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Inborn Errors Of Metabolism Classification Essay

The occurrence of seizures is most frequent in the neonatal period as compared to other age groups, given the unique vulnerability of the brain in terms of the excitation–inhibition imbalance. While common etiologies include birth asphyxia, hypoglycemia, hypocalcemia, intraventricular hemorrhage, and meningitis, IEM may present in the neonatal period with or without encephalopathy in the form of poor feeding and lethargy, accompanied by seizures. Excessive irritability, abnormal crying, abnormal sleep, and hiccups are typical clinical markers for the clinician to suspect an underlying IEM. Clinical clues that suggest IEM being a likely etiology for the seizures and/or encephalopathy in the neonatal period are listed below [3]. We discuss selected EIEMs in detail as these manifest with epilepsy as a primary manifestation and some are potentially treatable.

6.1. Pyridoxine-Dependent Epilepsy

Pyridoxine-dependent epilepsy (PDE) is characterized by early onset recurrent seizures that are resistant to conventional anti-epileptic drugs but responsive to pyridoxine [13]. Hunt et al. first described PDE in a newborn with drug-resistant seizures which responded immediately to the administration of a multivitamin cocktail containing vitamin B6 in 1954 [14]. The underlying molecular genetic defect was identified in 2006, to be causally linked to pathogenic mutations in ALDH7A1 gene resulting in the deficiency of α–aminoadipic semialdehyde dehydrogenase (antiquitin), which is involved in cerebral lysine metabolism [15]. Antiquitin deficiency results in the accumulation of intermediary substrates (α–aminoadipic semialdehyde (AASA), Δ-1-piperidine-6-carboxylate (P6C) and pipecolic acid) generated in the lysine degradation pathway. A condensation reaction (Knoevenagel) with P6C leads to the inactivation of pyridoxal 5′ phosphate (PLP) leading to a deficiency [16,17].

PDE usually presents very early, within hours or days of birth, with seizures that are refractory to conventional anti-epileptic (AED) therapy. In some patients, intrauterine seizures have been reported to occur, with onset at the end of the last trimester, with mothers perceiving excessive and jerky fetal movements. Infants may also develop emesis, abdominal distention, sleeplessness presenting as sepsis, or with features of hyperalertness, hyperacusis, irritability, paroxysmal facial grimacing, and abnormal eye movements [15]. Multifocal and generalized myoclonic jerks, often intermixed with tonic seizures, and focal onset motor seizures are typical initially. If left undiagnosed and untreated, or in the case of non-response to pyridoxine, affected infants develop focal dyscognitive seizures, infantile spasms, and myoclonic seizures that are treatment-resistant. Late onset and other atypical presentations of PDE have also been described in one-third of patients. These include infants with a delayed presentation (usually with infantile spasms), infants whose seizures initially respond to conventional anti-epileptic drugs, but relapse later with refractory seizures, and patients whose seizures are not controlled by initial administration of pyridoxine but respond later to a second trial [18].

Ictal and interictal EEGs in PDE pyridoxine-dependent epilepsy are variable and relatively non-specific, and may even be reported as normal [15]. However, asynchronous bursts of high-voltage generalized epileptiform activity, multifocal discharges, slow-spike wave complexes, burst-suppression pattern, and hypsarrhythmia (in infants with West syndrome presentation) have also been described [15].

PDE patients also develop neurodevelopmental disabilities, ranging from mild to severe developmental delay and intellectual disability, which usually affects the expressive language domain, associated with a low-normal motor and performance IQ scores [19]. Magnetic resonance imaging studies of the brain are variable, ranging from normal to the presence of white matter signal abnormalities, generalized cerebral atrophy, and hypoplasia or dysgenesis of corpus callosum [6,15].

Diagnostic confirmation of PDE is done through demonstration of elevated levels of AASA in urine and ⁄ or plasma and cerebrospinal fluid (CSF) [15]. Initiation of treatment with pyridoxine does not interfere with this assay. The molecular diagnosis is confirmed with the identification of a pathogenic mutation in the ALDH7A1 gene.

