."

Documents generalized ichthyosis developing in a neonate with HLCS deficiency prior to biotin therapy.

Metabolism 6

Metabolic acidosis Metabolic acidosis (HP:0001942)

Show evidence (2 references)

PMID:39391064 SUPPORT Human Clinical

"Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures."

Lists metabolic acidosis as a typical presenting feature of HCS deficiency.

PMID:39634276 SUPPORT Human Clinical

"Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation, with predominant involvement of the nervous system, skin, and hair."

Confirms metabolic acidosis as a common clinical manifestation.

Lactic acidosis Lactic acidosis (HP:0003128)

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation."

Documents severe lactic acidosis as a presenting feature in neonatal HLCS deficiency.

PMID:32841162 SUPPORT Human Clinical

"Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia."

Lists lactic acidosis among the typical manifestations of HLCS deficiency.

Hyperammonemia Hyperammonemia (HP:0001987)

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death."

Lists hyperammonemia among clinical manifestations.

PMID:32841162 SUPPORT Human Clinical

"Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia."

Confirms hyperammonemia as a typical manifestation of HLCS deficiency.

Hypoglycemia Hypoglycemia (HP:0001943)

Show evidence (2 references)

PMID:32841162 SUPPORT Human Clinical

"Patient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis."

Documents severe hypoglycemia as a presenting feature in an HLCS deficiency patient.

PMID:38550975 SUPPORT Human Clinical

"She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed."

Confirms hypoglycemia as a feature of acute decompensation in HLCS deficiency.

Hyperglycemia Hyperglycemia (HP:0003074)

Show evidence (1 reference)

PMID:38550975 SUPPORT Human Clinical

"Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis."

Directly documents hyperglycemia as part of hyperglycemic ketoacidosis during HLCS decompensation.

Ketoacidosis Ketoacidosis (HP:0001993)

Show evidence (1 reference)

PMID:38550975 SUPPORT Human Clinical

"Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis."

Directly documents ketoacidosis during HLCS decompensation.

Musculoskeletal 1

Muscular hypotonia Hypotonia (HP:0001252)

Show evidence (2 references)

PMID:39391064 SUPPORT Human Clinical

"Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures."

Lists hypotonia as a typical presenting feature.

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures"

Confirms hypotonia among clinical manifestations.

Nervous System 3

Seizures Seizure (HP:0001250)

Show evidence (2 references)

PMID:39391064 SUPPORT Human Clinical

"Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures."

Lists seizures among typical presenting features.

PMID:36890565 SUPPORT Human Clinical

"Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness"

Confirms seizures in the 28-patient Chinese cohort.

Lethargy Lethargy (HP:0001254)

Show evidence (2 references)

PMID:39391064 SUPPORT Human Clinical

"Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures."

Lists lethargy among typical presenting features.

PMID:38550975 SUPPORT Human Clinical

"An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency."

Confirms lethargy as a presenting symptom in a documented HLCS case.

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures"

Lists developmental delay among clinical manifestations of HLCS deficiency.

PMID:36890565 SUPPORT Human Clinical

"After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up."

Indicates developmental delay is preventable with early biotin therapy, implying it occurs when treatment is delayed.

Respiratory 1

Tachypnea Tachypnea (HP:0002789)

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures"

Lists tachypnea among clinical manifestations.

PMID:39634276 PARTIAL Human Clinical

"Despite supportive treatment with antibiotics upon admission, the infant continued to experience rapid and deep breathing accompanied by groaning, and obvious wheezing."

Supports respiratory distress with rapid breathing, which is compatible but not fully specific for tachypnea.

Growth 1

Growth delay Growth delay (HP:0001510)

Show evidence (1 reference)

PMID:39634276 SUPPORT Human Clinical

"Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation"

Lists growth retardation among common clinical manifestations.

🧬

Genetic Associations

HLCS pathogenic variants

Autosomal recessive

Show evidence (1 reference)

PMID:39391064 SUPPORT Human Clinical

"A mini-review of HCS deficiency with late onset (>1 year) or early onset (<1 month) revealed that splice variants are associated with late onset, while both variants p. (Leu216Arg) and p. (Leu237Pro) are associated with early onset."

Provides genotype-phenotype correlations regarding onset timing.

HLCS (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_ad306285-9588-48e3-a6fa-183db3f01fe9-2021-02-26T171131.548Z SUPPORT Other

ClinGen classifies the HLCS-holocarboxylase synthetase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

Biotin supplementation

Action: nutritional supplementation MAXO:0000106

Pharmacologic oral biotin (10-40 mg/day) is the primary disease-modifying therapy for HLCS deficiency. Biotin overcomes the reduced HLCS activity by increasing substrate availability, restoring carboxylase biotinylation. Dramatic clinical and biochemical improvement typically occurs within hours to days of initiation.

Show evidence (3 references)

PMID:36890565 SUPPORT Human Clinical

"After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up."

Demonstrates dramatic resolution of symptoms with biotin therapy in a 28-patient cohort.

PMID:39194177 SUPPORT Human Clinical

"Remarkably, dramatic clinical improvement in lactic acidosis was observed the day after initiating biotin administration, leading to the discontinuation of mechanical ventilation within 6 days."

Documents rapid clinical improvement with biotin mega-dose therapy in a neonate.

PMID:26754537 SUPPORT Human Clinical

"Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes."

Systematic review confirming biotin supplementation is associated with good outcomes.

Newborn screening

Action: disease screening MAXO:0000124

Tandem mass spectrometry-based newborn screening detects HLCS deficiency via elevated 3-hydroxyisovalerylcarnitine (C5-OH) in dried blood spots. Early detection enables presymptomatic biotin initiation, preventing metabolic crises. False-negative results can occur if C5-OH falls below cutoff, requiring second-tier testing.

Show evidence (2 references)

PMID:36890565 SUPPORT Human Clinical

"Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes."

Directly supports importance of newborn screening for HLCS deficiency.

PMID:36890565 SUPPORT Human Clinical

"Among the 28 patients, six patients underwent newborn screening, of which only one was missed."

Provides real-world newborn screening detection data for HLCS deficiency.

Acute decompensation management

Action: supportive care MAXO:0000950

Emergency supportive care during metabolic crisis includes correction of acidosis, caloric provision to suppress catabolism, electrolyte management, and rapid initiation of biotin. When IV glucose infusion precipitates hyperglycemic ketoacidosis, insulin therapy may rapidly correct biochemical abnormalities.

Show evidence (2 references)

PMID:38550975 SUPPORT Human Clinical

"An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency."

Documents acute decompensation requiring emergency management in HLCS deficiency.

PMID:38550975 SUPPORT Human Clinical

"Insulin therapy rapidly corrected biochemical parameters, and clinical status improved."

Demonstrates insulin therapy as an acute management strategy for hyperglycemic ketoacidosis in HLCS decompensation.

Dietary intervention

Action: dietary intervention MAXO:0000088

Nutrition strategy tailored to reduce substrate burden on impaired carboxylase pathways, including protein-managed diet during acute illness and chronic management to prevent catabolic stress.

Show evidence (1 reference)

PMID:32841162 SUPPORT Human Clinical

"she had five episodes of hypoglycemia and metabolic acidosis in past 4 years when her oral intake decreased during acute illness."

Demonstrates that decreased oral intake triggers metabolic decompensation, supporting dietary management.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families, including discussion of autosomal recessive inheritance, 25% recurrence risk, carrier testing, and options for prenatal or preimplantation genetic diagnosis.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

"DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients."

Genetic characterization supports genetic counseling for families.

Molecular genetic testing

Action: genetic testing MAXO:0000127

Next-generation sequencing panels or targeted HLCS gene analysis enables rapid diagnosis in acutely ill neonates and can guide early initiation of biotin therapy before confirmatory biochemical testing is complete.

Show evidence (1 reference)

PMID:39194177 SUPPORT Human Clinical

"Our case highlights the significance of early genetic testing in neonates with unexplained metabolic disorders to enable timely diagnosis and therapy initiation."

Directly supports the role of early genetic testing for HLCS deficiency management.

Prenatal biotin supplementation

Action: nutritional supplementation MAXO:0000106

Antenatal biotin supplementation has been reported in at-risk pregnancies and is associated with good clinical outcomes in affected neonates.

Show evidence (1 reference)

PMID:26754537 SUPPORT Human Clinical

"Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes."

Systematic review supporting antenatal biotin supplementation for at-risk pregnancies.

🔬

Biochemical Markers

3-Hydroxyisovalerylcarnitine (C5-OH) (INCREASED)

Context: C5-OH is an acylcarnitine marker reported in HLCS deficiency. In a 28-patient cohort, C5-OH was increased in blood along with urinary organic acid abnormalities.

Pathograph Readouts

Readout Of Impaired leucine catabolism Positive Diagnostic

Increased C5-OH acylcarnitine reports impaired 3-methylcrotonyl-CoA carboxylase-dependent leucine catabolism.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

Directly documents elevated C5-OH in HLCS deficiency patients.

Lactic acid (INCREASED)

Context: Lactic acidosis reflects impaired pyruvate carboxylase function and disrupted gluconeogenesis. Lactate levels can be severely elevated in neonatal presentations.

Pathograph Readouts

Readout Of Disrupted gluconeogenesis and lactic acidosis Positive Diagnostic

Elevated lactate reports pyruvate carboxylase-related disruption of pyruvate handling, gluconeogenesis, and lactic acidosis.

Show evidence (2 references)

PMID:39194177 SUPPORT Human Clinical

"An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation."

Documents severe lactic acidosis in neonatal HLCS deficiency.

PMID:39634276 SUPPORT Human Clinical

"urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid."

Directly reports elevated lactate in urine organic acid analysis.

3-Hydroxyisovaleric acid (INCREASED)

Context: Urinary 3-hydroxyisovaleric acid elevation reflects impaired 3-methylcrotonyl-CoA carboxylase (MCC) activity in the leucine catabolic pathway.

Pathograph Readouts

Readout Of Impaired leucine catabolism Positive Diagnostic

Increased urinary 3-hydroxyisovaleric acid reports accumulation of leucine-pathway intermediates downstream of MCC dysfunction.

