Neonatal-onset PA largely resembles hyperammonemic encephalopathy that manifests within the first few days of life. Parents may claim feeding difficulties, note their children to become increasingly somnolent or lethargic. Vomiting and hyperventilation are frequently observed; seizures may be reported. While hyperventilation may provoke respiratory alkalosis, most patients present with metabolic acidosis due to further metabolic disturbances. Eventually, neonates may fall into a coma and die.

Patients suffering from late-onset PA may have a history of cognitive and motor deficits as well as mental retardation (55%); language acquisition may be impaired (55%) [9]. Muscular hypotonia (51%), ataxia (9%), hearing or visual impairment (13% and 7%, respectively), and an aversion to or intolerance of protein-rich food may be reported. Symptoms, as described for neonatal-onset PA, may be experienced chronically or recurrently. An exacerbation of symptoms may be triggered by situations inducing a catabolic state, e.g., by infectious disease, surgery or other forms of stress. Most frequently, affected individuals suffer from vomiting, but an acute metabolic decompensation may also provoke complications as mentioned above.

Cardiomyopathy is common in PA patients (9%), and may occasionally be the only symptom of PA [10]. A considerable share of patients also present with long QT syndrome (22%). Less frequently, pancreatitis, renal failure, premature ovarian failure, and an altered mental status have been described.

• Poor Feeding

  In the severe neonatal onset form, the affected infants present with symptoms of metabolic intoxication (poor feeding, vomiting, altered sensorium) and pancytopenia within several hours to weeks after birth. [orpha.net]

  A new case of propionic acidemia is presented, paying special attention to the early symptoms of this disease, such as increased drowsiness, muscular hypotonia, poor feeding, hypothermia, metabolic acidosis, ketonuria and vomiting. [ncbi.nlm.nih.gov]

• Anemia

  Commonly reported findings included seizures, arrhythmia, leucopenia, and anemia. Developmental and cognitive disabilities were reported in the majority of individuals. [ncbi.nlm.nih.gov]

  Some of these might include: Basic blood work (to assess for response to infection, anemia, glucose levels, basic organ function, etc.) [verywellhealth.com]

  […] deficiency Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome Congenital disorder of glycosylation Congenital dyserythropoietic anemia [se-atlas.de]

• Short Stature

  In few cases of delayed-onset propionic acidemia, patient present long-term effects including: Delay in development of communication and motor skills Mental retardation with learning disabilities Poor growth and short stature Rigid muscle tone (spasticity [healthhype.com]

  So we recognise now that the slow growth in childhood, the failure of a growth spurt prior to puberty and the short stature characteristic of people with Prader-Willi syndrome is because of a relative growth hormone deficiency. [nhs.uk]

  stature Decreased body height Small stature [ more ] 0004322 Tachypnea Increased respiratory rate or depth of breathing 0002789 Thrombocytopenia Low platelet count 0001873 Vomiting Throwing up 0002013 Showing of 42 | Last updated: 6/1/2019 Making a diagnosis [rarediseases.info.nih.gov]

  Short stature/stunting (height < normal for age) percentage was calculated and categorised according to Waterlow classification of malnutrition [10]. [hindawi.com]

• Falling

  Regardless of the payload, gene, mRNA, or genome editing approaches will stand or fall based on their ability to hit the right tissue targets. [mayoclinic.pure.elsevier.com]

  Eventually, neonates may fall into a coma and die. Patients suffering from late-onset PA may have a history of cognitive and motor deficits as well as mental retardation (55%); language acquisition may be impaired (55%). [symptoma.com]

  Hematological investigations revealed: Hb 15gm% TLC 9800 /cumm (polymorphonuclears 70%, lymphocytes 30%, immature to total neutrophil ratio 0.07) platelet count 7 lacs/cmm and µESR 1 mm fall in 1st hour. [webmedcentral.com]

  Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions. [invitae.com]

  The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue.”[ 23 ] Does the fall in brain glutamine during [omicsgroup.org]

• Feeding Difficulties

  The third patient was diagnosed at the age of 5 d when she presented with feeding difficulties, hypotonia, and respiratory insufficiency. [ncbi.nlm.nih.gov]

