Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia.

POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype-phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46-55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337-11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype-phenotype correlation in POLR3A-related disorders.

Neurologic complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Ectopic Muscle Expression of Neurotrophic Factors Improves Recovery After Nerve Injury.

Sciatic nerve damage is a common medical problem. The main causes include direct trauma, prolonged external nerve compression, and pressure from disk herniation. Possible complications include leg numbness and the loss of motor control. In mild cases, conservative treatment is feasible. However, following severe injury, recovery may not be possible. Neuronal regeneration, survival, and maintenance can be achieved by neurotrophic factors (NTFs). In this study, we examined the potency of combining brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) on the recovery of motor neuron function after crush injury of the sciatic nerve. We show that combined NTF application increases the survival of motor neurons exposed to a hypoxic environment. The ectopic expression of NTFs in the injured muscle improves the recovery of the sciatic nerve after crush injury. A significantly faster recovery of compound muscle action potential (CMAP) amplitude and conduction velocity is observed after muscle injections of viral vectors expressing a mixture of the four NTF genes. Our findings suggest a rationale for using genetic treatment with a combination of NTF-expressing vectors, as a potential therapeutic approach for severe peripheral nerve injury.

The impact of transient and persistent acute kidney injury on long-term outcomes after acute myocardial infarction.

Acute kidney injury is a common complication of acute myocardial infarction and is generally associated with adverse outcomes. We studied the incidence and clinical significance of transient versus persistent acute kidney injury in 1957 patients who survived an ST-elevation acute myocardial infarction. We divided the patients into 5 groups based on changes in serum creatinine level during hospitalization. Mild acute kidney injury (creatinine 0.3-0.49 mg/dl above baseline) occurred in 156 patients and was transient (resolved during their hospital stay) in 61. Moderate/severe acute kidney injury (creatinine more than or 0.5 mg/dl above baseline) was found in 138 patients and was transient in 60. Compared to patients without acute kidney injury, the adjusted hazard ratio for mortality was 1.2 in patients with mild, transient acute kidney injury and 1.8 in patients with mild, persistent injury where the creatinine remained elevated. Patients with persistent moderate/severe acute kidney injury had the highest mortality (hazard ratio 2.4), whereas patients with transient moderate/severe injury had an intermediate risk (hazard ratio of 1.7). A similar relationship was present between acute kidney injury and admissions for heart failure. Our study shows that dynamic changes in renal function during acute myocardial infarction are strongly related to long-term mortality and heart failure.

Single-dose quinolone treatment in acute gastroenteritis.

BACKGROUND: Acute diarrhea is a common disease worldwide and in Israel, a Mediterranean country. Acute bacterial gastroenteritis (ABGE) is the leading cause of severe diarrhea in Israel in summer and early autumn. Although there are some reports showing some benefit from empiric antibiotic therapy in acute gastroenteritis, most are old reports using nondefinitive diagnostic criteria and using 5-day antibiotic regimens. AIMS: 1. To examine the efficiency of antibiotic therapy in relatively severe ABGE in general. 2. To check the efficiency of the different types of quinolones in the treatment of ABGE. 3. To compare various therapy regimens. METHODS: All patients admitted to the Barzilai Medical Center emergency room during the period June to October in 2002-2004 who were defined by protocol as having relatively severe gastroenteritis and required hospitalization in the Department of Internal Medicine were included in the study. All were randomized either to a supportive treatment only group (STG) or to the antibiotic treatment group (ATG) of ofloxacin or levofloxacin with a single dose or BID for 5 days in addition to STGs. All patients were interviewed a week later about their medical history and duration of symptomatology. RESULTS: One hundred thirty-nine patients were found eligible for the study in the above-mentioned period. Abdominal pain resolved 1.3 days earlier in the ATG in comparison to the STG whereas vomiting and diarrhea disappeared 1.0 and 0.8 days earlier, respectively, in the ATG versus the STG. In terms of fever abatement there was no difference between the regimens and no significant difference in symptomatology disappearance between various types of quinolones used or between the single antibiotic dose regimen and the 5-day antibiotic regimen groups. CONCLUSIONS: 1. Antibiotic therapy was found to shorten duration of symptoms in patients with relatively severe gastroenteritis. 2. Single-dose therapy is as effective and certainly significantly more cost effective in comparison to the 5-day antibiotic treatment regimen.