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.

Dermatitis herpetiformis presenting as digital petechiae.

We present a 15-year-old female patient with a 6-month history of recurrent painful petechiae on the fingers and feet. Trauma or pressure were denied, but she reported recurrent tonsillitis and urinary tract infections and a single event of bilateral scotoma. Extensive investigations (e.g., echocardiography) for a suspected diagnosis of septic emboli were unremarkable. Routine histopathology, direct and indirect immunofluorescence, and esophagogastroduodenoscopy led to the diagnosis of dermatitis herpetiformis. The therapeutic strategy comprised gluten-free diet and dapsone to alleviate the symptoms. Dermatitis herpetiformis should be included in the differential diagnosis of palmar or plantar petechiae, especially when occurring in children or young adults.

Multiple sources of metabolic disturbance in ETHE1-related ethylmalonic encephalopathy.

Ethylmalonic encephalopathy (EE) is a rare metabolic disorder caused by dysfunction of ETHE1, a mitochondrial dioxygenase involved in hydrogen sulfide (H2S) detoxification. Patients present in infancy with psychomotor retardation, chronic diarrhea, orthostatic acrocyanosis and relapsing petechiae. High levels of lactic acid, ethymalonic acid (EMA) and methylsuccinic acid (MSA) are detected in body fluids. Several pathways may contribute to the pathophysiology, including isoleucine, methionine and fatty acid metabolism. We report on a 15-month-old male presenting with typical EE associated with a homozygous ETHE1 mutation. We investigated oral isoleucine (150 mg/kg), methionine (100 mg/kg), fatty acid loading tests and isoleucine-restricted diet (200 mg/day) for any effects on several metabolic parameters. Before loading tests or specific dietary interventions, EMA, C4-C5 acylcarnitines and most acylglycines were elevated, indicating functional deficiency of short chain acyl-CoA (SCAD) as well as all branched acyl-CoA dehydrogenases. Excretion of EMA and n-butyrylglycine increased following each of the loads, and isoleucine led to increased levels of derivative metabolites. An isoleucine-restricted diet for 8 days corrected some of the abnormalities but led to no obvious clinical improvement and only partial effects on EMA. A principal component analysis supports the inference that these dietary conditions have consistent effects on the global metabolic profile. Our results suggest that multiple pathways modulate EMA levels in EE. They might all interact with H2S toxicity. Prolonged dietary interventions involving the restriction for branched aminoacids, fatty acids and methionine could be discussed as auxiliary therapeutical strategies in EE.

Fish-oil fatty acid supplementation in mixed cryoglobulinemia: a preliminary report.

OBJECTIVE: Since fish oils seem to play a potential role in the treatment of inflammatory disorders by inhibiting arachidonic acid metabolism, the purpose of this study was to determine their therapeutic efficacy in mixed cryoglobulinemia (MC), an inflammatory condition caused by the deposition of immune complexes in vessel walls. METHODS: In an 8-week double-blind randomized trial, ten MC patients received a daily dietary supplement of 3 gm of eicosapentaenoic acid (EPA) and 2 gm of docosahexenoic acid (DHA), while 10 other MC patients received placebo (olive oil). The severity of purpura, arthralgias, paresthesias, asthenia and Raynaud's phenomenon were monitored daily, and serological assays were performed at the beginning of the study, at the end of the treatment period, and after 4 weeks of wash-out. RESULTS: No significant differences were found between the two groups with regard to the clinical symptoms, although the percentage of patients who reported a clinical improvement was higher in the group treated with fish oils. As for the serological parameters, no variation was found in the placebo group, while in the group receiving fish oils a significant decrease in cryocrit and rheumatoid factor levels was observed, which in the case of rheumatoid factor persisted at the end of the wash-out period. CONCLUSIONS: Under the experimental conditions employed in this study, we could not demonstrate a significant improvement in clinical symptoms in patients with mixed cryoglobulinemia treated with fish oils. However, since our results indicated some improvement in the serological parameters potentially involved in the pathogenesis of the disorder, further studies are warranted to establish the optimal dose and duration of fish oil supplementation in the treatment of MC.