  Parents may claim feeding difficulties, note their children to become increasingly somnolent or lethargic. Vomiting and hyperventilation are frequently observed; seizures may be reported. [symptoma.com]

  They usually experience poor feeding, vomiting, loss of appetite, weak muscle tone ( hypotonia ), and lack of energy (lethargy). [rarediseases.info.nih.gov]

  The clinical symptoms of the patients are mainly caused by these intermediate metabolites, and manifested as neurological symptoms such as feeding difficulties, vomiting, lethargy, coma, metabolic acidosis, and hyperammonemia. [frontiersin.org]

• Tachypnea

  At 3 months of life, he presented with tachypnea and altered mental status, which lead to the diagnosis of PA. [ncbi.nlm.nih.gov]

  Pancreatitis Pancreatic inflammation 0001733 Pancytopenia Low blood cell count 0001876 Poor appetite Decreased appetite 0004396 Psychomotor retardation 0025356 Seizures Seizure 0001250 Short stature Decreased body height Small stature [ more ] 0004322 Tachypnea [rarediseases.info.nih.gov]

  Primary Care Management Upon Notification of the + Screen Contact the family and evaluate the infant for poor feeding, lethargy, vomiting, and tachypnea. [medicalhomeportal.org]

  Thus, propionic acidemia manifests as clinical signs and symptoms of acidosis and hyperammonemia, including tachypnea, vomiting, lethargy, irritability, shock, coma, and death. [emedicine.com]

• Respiratory Insufficiency

  The third patient was diagnosed at the age of 5 d when she presented with feeding difficulties, hypotonia, and respiratory insufficiency. [ncbi.nlm.nih.gov]

• Vomiting

  In the chronic progressive form, the disease presents as failure to thrive, chronic vomiting, psychomotor delay, hypotonia, seizures and movement disorders. [orpha.net]

  • Three siblings suffering from recurrent vomiting, hypotonia, hyperpnea, dehydration, and ketoacidosis were diagnosed as having ketotic hyperglycinemia secondary to propionic acidemia. [jamanetwork.com]

  The initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). [flipper.diff.org]

• Nausea

  This disorder most commonly is characterized by episodic decompensations with dehydration, lethargy, nausea, and vomiting as well as a risk for neurologic sequelae. [ncbi.nlm.nih.gov]

  Anorexia and nausea/vomiting during the acute crisis period makes a significant oral intake unlikely. [newenglandconsortium.org]

  Urea cycle disorders can present at any age, with episodes of confusion or coma, often preceded by digestive signs (nausea, diar-rhea, vomiting and anorexia) and cephalalgia. [vdocuments.us]

  […] feet, or other areas, decreased urine output; easy bruising or bleeding; frequent hiccups; general ill feeling (malaise); generalized itching; headache; increased skin pigmentation (skin may appear yellow or brown); muscle cramps; muscle twitching; nausea [mbtshoeswomen.us]

• Gagging

  During emergence, the patient exhibited spontaneous respirations with minimal gag in response to suction and was transported intubated to recovery. [journals.lww.com]

  ______________________________________________________________________ Neuro: Tone – Normal / Hypotonic / Hypertonic Arm / Leg Recoil _______________________________________________________________________ Suck ________ Swallow ________ Cry ________ Gag [slidex.tips]

• Visual Impairment

  Other authors have reported a visual impairment rate of 7% in OA, with no details provided regarding the aetiology of the visual loss. 2 Our findings suggest that the incidence of visual impairment is likely to be higher. [bjo.bmj.com]

  Muscular hypotonia (51%), ataxia (9%), hearing or visual impairment (13% and 7%, respectively), and an aversion to or intolerance of protein-rich food may be reported. [symptoma.com]

  Less common, visual impairment secondary to optic atrophy, hearing loss, and development of comorbidities such as attention-deficit disorder, autism, anxiety or acute psychosis, have been reported. [rarediseasesjournal.com]

