Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance.

BACKGROUND: Dysfunction in inwardly rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability, and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction. METHODS: We therefore performed whole-exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome. RESULTS: Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidylinositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch-clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant. CONCLUSION: Altogether, our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease.

BACKGROUND: Huntington's disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent 'incurability' often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n = 81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p < 0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

Complexities in Genetic Counseling and Testing of Huntington's Disease: A Perspective from India.

Background: Huntington's Disease (HD) is an autosomal dominant, progressive neuropsychiatric illness caused by CAG repeat expansion. The high penetrance of the mutation and limited treatment options make it challenging for patients and caretakers. Proper counseling enables families to cope better and make informed life choices. Objective: To explore some complex issues in genetic counseling and testing (GCAT) in HD. Materials and Methods: Vignettes of patients who underwent genetic testing along with pre and post-test counseling at our GCAT clinic. Results: Case 1: Diagnosis of juvenile HD meant that the healthy parent was an obligate carrier of the mutation. Case 2: Consanguinity resulted in a dense prevalence of HD and >50% risk for the progeny. Case 3: Predictive testing in youth with healthy parents but affected uncles and aunts revealed a HD expansion. Conclusions: HD can present with complex inheritance patterns and proper counseling is necessary for better outcomes.

Prediction of Surgical Outcome for Acute Traumatic Brain Injury in Older Adults.

Background: Increasing patient age is strongly associated with a rising incidence of traumatic brain injury (TBI) and a higher mortality and morbidity rates. Objective: This study aimed to identify the predictors of mortality after craniotomy for TBI in elderly patients. Material and Methods: Data of all patients aged ≥65 years who underwent craniotomy for acute TBI, over a period from January 2015 to October 2019, were retrospectively reviewed. The standard clinical and imaging variables for TBI were recorded. The medical comorbidities, indication for surgery, and intraoperative complications were also recorded. The outcome of interest was survival at 6 months after surgery. Results and Conclusions: A total of 206 patients were available for analysis. The age of patients ranged from 65 to 80 years. The most frequent surgical procedure performed was craniotomy and evacuation of supratentorial subdural hematoma with or without evacuation of the traumatic parenchymal lesion. The in-hospital mortality was 46 out of 206 (22.3%), and 6 months mortality was 116 out of 206 (56.3%). Among the survivors at 6 months, good recovery was seen in 70.5%, moderate disability in 19.8%, and severe disability in 8.6% patients. Only 1.2% patients survived in a vegetative state at 6 months. The odds of death are nearly three times more for patients with dilated and nonreactive pupillary reaction. The odds of death are less by 72% for a unit increase in motor score. In older adults, the main determinants of survival after surgery for TBI are pupillary reaction and motor score.