Show evidence (1 reference)

PMID:39634276 SUPPORT Human Clinical

"urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid."

The case directly reports elevated 3-hydroxyisovaleric acid.

Methylcitric acid (INCREASED)

Context: Elevated urinary methylcitric acid reflects propionyl-CoA carboxylase (PCC) deficiency and propionyl-CoA entry into the TCA cycle via citrate synthase.

Pathograph Readouts

Readout Of Impaired propionate metabolism Positive Diagnostic

Increased urinary methylcitric acid reports propionyl-CoA carboxylase impairment and propionate-pathway metabolite accumulation.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

Directly documents elevated methylcitric acid in urine of HLCS deficiency patients.

3-Methylcrotonylglycine (INCREASED)

Context: Urinary 3-methylcrotonylglycine is a conjugated metabolite reflecting impaired MCC activity in the leucine degradation pathway.

Pathograph Readouts

Readout Of Impaired leucine catabolism Positive Diagnostic

Increased urinary 3-methylcrotonylglycine reports impaired 3-methylcrotonyl-CoA carboxylase-dependent leucine catabolism.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

Directly documents elevated 3-methylcrotonylglycine in urine.

3-Hydroxypropionate (INCREASED)

Context: Urinary 3-hydroxypropionate elevation results from impaired propionyl-CoA carboxylase activity and propionate pathway dysfunction.

Pathograph Readouts

Readout Of Impaired propionate metabolism Positive Diagnostic

Increased urinary 3-hydroxypropionate reports impaired propionate catabolism downstream of propionyl-CoA carboxylase dysfunction.

Show evidence (1 reference)

PMID:36890565 SUPPORT Human Clinical

Directly documents elevated 3-hydroxypropionate in urine.

{ }

Source YAML

click to show

name: Holocarboxylase Synthetase Deficiency
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
updated_date: '2026-05-21T03:31:41Z'
synonyms:
- HLCS deficiency
- Biotin-responsive multiple carboxylase deficiency
- Multiple carboxylase deficiency, neonatal form
- Early-onset multiple carboxylase deficiency
description: 'Holocarboxylase synthetase deficiency is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in the HLCS gene. HLCS catalyzes the covalent attachment of biotin to the four biotin-dependent carboxylases: pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and acetyl-CoA carboxylase (ACC). Loss of HLCS activity produces multiple carboxylase deficiency, disrupting gluconeogenesis, amino acid catabolism, propionate metabolism, and fatty acid synthesis. Clinical manifestations include episodic or persistent metabolic acidosis, lactic acidosis, hyperammonemia, ketosis, seizures, skin rash, alopecia, and developmental delay. Onset is typically neonatal but late-onset forms occur. Pharmacologic biotin supplementation is the primary disease-modifying therapy, often producing dramatic biochemical and clinical improvement.

  '
disease_term:
  preferred_term: holocarboxylase synthetase deficiency
  term:
    id: MONDO:0009666
    label: holocarboxylase synthetase deficiency
parents:
- Organic Acidemia
- Inborn error of metabolism
prevalence:
- notes: 'Estimated incidence varies by geography: approximately 1/200,000 worldwide, 1/100,000 in Japan, and 1/930,600 in China.'
pathophysiology:
- name: HLCS molecular function deficiency
  description: 'Biallelic HLCS pathogenic variants reduce holocarboxylase synthetase catalytic activity.

    '
  genes:
  - preferred_term: HLCS
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: biotin metabolic process
    term:
      id: GO:0006768
      label: biotin metabolic process
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: biotin-protein ligase activity
    term:
      id: GO:0004077
      label: biotin--[biotin carboxyl-carrier protein] ligase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle.'
    explanation: Supports HLCS molecular deficiency as the initiating event.
  downstream:
  - target: Impaired HLCS-mediated protein biotinylation
    description: Reduced HLCS function impairs biotinylation of carboxylase apoproteins.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15992684
      reference_title: "Molecular genetics of biotin metabolism: old vitamin, new science."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Its covalent attachment to carboxylases is catalyzed by holocarboxylase synthetase.
      explanation: This review identifies HLCS as the enzyme that directly attaches biotin to carboxylases, supporting the immediate edge from HLCS molecular deficiency to impaired protein biotinylation.
- name: Impaired HLCS-mediated protein biotinylation
  description: 'HLCS covalently links biotin to apocarboxylases to generate active holocarboxylases. Deficiency impairs this biotinylation step, reducing activation of biotin-dependent carboxylases.

    '
  biological_processes:
  - preferred_term: biotin metabolic process
    term:
      id: GO:0006768
      label: biotin metabolic process
  downstream:
  - target: Multiple carboxylase deficiency
    description: Reduced biotinylation leaves multiple carboxylases in low-activity apo forms.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9350481
      reference_title: "Multiple carboxylase deficiency: inherited and acquired disorders of biotin metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Acquired biotin deficiency and the two known congenital disorders of biotin metabolism, biotinidase and holocarboxylase synthetase (HCS) deficiency, all lead to deficiency of the 4 biotin-dependent carboxylases, i.e. to multiple carboxylase deficiency (MCD).
      explanation: The review directly connects HCS deficiency to deficiency of the four biotin-dependent carboxylases.
  - target: Cutaneous and hair involvement
    description: Defective biotin-dependent enzyme activation is associated with cutaneous and hair manifestations in HLCS deficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39194177
      reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death.
      explanation: The clinical abstract places skin rash and alopecia in the HLCS deficiency phenotype; the intervening tissue-level mechanisms are compressed in this edge.
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up.
    explanation: Clinical reversibility with biotin is consistent with a primary defect in biotin-dependent enzyme activation.
- name: Multiple carboxylase deficiency
  description: 'Impaired HLCS activity produces concurrent functional deficiency of pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and acetyl-CoA carboxylase (ACC), creating a multi-pathway metabolic block.

    '
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: carboxylic acid metabolic process
    term:
      id: GO:0019752
      label: carboxylic acid metabolic process
    modifier: DYSREGULATED
  - preferred_term: fatty acid biosynthetic process
    term:
      id: GO:0006633
      label: fatty acid biosynthetic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: pyruvate carboxylase activity
    term:
      id: GO:0004736
      label: pyruvate carboxylase activity
    modifier: DECREASED
  - preferred_term: propionyl-CoA carboxylase activity
    term:
      id: GO:0004658
      label: propionyl-CoA carboxylase activity
    modifier: DECREASED
  - preferred_term: methylcrotonoyl-CoA carboxylase activity
    term:
      id: GO:0004485
      label: methylcrotonoyl-CoA carboxylase activity
    modifier: DECREASED
  - preferred_term: acetyl-CoA carboxylase activity
    term:
      id: GO:0003989
      label: acetyl-CoA carboxylase activity
    modifier: DECREASED
  downstream:
  - target: Disrupted gluconeogenesis and lactic acidosis
    description: PC dysfunction impairs pyruvate anaplerosis and glucose production.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired pyruvate carboxylase biotinylation and activity
    evidence:
    - reference: PMID:3918814
      reference_title: "Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "multiple deficiencies of the 3 mitochondrial biotin-dependent carboxylases: propionyl-CoA (PCC), 3-methylcrotonyl-CoA (MCC) and pyruvate carboxylase (PC)"
      explanation: The enzyme-assay paper identifies pyruvate carboxylase as one of the mitochondrial biotin-dependent carboxylases affected in multiple carboxylase deficiency.
  - target: Impaired leucine catabolism
    description: MCC dysfunction drives accumulation of leucine-pathway intermediates.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired 3-methylcrotonyl-CoA carboxylase biotinylation and activity
    evidence:
    - reference: PMID:3918814
      reference_title: "Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "multiple deficiencies of the 3 mitochondrial biotin-dependent carboxylases: propionyl-CoA (PCC), 3-methylcrotonyl-CoA (MCC) and pyruvate carboxylase (PC)"
      explanation: The enzyme-assay paper identifies 3-methylcrotonyl-CoA carboxylase as one of the mitochondrial biotin-dependent carboxylases affected in multiple carboxylase deficiency.
  - target: Impaired propionate metabolism
    description: PCC dysfunction drives accumulation of propionyl-derived metabolites.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired propionyl-CoA carboxylase biotinylation and activity
    evidence:
    - reference: PMID:3918814
      reference_title: "Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "multiple deficiencies of the 3 mitochondrial biotin-dependent carboxylases: propionyl-CoA (PCC), 3-methylcrotonyl-CoA (MCC) and pyruvate carboxylase (PC)"
      explanation: The enzyme-assay paper identifies propionyl-CoA carboxylase as one of the mitochondrial biotin-dependent carboxylases affected in multiple carboxylase deficiency.
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle.'
    explanation: Directly supports concurrent deficiency of multiple carboxylases in HLCS deficiency.
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Simultaneous elevation of multiple pathway metabolites supports a multi-carboxylase defect state.
- name: Disrupted gluconeogenesis and lactic acidosis
  description: 'Pyruvate carboxylase (PC) deficiency due to impaired biotinylation reduces conversion of pyruvate to oxaloacetate, impairing gluconeogenesis and TCA cycle anaplerosis. This contributes to lactic acidosis and hypoglycemia observed in affected patients.

    '
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
  - preferred_term: pyruvate metabolic process
    term:
      id: GO:0006090
      label: pyruvate metabolic process
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Secondary organic acidemia and ketotic decompensation
    description: Impaired carbohydrate flux contributes to metabolic decompensation under catabolic stress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Pyruvate and lactate accumulation
    - Impaired glucose production during catabolic stress
    evidence:
    - reference: PMID:32841162
      reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis.
      explanation: Hypoglycemia together with metabolic acidosis supports the decompensation branch downstream of impaired gluconeogenesis.
  - target: Lactic acidosis
    description: Pyruvate carboxylase-related impairment manifests clinically as lactic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39194177
      reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation.
      explanation: The case directly documents severe lactic acidosis in HLCS deficiency.
  - target: Hypoglycemia
    description: Reduced gluconeogenic capacity can present as hypoglycemia during illness or poor intake.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired gluconeogenesis during catabolic stress
    evidence:
    - reference: PMID:32841162
      reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis.
      explanation: The report documents severe hypoglycemia in HLCS deficiency.
  - target: Lactic acid
    description: Lactate elevation is the biochemical counterpart of lactic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39634276
      reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid.
      explanation: The case directly reports elevated lactate in urine organic acid analysis.
  evidence:
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia.
    explanation: Confirms lactic acidosis as a typical manifestation of HLCS deficiency, consistent with impaired PC-dependent gluconeogenesis.
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation.
    explanation: Illustrates severe lactic acidosis in neonatal HLCS deficiency from impaired gluconeogenesis.
- name: Impaired leucine catabolism
  description: 'Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) disrupts leucine catabolism, leading to accumulation of C5-hydroxylated leucine-pathway metabolites and 3-methylcrotonylglycine.

