Translational Science of Rare Diseases

In 2017, 24 European Reference Networks (ERNs) have been recognized in order to improve rare diseases’ management. However, a lack of practical information persists regarding the most adequate ways to fulfil ERNs’ quality criteria.

Identify the most efficient strategies to improve ERNs’ quality.

67 strategies, related to 8 activity domains (Quality Management System, healthcare coordination, clinicians’ training, inter-ERNs’ members collaborations, clinical data management, ERNs’ external collaborations/supports, information provided to patients, and ERNs’ financing) were selected from peer-reviewed scientific publications. Their usefulness, feasibility and adequacy was evaluated by 17 ERNs-related clinicians and 10 Belgian health policy makers.

Results showed that the most efficient strategies are the participation of quality controls, satisfaction surveys among patients and external physicians, diffusion of information about the hospitals’ research activities, specific trainings addressed to clinicians, exchange of medical samples between hospitals, and development of adequate clinical databases. The poor practical feasibility of 7 highly-useful strategies was also highlighted, such as major clinicians’ concerns regarding legal/ethical frameworks for the reimbursement of cross-country care and exchange of patients’ data.

This study enabled identification of efficient strategies to improve and validate ERNs’ quality, expertise and functioning, as well as weaknesses that should be addressed.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder characterized by deficient membrane transport of cationic amino acids. It is caused by pathogenic variants in SLC7A7, resulting in impairment of intestinal import and renal proximal tubule loss of the affected amino acids. LPI typically presents with gastrointestinal symptoms, such as vomiting, diarrhea, and failure to thrive.

A 4-year-old African-American boy presented with multiple respiratory tract infections, weight loss in the setting of chronic diarrhea and worsening abdominal distention, and multiple episodes of rectal prolapse. Development was unaffected. Laboratory examination demonstrated mild anemia, hypokalemia and hypoalbuminemia, transaminitis, and normal ammonia. Initial urine amino acid analysis did not show major elevations of lysine and ornithine, often lower than expected in the setting of malnutrition. Upon initiation of total parenteral nutrition (TPN), his urine amino acids showed a characteristic profile of dibasic aminoaciduria.

Failure to thrive, chronic diarrhea, and hepatomegaly should raise suspicion for LPI. Urine amino acids can be normal in this condition in the setting of malnutrition, a common complication of the disease. Additionally, it has been previously shown that the plasma arginine and ornithine concentration is higher in LPI subjects.

Urea cycle-related brain disease may take on variable neuroimaging manifestations, ranging from normal to abnormal with or without a signature appearance. In the past, we have described the usefulness of multimodal imaging in identifying biomarkers of neuronal injury in UCD patients. In this study, we report unique findings in an adolescent male with neonatal-onset OTC deficiency after an episode of hyperammonemia.

Multiplanar, multisequence MR imaging (T1WI, T2WI, T2 FLAIR, diffusion weighted images and gradient echo) of the brain was performed on seven separate occasions over the course following the acute illness; first five exams were performed within 28 days of admission and the final two exams were performed approximately 3 and 5 months later.

1.The initial MR revealed increased signal on T2WI in the basal ganglia, claustrum and frontoparietal white matter; which remained stable over time. By the 5th exam, signal changes had developed in frontal cortex; reflecting permanent injury. 2. DTI tractography of the corticospinal tracts displayed revealed diminution of the number of projectional and commissural fibers over time. 3. Blood flow measurements demonstrated hypoperfusion on the fifth exams followed by hyperperfusion on the final two studies. 4. MR spectroscopy demonstrated that glutamine was elevated during hyperammonemia with myoinositol reduction, reflecting osmotic buffering.

This particular multimodal magnetic resonance neuroimaging showed novel, temporally specific manifestations over the disease course in OTC deficiency. This prospective imaging study expands our understanding of the effect of hyperammonemia on the structure and biochemistry of the nervous system.