Metabolic Disorders Presenting with Seizures in the Neonatal Period

Abstract

Metabolic disorders represent rare but often treatable causes of seizures and epilepsy of neonatal onset. As seizures are relatively common in the neonatal period, systemic clues to a specific diagnosis may be lacking or shrouded by acute illness. An important role of the consulting pediatric neurologist is to identify neonates with a possible metabolic or otherwise genetic diagnosis. In this review, the authors describe presenting signs and symptoms, a diagnostic framework, and disorder-specific treatment options for inborn errors of metabolism that may present in the neonatal period. Specific attention is given to the neurologic aspects of each condition, including the electroclinical phenotype and findings on brain imaging. As expedited diagnosis and prompt initiation of available therapies have been demonstrated to result in improved epilepsy and developmental outcomes, this work acts as a framework to guide evaluation when an inherited metabolic disorder is suspected. In addition to informing treatment, a definitive diagnosis allows for appropriate counseling regarding prognosis, any associated screening or preventive measures, and family planning.

2022 Overview of Metabolic Epilepsies

“…Although seizure semiology can be highly variable, the presence of certain types of seizures such as progressive myoclonic seizures [ 17 ], infantile spasms [ 31 ], epilepsia partialis continua [ 8 ] or refractory myoclonic or tonic seizures in the context of a burst suppression pattern on electroencephalogram (EEG) in the neonatal period [ 14 ] should raise the suspicion of metabolic epilepsy. Besides, although metabolic epilepsies are more frequently associated with generalized seizures, focal epilepsy may be a symptom in a number of IMDs, especially those associated with cortical malformations (e.g., peroxisomal disorders or congenital disorders of glycosylation) [ 32 ].…”

“…The age of presentation can be a diagnostic indication in some metabolic epilepsies [8,28]; however, it must be emphasized that there can be a considerable overlap among age groups, many disorders (e.g., mitochondriopathies) may present at any age and there is a general trend for the expansion of the clinical spectrum of many IMDs towards adolescent or adult-onset phenotypes with improved diagnostics [29,30]. Although seizure semiology can be highly variable, the presence of certain types of seizures such as progressive myoclonic seizures [17], infantile spasms [31], epilepsia partialis continua [8] or refractory myoclonic or tonic seizures in the context of a burst suppression pattern on electroencephalogram (EEG) in the neonatal period [14] should raise the suspicion of metabolic epilepsy. Besides, although metabolic epilepsies are more frequently associated with generalized seizures, focal epilepsy may be a symptom in a number of IMDs, especially those associated with cortical malformations (e.g., peroxisomal disorders or congenital disorders of glycosylation) [32].…”

“…Meanwhile, more than 1000 human genes have been associated with monogenic disorders that involve epilepsy or seizures and a considerable portion of them (373 genes out of a list of 880 genes (42%) in our previous study) are IMDs [ 13 ]. Metabolic epilepsies comprise a significant part of the etiologies in certain groups of epilepsy patients, such as neonatal epilepsy [ 14 ], refractory epilepsy [ 15 ], status epilepticus [ 16 ] and progressive myoclonus epilepsies [ 17 ], among others. Besides, although it is generally perceived that metabolic epilepsies account for a very small proportion of all patients with epilepsy [ 1 , 18 ], IMDs are frequently diagnosed through genomic testing in various cohorts of patients with epilepsy, including unselected cohorts of patients with variable epilepsy phenotypes, early-onset epilepsy, progressive myoclonic epilepsy and even adult or elderly patients with epilepsy ( Table 1 ).…”

Severe isolated sulfide oxidase deficiency with a novel mutation

“…Inborn errors of metabolism account for approximately 1-3% of neonatal seizure cases, while HIE is the most common cause of neonatal seizures accounting for about two-thirds of cases. 5,6 Among them, the inherited inability of conversion of sulfite to sulfate caused by SO deficiency has clinical presentation resembling those in neonatal HIE. SO deficiency may be caused by ISOD or defects in the biosynthesis of molybdenum cofactor which is an essential component of three molybdenum-requiring enzymes including SO.…”

Neonatal seizures as onset of Inborn Errors of Metabolism (IEMs): from diagnosis to treatment. A systematic review

“…Ketogenic diet) (Ismayilova et al 2018) as soon as possible. Moreover, it should be noticed that for those IEMs for which therapy is not available, the diagnosis is still important for genetic counselling and recurrence risk (Brimble and Ruzhnikov 2020).…”