Molecular basis and clinical management of Gaucher disease

Gaucher disease (GD) type I is an autosomal recessive disease caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of undergraded substrate glucocerebroside and other glycolipids, thus causing damage in different organs. GBA is the only gene in which mutations are known to cause GD. Nearly 300 mutations have been identified in GD patients, including frame-shift mutations, point mutations, deletions, insertions, splice site mutations and recombinants. The variety of phenotypes associated to GD shows imperfect correlation with mutations. GD encompasses a spectrum of clinical findings from a perinatal lethal form to an asymptomatic form. However the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated: type I (chronic nonneuropathic), type II (acute neuropathic), and type III (chronic neuropathic). Patients with type I GD present with visceromegaly, hematological complications, and bone disease. Cardiac and pulmonary complications are rare. Type I GD adult patients have elevated risk of malignancies, Parkinson’s disease or Parkinsonism. Neuropathic forms of GD are rare and clinically ranging from lethal perinatal form to very mild form limited to abnormalities of horizontal ocular saccades. Diagnosis of acid β-glucosylceramidase relies on enzyme activity in peripheral blood leukocytes or skin fibroblasts and/or identification of GBA mutations. Enzyme replacement therapy is an effective treatment for non-neuropathic GD. Substrate inhibitor is the alternative therapy for some patients with GD is miglustat, iminosugar inhibitor of glucocerebroside synthase

Paradoxical worsening of seizure activity with pregabalin in an adult with isodicentric 15 (IDIC-15) syndrome involving duplications of the GABRB3, GABRA5 and GABRG3 genes

Background: Isodicentric 15 syndrome (IDIC-15) is due to partial duplications of chromosome 15 that may includes the q11–13 region that includes genes encoding the α5 (GABRA5) and β3 - γ3 (GABRB3) receptor subunits. The disease causes intellectual and physical developmental delay, seizures, intellectual disability and behavioral disorders that may be related to abnormal GABA receptor function and morphology. Seizures are often severe and may be refractory to treatment. There are however no specific guidelines for the treatment of the seizures and it is unknown whether drugs that affect the GABAergic system have a different effect in IDIC-15 seizures. Case presentation: We report the case of an adult individual with IDIC-15 whose complex-partial seizures worsened dramatically after the introduction of pregabalin, with increased seizure frequency, frequent generalization, and appearance of new seizure pattern. Her cognitive function and verbal skills also worsened during treatment with pregabalin. Her seizures and cognitive skills quickly improved after pregabalin was discontinued and treatment with lacosamide started. Conclusion: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin.This case may help define proper therapeutic strategies for the treatment of IDIC-15 associated seizures

Molecular basis and clinical management of Gaucher disease

Gaucher disease (GD) type I is an autosomal recessive disease caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of undergraded substrate glucocerebroside and other glycolipids, thus causing damage in different organs. GBA is the only gene in which mutations are known to cause GD. Nearly 300 mutations have been identified in GD patients, including frame-shift mutations, point mutations, deletions, insertions, splice site mutations and recombinants. The variety of phenotypes associated to GD shows imperfect correlation with mutations. GD encompasses a spectrum of clinical findings from a perinatal lethal form to an asymptomatic form. However the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated: type I (chronic nonneuropathic), type II (acute neuropathic), and type III (chronic neuropathic). Patients with type I GD present with visceromegaly, hematological complications, and bone disease. Cardiac and pulmonary complications are rare. Type I GD adult patients have elevated risk of malignancies, Parkinson’s disease or Parkinsonism. Neuropathic forms of GD are rare and clinically ranging from lethal perinatal form to very mild form limited to abnormalities of horizontal ocular saccades. Diagnosis of acid β-glucosylceramidase relies on enzyme activity in peripheral blood leukocytes or skin fibroblasts and/or identification of GBA mutations. Enzyme replacement therapy is an effective treatment for non-neuropathic GD. Substrate inhibitor is the alternative therapy for some patients with GD is miglustat, iminosugar inhibitor of glucocerebroside synthase

Validation of Prognostic Scales for Functional Outcome in Ischemic Stroke Patients Treated with Intravenous Thrombolysis in a Rural Setting

Introduction: Early prediction of functional outcome after rtPA helps clinicians in prognostic conversations with stroke patients and their families. Three prognostic tools have been developed in this regard: DRAGON, MRI-DRAGON, and S-TPI scales. These tools, all performing with comparable accuracy, have been internally and externally validated in tertiary care centers. However, their performance in rural areas remains uncertain. This study addresses this gap in the literature by evaluating the effectiveness of those prognostic tools in stroke patients treated in a rural area of the Midwest. Methods: We conducted a retrospective study of stroke patients treated with thrombolytics at Southern Illinois Healthcare Stroke Network from July 2017 to June 2024. Data on demographics, clinical presentations, laboratory values, neuroimaging, and stroke metrics were collected. Modified Rankin Scale (mRS) at 1 month, classified into good (mRS ≤2) and poor (mRS ≥5) outcomes were noted. DRAGON and MRI-DRAGON scores were calculated. S-TPI model was built. Area under the receiver operating characteristic curve (AUC) with its 95% confidence interval was calculated for each prognostic model. Results: A total of 279 patients were included in this study. Of those, 43% (n = 119) were male. Median age (interquartile range [IQR]) was 69 (57–80) years. NIHSS at presentation (IQR) was 7 (4–13). 12% of the cohort (n = 34) had posterior circulation stroke. At 1 month, 66% of patients (n = 185) had mRS ≤2, whereas 14% of patients (n = 39) had mRS ≥5. MRI-DRAGON showed the highest accuracy in predicting both good (AUC = 0.86, 95% CI: 0.81–0.90) and poor outcomes (AUC = 0.84, 95% CI: 0.76–0.91). DRAGON also demonstrated high accuracy for good (AUC = 0.85, 95% CI: 0.80–0.89) and poor (AUC = 0.82, 95% CI: 0.75–0.90) outcomes. Conversely, in our population, the S-TPI model had the lowest accuracy for good (AUC = 0.56, 95% CI: 0.49–0.63) and poor (AUC = 0.68, 95% CI: 0.61–0.76) outcomes. Conclusion: Among the available grading scores, MRI-DRAGON score can be considered the more accurate short-term prognostic tool for stroke patients treated with rtPA in the rural setting