    '
  biological_processes:
  - preferred_term: leucine catabolic process
    term:
      id: GO:0006552
      label: L-leucine catabolic process
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Secondary organic acidemia and ketotic decompensation
    description: Leucine-pathway metabolite accumulation contributes to acute metabolic crisis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - 3-hydroxyisovalerylcarnitine and 3-methylcrotonylglycine accumulation
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
      explanation: Elevation of leucine-pathway metabolites supports this contribution to organic acidemia.
  - target: 3-Hydroxyisovalerylcarnitine (C5-OH)
    description: MCC pathway impairment increases the C5-OH acylcarnitine marker.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
      explanation: The cohort directly reports increased C5-OH.
  - target: 3-Hydroxyisovaleric acid
    description: MCC pathway impairment increases urinary hydroxyisovalerate-class metabolites.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39634276
      reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid.
      explanation: The case directly reports elevated 3-hydroxyisovaleric acid.
  - target: 3-Methylcrotonylglycine
    description: MCC pathway impairment increases urinary 3-methylcrotonylglycine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
      explanation: The cohort directly reports increased urinary 3-methylcrotonylglycine.
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Documents increased MCC-related metabolites in HLCS deficiency.
- name: Impaired propionate metabolism
  description: 'Deficiency of propionyl-CoA carboxylase (PCC) impairs propionate catabolism, contributing to elevations of methylcitric acid and 3-hydroxypropionate.

    '
  biological_processes:
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Secondary organic acidemia and ketotic decompensation
    description: Propionyl-derived metabolite accumulation contributes to decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - 3-hydroxypropionate and methylcitric acid accumulation
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
      explanation: Elevation of propionate-pathway metabolites supports this contribution to organic acidemia.
  - target: 3-Hydroxypropionate
    description: PCC pathway impairment increases urinary 3-hydroxypropionate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
      explanation: The cohort directly reports increased urinary 3-hydroxypropionate.
  - target: Methylcitric acid
    description: PCC pathway impairment increases urinary methylcitric acid.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
      explanation: The cohort directly reports increased urinary methylcitric acid.
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Documents increased PCC-related metabolites in HLCS deficiency.
- name: Secondary organic acidemia and ketotic decompensation
  description: 'Combined pathway dysfunction causes recurrent high-anion-gap metabolic acidosis and ketotic decompensation, particularly during catabolic stress.

    '
  downstream:
  - target: Secondary hyperammonemia
    description: Acute metabolic stress can secondarily impair nitrogen handling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed.
      explanation: The case documents hyperammonemia arising during a severe acidotic decompensation; the precise nitrogen-handling intermediates are not specified in the abstract.
  - target: Glucose dysregulation and hyperglycemic ketoacidosis
    description: Stress-state management can unmask insulin secretion abnormalities.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Secondary Krebs cycle disturbance in pancreatic beta cells
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia.
      explanation: The authors propose a Krebs cycle to beta-cell insulin secretion mechanism connecting decompensation to hyperglycemic ketoacidosis.
  - target: Neurologic metabolic decompensation
    description: Acidotic decompensation, organic acid accumulation, hypoglycemia, and hyperammonemia can produce acute neurologic dysfunction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Severe metabolic acidosis
    - Hypoglycemia
    - Secondary hyperammonemia
    evidence:
    - reference: PMID:39391064
      reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
      explanation: The review links severe metabolic acidosis to acute neurologic features in typical presentations.
  - target: Systemic feeding and growth involvement
    description: Multisystem decompensation and chronic illness can include feeding difficulty and impaired growth.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39634276
      reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
      explanation: The abstract reports feeding difficulties and growth retardation as common clinical manifestations alongside metabolic acidosis.
  - target: Metabolic acidosis
    description: Organic acid accumulation manifests clinically as metabolic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39391064
      reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
      explanation: This directly supports metabolic acidosis as a manifestation of the decompensation state.
  - target: Vomiting
    description: Acute metabolic decompensation commonly presents with vomiting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency.
      explanation: The acute decompensation case directly includes vomiting.
  - target: Tachypnea
    description: Severe acidosis can drive rapid breathing as respiratory compensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Respiratory compensation for metabolic acidosis
    evidence:
    - reference: PMID:39194177
      reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures
      explanation: The abstract lists tachypnea together with severe metabolic acidosis in HLCS deficiency.
  evidence:
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency.
    explanation: Documents severe metabolic decompensation in HLCS deficiency.
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration.
    explanation: Confirms that acute acidotic decompensation can also occur in late-onset HLCS deficiency.
- name: Secondary hyperammonemia
  description: 'Hyperammonemia can emerge during acute decompensation, likely from catabolic stress and secondary disturbance of nitrogen disposal.

    '
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
  evidence:
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia.
    explanation: Directly lists hyperammonemia as a typical manifestation.
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed.
    explanation: Documents hyperammonemia during acute HLCS decompensation.
  downstream:
  - target: Hyperammonemia
    description: The secondary nitrogen-disposal disturbance manifests as elevated circulating ammonia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed.
      explanation: The case directly documents hyperammonemia during HLCS decompensation.
- name: Glucose dysregulation and hyperglycemic ketoacidosis
  description: 'In some patients, secondary Krebs cycle disturbances may impair pancreatic beta-cell insulin secretion, leading to hyperglycemic ketoacidosis during glucose infusion therapy.

    '
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
  evidence:
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved.
    explanation: Documents hyperglycemic ketoacidosis during HLCS decompensation and proposes secondary Krebs cycle disturbance mechanism.
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia.
    explanation: Provides mechanistic hypothesis for glucose dysregulation in HLCS decompensation.
  downstream:
  - target: Hyperglycemia
    description: Impaired glucose-stimulated insulin secretion can cause hyperglycemia during glucose infusion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Insulinopenia during decompensation
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis.
      explanation: Hyperglycemic ketoacidosis directly supports hyperglycemia in this branch.
  - target: Ketoacidosis
    description: Insulinopenia during decompensation can produce ketoacidosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Insulinopenia during decompensation
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis.
      explanation: The case directly reports ketoacidosis as part of the hyperglycemic decompensation state.
- name: Neurologic metabolic decompensation
  description: 'Severe acidotic crises, hypoglycemia, hyperammonemia, and organic acid accumulation can produce acute neurologic dysfunction, including lethargy, hypotonia, and seizures. Delayed or severe crises can also contribute to developmental delay.

    '
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
    explanation: Lists acute neurologic manifestations in the typical severe acidotic presentation.
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death.
    explanation: Supports neurologic involvement including hypotonia, developmental delay, and seizures.
  downstream:
  - target: Seizures
    description: Severe metabolic decompensation can produce seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39391064
      reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
      explanation: The review lists seizures as part of the typical severe neonatal presentation.
  - target: Lethargy
    description: Severe metabolic decompensation can reduce alertness.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38550975
      reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency.
      explanation: The acute decompensation case directly includes lethargy.
  - target: Muscular hypotonia
    description: Acute neurologic metabolic dysfunction can manifest as hypotonia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39391064
      reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
      explanation: The review lists hypotonia as a typical presenting feature.
  - target: Global developmental delay
    description: Severe or delayed metabolic control can contribute to developmental delay.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39194177
      reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures
      explanation: The abstract lists developmental delay among clinical manifestations, though it does not specify the exact intervening injury mechanism.
- name: Cutaneous and hair involvement
  description: 'HLCS deficiency includes cutaneous and hair findings such as rash, alopecia, and sometimes generalized ichthyosis. The graph groups these findings as downstream consequences of impaired biotin-dependent enzyme activation while leaving the tissue-level intermediates unspecified.

    '
  locations:
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death.
    explanation: Lists rash and alopecia among the clinical manifestations of HLCS deficiency.
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis.
    explanation: Documents generalized ichthyosis before biotin therapy in a neonatal case.
  downstream:
  - target: Skin rash
    description: The cutaneous involvement includes eczematous or erythematous rash.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness
      explanation: The cohort reports rash among symptomatic HLCS deficiency patients.
  - target: Alopecia
    description: The hair involvement includes alopecia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32841162
      reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia.
      explanation: The report lists alopecia as a typical manifestation.
  - target: Ichthyosis
    description: Severe cutaneous involvement may include generalized ichthyosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39194177
      reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis.
      explanation: The neonatal case directly documents generalized ichthyosis.
- name: Systemic feeding and growth involvement
  description: 'Infantile HLCS deficiency can involve feeding difficulties and growth retardation as part of the multisystem clinical state. These endpoints may reflect systemic illness, poor intake, and recurrent decompensation rather than a single defined molecular intermediate.

    '
  evidence:
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
    explanation: Directly supports feeding and growth involvement in HLCS deficiency.
  downstream:
  - target: Feeding difficulties
    description: Multisystem illness can present with feeding difficulties.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39634276
      reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
      explanation: The case report abstract directly lists feeding difficulties.
  - target: Growth delay
    description: Chronic feeding and systemic involvement can manifest as growth retardation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39634276
      reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
      explanation: The case report abstract directly lists growth retardation.
phenotypes:
- name: Metabolic acidosis
  description: 'High-anion-gap metabolic acidosis is a recurring presenting feature, often severe and difficult to correct. It results from accumulation of organic acids from multiple blocked carboxylase pathways.

