Inborn Errors of Metabolism

The major use of the KD is as a treatment for intractable epilepsy. In a few inborn errors of metabolism, however, the metabolic defects in carbohydrate metabolism are "bypassed" by using ketone bodies as the primary energy source. We discuss these disorders because the KD, with the steady production of ketone bodies, is the treatment of choice, and early diagnosis and treatment may prolong life and reduce morbidity in these patients.

1.7.1. Facilitated Glucose Transporter Protein Deficiency

Glucose transporter protein deficiency is a group of recently recognized disorders resulting in impaired glucose transport across blood-tissue barriers (36,37). Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome results from impaired glucose transport across the blood-brain barrier (38). Although a rare disorder, it is now increasingly recognized and over 70 cases have been reported in the literature (39).

The brain has limited abilities to use alternative nonglucose energy sources; ketone bodies can be metabolized, but not fatty acids (40). D-Glucose is therefore an essential fuel for the brain. The adult brain utilizes 20% of whole-body glucose, whereas the neonatal brain has a much higher requirement, and up to 80% of whole-body glucose is utilized (41). An impaired glucose supply to the developing brain, without sufficient alternative fuels, will therefore affect both brain function and development (42).

The clinical presentation of GLUT1 deficiency syndrome is nonspecific and heterogeneous. The pregnancy, delivery, and neonatal period are usually normal. In infancy or early childhood, seizures develop that are difficult to control with anticonvulsant medications. There is variation in seizure type, frequency, and character. During infancy, cyanotic, atonic, and partial seizures predominate. Myoclonic and generalized seizures develop later in childhood (43). Peculiar eye movements, developmental delay, acquired microcephaly, hypotonia with ataxia, dysmetria, dystonia, and spasticity are also common clinical features. The degree of intellectual impairment varies from profound mental retardation to normal cognitive abilities and may diminish with time (44). Clinical symptoms worsen with fasting, are often seen in the preprandial setting, and improve with food intake (45,46).

There are no specific anatomical brain abnormalities associated with GLUT1 deficiency syndrome, and brain imaging is usually normal or may show nonspecific findings. Electroencephalograph^ (EEG) changes include both focal and generalized epileptiform discharges and slowing, which may be reversible with food intake (47). Hypoglycorrhachia (low cerebral spinal fluid [CSF] glucose concentration) in the presence of a normal blood glucose (or a CSF/blood glucose ratio < 0.4) is the hallmark of the disease. The lumbar puncture should be performed during the metabolic steady state, such as 4-6 h after the last meal. In children, blood glucose should be determined before the lumbar puncture to avoid stress-related serum hyperglycemia. The CSF should be examined for cells, glucose, protein, and lactate and pyruvate concentrations. In GLUT1 deficiency syndrome, CSF concentrations of lactate are usually low to normal. For other causes of hypoglycorrhachia (meningitis, subarach-noid hemorrhage, sarcoidosis, trichinosis, lupus erythematosus), CSF lactate is usually elevated.

The human erythocyte glucose transporter is immunochemically identical to brain GLUT1. Therefore, the defect is in the GLUT1 gene and can be diagnosed by means of erythocyte glucose uptake studies (48). The glucose transport may be impaired from either a functional or a quantitative GLUT1 defect. GLUT1 -specific immunoreactivity in the erythocyte membrane will help in distinguishing the two. A normal GLUT1 immunoreactivity suggests a functional impairment, whereas reduced immunoreactiv-ity indicates a reduced number of transporters at the cell membrane.

The gene for GLUT1 has been identified on chromosome 1 (p35-31.3), and 21 different mutations have been detected. Prenatal diagnosis is currently not available unless a mutation has been identified in an affected child in the family. Two families with an autosomal dominant transmission of the GLUT1 disease have been described; but in other children, all mutations have been de novo, with family members unaffected. As this is a rare and novel disorder, long term outcomes are not known.

