Rare Diseases Are Not Rare

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The GRM1 gene is expressed mainly in the brain, with the highest expression in the cerebellum. Mutations in the GRM1 gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the GRM1 gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the GRM1 gene to date. We demonstrated that multiple rare variants in the GRM1 underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation. Full article

In this article, we identified a novel epileptogenic variant (G307R) of the gene SLC6A1, which encodes the GABA transporter GAT-1. Our main goal was to investigate the pathogenic mechanisms of this variant, located near the neurotransmitter permeation pathway, and compare it with other variants located either in the permeation pathway or close to the lipid bilayer. The mutants G307R and A334P, close to the gates of the transporter, could be glycosylated with variable efficiency and reached the membrane, albeit inactive. Mutants located in the center of the permeation pathway (G297R) or close to the lipid bilayer (A128V, G550R) were retained in the endoplasmic reticulum. Applying an Elastic Network Model, to these and to other previously characterized variants, we found that G307R and A334P significantly perturb the structure and dynamics of the intracellular gate, which can explain their reduced activity, while for A228V and G362R, the reduced translocation to the membrane quantitatively accounts for the reduced activity. The addition of a chemical chaperone (4-phenylbutyric acid, PBA), which improves protein folding, increased the activity of GAT-1WT, as well as most of the assayed variants, including G307R, suggesting that PBA might also assist the conformational changes occurring during the alternative access transport cycle. Full article

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries. Full article

Abdominopelvic actinomycosis is a rare chronic or subacute bacterial infection caused by Actinomyces israelii, a Gram-positive anaerobic bacterium that normally colonizes the digestive and genital tracts, clinically presented as an inflammatory mass or abscess formation. Methods: We reviewed the medical records of the patients from our clinic with abdominopelvic actinomycosis who underwent surgery between 2002 and 2022. In this period, 28 cases (9 men and 19 women) were treated. The mean age was 43.36 years and they were hospitalized for abdominopelvic tumors or inflammatory tumors in 15 cases and inflammatory disease in 13 cases. Results: Causes of actinomycosis in the studied group were an intra-uterine contraceptive device in 17 cases, foreign bodies in 2 cases, diabetes in 4 cases, stenting of the bile duct in 1 case, and immunodepression. For 6 patients, we performed surgery by open approach and for 21 patients by a laparoscopic approach. For nine patients, abdominopelvic actinomycosis had been mimicking a colon malignancy (cecum and ascending colon, four cases; transverse colon, two cases; and on the greater omentum, three cases) and for six patients, a pelvic tumor (advanced ovarian cancer). After surgery the patients underwent specific treatment with antibiotics, with good results. In two cases we discovered and treated hepatic actinomycosis, one case by a laparoscopic approach and one case by a percutaneous approach. In our lot we noticed three recurrences that required reintervention in patients who had had short-term antibiotics due to non-compliance with treatment out of four such cases. Conclusions: For abdominopelvic malignancies, actinomycosis should be included in the differential diagnosis, as well as for inflammatory bowel diseases and bowel obstructions. We have a wide range of patients considering the rarity of this condition. Long-term antibiotics are necessary to prevent recurrence. Full article