    '
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
    explanation: Lists metabolic acidosis as a typical presenting feature of HCS deficiency.
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation, with predominant involvement of the nervous system, skin, and hair.
    explanation: Confirms metabolic acidosis as a common clinical manifestation.
- name: Lactic acidosis
  description: 'Lactic acidosis results from impaired pyruvate carboxylase function disrupting gluconeogenesis and TCA cycle anaplerosis. Severity can be extreme in neonatal presentations.

    '
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation.
    explanation: Documents severe lactic acidosis as a presenting feature in neonatal HLCS deficiency.
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia.
    explanation: Lists lactic acidosis among the typical manifestations of HLCS deficiency.
- name: Seizures
  description: 'Seizures occur in acute metabolic decompensation, reflecting brain vulnerability to organic acid accumulation and energy failure.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
    explanation: Lists seizures among typical presenting features.
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness
    explanation: Confirms seizures in the 28-patient Chinese cohort.
- name: Skin rash
  description: 'Eczematous or erythematous skin rash is a reported dermatologic feature, often presenting early. It reflects cutaneous consequences of biotin cofactor deficiency.

    '
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness
    explanation: Documents rash as a common symptom in the 28-patient cohort.
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
    explanation: Confirms rash among common clinical manifestations of HLCS deficiency.
- name: Alopecia
  description: 'Hair loss is a reported clinical feature of HLCS deficiency, reflecting biotin deficiency at the level of hair follicle biology.

    '
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death.
    explanation: Lists alopecia among clinical manifestations of HLCS deficiency.
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia.
    explanation: Confirms alopecia as a typical manifestation.
- name: Hyperammonemia
  description: 'Hyperammonemia occurs during metabolic decompensation, likely from catabolic stress and secondary urea cycle impairment.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death.
    explanation: Lists hyperammonemia among clinical manifestations.
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typical manifestations of HCSD include eczema, alopecia, lactic acidosis and hyperammonemia.
    explanation: Confirms hyperammonemia as a typical manifestation of HLCS deficiency.
- name: Lethargy
  description: 'Reduced alertness and drowsiness during acute metabolic decompensation, which may progress to coma in untreated or severe cases.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
    explanation: Lists lethargy among typical presenting features.
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency.
    explanation: Confirms lethargy as a presenting symptom in a documented HLCS case.
- name: Muscular hypotonia
  description: 'Generalized hypotonia is a neurological finding, particularly during acute metabolic crises in neonates and infants.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
    explanation: Lists hypotonia as a typical presenting feature.
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures
    explanation: Confirms hypotonia among clinical manifestations.
- name: Vomiting
  description: 'Vomiting with poor oral intake can occur during metabolic instability.

    '
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness
    explanation: Documents vomiting as a common symptom in the 28-patient cohort.
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures.
    explanation: Lists vomiting among typical presenting features.
- name: Tachypnea
  description: 'Rapid breathing occurs as a compensatory response to metabolic acidosis during decompensation. Respiratory symptoms may be the initial presenting manifestation in some patients.

    '
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures
    explanation: Lists tachypnea among clinical manifestations.
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Despite supportive treatment with antibiotics upon admission, the infant continued to experience rapid and deep breathing accompanied by groaning, and obvious wheezing.
    explanation: Supports respiratory distress with rapid breathing, which is compatible but not fully specific for tachypnea.
- name: Global developmental delay
  description: 'Developmental delay may occur, particularly in patients with delayed diagnosis or severe metabolic crises. Early biotin treatment is associated with normal developmental outcomes.

    '
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures
    explanation: Lists developmental delay among clinical manifestations of HLCS deficiency.
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up.
    explanation: Indicates developmental delay is preventable with early biotin therapy, implying it occurs when treatment is delayed.
- name: Feeding difficulties
  description: 'Poor feeding and feeding intolerance occur in neonatal and infantile presentations, contributing to failure to thrive.

    '
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures
    explanation: Lists feeding problems among clinical manifestations.
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
    explanation: Confirms feeding difficulties as a common manifestation.
- name: Growth delay
  description: 'Growth retardation may occur in the setting of chronic metabolic disease and feeding difficulties.

    '
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation
    explanation: Lists growth retardation among common clinical manifestations.
- name: Hypoglycemia
  description: 'Hypoglycemia results from impaired gluconeogenesis secondary to pyruvate carboxylase deficiency. Recurrent episodes may occur during intercurrent illness.

    '
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 1 was a 7-year-old girl with normal growth and development, presenting with severe hypoglycemia and metabolic acidosis.
    explanation: Documents severe hypoglycemia as a presenting feature in an HLCS deficiency patient.
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed.
    explanation: Confirms hypoglycemia as a feature of acute decompensation in HLCS deficiency.
- name: Hyperglycemia
  description: 'Hyperglycemia can occur during acute decompensation when intravenous glucose is given to suppress catabolism and secondary insulin secretion defects emerge.

    '
  phenotype_term:
    preferred_term: Hyperglycemia
    term:
      id: HP:0003074
      label: Hyperglycemia
  evidence:
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis.
    explanation: Directly documents hyperglycemia as part of hyperglycemic ketoacidosis during HLCS decompensation.
- name: Ketoacidosis
  description: 'Ketoacidosis can occur during acute decompensation when secondary insulinopenia develops during glucose infusion.

    '
  phenotype_term:
    preferred_term: Ketoacidosis
    term:
      id: HP:0001993
      label: Ketoacidosis
  evidence:
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis.
    explanation: Directly documents ketoacidosis during HLCS decompensation.
- name: Ichthyosis
  description: 'Generalized ichthyosis has been observed as a severe dermatologic manifestation in neonatal HLCS deficiency.

    '
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis.
    explanation: Documents generalized ichthyosis developing in a neonate with HLCS deficiency prior to biotin therapy.
biochemical:
- name: 3-Hydroxyisovalerylcarnitine (C5-OH)
  presence: INCREASED
  readouts:
  - target: Impaired leucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased C5-OH acylcarnitine reports impaired
      3-methylcrotonyl-CoA carboxylase-dependent leucine catabolism.
  context: 'C5-OH is an acylcarnitine marker reported in HLCS deficiency. In a 28-patient cohort, C5-OH was increased in blood along with urinary organic acid abnormalities.

    '
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Directly documents elevated C5-OH in HLCS deficiency patients.
- name: Lactic acid
  presence: INCREASED
  readouts:
  - target: Disrupted gluconeogenesis and lactic acidosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated lactate reports pyruvate carboxylase-related disruption of
      pyruvate handling, gluconeogenesis, and lactic acidosis.
  context: 'Lactic acidosis reflects impaired pyruvate carboxylase function and disrupted gluconeogenesis. Lactate levels can be severely elevated in neonatal presentations.

    '
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation.
    explanation: Documents severe lactic acidosis in neonatal HLCS deficiency.
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid.
    explanation: Directly reports elevated lactate in urine organic acid analysis.
- name: 3-Hydroxyisovaleric acid
  presence: INCREASED
  readouts:
  - target: Impaired leucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary 3-hydroxyisovaleric acid reports accumulation of
      leucine-pathway intermediates downstream of MCC dysfunction.
  context: 'Urinary 3-hydroxyisovaleric acid elevation reflects impaired 3-methylcrotonyl-CoA carboxylase (MCC) activity in the leucine catabolic pathway.

    '
  evidence:
  - reference: PMID:39634276
    reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid.
    explanation: The case directly reports elevated 3-hydroxyisovaleric acid.
- name: Methylcitric acid
  presence: INCREASED
  readouts:
  - target: Impaired propionate metabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary methylcitric acid reports propionyl-CoA carboxylase
      impairment and propionate-pathway metabolite accumulation.
  context: 'Elevated urinary methylcitric acid reflects propionyl-CoA carboxylase (PCC) deficiency and propionyl-CoA entry into the TCA cycle via citrate synthase.

    '
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Directly documents elevated methylcitric acid in urine of HLCS deficiency patients.
- name: 3-Methylcrotonylglycine
  presence: INCREASED
  readouts:
  - target: Impaired leucine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary 3-methylcrotonylglycine reports impaired
      3-methylcrotonyl-CoA carboxylase-dependent leucine catabolism.
  context: 'Urinary 3-methylcrotonylglycine is a conjugated metabolite reflecting impaired MCC activity in the leucine degradation pathway.

    '
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Directly documents elevated 3-methylcrotonylglycine in urine.
- name: 3-Hydroxypropionate
  presence: INCREASED
  readouts:
  - target: Impaired propionate metabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary 3-hydroxypropionate reports impaired propionate
      catabolism downstream of propionyl-CoA carboxylase dysfunction.
  context: 'Urinary 3-hydroxypropionate elevation results from impaired propionyl-CoA carboxylase activity and propionate pathway dysfunction.

    '
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals.
    explanation: Directly documents elevated 3-hydroxypropionate in urine.
genetic:
- name: HLCS pathogenic variants
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39634276
      reference_title: "Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Holocarboxylase synthetase deficiency (HLCSD) is a rare autosomal recessive genetic disorder caused by mutations in the holocarboxylase synthetase (HLCS) gene, which affects multiple systems.
      explanation: Directly states autosomal recessive inheritance for HLCS deficiency.
  variants:
  - name: HLCS - c.1522C>T (p.R508W)
    description: 'The most common variant in a Chinese HLCS deficiency cohort, representing 41.1% of alleles. Located in the C-terminal biotin-binding domain of the HLCS protein.

      '
    evidence:
    - reference: PMID:36890565
      reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among them, the variant of c.1522C > T was the most common.
      explanation: Directly supports c.1522C>T as the most common variant in the Chinese cohort.
  - name: HLCS - c.710T>C (p.Leu237Pro)
    description: 'A pathogenic missense variant associated with early-onset severe neonatal presentation. Located in the N-terminal region of the HLCS protein.

      '
    evidence:
    - reference: PMID:39194177
      reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Genetic analysis of actionable metabolic disorders revealed compound heterozygous variants of HLCS (NM_000411.8), specifically c.[710T>C (p.Leu237Pro)]; [1544G>A (p.Ser515Asn)]
      explanation: Documents this variant in a neonatal case with severe lactic acidosis.
  - name: HLCS - c.995A>G (p.Gln332Arg)
    description: 'A novel pathogenic variant identified in homozygous state in siblings with very late onset HLCS deficiency, with symptomatic presentation at 11 years.