Treatment should be initiated in an intensive care setting with available ventilator support as these infants may develop apnea, profound hypotonia, and hypotension in response to the administration of pyridoxine [20]. An initial dose 100 mg of pyridoxine can be given intravenously under careful monitoring. This should be followed by oral pyridoxine supplementation (30 mg/kg/day in two divided doses) for 3–7 days [11]. The duration of treatment is important before concluding the seizures are not pyridoxine-responsive as delayed responses occur. Pyridoxal phosphate (PLP) is also effective, but its use is limited by access to the product in different regions and countries and higher cost as compared to pyridoxine.

If the treatment is successful and/or the diagnosis confirmed by biochemical and/or molecular genetic testing, pyridoxine treatment must be continued indefinitely. Pyridoxine treatment has been associated with sensory peripheral neuropathy; thus, annual monitoring of nerve conduction is recommended where testing is possible [11]. If there is any evidence of abnormality on neurophysiological testing or clinical symptoms of neuropathy, the dose of pyridoxine should be reduced to the lowest effective dose. Recently, the addition of a lysine-restricted diet has been shown to be potentially beneficial, as it reduces the levels of the neurotoxic AASA [18]. An additional therapeutic option is high-dose arginine supplementation, which works by competitive inhibition of lysine uptake in the gut and the blood brain barrier [6,11].

In the long term, most treated children with PDE remain seizure-free; however, some children may have breakthrough seizures during periods of intercurrent infection and fever. In such situations, doubling the regular dose of pyridoxine during the first few days of a febrile illness may be effective at preventing breakthrough seizures [6,21].

Recently, a new genetic condition has been found to be responsible for pyridoxine-dependent epilepsy. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function [15]. Subsequent sequencing of 29 unrelated individuals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. Although the mechanism involved is not fully understood, the authors suggested that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side effects.

6.2. Pyridox(am)ine 5′-Phosphate oxidase (PNPO) Deficiency

Pyridox(am)ine 5′phosphate oxidase (PNPO) is essential for the synthesis of pyridoxal phosphate (PLP), which is the active form of vitamin B6. Deficiency of this enzyme has been described in a small number of infants worldwide who presented with seizures that were pyridoxine-resistant but PLP-responsive. Babies with PNPO deficiency are often premature, presenting with encephalopathy, seizures, lactic acidosis, and hypoglycemia [11]. The seizure semiology and EEG findings described are similar to those encountered in PDE. Maternal reports of in utero seizures are frequent. A burst-suppression pattern on EEG is frequently encountered in comparison to PDE. In contrast to PDE, breakthrough seizures while on PLP are frequently observed and patients may be sensitive to precise time intervals employed in daily PLP dosing schedule [22]. If left untreated, the disorder results in death or profound developmental impairment, with global brain atrophy and an abnormal pattern of myelination [6]. In patients identified and treated early, the outcome is usually much better [6]. Unlike PDE, PNPO deficiency lacks a specific biochemical marker in body fluids, but can be suspected on the basis of assays in blood and urine suggestive of l-aromatic acid decarboxylase deficiency (elevations in glycine, threonine, taurine, histidine, and low arginine) and treatment resistance to pyridoxine [23]. However, a definitive diagnosis can only be established by molecular genetic testing for mutations in the PNPO gene.

It is noted that patients carrying certain mutations in the PNPO gene are associated with pyridoxine responsiveness, but display resistance to treatment with PLP [6]. These patients had refractory seizures that respond to pyridoxine but had normal biomarkers and no pathogenic mutations in the antiquitin gene. They were demonstrated to have mutations in the PNPO gene. Two of these patients developed status epilepticus when they were switched to PLP. The authors hence recommend sequential trial of pyridoxine followed by PLP in all newborns with refractory seizures.

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