Pyruvate carboxylase deficiency patients may be divided, depending on manifestations and underlying biochemical abnormalities into three groups [1] [2]: the North American phenotype (type A), the French phenotype (type B), and the benign phenotype (type C). Clinical abnormalities in patients belonging to the first two groups have early onset. Type A patients exhibit signs of disease during infancy and type B during the neonatal period. Children in the first group exhibit mental retardation and motor delay, but survive beyond the adolescence period (although deaths within the first 5 years of life have also been reported), whereas the second group has up to a 3 months lifespan. These children have low Apgar scores and are born small for gestational age. Type C patients have no neurologic abnormalities because lactate elevation is not persistent, but occurs in an episodic manner and is mild or moderate.

When symptomatic, pyruvate carboxylase deficiency causes accentuated lethargy, ataxia, tremor, choreoathetosis, seizures, abnormal eye movements, vomiting, hypotonia, mottled skin, and poor feeding. Progressive illness leads to spastic diplegia or quadriplegia and positive Babinski sign. Patients fail to thrive and to achieve developmental milestones, may have episodes of incoordination, and have a diminished response to visual stimuli [3]. Respiratory manifestations include dyspnea, tachypnea, apneic episodes, respiratory depression, as well as resting hyperpnea and Cheyne-Stokes respiration [4]. Hepatomegaly and splenomegaly could be present, while macrocephaly has also been reported [5]. On the other hand, some patients present with microcephaly, that can be diagnosed before or after birth.

• Developmental Delay

  He survived from neonatal lactic acidemia and is alive at 9 years of age with a mild developmental delay. A brain MRI performed by the age of 18 months disclosed an unusual subcortical leucodystrophic process. [ncbi.nlm.nih.gov]

  Overview Background Pyruvate carboxylase deficiency (PCD) is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early infantile period. [emedicine.com]

  Diagnosis PC deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. PC deficiency is diagnosed by physical symptoms and laboratory studies. [rarediseases.org]

  Overview Overview Pyruvate carboxylase (PC) deficiency is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early infantile period. [emedicine.medscape.com]

• Disability

  The devastating nature of a pyruvate carboxylase deficiency is underscored by the uniformly fatal outcome of the neonatal (French) type and the severely disabling and ultimately fatal outcome of the infantile (North American) type. [ncbi.nlm.nih.gov]

  Some will survive for a longer period, with severe physical and mental disabilities. The extremely rare, milder 'C' form of the disease may be associated with mild disability and recurrent episodes of lactic acidosis. [patient.info]

  Most of the affected children die within the first 6 months of life Children, who survive for a longer period, have to cope with severe mental and physical disabilities Infants suffering from milder (benign) forms of the deficiency disorder experience [dovemed.com]

  Liver failure, decreased muscle tone (hypotonia), intellectual disability, abnormal eye movements, irregular signs and reflexes due to damage of upper motor neurons (pyramidal tract signs), seizures and coma are common. [rarediseases.org]

• Developmental Disorder

  The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. [ncbi.nlm.nih.gov]

• Tachypnea

  RESULTS: All patients had axial hypotonia and tachypnea during the first hours of life. The initial level of consciousness was preserved in most patients. [ncbi.nlm.nih.gov]

  Respiratory manifestations include dyspnea, tachypnea, apneic episodes, respiratory depression, as well as resting hyperpnea and Cheyne-Stokes respiration. Hepatomegaly and splenomegaly could be present, while macrocephaly has also been reported. [symptoma.com]

• Abdominal Pain

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. In some cases, episodes of lactic acidosis are triggered by an illness or periods without food (fasting). [ghr.nlm.nih.gov]

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness ( fatigue ), muscle weakness, and difficulty breathing. In some cases, episodes of lactic acidosis are triggered by an illness or periods without food. [en.wikipedia.org]

  The signs and symptoms may include: Developmental delays and mental retardation Poor feeding, loss of appetite Lethargy and fatigue Seizures, neonatal fits Abdominal pain and vomiting Breathing difficulties Psychomotor retardation: Mental or emotional [dovemed.com]

• Alopecia

  The juvenile form presents with lactic acidosis, alopecia, intermittent ataxia; seizures; and an erythematous rash. [icd10data.com]

  Older children may also have alopecia, ataxia, developmental delay, sensorineural hearing loss, optic atrophy, and recurrent infections. [ncbi.nlm.nih.gov]

