Liver and liver/kidney transplantation are increasingly used in methylmalonic aciduria, but little is known on their impact on CNS. The effect of transplantation on neurological outcome was prospectively assessed in six patients preand post-transplant by clinical evaluation and by measuring disease biomarkers in plasma and CSF, in combination with psychometric tests and brain MRI studies. Primary (methylmalonic-and methylcitric acid) and secondary biomarkers (glycine and glutamine) significantly improved in plasma, while they remained unchanged in CSF. Differently, biomarkers of mitochondrial dysfunction (lactate, alanine, and related ratios) significantly decreased in CSF. Neurocognitive evaluation documented significant higher post-transplant developmental/cognitive scores and maturation of executive functions corresponding to improvement of brain atrophy, cortical thickness, and white matter maturation indexes at MRI. Three patients presented post-transplantation reversible neurological events, which were differentiated, by means of
Pompe disease (PD) is caused by deficiency of the enzyme acid α‐glucosidase resulting in glycogen accumulation in lysosomes. Clinical symptoms include skeletal myopathy, respiratory failure, and cardiac hypertrophy. We studied plasma proteomic and lipidomic profiles in 12 PD patients compared to age‐matched controls. The proteomic profiles were analyzed by nLC‐MS/MS SWATH method. Wide‐targeted lipidomic analysis was performed by LC‐IMS/MS, allowing to quantify >1100 lipid species, spanning 13 classes. Significant differences were found for 16 proteins, with four showing the most relevant changes (GPLD1, PON1, LDHB, PKM). Lipidomic analysis showed elevated levels of three phosphatidylcholines and of the free fatty acid 22:4, and reduced levels of six lysophosphatidylcholines. Up‐regulated glycolytic enzymes (LDHB and PKM) are involved in autophagy and glycogen metabolism, while down‐regulated PON1 and GPLD1 combined with lipidomic data indicate an abnormal phospholipid metabolism. Reduced GPLD1 and dysregulation of lipids with acyl‐chains characteristic of GPI‐anchor structure suggest the potential involvement of GPI‐anchor system in PD. Results of proteomic analysis displayed the involvement of multiple cellular functions affecting inflammatory, immune and antioxidant responses, autophagy, Ca2+‐homeostasis, and cell adhesion. The combined multi‐omic approach revealed new biosignatures in PD, providing novel insights in disease pathophysiology with potential future clinical application.
Background
Ethylmalonic encephalopathy (EE) is a severe intoxication-type metabolic disorder with multisystem clinical features and leading to early death. In 2014, based on the promising results obtained by liver-targeted gene therapy in Ethe1−/− mouse model, we successfully attempted liver transplantation in a 9-month-old EE girl. Here we report her long-term follow-up, lasting over 6 years, with a comprehensive evaluation of clinical, instrumental and biochemical assessments.
Results
Neurological signs initially reverted, with a clinical stabilization during the entire follow-up course. Accordingly, gross motor functions improved and then stabilized. Psychomotor evaluations documented an increasing communicative intent, the acquisition of new social skills and the capability to carry out simple orders. Neurophysiological assessments, which included EEG, VEP/ERG and BAEPs, remained unchanged. Brain MRI also stabilized, showing no further lesions and cerebral atrophy improvement. Compared to pre-transplant assessments, urinary ethylmalonic acid strikingly reduced, and plasma thiosulphate fully normalized. The child maintained good clinical conditions and never experienced metabolic crises nor epileptic seizures.
Conclusions
The long-term follow-up of the first EE transplanted patient demonstrates that liver transplantation stabilizes, or even improves, disease course, therefore representing a potentially elective option especially in early-diagnosed patients, such as those detected by newborn screening, before irreversible neurological damage occurs.
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