  Less common neurologic symptoms comprised impaired hearing ability (13%), ataxia (9%) and visual impairment (7%). After completion of data collection, one patient developed bilateral optic atrophy at the age of 9.5 years. [ojrd.biomedcentral.com]

• Hearing Impairment

  It can be assumed that acute and chronic effects of accumulating metabolites on the KvLQT1/KCNE1 channel protein may similarly cause the hearing impairment of patients with propionic acidemia. [ncbi.nlm.nih.gov]

  Hearing impairment. PEROXISOMAL DISORDERS PEROXISOMAL DISORDERS Clinical Manifestations: Slide 62 Peroxisomal Disorders Zellweger Syndrome is autosomal recessive disorder. [vdocuments.mx]

   Hearing impairment. 61 Peroxisomal Disorders • Zellweger Syndrome is autosomal recessive disorder. [nanopdf.com]

• Muscle Hypotonia

  (hypotonia) learning difficulties lack of sexual development behavioural problems, such as temper tantrums or stubbornness Read more about symptoms of Prader-Willi syndrome. [nhs.uk]

• Eczema

  […] through HPO Acute encephalopathy 0006846 Anemia Low number of red blood cells or hemoglobin 0001903 Apnea 0002104 Autosomal recessive inheritance 0000007 Cerebral atrophy Degeneration of cerebrum 0002059 Coma 0001259 Dehydration 0001944 Dystonia 0001332 Eczema [rarediseases.info.nih.gov]

  AMINO ACID DISORDERS Phenyl Ketonuria (PKU)*PhenylalanineTyrosineHydroxylasePhenylalaninePhenyl ethylamine Phenyl pyruvic acid Phenylketonuria PKU*Hyperactivity, athetosis, vomiting.Blond.Seborric dermatitis or eczema skin.Hypertonia.Seizures.Severe mental [vdocuments.site]

  Slide 26 26 Phenylketonuria PKU Slide 27 27 1.Hyperactivity, athetosis, vomiting. 2.Blond. 3.Seborric dermatitis or eczema skin. 4.Hypertonia. 5.Seizures. 6.Severe mental retardation. 7.Unpleasant odor of phenyl acetic acid. [vdocuments.mx]

  Seborric dermatitis or eczema skin. 4. Hypertonia. 5. Seizures. 6. Severe mental retardation. 7. Unpleasant odor of phenyl acetic acid. [nanopdf.com]

• Alopecia

  Multiple carboxylase deficiency is differentiated from propionic acidemia by skin manifestations, which include generalized erythematous rash with exfoliation and alopecia totalis. [webmedcentral.com]

  Available enzyme assays include: -Biotinidase assay- in cases with suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia); -GALT (galactose 1-phosphate uridyl transferase ) assay- in cases with suspected galactosemia (hypoglycemia [slideshare.net]

  Biotinidase deciency results Diagnosis of Leukodystrophies and Other White Matter Disease Vanderver 111in a clinical picture that includes seizures, hypotonia, ataxia, breathing problems, hearing loss, optic atrophy, skin rash, and alopecia. [docslide.us]

  […] deafness, cerebellar ataxia, spinal amyotrophyLow MTHF in CSF, normal folates in bloodFolinic acid MTHF in blood and CSFBiotinidase deficiencyAR Child or adolescentBilateral optic atrophy, spastic paraparesis, cerebellar ataxia, motor neuropathy, deafness, alopecia [vdocuments.us]

  […] carboxylases • Clinical Manifestations Autosomal recessive Most infants first exhibit clinical symptoms between 3-6 months of age CNS and skin – most commonly affected Myoclonic seizures, hypotonia, seborrheic or atopic dermatitis, partial or complete alopecia [slidex.tips]

• Psychomotor Retardation

  The clinical picture varies from patients presenting with mild psychomotor retardation to those with severe metabolic decompensation with vomiting, dehydration, encephalopathy and in rare instances fatal outcome. [webmedcentral.com]