• Eruptions

  Vitamin B6 Pyridoxine, pyridoxal, pyridoxamine Vitamin B6 deficiency causes seborrhoeic dermatitis-like eruptions, pink eye and neurological symptoms (e.g. epilepsy). [en.wikipedia.org]

• Psychomotor Retardation

  The most severe form (form B) is characterized by neonatal lethal lactic acidosis, whereas patients with form A suffer chronic lactic acidosis with psychomotor retardation. [ncbi.nlm.nih.gov]

  Psychomotor retardation with seizures and spasticity are the major clinical manifestations. [msdmanuals.com]

• Phenylketonuria

  Carboxylase Deficiency 245 Multiple Carboxylase Deficiency 248 Cerebrotendinous Xanthomatosis 252 Cockayne Syndrome 259 Trichothiodystrophy with Photosensitivity 268 PelizaeusMerzbacher Disease and Xlinked Spastic Paraplegia Type 2 272 18q Syndrome 281 Phenylketonuria [books.google.com]

  […] hyperphenylalaninemia，新生児一過性高フェニルアラニン血症 70～90% 6. secondary mild phenylketonuria due to total parenteral nutrition，中心静脈栄養長期施行下にまれにみられる二次性フェニルケトン尿症 90～99% 7. secondary mild phenylketonuria due to methotrexate，メトトレキサート使用下にまれにみられる二次性フェニルケトン尿 C. [jc-metabolomics.com]

• Seizure

  Hypoxia, hypotonia, respiratory distress, facial dysmorphism Facial dysmorphism, seizures Brain imaging N.d. [ncbi.nlm.nih.gov]

• Ataxia

  From Wikidata Jump to navigation Jump to search Human disease deficiency of pyruvic carboxylase Ataxia with lactic acidosis type 2 PYRUVATE CARBOXYLASE DEFICIENCY Ataxia with lactic acidosis type II Leigh Syndrome Due to Pyruvate Carboxylase Deficiency [wikidata.org]

  Identifiant IdRef : 040803813 Notice de type FMeSH Point d'accès autorisé Déficit en pyruvate carboxylase Variantes de point d'accès Ataxia with Lactic Acidosis II [Nom commun] Ataxia with Lactic Acidosis, Type II [Nom commun] Lactic Acidosis with Ataxia [idref.fr]

  Also periodic hypoglicemia, failure to thrive, vomiting and hypotonia and ataxia. i don't know why ataxia but that's it. drpkaur Forum Junior Topics: 197 Posts: 813 Aug 15, 2006 - 12:47 PM #3 nice explanation .thanx vallia...so in short PC deficiency [prep4usmle.com]

  The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. ataxia with lactic acidosis, type II Leigh necrotizing encephalopathy due to [ghr.nlm.nih.gov]

  II ataxia with lactic acidosis References Carbone MA, MacKay N, Ling M, Cole DE, Douglas C, Rigat B, Feigenbaum A, Clarke JT, Haworth JC, Greenberg CR, Seargeant L, Robinson BH. [medlineplus.gov]

• Encephalopathy

  Infants with subacute necrotizing encephalopathy or Leigh's encephalopathy usually are first examined before the age of 2 years with degenerative neurologic disease with variable clinical appearance. [ncbi.nlm.nih.gov]

  Jump to search Human disease deficiency of pyruvic carboxylase Ataxia with lactic acidosis type 2 PYRUVATE CARBOXYLASE DEFICIENCY Ataxia with lactic acidosis type II Leigh Syndrome Due to Pyruvate Carboxylase Deficiency Pc Deficiency Leigh necrotizing encephalopathy [wikidata.org]

  […] with neonatal epileptic encephalopathy is given. [yumpu.com]

  The abnormal muscle and mitochondrial morphology in a variety of clinical presentations from isolated ophthalmoplegia to severe encephalopathy are also elaborated. [books.google.com]

  Primary forms of PC deficiency are characterized by metabolic crises of lactic acidosis, hypotonia, encephalopathy and are refractory to current therapies. [grantome.com]

• Lethargy

  When symptomatic, pyruvate carboxylase deficiency causes accentuated lethargy, ataxia, tremor, choreoathetosis, seizures, abnormal eye movements, vomiting, hypotonia, mottled skin, and poor feeding. [symptoma.com]

