We present the case of a 40-year-old man who developed progressive ataxia and palatal tremor (PAPT), in association with bilateral optic atrophy and upper motor neuron signs. MRI showed evidence of hypertrophy of the inferior olivary nuclei, marked cerebellar atrophy and bilateral optic nerve atrophy which was further supported by bilateral thinning of the retinal fibre layer detected using optical coherence tomography. No further pathological findings were detected. This syndrome has never been reported before. A wide range of differential diagnoses was excluded including spino-cerebellar ataxias type 1–8, 12 and 20, mitochondrial diseases including Leber9s hereditary optic neuropathy, autosomal dominant optic atrophy and polymerase gamma 1 POLG1 gene mutations. It is unclear whether PAPT with optic atrophy is a disease entity or yet another addition to the spectrum of PAPT phenotypes. The presentation will include a video of the clinical features.
Abstract The different cellular phenotypes that compose multicellular organisms are generated by the expression of housekeeping and cell-type-specific genes and by the repression of inappropriate ones. The pattern of gene expression that defines a cell type is termed the ‘‘epigenotype,’’ which is established and maintained by ‘‘epigenetic’’ mechanisms that are able to govern gene expression regardless of the underlying genetic code (Holliday, 2005). Genomic imprinting, where genes are expressed from only one of the inherited parental alleles, represents a classical example of epigenetic gene regulation; memory of the expression state, presumably established during gametic meiosis, is thus transmitted to the zygote, maintained throughout embryonic and postembryonic development, and reestablished during gametogenesis of the newly formed organism in a sex-specific manner (Reik and Walter, 2001). It follows that epigenetic ‘‘plasticity’’ would enable pluripotent stem cells to give rise to a variety of epigenotypes. In contrast, lineage commitment of cells toward postmitotic differentiated epigenotypes requires a more stable epigenetic memory that confers their phenotypic identity.
Physicians still encounter hypertensive crises, which merit rapid diagnosis and treatment. Posterior reversible encephalopathy syndrome (PRES) is usually associated with acute changes in blood pressure in patients with complex medical problems. We present the case of a patient with PRES as a presenting feature of essential hypertension.
Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement.We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology.We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450.Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.
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