      '
    evidence:
    - reference: PMID:39391064
      reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration.
      explanation: Supports very late symptomatic onset (11 years) in the sibling pair.
    - reference: PMID:39391064
      reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'genetic testing revealed a novel pathogenic variant in the HLCS gene (NM_000411.8) in the homozygous state: c.995A>G; p. (Gln332Arg).'
      explanation: Directly supports the c.995A>G (p.Gln332Arg) variant assignment.
  features: 'Biallelic pathogenic variants in HLCS cause holocarboxylase synthetase deficiency. In a 28-patient Chinese cohort, 17 different mutations were observed and 89.3% of alleles were missense. Genotype correlates with biotin responsiveness: variants in the C-terminal biotin-binding domain (aa 448-701) are generally biotin-responsive, while variants in the N-terminal extension/substrate-binding region (aa 159-314) may be less responsive. Onset age varies from neonatal to very late (23 years at diagnosis), without clear genotype-phenotype correlation for timing.

    '
  evidence:
  - reference: PMID:39391064
    reference_title: "Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A mini-review of HCS deficiency with late onset (>1 year) or early onset (<1 month) revealed that splice variants are associated with late onset, while both variants p. (Leu216Arg) and p. (Leu237Pro) are associated with early onset.
    explanation: Provides genotype-phenotype correlations regarding onset timing.
- name: HLCS
  gene_term:
    preferred_term: HLCS
    term:
      id: hgnc:4976
      label: HLCS
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_ad306285-9588-48e3-a6fa-183db3f01fe9-2021-02-26T171131.548Z
    reference_title: "HLCS / holocarboxylase synthetase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HLCS | HGNC:4976 | holocarboxylase synthetase deficiency | MONDO:0009666 | AR | Definitive"
    explanation: ClinGen classifies the HLCS-holocarboxylase synthetase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Biotin supplementation
  description: 'Pharmacologic oral biotin (10-40 mg/day) is the primary disease-modifying therapy for HLCS deficiency. Biotin overcomes the reduced HLCS activity by increasing substrate availability, restoring carboxylase biotinylation. Dramatic clinical and biochemical improvement typically occurs within hours to days of initiation.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up.
    explanation: Demonstrates dramatic resolution of symptoms with biotin therapy in a 28-patient cohort.
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Remarkably, dramatic clinical improvement in lactic acidosis was observed the day after initiating biotin administration, leading to the discontinuation of mechanical ventilation within 6 days.
    explanation: Documents rapid clinical improvement with biotin mega-dose therapy in a neonate.
  - reference: PMID:26754537
    reference_title: "Antenatal and postnatal radiologic diagnosis of holocarboxylase synthetase deficiency: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes.
    explanation: Systematic review confirming biotin supplementation is associated with good outcomes.
- name: Newborn screening
  description: 'Tandem mass spectrometry-based newborn screening detects HLCS deficiency via elevated 3-hydroxyisovalerylcarnitine (C5-OH) in dried blood spots. Early detection enables presymptomatic biotin initiation, preventing metabolic crises. False-negative results can occur if C5-OH falls below cutoff, requiring second-tier testing.

    '
  treatment_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes.
    explanation: Directly supports importance of newborn screening for HLCS deficiency.
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among the 28 patients, six patients underwent newborn screening, of which only one was missed.
    explanation: Provides real-world newborn screening detection data for HLCS deficiency.
- name: Acute decompensation management
  description: 'Emergency supportive care during metabolic crisis includes correction of acidosis, caloric provision to suppress catabolism, electrolyte management, and rapid initiation of biotin. When IV glucose infusion precipitates hyperglycemic ketoacidosis, insulin therapy may rapidly correct biochemical abnormalities.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency.
    explanation: Documents acute decompensation requiring emergency management in HLCS deficiency.
  - reference: PMID:38550975
    reference_title: "Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Insulin therapy rapidly corrected biochemical parameters, and clinical status improved.
    explanation: Demonstrates insulin therapy as an acute management strategy for hyperglycemic ketoacidosis in HLCS decompensation.
- name: Dietary intervention
  description: 'Nutrition strategy tailored to reduce substrate burden on impaired carboxylase pathways, including protein-managed diet during acute illness and chronic management to prevent catabolic stress.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:32841162
    reference_title: "Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she had five episodes of hypoglycemia and metabolic acidosis in past 4 years when her oral intake decreased during acute illness.
    explanation: Demonstrates that decreased oral intake triggers metabolic decompensation, supporting dietary management.
- name: Genetic counseling
  description: 'Genetic counseling for affected families, including discussion of autosomal recessive inheritance, 25% recurrence risk, carrier testing, and options for prenatal or preimplantation genetic diagnosis.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:36890565
    reference_title: "Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients.
    explanation: Genetic characterization supports genetic counseling for families.
- name: Molecular genetic testing
  description: 'Next-generation sequencing panels or targeted HLCS gene analysis enables rapid diagnosis in acutely ill neonates and can guide early initiation of biotin therapy before confirmatory biochemical testing is complete.

    '
  treatment_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  notes: 'Molecular testing is used for both diagnostic confirmation and to guide genotype-specific biotin dosing. Rapid turnaround is critical in the acute neonatal setting.

    '
  evidence:
  - reference: PMID:39194177
    reference_title: "Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our case highlights the significance of early genetic testing in neonates with unexplained metabolic disorders to enable timely diagnosis and therapy initiation.
    explanation: Directly supports the role of early genetic testing for HLCS deficiency management.
- name: Prenatal biotin supplementation
  description: 'Antenatal biotin supplementation has been reported in at-risk pregnancies and is associated with good clinical outcomes in affected neonates.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  evidence:
  - reference: PMID:26754537
    reference_title: "Antenatal and postnatal radiologic diagnosis of holocarboxylase synthetase deficiency: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes.
    explanation: Systematic review supporting antenatal biotin supplementation for at-risk pregnancies.
progression:
- notes: HLCS deficiency follows a progression from genetic defect through multi-enzyme deficiency to metabolic crisis. (1) Biallelic HLCS variants reduce holocarboxylase synthetase activity. (2) Impaired biotinylation of PC, PCC, MCC, and ACC produces multiple carboxylase deficiency. (3) Accumulation of organic acids and acylcarnitines causes metabolic acidosis, lactic acidosis, ketosis, and hyperammonemia. (4) Systemic decompensation produces neurologic injury (seizures, encephalopathy), dermatologic features (rash, alopecia), and respiratory distress. (5) Without treatment, progression to coma and death can occur. With prompt biotin therapy, 82% of patients in a large cohort developed normally. Onset is typically neonatal but very late-onset forms (11 years symptomatic, 23 years diagnosed) demonstrate phenotypic heterogeneity.
notes: 'Key clinical pearls: (1) HLCS deficiency is one of the treatable inborn errors of metabolism -- pharmacologic biotin often produces dramatic improvement within hours. (2) Deaths in the 28-patient Chinese cohort occurred during initial crises without timely biotin. (3) Genotype may predict biotin responsiveness: C-terminal biotin-binding domain variants (aa 448-701) tend to be more responsive than N-terminal variants (aa 159-314). (4) Biotin dosing typically ranges from 10-40 mg/day with tapering under biochemical monitoring. (5) Newborn screening via C5-OH is feasible but false negatives occur. (6) HLCS deficiency should be considered in any child or adult with unexplained metabolic acidosis, even beyond the neonatal period.

  '

📚

References & Deep Research

Deep Research

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Disease Pathophysiology Research Template

Edison Scientific Literature 23 citations 2026-02-23T23:37:11.578171

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Holocarboxylase Synthetase Deficiency
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Holocarboxylase Synthetase Deficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Holocarboxylase Synthetase Deficiency (HLCS deficiency; biotin‑responsive multiple carboxylase deficiency)

MONDO / classification Holocarboxylase synthetase deficiency is an autosomal recessive inborn error of metabolism caused by loss‑of‑function variants in HLCS, resulting in “multiple carboxylase deficiency” due to impaired biotinylation (activation) of biotin‑dependent carboxylases. OpenTargets lists the disease as MONDO_0009666 (“holocarboxylase synthetase deficiency”) with HLCS as the associated target (MONDO_0009666 as returned by OpenTargets search; primary literature PMIDs in that resource were not retrieved as full texts here). (ling2023clinicalbiochemicaland pages 1-2)

Executive mechanistic summary (current understanding) Holocarboxylase synthetase (HLCS; also called holocarboxylase synthase) is responsible for covalently attaching biotin to specific apocarboxylases, thereby converting inactive apo‑carboxylases into active holo‑carboxylases. The principal human targets highlighted in recent clinical literature include pyruvate carboxylase (PC), propionyl‑CoA carboxylase (PCC), 3‑methylcrotonyl‑CoA carboxylase (MCC), and acetyl‑CoA carboxylase (ACC). Loss of HLCS activity reduces activities of these enzymes and disrupts major metabolic pathways: gluconeogenesis, fatty acid synthesis, and amino‑acid catabolism (particularly leucine and propionyl/odd‑chain fatty acid metabolism). Clinically, this manifests as episodic or persistent metabolic decompensation characterized by metabolic acidosis (often with lactic acidosis), organic aciduria, ketosis, and hyperammonemia; dermatologic and neurologic features are common; untreated disease can progress to coma and death. (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2, gaschignard2024casereporttwo pages 1-3)

1) Core pathophysiology 1.1 Primary mechanism: impaired protein biotinylation → multi‑enzyme deficiency Recent cohort and case reports describe the central mechanism as failure of HLCS‑mediated biotinylation of carboxylases, causing “multiple carboxylase deficiency.” (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2)

Direct mechanistic phrasing from the literature includes that HLCS is “responsible for covalently linking biotin” to biotin‑dependent carboxylases and that this biotinylation is “crucial for their enzymatic activities.” (kim2024dramaticclinicalimprovement pages 1-2)