  Metabolic acidosis caused by abnormal lactate production is associated with nonspecific symptoms such as severe lethargy, poor feeding, vomiting, and seizures, especially during periods of illness and metabolic stress. [emedicine.medscape.com]

  The signs and symptoms may include: Developmental delays and mental retardation Poor feeding, loss of appetite Lethargy and fatigue Seizures, neonatal fits Abdominal pain and vomiting Breathing difficulties Psychomotor retardation: Mental or emotional [dovemed.com]

• Convulsions

  The patients showed periodic elevation of blood lactate, pyruvate and alanine, which was accompanied by vomiting, hypotonia or convulsions. The concentrations of lactate and pyruvate in cerebrospinal fluid were found to be increased. [ncbi.nlm.nih.gov]

  An infantile form (Type A) is characterized by onset between two and five months of age with lactic acidemia and delayed mental and motor development, failure to thrive, pyramidal tract signs, ataxia, nystagmus, convulsions and often death in infancy [genedx.com]

Blood workup should include lactate and pyruvate levels, which are high, as is a lactate-to-pyruvate ratio in most serious cases. These substances, as well as glutamic acid and proline, are also high in the cerebrospinal fluid. Glycemia is low, especially during fasting periods, while blood ammonia is high. More sophisticated assays, not widely available, include leukocytes, fibroblasts or chorionic villi enzyme testing. Postmortem studies of the brain demonstrated defective myelination and decreased neuron numbers. Affected regions include the cortex, cerebellum and basal ganglia. The hypotonia may be due to these neurological abnormalities or due to a form of myopathy, suggested by nemaline rods on muscle biopsy [6]. If amino acid level measurements are available, they will demonstrate high alanine, citrulline, and lysine levels, while aspartic acid levels would be low. Lactate levels are high in the brain, as demonstrated by magnetic resonance spectroscopy. Classical magnetic resonance imaging reveals brain atrophy, ventricular dilatation, gliosis, and white matter cysts.

Genetic analysis reveals several mutations which interfere with biotin metabolism [7]. Mutations are frameshift, intron retention, or splice site types [8] [9].

If ocular abnormalities are noticed, an ophthalmologic consultation should be in order. The ophthalmologist may describe disconjugate eye movements, decreased visual tracking and pupillary response, or frank blindness.

• Hyperlactacidemia

  Hyperlactacidemia was associated with dramatic increase in lactate/pyruvate ratio, without anoxia, in contrast with decreased beta hydroxybutyrate/acetoacetate ratio. [ncbi.nlm.nih.gov]

• Alanine Increased

  […] blood alanine Increased serum alanine [ more ] 0003348 Hypoglycemia Low blood sugar 0001943 Increased serum lactate 0002151 Increased serum pyruvate 0003542 Intellectual disability Mental deficiency Mental retardation Mental retardation, nonspecific [rarediseases.info.nih.gov]

A 1.4 fold increase of PC mRNA expression was found in β-cells of rat pancreatic islets after an 8 h treatment by 300 μM bezafibrate and persists after a 48 h treatment [48]. [ncbi.nlm.nih.gov]

[…] of Manifestations Treatment focuses on providing alternative energetic fuels, hydration, and correction of the metabolic acidosis during acute decompensation. [werathah.com]

Pharmacologic and Dietary Therapy Treatments are aimed at stimulating the pyruvate dehydrogenase complex and providing alternative fuels. [emedicine.medscape.com]

(Outcomes/Resolutions) The prognosis of Pyruvate Carboxylase Deficiency is poor. [dovemed.com]

This concept has been used in PCD. [ 8 ] Prognosis Despite all therapeutic interventions, the prognosis remains poor, with the majority of affected children dying before the age of six months. [patient.info]

Prognosis Type A patients usually die in infancy or early childhood. Type B most commonly has a fatal outcome within the first three months of life. Type C is mostly a benign form of the disorder with little or no effect on life-expectancy. [orpha.net]

Consultations Evaluation of the patient by an expert in metabolic and genetic disease is necessary to confirm the diagnosis, guide appropriate treatment, and determine prognosis. Enzyme testing and DNA confirmation are available. [emedicine.medscape.com]

These results demonstrate heterogeneity in the etiology of pyruvate carboxylase deficiency. [ncbi.nlm.nih.gov]

Their etiology is not precisely century with the first clinical recognition of known, so we have included chapters that dis symptoms and patterns for diagnosis of car cuss many aspects of congenital cardiac mal diovascular diseases. [books.google.com]

