A Midsummer Night’s Gene: The familial Neurological Illness of Felix Mendelssohn

Felix Mendelssohn Bartholdy (1805–1847) is widely regarded as one of the musical geniuses of the Romantic period. A prodigy akin to Mozart, Mendelssohn composed piano works, symphonies, and concertos at an early age but died young, at 38. His death has been attributed to neurological disease, but the mystery of his diagnosis is amplified by the fact that his sisters died under similar circumstances, including the renowned composer, Fanny Mendelssohn Hensel. Mendelssohn died after years of suffering from headaches, earaches, and mood disturbances. In the final year of his life, his acute decline was marked by stepwise, progressive neurologic deficits: gait disturbance, loss of sensation in the hands, partial paralysis, and, finally, loss of consciousness. The similar pattern of disease within his family suggests an underlying genetic link, though this may be multifactorial in nature. We present a thorough, posthumous differential diagnosis for Mendelssohn's illness, given his medical history, the familial pattern, and hints from within his music. Possible diagnoses include ruptured cerebral aneurysm with resultant subarachnoid hemorrhage, familial cerebral cavernous malformation, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Continued research into Mendelssohn's life may yield more information about his illness, death, and possibly true diagnosis.

Fetal Familial Cerebral Cavernous Malformation With a Novel Heterozygous KRIT1 Pathogenic Variant

Objectives:To identify fetal familial cerebral cavernous malformation (CCMs) and a novel mutation.Methods:A 37-year-old pregnant woman (G4P0) presented right-handed numbness since two weeks at 31 weeks of gestation. Evaluation with brain magnetic resonance imaging (MRI) revealed multiple CCMs. As a result, fetal MRI, fetal Whole Exome Sequencing (WES), and maternal Sanger sequencing were performed.Results:The mother’s brain MRI demonstrated numerous CCMs involving the brain stem, cerebral hemispheres, and cerebellum. Fetal MRI showed a CCM located in the left frontal lobe in SWI. The neuroimaging characteristics of the mother and the fetus suggested that their CCMs may be familial. Genetic analysis revealed a novel mutation in KRIT1 (c.1A>G, p.0?), also called CCM1, in the mother and the baby. The mother delivered a daughter at 32 weeks of gestation with an Apgar score of 10 by cesarean section.Discussion:This mutation of the initial codon in the KRIT1 gene leads to a phenotype with an early-onset. To our knowledge, this is the first-ever reported case of fetal familial CCM and this novel mutation. Brain MRI has excellent sensitivity and specificity, providing the best option for detecting CCMs, even in utero, primarily when SWI is used.

Familial Cerebral Cavernous Malformation Mimicking Cerebral Amyloid Angiopathy

A 67-year-old man was referred from ophthalmology for possible cerebral amyloid angiopathy (CAA) discovered during work-up of possible optic neuropathy. MRI (figure 1) demonstrated innumerable periventricular, brainstem, and cortical cerebral microhemorrhages (CMH). Scattered, non-specific white matter hyperintensities was seen on T2-weighted imaging without surrounding hypointense rim. He had no hypertension, and the distribution was uncharacteristic for CAA. Despite absent family history of stroke or seizure, testing for familial cerebral cavernous malformation (FCCM) identified a pathogenic mutation of KRIT1 (c.382G>T).