Pyruvate carboxylase deficiency is an infrequent autosomal recessive disorder characterized by an insufficient activity of pyruvate carboxylase, a mitochondrial enzyme that turns bicarbonate and pyruvate to oxaloacetate. Decreased pyruvate carboxylase activity causes decreased glutamate production and lactic acid accumulation. Pyruvate carboxylase also plays an important role in lipogenesis and neurotransmitter biosynthesis, which explains neurologic signs.
Pyruvate carboxylase deficiency patients may be divided, depending on manifestations and underlying biochemical abnormalities into three groups  : 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 . 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 . On the other hand, some patients present with microcephaly, that can be diagnosed before or after birth.
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 . 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.
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.