1.2 Dysregulated pathways Because PCC, MCC, PC, and ACC sit at key junctions of intermediary metabolism, HLCS deficiency produces pathway‑level dysfunction across:

• Gluconeogenesis/anaplerosis: PC deficiency reduces conversion of pyruvate to oxaloacetate, contributing to lactic acidosis and impaired glucose homeostasis (hypoglycemia in some cases). (kim2024dramaticclinicalimprovement pages 1-2, wu2020impairedglucosehomeostasis pages 4-5) • Amino‑acid catabolism: MCC deficiency disrupts leucine catabolism, contributing to elevations of 3‑hydroxyisovalerate/3‑methylcrotonylglycine and related acylcarnitines (e.g., C5OH). (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2) • Propionate metabolism: PCC deficiency contributes to elevations of propionyl‑derived metabolites (e.g., methylcitrate) and acylcarnitine perturbations (C3). (ling2023clinicalbiochemicaland pages 1-2, ling2023clinicalbiochemicaland pages 4-5) • Fatty acid metabolism: ACC impairment affects fatty acid synthesis; more broadly, energy failure is invoked in severe decompensations. (kim2024dramaticclinicalimprovement pages 1-2, zou2024casereporta pages 2-4)

1.3 Biotin cycle / homeostasis framing A 2024 review situates HLCS deficiency within the “biotin cycle,” in which HLCS biotinylates apocarboxylases to form active holocarboxylases; subsequent proteolysis yields biocytin/biotinyl‑peptides, and biotinidase releases free biotin for recycling. Deficient HLCS therefore “impairs formation of biotinylated proteins” and functionally mimics severe biotin deficiency at the enzyme‑activity level. (karachaliou2024biotinhomeostasisand pages 4-5)

2) Key molecular players 2.1 Genes/proteins (causal and proximal) Causal gene: • HLCS (holocarboxylase synthetase). Cohort genetics demonstrate many missense and other variants; in one 28‑patient cohort, 17 different mutations were observed and 89.3% of alleles were missense; a frequent allele in that cohort was c.1522C>T (p.R508W), representing 41.1% of alleles. (ling2023clinicalbiochemicaland pages 4-5)

Direct biochemical targets (biotin‑dependent carboxylases emphasized in recent clinical reports): • PC (pyruvate carboxylase), PCC (propionyl‑CoA carboxylase), MCC (3‑methylcrotonyl‑CoA carboxylase), ACC (acetyl‑CoA carboxylase). (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2)

2.2 Chemical entities / metabolites / biomarkers Key diagnostic and pathophysiology‑linked biomarkers used in newborn screening and confirmatory testing:

Blood (MS/MS) biomarkers: • 3‑hydroxyisovalerylcarnitine (C5‑OH): described as an NBS marker; in the 28‑patient cohort, C5OH was “far beyond the cutoff” in all patients. (ling2023clinicalbiochemicaland pages 1-2, ling2023clinicalbiochemicaland pages 4-5) • C3 (propionylcarnitine), C2, and ratios such as C3/C2 and C5OH/C3 may show characteristic patterns (C3/C2 only slightly elevated in ~half the cohort, while C5OH/C3 often elevated). (ling2023clinicalbiochemicaland pages 4-5)

Urine (GC/MS) organic acid biomarkers: • Increased lactic acid, 3‑hydroxyisovaleric acid, 3‑hydroxypropionic acid, 3‑methylcrotonylglycine, methylcitric acid, tiglylglycine, pyruvate (and others) recur across reports. (kim2024dramaticclinicalimprovement pages 1-2, demaret2024insulintherapyin pages 1-2)

Quantitative examples from a 2024 neonatal case (illustrating severity of metabolic intoxication): • C5‑OH 3.6955 μmol/L; plasma lactate 10.09 mmol/L; ammonia 392 μg/dL; urine lactic acid 6419.9 mmol/mol creatinine; urine 3‑hydroxyisovaleric acid 1956.4 mmol/mol creatinine. (kim2024dramaticclinicalimprovement pages 1-2)

Key therapeutic chemical entity: • Biotin (vitamin B7). Pharmacologic/high‑dose biotin is the main disease‑modifying therapy. (ling2023clinicalbiochemicaland pages 5-6, ling2023clinicalbiochemicaland pages 4-5)

2.3 Cell types and tissues (functional involvement) Although the cited clinical papers focus more on systemic metabolism than specific cell biology, the phenotypes and mechanistic pathways strongly implicate: • Hepatic metabolism (gluconeogenesis and organic acid handling), • Central nervous system (seizures, encephalopathy, developmental outcomes), • Skin/hair follicle biology (rash, eczema, alopecia), • Respiratory system during decompensation (tachypnea/respiratory distress as a response to acidosis and/or energy deficit). (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2, zou2024casereporta pages 2-4)

A 2024 review of biotin homeostasis notes that intracellular biotin is “mainly in mitochondria and the cytosol,” with “minor amounts in nuclei (histones) and microsomal fractions,” supporting a mitochondria/cytosol‑centric view of metabolic dysfunction while leaving open additional nuclear roles. (karachaliou2024biotinhomeostasisand pages 4-5)

2.4 Anatomical locations involved Clinically and mechanistically, the highest‑impact organs are those with high flux through affected pathways: • Liver (gluconeogenesis; propionate handling), • Brain (energy failure and excitability → seizures/encephalopathy), • Skin/hair. (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2)

3) Biological processes disrupted (GO‑oriented) The following biological processes are directly supported or strongly implied by the enzyme‑defect narrative: • Protein biotinylation / covalent protein modification (HLCS function as the biotin‑attaching enzyme). (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2) • Gluconeogenesis and pyruvate metabolic process (via PC impairment and lactic acidosis/hypoglycemia presentations). (kim2024dramaticclinicalimprovement pages 1-2, wu2020impairedglucosehomeostasis pages 4-5) • Leucine catabolic process (via MCC impairment and 3‑hydroxyisovalerate/3‑methylcrotonylglycine accumulation). (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2) • Propionate metabolic process / anaplerotic replenishment of TCA intermediates (via PCC dysfunction; methylcitrate elevation). (ling2023clinicalbiochemicaland pages 1-2, demaret2024insulintherapyin pages 1-2) • Fatty acid biosynthetic process (via ACC as a biotin‑dependent enzyme). (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2) • Response to metabolic acidosis / detoxification of organic acids (clinical consequence of pathway failure). (gaschignard2024casereporttwo pages 1-3, ling2023clinicalbiochemicaland pages 1-2)

4) Cellular components (where processes occur) The disease is driven by enzyme dysfunction in core metabolic compartments: • Mitochondrion (mitochondrial carboxylase activity is described as affected; intracellular biotin is mainly mitochondrial). (kim2024dramaticclinicalimprovement pages 2-4, karachaliou2024biotinhomeostasisand pages 4-5) • Cytosol (intracellular biotin mainly cytosolic; ACC is cytosolic). (karachaliou2024biotinhomeostasisand pages 4-5, kim2024dramaticclinicalimprovement pages 1-2) • Nucleus (minor biotin in nuclei/histones suggests potential regulatory layer, though not essential for the clinical metabolic phenotype as presented in the clinical cohort). (karachaliou2024biotinhomeostasisand pages 4-5)

5) Disease progression (sequence of events) A mechanistically consistent sequence supported by cohort/case observations is:

Step 1: Genetic HLCS deficiency → reduced HLCS enzymatic activity or reduced functional biotinylation capacity. • Reported as impaired biotinylation/activation of biotin‑dependent carboxylases. (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2)

Step 2: Multi‑carboxylase dysfunction → metabolic pathway block(s). • Leads to accumulation of characteristic organic acids and acylcarnitines (e.g., C5OH, methylcitrate, lactate). (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2)

Step 3: Systemic metabolic decompensation. • Manifests as metabolic acidosis (often severe), lactic acidosis, ketosis, and hyperammonemia; can include hypoglycemia or hyperglycemic ketoacidosis in certain contexts. (gaschignard2024casereporttwo pages 1-3, demaret2024insulintherapyin pages 1-2, wu2020impairedglucosehomeostasis pages 1-2)

Step 4: Tissue injury and phenotype. • Neurologic: lethargy, hypotonia, seizures, coma; MRI abnormalities reported in a subset. (ling2023clinicalbiochemicaland pages 1-2, ling2023clinicalbiochemicaland pages 4-5) • Dermatologic: rash/eczema and alopecia. (ling2023clinicalbiochemicaland pages 1-2, wu2020impairedglucosehomeostasis pages 1-2) • Respiratory: tachypnea and respiratory distress, sometimes as presenting features. (kim2024dramaticclinicalimprovement pages 1-2, zou2024casereporta pages 2-4)

Step 5: Treatment modifies course. • Prompt pharmacologic biotin often produces rapid clinical and biochemical improvement and strongly improves prognosis; delayed recognition can be fatal. (ling2023clinicalbiochemicaland pages 4-5, kim2024dramaticclinicalimprovement pages 1-2)

Distinct phases / age‑of‑onset heterogeneity Classic descriptions emphasize neonatal/infant onset with severe acidosis; however, late‑onset and even very late‑onset cases occur. A 2024 report documents symptomatic presentation as late as 11 years and diagnosis at 23 years in siblings, stressing that unexplained metabolic acidosis beyond infancy should still trigger evaluation. (gaschignard2024casereporttwo pages 1-3)

6) Phenotypic manifestations (HP‑oriented) and mechanistic links Key phenotypes in recent cohort/case literature include: • Metabolic acidosis / ketoacidosis (from organic acid accumulation and energy failure). (gaschignard2024casereporttwo pages 1-3, demaret2024insulintherapyin pages 1-2) • Lactic acidosis (from impaired gluconeogenesis/anaplerosis and secondary mitochondrial/TCA dysfunction). (kim2024dramaticclinicalimprovement pages 1-2, demaret2024insulintherapyin pages 1-2) • Hyperammonemia (likely from catabolic stress/secondary urea cycle impairment during decompensation). (kim2024dramaticclinicalimprovement pages 1-2, gaschignard2024casereporttwo pages 1-3) • Seizures and encephalopathy (brain vulnerability to metabolic crisis); one cohort reports that seizures can be “particularly sensitive to biotin therapy, often stopping within minutes to hours of administration.” (ling2023clinicalbiochemicaland pages 4-5) • Rash/eczema and alopecia (consistent clinical hallmarks). (ling2023clinicalbiochemicaland pages 1-2, wu2020impairedglucosehomeostasis pages 1-2) • Hypotonia and developmental delay, which may improve with early treatment. (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2) • Glucose homeostasis disturbances: hypoglycemia is reported in some cases (with profound acidosis), but hyperglycemic ketoacidosis also occurs, particularly during acute management with high glucose infusion. (wu2020impairedglucosehomeostasis pages 1-2, demaret2024insulintherapyin pages 1-2)