  Mental retardation, nonspecific Mental-retardation [ more ] 0001249 5%-29% of people have these symptoms Cardiomyopathy Disease of the heart muscle 0001638 Cerebellar hemorrhage 0011695 Percent of people who have these symptoms is not available through [rarediseases.info.nih.gov]

  retardation-progressive brain atrophy-basal ganglia disease syndrome Intermediate maple syrup urine disease Intermediate severe Salla disease Intermittent maple syrup urine disease Isobutyryl-CoA dehydrogenase deficiency Isolated ATP synthase deficiency [se-atlas.de]

  Patients with MMA and PA usually present in the neonatal period with acute metabolic distress (AMD) and encephalopathy, but may present later in infancy in less severe deficiencies with recurrent ketoacidosis, psychomotor retardation and chronic vomiting [bjo.bmj.com]

• Kidney Failure

  KEYWORDS: Clinical research/practice; kidney failure/injury; liver transplantation/hepatology; metabolism/metabolite; pediatrics [Indexed for MEDLINE] Free full text [ncbi.nlm.nih.gov]

  Whenever it begins, propionic acidemia can also lead to more chronic problems: Chronic Problems Decreased overall growth Developmental delay and intellectual disability Seizures Gastrointestinal symptoms Pancreatitis Movement disorders Cardiomyopathy Kidney [verywellhealth.com]

  See Renal failure Kidney stones, 194 327 Kimmelstiel–Wilson disease. [mbtshoeswomen.us]

• Seizure

  If untreated, encephalopathy, coma, seizures, and cardiorespiratory failure can ensue. [flipper.diff.org]

  All nine patients with pathological EEG discharges developed seizures compatible with the definition of symptomatic epilepsy. Five of these nine patients showed fever induced seizures at the beginning. [ncbi.nlm.nih.gov]

  In the chronic progressive form, the disease presents as failure to thrive, chronic vomiting, psychomotor delay, hypotonia, seizures and movement disorders. [orpha.net]

  The seizure was partially controlled and he was started on phenobarbitone loading(total of 40mg/kg) then to phenytoin loading (40mg/kg), midazolam bolus 0.1 mg/kg but seizure was not controlled and baby was started on midazolam infusion and started on [webmedcentral.com]

• Lethargy

  The condition causes lethargy and striatal degeneration with motor impairment in humans. How propionate exerts its toxic effect is unclear. [ncbi.nlm.nih.gov]

  The initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). [flipper.diff.org]

• Encephalopathy

  Despite intensive medical care, this particular case proved fatal, highlighting the importance of metabolic testing in cases of acute mental-status changes and encephalopathy of unknown etiology. [ncbi.nlm.nih.gov]

  This condition interferes with other metabolic processes and may cause life-threatening ketoacidosis, cardiomyopathy, and encephalopathy. [symptoma.com]

  Ehlers-Danlos syndrome, musculocontractural type Encephalopathy due to GLUT1 deficiency Encephalopathy due to hydroxykynureninuria Encephalopathy due to prosaposin deficiency Encephalopathy due to sulfite oxidase deficiency Encephalopathy-hypertrophic [se-atlas.de]

• Ataxia

  Onset may be later in childhood or adolescence with progressive psychomotor / intellectual impairment, hypotonia and ataxia, digestive disorders, and for some epsiodes of lethargy and coma. [treatable-id.org]

  […] due to ubiquinone deficiency Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency Autosomal recessive congenital cerebellar ataxia due to [se-atlas.de]

  ataxia triggered by fever can be observed in patients with PDH deficiency.23 Chronic ataxia might be the presenting feature of vitamin E deficiency. [vdocuments.us]

  […] and thiamine responsive subtypes; classic form presents in the first week of life with ketoacidosis, hypoglycemia, emesis, neonatal seizures, and hypertonia; the intermediate and intermittent forms present in childhood or later with acute episodes of ataxia [icd9data.com]

  Classic ndings on physical exam include transitory nystagmoid eye movements with rotatory movements of the head, spastic quadraparesis, ataxia, parkinson-ism, and dementia. [docslide.us]

• Somnolence

  Neonatal-onset propionic acidemia (PA), the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, and can progress to coma if not identified [ncbi.nlm.nih.gov]

  Neonatal-onset PA, the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. [flipper.diff.org]

