Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

Auditory processing following infantile spasms: An event-related potential study.

OBJECTIVES: To investigate acoustic auditory processing in patients with recent infantile spasms (IS). METHODS: Patients (n = 22; 12 female; median age 8 months; range 5-11 months) had normal preceding development, brain magnetic resonance imaging (MRI), and neurometabolic testing (West syndrome of unknown cause, uWS). Controls were healthy babies (n = 22; 11 female; median age 6 months; range 3-12 months). Event-related potentials (ERPs) and psychometry (Bayley Scales of Infant Development, Second Edition, BSID-II) took place at a month following IS remission. RESULTS: Following a repeated pure tone, uWS patients showed less suppression of the N100 at the mid-temporal electrodes (p = 0.006), and a prolonged response latency (p = 0.019). Their novelty P300 amplitude over the mid-temporal electrodes was halved (p = 0.001). The peak of the novelty P300 to environmental broadband sounds emerged later over the left temporal lobe in patients (p = 0.015), the lag correlating with duration of spasms (r = 0.547, p = 0.015). BSID-II scores were lower in patients (p < 0.001), with no correlation to ERP. SIGNIFICANCE: Complex acoustic information is processed poorly following IS. This would impair language. Treatment did not reverse this phenomenon, but may have limited its severity. The data are most consistent with altered connectivity of the cortical acoustic processing areas induced by IS.

Temporal lobe impairment in West syndrome: event-related potential evidence.

OBJECTIVE: This study investigates auditory processing in infants with West syndrome (WS) using event-related potentials (ERPs). METHODS: ERPs were measured in 25 infants with mainly symptomatic WS (age range = 3-10 months) and 26 healthy term infants (age range = 3-9 months) using an auditory novelty oddball paradigm. The ERP recordings were made during wakefulness and repeated in stage II sleep. RESULTS: The obligatory components (P150, N250, P350) and novelty response components (P300, Nc) were recordable during both sleep and wakefulness in patients and controls. All ERP latencies decreased with age in controls but not in the WS group (age × group interaction, F = 22.3, p < 0.0001). These ERP latency alterations were not affected by pharmacological treatment for WS. INTERPRETATION: This study demonstrated a persistently altered ERP signature in patients with a recent history of infantile spasms. The prolongation of auditory obligatory and novelty ERPs in WS patients indicates a severe failure of temporal lobe maturation during infancy. It remains to be investigated whether this predicts long-term cognitive impairments characteristic for this epileptic encephalopathy.

Pyridoxine-dependent seizures: a family phenotype that leads to severe cognitive deficits, regardless of treatment regime.

The neuropsychological and clinical histories of three male siblings affected by pyridoxine-dependent seizures with known homozygous antiquitin mutations are presented. Neuropsychological evaluation is reported from when the siblings were 11, 9, and 7 years of age. Two of the siblings had received early pyridoxine treatment (antenatal, 2-4 wks into pregnancy) and one had received late treatment (2mo postnatal). However, there was no differential effect on cognitive outcome, with all three siblings having moderate to severe learning disability. Unlike previously reported cases that received early postnatal treatment, none of the siblings had relatively preserved non-verbal cognitive skills. Equally, their intellectual performance over time did not increase above the 1st centile despite high maintenance doses of vitamin B6 (range 16-26 mg/kg/d), and mild sensory neuropathy was reported on nerve conduction studies. The findings in these siblings challenge assumptions that early and high dose pyridoxine treatment can benefit cognition in this population and suggest routine electromyography monitoring may be beneficial.

A neurophysiological perspective on sleep and its maturation.

Neurophysiological studies of sleep have increasingly focused on underlying dynamic processes. This would appear particularly relevant to the developmental aspects of sleep. Involvement of sleep-dependent mechanisms in emotional processing, as well as perceptual-sensory, perceptual-motor, and cognitive learning, mostly studied in adults, may play major roles in development. Rapid eye movement (REM) sleep, which is generated by complex neuronal interactions within the pontine reticular formation, and non-REM sleep, which arises from activities in the thalamocortical network, are specifically implicated in different aspects of long-term memory systems. They evolve from previous physiological and behavioural states which can be traced back to the fetal period. Further studies are needed to clearly identify functions reflected by hallmarks of sleep stages, such as spindles and K complexes. A better understanding of the maturational aspects of sleep should provide important insights into physiological development. Assessment approaches taking dynamic characteristics of sleep into account may contribute to the design of better targeted management of sleep-related problems in neurodevelopmental conditions.

Speech and non-speech processing in hemispherectomised children: an event-related potential study.

Although hemispherectomy is now used as a radical treatment for intractable seizures in a number of centres, there have been limited electrophysiological studies investigating post-procedure auditory-speech processing and recovery or reorganisation. We therefore recorded auditory event-related potentials (ERPs) evoked by pure tones and syllables employing a 51-channel electrode array concentrated over the functional hemisphere in 17 patients (nine males, mean age 14.2 years) who had undergone hemispherectomy for intractable seizures; eight of the patients had congenital brain damage and nine had sustained their initial insult at an age of 1 year or older. For comparison, recordings were made from 10 controls (five males, mean age 13.5 years). Responses from patients consisted of five small amplitude components restricted to the functional hemisphere whose scalp polarity was opposite to the ERPs observed in control subjects. The topography of the auditory ERPs in the patients was localised to the centro-temporal regions of the functional hemisphere in comparison to the midline distribution observed in control subjects. As in the control subjects, the latencies of the components evoked by tones were shorter than those evoked by syllables in both left and right hemispherectomised children. In addition, further analysis of the N1 and P2 component revealed increased syllable latencies in left hemispherectomised children only. The results of this study suggest that the left hemisphere alone may be more efficient at processing both pure tones and syllables compared to the right or both together.