Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy.

Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2S. Patients are typically identified after the onset of clinical symptoms and there is limited information about long term response to treatment. We report the findings of two unrelated patients with EE, identified through newborn screening, who were managed with conventional treatment (NAC, metronidazole alternated with neomycin) and in patient 2, a novel dietary treatment restricting sulfur containing amino acids. Pathogenic mutations were confirmed in the ETHE1 gene (homozygous splice site mutation in patient 1, c.505 + 1G > A; compound heterozygous mutations in patient 2, c.131_132delAG + c.566delG). Both patients were started on metronidazole and NAC by 10 weeks of age and treated for 23 months. Patient 1 did not accept the metabolic formula due to palatability and parental refusal for gastrostomy tube placement. She demonstrated improved biomarkers (EMA, lactic acid and thiosulfate) and an attenuated clinical course. Patient 2 was started on a low methionine and cysteine diet at 8 months of age utilizing SOD Anamix® Early Years, (Nutricia). Baseline EMA levels were (642 mg/g Cr; n = 2) and decreased with medical treatment by 38% to a mean of 399 (n = 4, SD = 71, p 0.0013). With dietary treatment EMA levels were further reduced by 42% to a mean of 233 (n = 8, SD = 52, p 0.0030). Lactic acid, thiosulfates and clinical outcomes were also improved. Our long-term follow-up confirms previous reports of clinical improvement with NAC and metronidazole treatment. Additionally, our studies suggest that a diet restricted in sulfur-containing amino acids results in further improvement in clinical outcomes and biochemical markers.

Working memory, psychiatric symptoms, and academic performance at school.

Previous studies of the relationship among working memory function, academic performance, and behavior in children have focused mainly on clinical populations. In the present study, the associations of the performance in audio- and visuospatial working memory tasks to teacher reported academic achievement and psychiatric symptoms were evaluated in a sample of fifty-five 6-13-year-old school children. Working memory function was measured by visual and auditory n-back tasks. Information on incorrect responses, reaction times, and multiple and missed responses were collected during the tasks. The children's academic performance and behavioral and emotional status were evaluated by the Teacher Report Form. The results showed that good spatial working memory performance was associated with academic success at school. Children with low working memory performance, especially audiospatial memory, were reported to have more academic and attentional/behavioral difficulties at school than children with good working memory performance. An increased number of multiple and missed responses in the auditory and visual tasks was associated with teacher reported attentional/behavioral problems and in visual tasks with teacher reported anxiety/depressive symptoms. The results suggest that working memory deficits may underlie some learning difficulties and behavioral problems related to impulsivity, difficulties in concentration, and hyperactivity. On the other hand, it is possible that anxiety/depressive symptoms affect working memory function, as well as the ability to concentrate, leading to a lower level of academic performance at school.