  Parents may claim feeding difficulties, note their children to become increasingly somnolent or lethargic. Vomiting and hyperventilation are frequently observed; seizures may be reported. [symptoma.com]

  Variables Current study in % Lehnert et al. 1994 [2] Other studies value Symptoms         Lethargy/apathy/somnolence 68 73 55‡ <0.001 Poor feeding and vomiting 77 83 91‡ <0.001 Dyspnoea, cough, and others† 36 57 — <0.001 Seizures 13 43 <0.001 Loss of [hindawi.com]

  The severe, neonatal-onset presentation is the classic and most-common form; patients present in the first days of life, after protein catabolism has taken place, and is characterized by poor feeding, vomiting, somnolence, and acute clinical deterioration [invitae.com]

Laboratory analyses of blood and urine samples usually yield results that prompt a strong suspicion of organic acidemia in general and PA in particular:

• Anemia is very common (82%), while only about a third of PA patients presents with neutropenia or thrombocytopenia; pancytopenia is diagnosed in 11% of PA patients [9]
• Hyperammonemia
• Hypoglycemia
• Hyperglycinemia
• Acylcarnitine profile with an elevation of C3 (propionyl carnitine) [11]
• Metabolic acidosis with high anion gap (pH as low as 6.8)
• Ketosis with ketonemia and ketonuria
• Enhanced concentrations of 3-hydroxypropionate, propionyl carnitine, propionyl glycine, and methyl citrate in urine samples

Patients presenting with neonatal-onset PA show most of the aforementioned metabolic anomalies, while the diagnosis of late-onset PA strongly relies on the detection of propionyl-CoA metabolites in blood and urine specimens [12].

For confirmation of a tentative diagnosis of PA, the activity of propionyl-CoA carboxylase may be determined in peripheral blood leukocytes or cultured skin fibroblasts. Molecular biological techniques may be applied to identify mutations of PCCA and/or PCCB.

• Ketonuria

  A new case of propionic acidemia is presented, paying special attention to the early symptoms of this disease, such as increased drowsiness, muscular hypotonia, poor feeding, hypothermia, metabolic acidosis, ketonuria and vomiting. [ncbi.nlm.nih.gov]

  […] seizures, and hypertonia; the intermediate and intermittent forms present in childhood or later with acute episodes of ataxia and vomiting Applies To Disturbances of metabolism of leucine, isoleucine, and valine Hypervalinemia Intermittent branched-chain ketonuria [icd9data.com]

  It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. [flipper.diff.org]

  Fasting blood was obtained while she was freefrom any ketonuria. [docslide.us]

• Hyperammonemia

  Symptomatic cases present during metabolic decompensation with acidosis, ketosis, increased anion gap, hyperlactatemia, hyperglycinemia, hyperammonemia, hypoglycemia and cytopenias. [orpha.net]

  Both occurred apparently only during attacks of hyperammonemia. Propionic acidemia was ruled out by enzyme studies. [ncbi.nlm.nih.gov]

  One factor is the hyperammonemia. In case 1, hyperammonemia was documented over a 3-week period in the hospital at age 15 years; there may well have been many such episodes. [jamanetwork.com]

• Neutropenia

  In the infantile chronic form, failure to thrive, chronic vomiting and neutropenia may mimic cow milk intolerance, celiac disease (see this term) or immune deficiencies. [orpha.net]

  Genetics Home Reference :Propionic Acidemia,2007 COMPLICATIONS The most common complications in patients were hematological abnormalities including anemia, neutropenia, thrombocytopenia or pancytopenia. [flipper.diff.org]

  Laboratory findings include metabolic acidosis, hyperglycinemia, ketone bodies, ketosis, hyperammonemia, and possible thrombocytopenia and neutropenia. Long-term management includes dietary protein restriction and supplementary amino acids. [visualdx.com]

  B cell lymphopenia (20 cells microliters-1) was associated with transient neutropenia, anemia and subsequent hypogamma-globulinemia (IgG < 294 mg dl-1, IgM < 8 mg dl-1, IgA < 8 mg dl-1), while T cells were normal. [ncbi.nlm.nih.gov]