Recent developments and latest research (prioritized 2023–2024) A. Larger contemporary cohort quantifying outcomes and biomarker response (2023) Ling et al. (Orphanet J Rare Dis; publication date Mar 2023; URL https://doi.org/10.1186/s13023-023-02656-y) analyzed 28 Chinese patients and provided cohort‑level statistics: • Outcomes: 23/28 (82.1%) “developed healthy,” 3/28 (10.7%) died, and 2/28 (7.1%) were lost to follow‑up; deaths occurred during initial unrecognized metabolic crises without timely biotin. (ling2023clinicalbiochemicaland pages 4-5) • Biochemical response: median C5OH decreased from 7.01 (3.26–15.01) to 0.35 (0.08–1.87) after biotin therapy (P < 0.001). (ling2023clinicalbiochemicaland pages 4-5, ling2023clinicalbiochemicaland media bf654274) • Newborn screening: 6 were screened and only 1 was missed, illustrating both feasibility and false‑negative risk if C5OH falls below cutoff. (ling2023clinicalbiochemicaland pages 1-2, ling2023clinicalbiochemicaland pages 5-6)

B. Genotype–biotin responsiveness framework (2023) The same cohort/report also provides a clinically actionable interpretation of biotin responsiveness: • Variants in the C‑terminal biotin‑binding domain (aa 448–701) are described as generally biotin‑responsive. • Variants in the N‑terminal extension/substrate‑binding region (aa 159–314) may be less responsive. • Dosing guidance summarized: oral biotin commonly 10–40 mg/day, with tapering possible under biochemical monitoring. (ling2023clinicalbiochemicaland pages 5-6)

C. Biotin homeostasis review and subcellular context (2024) Karachaliou & Livaniou (Int J Mol Sci; Jun 2024; URL https://doi.org/10.3390/ijms25126578) synthesize “recent findings and perspectives” on biotin homeostasis, emphasizing the biotin cycle and the role of HLCS and biotinidase, and noting intracellular distribution of biotin predominantly in mitochondria/cytosol with minor nuclear fractions. This provides an updated conceptual scaffold for HLCS deficiency as a disorder of cofactor activation and recycling. (karachaliou2024biotinhomeostasisand pages 4-5)

D. Acute management innovation: insulin for hyperglycemic ketoacidosis (2024) Demaret et al. (Mol Genet Metab Rep; Jun 2024; URL https://doi.org/10.1016/j.ymgmr.2024.101073) report hyperglycemic ketoacidosis in HLCS deficiency precipitated by IV glucose intended to promote anabolism; insulin “rapidly corrected biochemical abnormalities and clinical status.” They hypothesize insulinopenia from secondary Krebs cycle disturbances impairing glucose‑stimulated insulin secretion in beta cells. This adds a practical, mechanistically motivated management insight for acute crises. (demaret2024insulintherapyin pages 1-2)

E. Expanded phenotypic spectrum: very late onset (2024) Gaschignard et al. (Front Genet; Sep 2024; URL https://doi.org/10.3389/fgene.2024.1249480) emphasize that very late onset can occur (11 years symptomatic; 23 years diagnosed), underscoring a need for awareness beyond infancy and potential value of newborn screening to prevent decompensation even in late‑onset genotypes. (gaschignard2024casereporttwo pages 1-3)

Current applications and real‑world implementations 1) Newborn screening • Many settings use tandem mass spectrometry newborn screening based on elevated C5‑OH (3‑hydroxyisovalerylcarnitine) in dried blood spots; abnormal screens are typically followed by confirmatory urine organic acids by GC/MS and molecular testing of HLCS. (ling2023clinicalbiochemicaland pages 1-2) • The 2023 cohort explicitly highlights that C5OH can be below cutoff in some cases (false negatives), so second‑tier testing (e.g., urine 3‑hydroxypropionate and methylcitrate) supports differentiation from primary 3‑MCC deficiency and other conditions. (ling2023clinicalbiochemicaland pages 5-6)

2) Molecular diagnosis / precision treatment • Next‑generation sequencing panels are used for rapid diagnosis in acute neonatal illness and can guide early initiation of biotin therapy. (kim2024dramaticclinicalimprovement pages 2-4)

3) Biotin therapy (disease‑modifying) • Oral pharmacologic biotin is the primary therapy; a consensus range of 10–40 mg/day is summarized in cohort analysis, with some patients initially treated at 40 mg/day then tapered to 10 mg/day with metabolic monitoring. (ling2023clinicalbiochemicaland pages 5-6) • Rapid biochemical response is demonstrated in a 2024 neonatal case: lactate decreased from 10.76 to 2.87 mmol/L within one day after biotin, with associated clinical stabilization and subsequent discharge. (kim2024dramaticclinicalimprovement pages 2-4)

4) Acute crisis management • Standard acute care includes correction of acidosis, provision of calories to suppress catabolism, and rapid initiation of biotin. • A notable 2024 management update is the use of insulin when high‑glucose infusion precipitates hyperglycemic ketoacidosis during HLCS decompensation, with rapid biochemical and clinical improvement reported. (demaret2024insulintherapyin pages 1-2)

Relevant statistics and data (recent) Epidemiology: • Reported incidence estimates vary by source and geography: worldwide ~1/200,000; China ~1/930,600; Japan ~1/100,000 (from a 2023 cohort paper). (ling2023clinicalbiochemicaland pages 1-2) • A 2024 neonatal case report also cites a broader prevalence range of ~1/100,000 to 1/930,000 live births. (kim2024dramaticclinicalimprovement pages 1-2)

Cohort outcomes and treatment effect (2023): • In 28 Chinese patients (2006–2021), 23 (82.1%) developed healthy, 3 (10.7%) died, 2 were lost to follow‑up. (ling2023clinicalbiochemicaland pages 4-5) • Median C5OH improved from 7.01 to 0.35 μmol/L after biotin (P < 0.001). (ling2023clinicalbiochemicaland pages 4-5, ling2023clinicalbiochemicaland media bf654274)

Case‑based quantitative physiology (2024): • Neonatal HLCS deficiency can present with severe lactic acidosis and hyperammonemia; the 2024 case report provides concrete values (e.g., ammonia 392 μg/dL; lactate 10.09 mmol/L). (kim2024dramaticclinicalimprovement pages 1-2)

Expert opinions / analysis synthesized from authoritative sources 1) Biotin responsiveness is mechanistically and clinically heterogeneous Cohort analysis indicates that not all genotypes have the same responsiveness and dosing requirements, with domain‑dependent effects (C‑terminal biotin‑binding domain generally responsive vs N‑terminal extension/substrate‑binding region often less responsive). This is a pragmatic genotype‑to‑therapy model that can inform clinical decision‑making and follow‑up biochemical monitoring. (ling2023clinicalbiochemicaland pages 5-6)

2) Early recognition is the major modifiable determinant of outcome The cohort’s deaths occurred during initial crises without timely biotin, whereas prompt supplementation is repeatedly described as dramatically resolving biochemical abnormalities and supporting normal development for most survivors. The implication is that health‑system interventions (newborn screening, rapid confirmatory testing, and emergent empiric biotin in suspected cases) are central to preventing irreversible neurologic injury and mortality. (ling2023clinicalbiochemicaland pages 4-5, kim2024dramaticclinicalimprovement pages 2-4)

3) Acute management must anticipate atypical metabolic phenotypes Recent case literature emphasizes that HLCS deficiency can present with glucose dysregulation spanning hypoglycemia to hyperglycemic ketoacidosis. The insulin‑therapy report provides a mechanistic hypothesis (secondary TCA/Krebs cycle disturbance → impaired insulin secretion) and a practical intervention for a potentially iatrogenic complication of high‑glucose therapy during acute organic acidemia management. (demaret2024insulintherapyin pages 1-2, wu2020impairedglucosehomeostasis pages 1-2)

Knowledge‑base–style structured annotations (suggested)

A) Gene/protein annotations • HLCS (HGNC symbol: HLCS; protein: holocarboxylase synthetase) – causal; GO: “protein biotinylation” (process). Evidence: HLCS deficiency causes loss of biotinylation of multiple carboxylases (PCC, MCC, PC, ACC). (ling2023clinicalbiochemicaland pages 1-2, kim2024dramaticclinicalimprovement pages 1-2)

Proximal enzyme targets: • PC, PCC, MCC, ACC – decreased activity due to impaired biotinylation. (ling2023clinicalbiochemicaland pages 1-2)

B) GO biological process candidates (dysregulated) • Protein biotinylation (central). • Gluconeogenesis / pyruvate metabolism. • Leucine catabolism. • Propionate metabolism. • Fatty acid biosynthesis. Evidence: described pathway roles for affected carboxylases and associated metabolite changes. (kim2024dramaticclinicalimprovement pages 1-2, ling2023clinicalbiochemicaland pages 1-2)

C) Cellular component candidates • Mitochondrion; cytosol; nucleus (minor biotin pool). Evidence: intracellular biotin distribution and mitochondrial carboxylase impact statements. (kim2024dramaticclinicalimprovement pages 2-4, karachaliou2024biotinhomeostasisand pages 4-5)

D) Phenotype (HP) candidates (with mechanistic linkage) • Metabolic acidosis; lactic acidosis; hyperammonemia; ketosis; seizures; hypotonia; developmental delay; dermatitis/eczema; alopecia; respiratory distress/tachypnea; hypoglycemia; hyperglycemia/ketoacidosis. Evidence: cohort and multiple case reports. (ling2023clinicalbiochemicaland pages 1-2, ling2023clinicalbiochemicaland pages 4-5, kim2024dramaticclinicalimprovement pages 1-2, demaret2024insulintherapyin pages 1-2)

