Progressive external ophthalmoplegia associated with novel MT-TN mutations.

OBJECTIVES: To describe two patients with progressive external ophthalmoplegia (PEO) and mitochondrial myopathy associated with mutations in mitochondrial DNA, encoding the tRNAAsn gene (MT-TN), which have not previously been published with clinical descriptions. MATERIALS & METHODS: Two unrelated patients with PEO were clinically examined. Muscle biopsy was performed and investigated by exome sequencing, enzyme histochemistry, and immunohistochemistry. The level of heteroplasmy was investigated in single muscle fibers and in other tissues. RESULTS: Patient 1 was a 52-year-old man with ptosis, PEO, and exercise intolerance since childhood. Muscle biopsy demonstrated mitochondrial myopathy with frequent cytochrome c oxidase (COX)-deficient fibers and a heteroplasmic mutation, m.5669G>A in the MT-TN gene, resulting in a substitution of a highly conserved C to T in the T stem of tRNAAsn . Patient 2 was a 66-year-old woman with ptosis, PEO, and exercise intolerance since many years. Muscle biopsy demonstrated mitochondrial myopathy with frequent COX-deficient fibers. She had a novel m.5702delA mutation in MT-TN, resulting in loss of a highly conserved U in the anticodon stem of tRNAAsn . Single fiber analysis in both cases showed highly significant differences in mutation load between COX-deficient and COX-normal fibers and a high threshold level for COX deficiency. The mutations were not found in blood, urine sediment or buccal cells. CONCLUSION: We describe two MT-TN mutations associated with PEO and mitochondrial myopathy, and their pathogenicity was demonstrated. Together with previous reports, the results indicate that MT-TN is a hot spot for mutations causing sporadic PEO.

Cerebrospinal fluid CD4+ /CD8+ ratio in diagnosing neurosarcoidosis.

OBJECTIVE: Neurosarcoidosis affects 5%-10% of patients with sarcoidosis. CD4+ /CD8+ ratio in bronchoalveolar lavage is included in diagnostic routine for pulmonary sarcoidosis. Previously, it has been suggested that a cerebrospinal fluid CD4+ /CD8+ ratio ≥5 can be an aid in diagnosing neurosarcoidosis. MATERIALS AND METHODS: This study included 66 cases where neurosarcoidosis was a differential diagnosis and hence subjected to the analysis of CSF CD4+ /CD8+ ratio by flow cytometry. RESULTS: Eleven cases of neurosarcoidosis, had a significantly higher median CSF CD4+ /CD8+ ratio than the other group, P = .024. The median CSF CD4+ /CD8+ ratio was 4.2, hence not reaching the suggested level of ≥5 for diagnosing neurosarcoidosis. When combined, the elevated CSF CD4+ /CD8+ ratio ≥5 and an elevated CSF lymphocyte count (>3 lymphocytes/uL) gave a positive predictive value of 57% and a high negative predictive value of 88%, with a specificity of 95% for neurosarcoidosis. CONCLUSION: The study confirms that increased CSF CD4+ /CD8+ ratio is associated with neurosarcoidosis but cannot alone distinguish the conditions from other neurological diagnoses. However, a ratio below <5 combined with an absence of pleocytosis in CSF yields a negative predictive value (NPV) of 88% suggesting a role for the analysis in differential diagnosing neuroinflammatory conditions.

Neurocognitive disorder in Myotonic dystrophy type 1.

Cognitive deficits and abnormal cognitive aging have been associated with Myotonic dystrophy type 1 (DM1), but the knowledge of the extent and progression of decline is limited. The aim of this study was to examine the prevalence of signs of neurocognitive disorder (mild cognitive impairment and dementia) in adult patients with DM1. A total of 128 patients with childhood, juvenile, adult, and late onset DM1 underwent a screening using the Montreal Cognitive Assessment (MoCA). Demographic and clinical information was collected. The results revealed that signs of neurocognitive disorder were relatively rare among the participants. However, 23.8 % of patients with late onset DM1 (aged over 60 years) scored below MoCA cut-off (=23), and this group also scored significantly worse compared to patients with adult onset. Age at examination were negatively correlated with MoCA scores, although it only explained a small portion of the variation in test results. Other demographic and clinical factors showed no association with MoCA scores. In conclusion, our findings indicate a low prevalence of signs of neurocognitive disorder in adult patients with DM1, suggesting that cognitive deficits rarely progress to severe disorders over time. However, the performance of patients with late onset DM1 suggests that this phenotype warrants further exploration in future studies, including longitudinal and larger sample analyses.