• Hypoglycemia

  Symptomatic cases present during metabolic decompensation with acidosis, ketosis, increased anion gap, hyperlactatemia, hyperglycinemia, hyperammonemia, hypoglycemia and cytopenias. [orpha.net]

  It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. [ncbi.nlm.nih.gov]

  Hence, the constellation of laboratory findings in PA is the following: Metabolic acidosis with anion gap Ketonuria Hypoglycemia Hyperammonemia Hyperglycinemia The ketoacidosis, hyperammonemia and hypoglycemia can explain the lethargy and obtundation [newenglandconsortium.org]

• Leukopenia

  They also had leukopenia and thrombocytopenia, and two of them had anorectal malformations, one an imperforate anus with rectoperineal fistula, and the other an ectopic anus. [jamanetwork.com]

  […] sugar for energy ketotic II glycinemia ketotic glycinemia propionic aciduria propionyl-CoA carboxylase deficiency glycinemia, ketotic ketotic hyperglycinemia PROP Propionicacidemia PROPIONIC ACIDEMIA Pcc Deficiency Hyperglycinemia With Ketoacidosis and Leukopenia [wikidata.org]

  Propionic Aciduria; Ketotic Hyperglycinemia; Hyperglycinemia with Ketoacidosis and Leukopenia; Propionyl-CoA Carboxylase Deficiency. First described in 1961 by B. Childs, an American pediatrician. [accessanesthesiology.mhmedical.com]

  Review. hyperglycinemia with ketoacidosis and leukopenia ketotic glycinemia ketotic hyperglycinemia PCC deficiency PROP propionicacidemia propionyl-CoA carboxylase deficiency Baumgartner D, Scholl-Bürgi S, Sass JO, Sperl W, Schweigmann U, Stein JI, Karall [ghr.nlm.nih.gov]

• Glucose Decreased

  Meningitis results in: a. decreased CSF glucose and decreased CSF protein b. decreased CSF glucose and increased CSF protein c. increased CSF glucose and decreased CSF protein d. increased CSF glucose and increased CSF protein 11. [mbtshoeswomen.us]

PA patients are required to maintain a diet with a low content of proteins, although fasting should be discouraged. Such a diet diminishes the formation of propionyl-CoA and its metabolites. In periods of stress, patients should augment their daily caloric intake to prevent protein catabolism. A detailed table of protein requirements and maximum daily protein intake dependent on the age of the patient is provided elsewhere [13]. Some experts recommend the supplementation of precursor free amino acids. Further medication may comprise intermittent application of metronidazole (10–20 mg/kg/day in up to 3 doses) or other antimicrobials to decrease propionic acid production by anaerobic bacteria in the gastrointestinal tract, L-carnitine to promote the elimination of propionyl groups (100-200 mg/kg/d in up to 4 doses), and N-carbamoyl glutamate to compensate for the inhibition of N-acetyl-glutamate synthase. Ammonia scavengers like sodium benzoate (150-250 mg/kg per day) have occasionally been used for the long-term therapy of PA.

Acute metabolic decompensation is a medical emergency and requires immediate attention. There is a negative correlation between the duration of coma and maximum ammonia levels, and the neurological outcome. Briefly, protein intake should be stopped entirely for up to 36 hours. Patients are to be infused with dextrose, possibly plus insulin, to slow down catabolic processes. L-carnitine and ammonia scavengers are to be administered. For a detailed description of the treatment of hyperammonemia, the reader is referred to the article treating with urea cycle disorder. With regards to decompensated PA patients, disturbances of acid-base and electrolyte balance have to be corrected. Besides fluid therapy and dextrose application, bicarbonate and potassium may become necessary.

Patients who frequently present with metabolic decompensation may be considered for liver transplantation.

