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.

• Turkish

  Ethnic origin Danish Somalian Turkish Turkish Turkish Turkish Turkish Pregnancy and birth N.a. [ncbi.nlm.nih.gov]

  The mutations found here are novel; it is noteworthy that four Turkish patients did not have any mutations in common, despite the rarity of PC deficiency. There is thus no evidence for recurrent mutations in the Turkish or other populations. [doi.org]

• 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. [en.wikipedia.org]

  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]

  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]

  pain, vomiting, tiredness and muscle weakness. [rarediseases.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. [merckmanuals.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]

  Some patients present with psychomotor retardation in the infantile period, an increase of plasma lactate with normal lactate to pyruvate ratio and survival up to 5 years (type A). [invitae.com]

• Generalized Seizure

  Her psychomotor development was retarded, her movements were dystonic and generalized seizures punctuated her course. [ncbi.nlm.nih.gov]

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.

• Alanine Increased

  This condition is caused by mutations in the PC gene and inherited in an autosomal recessive pattern. 0001290 Global developmental delay 0001263 Hepatomegaly Enlarged liver 0002240 Hyperalaninemia Increased blood alanine Increased serum alanine This means [rarediseases.info.nih.gov]

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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.
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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.