The only established treatment for GLUT1 deficiency syndrome is the KD, in which the ketone bodies P-hydroxybutyrate and acetoacetate are generated from fatty acid oxidation and provide an adequate supply of alternative fuel for brain metabolism. Patients placed on the KD usually have a quick cessation of seizure activity and concurrent improvement in the EEG. Ominously, however, one child with GLUT1 deficiency syndrome developed fatal pancreatitis while on the KD (49).

The duration of treatment with the KD in the GLUT1 deficiency syndrome is debated. Positron emission tomography studies suggest that cerebral glucose demand in children exceeds that is adults. The transition to greater glucose demand occurs during adolescence (50). It is therefore currently recommended that the KD be maintained into adolescence, to ensure adequate brain development in children with GLUT1 deficiency.

1.7.2. Pyruvate Dehydrogenase Deficiency

Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of lactic acidemia and represent relatively common inborn errors of metabolism in children (>200 cases described). PDH complex is a mitochondrial enzyme that catalyzes the irreversible oxidation of pyruvate to acetyl-Co A. PDH is the rate-limiting enzyme connecting glycolysis with the tricarboxylic acid cycle and oxidative phosphorylation. It therefore plays an important role in energy metabolism (51,52).

The PDH complex comprises three catalytic component enzymes, E1, E2, and E3, and a protein-X, necessary for the interactions of the E2 and E3 enzymes. The E1 component is a heterotetramer composed of two a and two P-subunits; there is also a cofac-tor (TPP) binding site. The activation of the PDH complex is tightly regulated through phosphorylation of the E1 a subunit by a specific deactivating kinase and an activating phosphatase. The PDH complex is present in all tissues. The vast majority of patients with PHD complex deficiency have a defect in the PDH-E1a subunit. Defects in the other complex components have also been reported (53,54).

The PDH-E1a subunit has been localized to the X chromosome (Xp22.1) (55). In males, all cells are affected, and the severe form of PDH deficiency is not compatible with life. In females, the X-chromosome inactivation pattern determines the tissue-specific PDH complex cellular activity (56). Most abnormalities are de novo point mutations, and asymptomatic carriers have been identified.

The clinical manifestations of the PDH-E1a deficiency are unusually heterogeneous. In general, the degree of clinical impairment correlates with the overall PDH complex activity. The severe neonatal form presents with overwhelming lactic acidemia, coma, and early death. These infants have a low birth weight and are hypotonic, with a weak suck, apnea, lethargy, and failure to thrive, usually they experience partial-onset seizures. Dysmorphic features, present in 25% of the children, include a broad nasal bridge, upturned nose, micrognathia, low-set and posteriorly rotated ears, short fingers and arms, simian creases, hypospadias, and anterior-placed anus. The less severe/moderate form presents at 3-6 mo of age with hypotonia, psychomotor retardation, intermittent ataxia and apnea, pyramidal signs, cranial nerve palsies, optic atrophy, deceleration of somatic and head growth, seizures (partial seizures and infantile spasms), and similar dysmorphic features. The milder form presents in childhood with intermittent ataxia, postexercise fatigue, and transient paraparesis, with normal neurological status in between episodes. Asymptomatic carriers have also been identified (57-60).

Neuropathological abnormalities include a small brain with gross dilatation of the ventricles, absent corpus callosum and medullary pyramids, olivary heterotopias, hypomyelination and cavitating cystic lesions in the brainstem, basal ganglia, and cortex (61).

The diagnosis of PDH deficiency is made by documenting an elevation of lactate and pyruvate (with a normal ratio) in blood and CSF, or in CSF only. Blood lactate levels may be elevated intermittently in children with less severe forms of PDH. Magnetic resonance spectroscopy may be helpful as an adjunctive test and will show lactic acid accumulation in the brain. Testing PDH complex residual activity in cultured fibroblasts is diagnostic in boys but is less reliable in girls owing to the tissue-specific variability.

Currently used treatments for PDH include high doses of the thiamine cofactor, attempts to activate the PDH complex with dichloroacetate (an inhibitor of PDH kinase), and use of a carbohydrate-restricted, high-fat KD (62-64). There are no large outcome studies comparing these interventions. However, individual case reports and a small case series suggest that early intervention with the KD is related to increased longevity and improved mental development (65,66).

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