E) Cell type (CL) candidates (inferred from affected processes) • Hepatocyte (gluconeogenesis/propionate metabolism), neuron/astrocyte (seizures/encephalopathy), keratinocyte (dermatitis), pancreatic beta cell (insulin secretion hypothesis in hyperglycemic ketoacidosis). Evidence: clinical phenotype + mechanistic hypothesis for insulinopenia in decompensation. (demaret2024insulintherapyin pages 1-2, ling2023clinicalbiochemicaland pages 1-2)

F) Anatomical location (UBERON) candidates • Liver; brain; skin; hair follicle; lung (during crisis physiology). Evidence: phenotype clusters and respiratory presentations. (ling2023clinicalbiochemicaland pages 1-2, zou2024casereporta pages 2-4)

G) Chemical entities (CHEBI) candidates • Biotin; 3‑hydroxyisovalerylcarnitine (C5OH); lactate; ammonia; methylcitric acid; 3‑hydroxyisovaleric acid; 3‑hydroxypropionic acid; 3‑methylcrotonylglycine; tiglylglycine. Evidence: screening/urine biomarker panels and case quantitation. (kim2024dramaticclinicalimprovement pages 1-2, demaret2024insulintherapyin pages 1-2)

Evidence items and identifiers (PMIDs) PMIDs were not provided in the extracted text for most 2023–2024 sources retrieved here; therefore, evidence is referenced using DOI/URL and the cited context IDs. One exception is that OpenTargets evidence for HLCS–holocarboxylase synthetase deficiency includes legacy PMIDs (e.g., 12633764; 27604308; 11735028; 8817339; 9396568) but those papers were not retrieved in full text within this run, so mechanistic quotations were not extracted from them here. (ling2023clinicalbiochemicaland pages 1-2)

Key references (publication date; URL) • Ling et al. “Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency.” Orphanet J Rare Dis. Mar 2023. https://doi.org/10.1186/s13023-023-02656-y (ling2023clinicalbiochemicaland pages 1-2, ling2023clinicalbiochemicaland pages 4-5) • Karachaliou & Livaniou. “Biotin Homeostasis and Human Disorders: Recent Findings and Perspectives.” Int J Mol Sci. Jun 2024. https://doi.org/10.3390/ijms25126578 (karachaliou2024biotinhomeostasisand pages 4-5) • Demaret et al. “Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis.” Mol Genet Metab Rep. Jun 2024. https://doi.org/10.1016/j.ymgmr.2024.101073 (demaret2024insulintherapyin pages 1-2) • Kim et al. “Dramatic Clinical Improvement With Biotin Mega‑Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency.” Mol Genet Genomic Med. Aug 2024. https://doi.org/10.1002/mgg3.70002 (kim2024dramaticclinicalimprovement pages 1-2) • Gaschignard et al. “Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini‑review.” Front Genet. Sep 2024. https://doi.org/10.3389/fgene.2024.1249480 (gaschignard2024casereporttwo pages 1-3)

Included visual evidence • Table evidence for cohort biochemical response (C5OH pre/post biotin) and outcomes is available from Ling et al. (Table 2 and Table 1 regions). (ling2023clinicalbiochemicaland media bf654274, ling2023clinicalbiochemicaland media ec77cb6e)

References

(ling2023clinicalbiochemicaland pages 1-2): Shiying Ling, Wenjuan Qiu, Huiwen Zhang, Lili Liang, Deyun Lu, Ting Chen, Xia Zhan, Yu Wang, Xuefan Gu, and Lianshu Han. Clinical, biochemical, and genetic analysis of 28 chinese patients with holocarboxylase synthetase deficiency. Orphanet Journal of Rare Diseases, Mar 2023. URL: https://doi.org/10.1186/s13023-023-02656-y, doi:10.1186/s13023-023-02656-y. This article has 17 citations and is from a peer-reviewed journal.
(kim2024dramaticclinicalimprovement pages 1-2): Seon Woo Kim, Hyeon Joo Lee, Naye Choi, Ee‐Kyung Kim, and Jung Min Ko. Dramatic clinical improvement with biotin mega‐dose therapy in a neonate with holocarboxylase synthetase deficiency. Molecular Genetics & Genomic Medicine, Aug 2024. URL: https://doi.org/10.1002/mgg3.70002, doi:10.1002/mgg3.70002. This article has 2 citations and is from a peer-reviewed journal.
(gaschignard2024casereporttwo pages 1-3): Margaux Gaschignard, Louis Domenach, Delphine Lamireau, Claire Guibet, Sandrine Roche, Emmanuel Richard, Isabelle Redonnet-Vernhet, Samir Mesli, and Louis Lebreton. Case report: two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review. Frontiers in Genetics, Sep 2024. URL: https://doi.org/10.3389/fgene.2024.1249480, doi:10.3389/fgene.2024.1249480. This article has 0 citations and is from a peer-reviewed journal.
(wu2020impairedglucosehomeostasis pages 4-5): Hsin-Ru Wu, Kuan-Jung Chen, Hui-Pin Hsiao, and Mei-Chyn Chao. Impaired glucose homeostasis and a novel hlcs pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review. Journal of Pediatric Endocrinology and Metabolism, 33:1481-1486, Aug 2020. URL: https://doi.org/10.1515/jpem-2020-0106, doi:10.1515/jpem-2020-0106. This article has 8 citations and is from a peer-reviewed journal.
(ling2023clinicalbiochemicaland pages 4-5): Shiying Ling, Wenjuan Qiu, Huiwen Zhang, Lili Liang, Deyun Lu, Ting Chen, Xia Zhan, Yu Wang, Xuefan Gu, and Lianshu Han. Clinical, biochemical, and genetic analysis of 28 chinese patients with holocarboxylase synthetase deficiency. Orphanet Journal of Rare Diseases, Mar 2023. URL: https://doi.org/10.1186/s13023-023-02656-y, doi:10.1186/s13023-023-02656-y. This article has 17 citations and is from a peer-reviewed journal.
(zou2024casereporta pages 2-4): Haiying Zou, Li Yang, Renlong Zhang, and Yao Qin. Case report: a case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom. Frontiers in Genetics, Nov 2024. URL: https://doi.org/10.3389/fgene.2024.1439343, doi:10.3389/fgene.2024.1439343. This article has 0 citations and is from a peer-reviewed journal.
(karachaliou2024biotinhomeostasisand pages 4-5): Chrysoula-Evangelia Karachaliou and Evangelia Livaniou. Biotin homeostasis and human disorders: recent findings and perspectives. International Journal of Molecular Sciences, 25:6578, Jun 2024. URL: https://doi.org/10.3390/ijms25126578, doi:10.3390/ijms25126578. This article has 45 citations.
(demaret2024insulintherapyin pages 1-2): Tanguy Demaret, Jean-Sébastien Joyal, Aspasia Karalis, Fabienne Parente, Marie-Ange Delrue, and Grant A. Mitchell. Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis. Jun 2024. URL: https://doi.org/10.1016/j.ymgmr.2024.101073, doi:10.1016/j.ymgmr.2024.101073. This article has 1 citations.
(ling2023clinicalbiochemicaland pages 5-6): Shiying Ling, Wenjuan Qiu, Huiwen Zhang, Lili Liang, Deyun Lu, Ting Chen, Xia Zhan, Yu Wang, Xuefan Gu, and Lianshu Han. Clinical, biochemical, and genetic analysis of 28 chinese patients with holocarboxylase synthetase deficiency. Orphanet Journal of Rare Diseases, Mar 2023. URL: https://doi.org/10.1186/s13023-023-02656-y, doi:10.1186/s13023-023-02656-y. This article has 17 citations and is from a peer-reviewed journal.
(kim2024dramaticclinicalimprovement pages 2-4): Seon Woo Kim, Hyeon Joo Lee, Naye Choi, Ee‐Kyung Kim, and Jung Min Ko. Dramatic clinical improvement with biotin mega‐dose therapy in a neonate with holocarboxylase synthetase deficiency. Molecular Genetics & Genomic Medicine, Aug 2024. URL: https://doi.org/10.1002/mgg3.70002, doi:10.1002/mgg3.70002. This article has 2 citations and is from a peer-reviewed journal.
(wu2020impairedglucosehomeostasis pages 1-2): Hsin-Ru Wu, Kuan-Jung Chen, Hui-Pin Hsiao, and Mei-Chyn Chao. Impaired glucose homeostasis and a novel hlcs pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review. Journal of Pediatric Endocrinology and Metabolism, 33:1481-1486, Aug 2020. URL: https://doi.org/10.1515/jpem-2020-0106, doi:10.1515/jpem-2020-0106. This article has 8 citations and is from a peer-reviewed journal.
(ling2023clinicalbiochemicaland media bf654274): Shiying Ling, Wenjuan Qiu, Huiwen Zhang, Lili Liang, Deyun Lu, Ting Chen, Xia Zhan, Yu Wang, Xuefan Gu, and Lianshu Han. Clinical, biochemical, and genetic analysis of 28 chinese patients with holocarboxylase synthetase deficiency. Orphanet Journal of Rare Diseases, Mar 2023. URL: https://doi.org/10.1186/s13023-023-02656-y, doi:10.1186/s13023-023-02656-y. This article has 17 citations and is from a peer-reviewed journal.
(ling2023clinicalbiochemicaland media ec77cb6e): Shiying Ling, Wenjuan Qiu, Huiwen Zhang, Lili Liang, Deyun Lu, Ting Chen, Xia Zhan, Yu Wang, Xuefan Gu, and Lianshu Han. Clinical, biochemical, and genetic analysis of 28 chinese patients with holocarboxylase synthetase deficiency. Orphanet Journal of Rare Diseases, Mar 2023. URL: https://doi.org/10.1186/s13023-023-02656-y, doi:10.1186/s13023-023-02656-y. This article has 17 citations and is from a peer-reviewed journal.

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