To date, causative treatment for PA is not available. During the last decades, survival times could be improved considerably, but the neurological outcome is still poor [9]. An individual patient's prognosis largely depends on complications present at the time of diagnosis: Irreversible cardiac or brain damage may severely shorten a patient's life expectancy and reduce their life quality. Indeed, heart failure is the leading cause of death in PA patients [4]. On the other hand, if treatment is started before such lesions occur, the risk of developmental delays and premature death can be reduced significantly. In this context, patients are to be advised as to the chronic nature of their disease, and to the necessity to strictly adhere to dietary recommendations. Residual activity of propionyl-CoA carboxylase is a favorable prognostic factor, although it cannot be deducted from the patient's genotype but requires an assessment in cell culture.

Metabolic disturbances characteristic of PA is caused by a functional defect of propionyl-CoA carboxylase. This enzyme is composed of six α and β subunits, respectively, and these are encoded by genes PCCA and PCCB, respectively. While PCCA is located on the long arm of chromosome 13, PCCB is part of the long arm of chromosome 3. Of note, elder literature may refer to PCCC mutations. This designation has been chosen for mutations of those sequence segments of PCCB that encode for the carboxy-terminus of the β subunit.

To date, more than 100 mutations of either gene have been associated with PA, and the genetic heterogeneity of PA patients is a major obstacle for the identification of genotype-phenotype relationships. Moreover, individual patients may present with more than one mutation of PCCA and PCCB. With regards to the nature of gene mutations, insertions, and deletions, missense mutations, as well as anomalies provoking alternative splicing, have been reported. Sequence anomalies may lead to the assembly of an unstable protein, may interfere with ATP binding or conformational changes upon ATP binding [1]. The majority of mutations diminishes the activity of propionyl-CoA carboxylase to less than 5%, but occasionally, residual activities of >25% have been described [2].

Although PA is a hereditary disorder, patients don't necessarily have a family history of the disease. This may be the result of underdiagnosing, of phenotypic changes due to the influence of additional genetic and non-genetic factors, or of de novo mutations of PCCA and PCCB. Reliable data cannot be provided to this end, but the heterogeneity of PA-associated mutations in some populations argues for a considerable share of sporadic cases, while homogeneity, likely due to the inheritance of gene defects, is observed in other ethnicities. In detail, no prevalent mutations have been identified in Caucasians, while the total allelic frequency of three mutations of PCCA was 56% in Japanese patients [3].

Some authors estimated the overall incidence of PA to be in the range of 1 in 165,000 to 1 in 300,000 persons [4], while an incidence of 1 in 100,000 people was reported elsewhere. In fact, it has been proposed that the true incidence of the disease is as high as 1 in 18,000 inhabitants, with the majority of cases remaining undiagnosed due to the disease following a mild course [5]. Furthermore, there are considerable geographic differences, and highest incidence rates have been calculated for the Arabian Peninsula. Here, more than 1 in 5,000 people may be affected. Consanguineous marriage has been identified as a risk factor for PA and is very common among the Arabian population [6].

Propionyl-CoA carboxylase is a mitochondrial enzyme that catalyzes the conversion of propionyl-CoA, ATP, and bicarbonate to (S)-methylmalonyl-CoA, ADP, and pyrophosphate.

Propionyl-CoA is an intermediate metabolite of amino acid and fatty acid metabolism and is primarily produced during the breakdown of isoleucine, methionine, valine, and threonine, of odd-chain fatty acids and methyl-branched fatty acids. Minor quantities originate from bile acid synthesis and nucleic acid metabolism. Under physiological conditions, conversion of propionyl-CoA to (S)-methylmalonyl-CoA is followed by racemization and isomerization to succinyl-CoA. These reactions are mediated by methylmalonyl-CoA epimerase and methylmalonyl-CoA mutase, respectively, and depend on the availability of vitamin B12. In contrast, propionyl-CoA carboxylase deficiency results in the accumulation of propionyl-CoA, propionic acid, 3-hydroxypropionate, propionyl carnitine, and methyl citrate, primarily in mitochondria of hepatocytes. Here, these compounds interfere with important metabolic pathways like the Krebs cycle and electron transport chain, proximal reactions of the urea cycle and the glycine cleavage system [7]. Direct results are lactic acidosis, hyperammonemia, and ketotic hyperglycinemia. The underlying pathophysiological mechanisms are complex. For instance, propionyl-CoA acts as a competitive inhibitor of N-acetyl-glutamate synthase reduces the production of N-acetyl-glutamate and thus the activity of carbamoyl phosphate synthase I, which catalyzes the initial reaction of ammonia detoxification in the urea cycle. Thus, PA may present clinically similar to hyperammonemia type 3 or carbamoyl phosphate synthase deficiency. These diseases differ, however, in blood and urine levels of metabolites like methyl citrate. Also, dysfunction of the Krebs cycle seems to contribute to hyperammonemia [8].