Etiology PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5), involved in the conversion of pyruvate to oxaloacetate, an intermediate in the citric acid cycle and gluconeogenesis. [orpha.net]

The treatment of epileptic encephalopathies due to inborn errors of metabolism generally relies on the use of one or more anticonvulsant medications along with evaluation and management of any underlying etiology. [yumpu.com]

(Etiology) Pyruvate carboxylase (PC) is an enzyme which plays a significant role in the process of converting pyruvate to oxaloacetate. [dovemed.com]

Summary Epidemiology The overall prevalence of PC deficiency is not known and annual incidence has been reported to be 1/250,000 births. The disorder affects males and females equally. [orpha.net]

[…] acidosis,presenting as a severe neonatal form with hyperammonemia and abnormal redox state,a milder form with mental retardation,and developmental delay and a benign form Relevant External Links for PC Genetic Association Database (GAD) PC Human Genome Epidemiology [genecards.org]

Epidemiology Three forms of this disorder have been described: A, B and C. [ 2 ] C is the least severe. Infantile form (type A) is most commonly seen in North America with an incidence of approximately 1 in 250,000. [patient.info]

Epidemiology Frequency United States Pyruvate carboxylase deficiency is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset pyruvate carboxylase deficiency (A type) is more common in the United States. [emedicine.com]

The investigators examined 9 novel mutations of the PC gene in 5 unrelated patients, 2 of whom had type A and 3 of whom had type B PC deficiency. [4, 5] Epidemiology Pyruvate carboxylase (PC) deficiency is a rare disorder, with an approximate incidence [emedicine.medscape.com]

A better comprehension of that field would increase understanding of the pathophysiology of neurological symptoms and neurotransmitter plasticity. [ncbi.nlm.nih.gov]

PMID 4536359. ^ a b "Pyruvate Kinase Deficiency: Practice Essentials, Background, Pathophysiology". 2016-08-23. ^ al.], [edited by] Ronald Hoffman ... [et (2013). Hematology basic principles and practice (6th ed.). [en.wikipedia.org]

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Pyruvic acid, an intermediate metabolite, plays an important role in linking carbohydrate and amino acid metabolism to the tricarboxylic [mayomedicallaboratories.com]

Pathophysiology Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that plays an important role in energy production and anaplerotic pathways. [1, 2] PC catalyzes the conversion of pyruvate to oxaloacetate. [emedicine.com]

Pathophysiology Pyruvate carboxylase (PC) deficiency affects metabolism in several major ways. [emedicine.medscape.com]

The lack of oxaloacetate prevents gluconeogenesis and urea cycle function. [emedicine.com]

Provide a high-carbohydrate and high-protein diet with frequent feedings to help prevent dependence on gluconeogenesis. Prevention of Secondary Complications Individuals with PC deficiency are very brittle metabolically. [ncbi.nlm.nih.gov]

Currently, there are no specific methods or guidelines to prevent Pyruvate Carboxylase Deficiency, since it is a genetic condition Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus [dovemed.com]

The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from functioning, shown in the figure below. [emedicine.medscape.com]

1. Robinson B. Lactic acidemia and mitochondrial disease. Mol Genet Metab. 2006;89(1-2):3-13.
2. Marin-Valencia I, Roe C, Pascual J. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab. 2010;101(1):9–17.
3. Ortez C, Jou C, Cortes-Saladelafont E, et al. Infantile parkinsonism and GABAergic hypotransmission in a patient with pyruvate carboxylase deficiency. Gene. 2013;532(2):302-306.
4. Schiff M, Levrat V, Acquaviva C, et al. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Molec Genet Metab. 2006;87:175-177.
5. Brun N, Robitaille Y, Grignon A, et al. Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am. J. Med. Genet. 1999;84:94-101.
6. Unal O, Orhan D, Ostergaard E, et al. A patient with pyruvate carboxylase deficiency and nemaline rods on muscle biopsy. J Child Neurol. 2013;28(11):1505-1508.
7. Monnot S, Serre V, Chadefaux-Vekemans B, et al. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat. 2009;30(5):734–740.
8. Carbone M, Applegarth D, Robinson B. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat. 2002;20(1):48–56.
9. Wexler I, Kerr D, Du Y, et al. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediat Res. 1998;43:579–584.