Affected families may benefit from genetic counseling. Molecular biological techniques allow for the identification of carriers and for prenatal screens. Moreover, increased levels of 3-hydroxypropionate, propionyl carnitine, or methyl citrate in amniotic fluid may indicate PA. If parents decide against the prenatal test, neonates may be tested for PA. A positive result allows for the initiation of therapy before metabolic disturbances result in permanent organ damage.

Propionic acidemia (PA) is a hereditary metabolic disorder; affected individuals carry a mutated gene encoding for a non-functional propionyl-CoA carboxylase. This enzyme is required for the carboxylation of propionyl-CoA, and this reaction yields (S)-methylmalonyl-CoA and finally succinyl-CoA, a compound that can be utilized as a substrate in the Krebs cycle. Propionyl-CoA, in turn, is an intermediate metabolite produced in amino acid, odd-chain and methyl-branched fatty acid catabolism. In the case of insufficient carboxylation, propionyl-CoA, and alternative metabolites, mainly propionic acid, accumulate. They interfere with a variety of metabolic processes in the whole organism, trigger life-threatening ketoacidosis, cardiomyopathy, and encephalopathy. The disease is inherited as an autosomal recessive trait [1].

Age at symptom onset and clinical presentation vary largely. On the one hand, PA may manifest shortly after birth, and this form of the disease is referred to as neonatal-onset PA. On the other hand, symptoms may not be experienced in childhood. This late-onset form of the disease may follow an intermittent course with recurrent bouts of metabolic decompensation, or a chronic course characterized by progressive worsening of the patient's condition. To date, it is not possible to predict the course of the disease in an individual patient.

PA patients may be identified prenatally, by means of analyses of chorionic villi or amniotic fluid samples, and this approach is recommended for families with a known history of PA. Moreover, PA may be diagnosed in a patient presenting with clinical symptoms. Because the outcome largely depends on an early diagnosis and a timely initiation of therapy, the former is preferred over the later. This way, the disease can be identified before vital organs sustain permanent damage. Diagnosis is based on the identification of metabolic disturbances and on molecular biological techniques to demonstrate gene defects. Long-term therapy consists of dietary adjustments, low protein intake, and symptomatic treatment during metabolic crises.

Propionic acidemia (PA) is a hereditary metabolic disorder characterized by the accumulation of propionyl-CoA and metabolites like propionic acid and methyl citrate in hepatocytes. Propionyl-CoA arises from the breakdown of determined amino acids, fatty acids, cholesterol, and thymine. Under physiological conditions, propionyl-CoA is carboxylated and utilized in other metabolic processes. Carboxylation of propionyl-CoA is mediated by an enzyme named propionyl-CoA carboxylase, but PA patients carry a gene defect that impairs the assembly of functional propionyl-CoA carboxylase. In detail, there are two genes encoding for this enzyme, and PA patients may present mutations in either one of both.

The accumulation of propionyl-CoA and its metabolites interferes with a myriad of biochemical reactions and pathways, e.g., with the Krebs cycle and electron transport chain, as well as proximal reactions of the urea cycle. Consequently, toxic compounds like ketone bodies and ammonia accumulate in the patient's body and provoke life-threatening ketoacidosis, cardiomyopathy, and encephalopathy. While there is no causative treatment for PA, strict adherence to a diet low in proteins and adequate medication may diminish the individual risk of such severe complications. Still, every PA patient remains at risk of acute metabolic decompensation, and this condition constitutes a medical emergency that requires immediate attention. Symptoms associated with metabolic decompensation are vomiting, seizures, and reduced consciousness or coma.

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