A Japanese family with a novel nonsense mutation in the TITF-1 gene (p.Y98X) is described.The proband showed severe generalized chorea, delayed motor development, subnormal intelligence, congenital hypothyroidism, bronchial asthma, and a history of pulmonary infection, all of which are characteristic features of Brain-Thyroid-Lung syndrome. On the other hand, her brother and mother showed a mild benign hereditary chorea (BHC) phenotype with congenital hypothyroidism.Intrafamilial phenotypic variation is common in BHC/Brain-Thyroid-Lung syndrome and suggests the existence of other genetic or environmental factors regulating TITF-1 function. Although choreic movement in BHC/Brain-Thyroid-Lung syndrome is recognized as non-progressive, the proband showed re-exacerbation of choreic movement at puberty. The dopamine agonist, ropinirole hydrochloride, reduced her choreic movements, suggesting that levodopa and/or dopamine agonists may compensate for underdeveloped dopaminergic pathways in this disorder.BHC with a novel TITF-1 mutation 3

Background and purpose: GLA is the causative gene of Fabry disease, an X-linked lysosomal storage disorder resulting from -galactosidase A (-GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiologiccal studies indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, we measured the frequency of GLA mutations in Japanese male ischemic stroke patients with various risk factors and ages.Methods: A total of 475 male ischemic stroke patients (average age 69.7±12.5 years), were enrolled in this study. A blood sample was obtained to produce blood spots for measurement of -GAL activity. Blood samples with decreased enzymatic activity were reassayed and the entire GLA gene was analyzed by direct DNA sequencing if -Gal A activity was consistently low.Results: -Gal A activity was decreased in 10 men, 5 of whom (1.1%) had the GLA gene mutation, p.E66Q. All ischemic stroke patients with p.E66Q mutation had substantial residual -Gal A activity, in contrast to patients with classic-type Fabry disease. Clinically, all patients with p.E66Q mutation were > 50 years old and had multiple small-vessel occlusions (lacunar infarctions). Statistical analysis using Fisher's exact test showed the allele frequency of GLA p.E66Q in patients with small-vessel occlusion to be significantly higher than that in the general Japanese population (odds ratio 3.34, P=0.025).Conclusions: GLA p.E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese males.

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Transthyretin (TTR) is a homotetrameric protein that must misfold in order to form amyloid fibrils. Misfolding includes rate limiting tetramer dissociation, followed by fast tertiary structural changes of the monomer that enable aggregation. Hereditary ATTR amyloidosis is an autosomal dominant genetic disorder with systemic deposition of amyloid fibrils induced by TTR gene mutation. We identified a rare Y114H (p.Y134H) TTR variant in a Japanese patient presenting with late-onset, very mild clinical course. The patient had an extremely low serum variant TTR concentration (18% of total TTR), whereas the composition of variant TTR was 55% in amyloid fibrils in tenosynovial tissues obtained at carpal tunnel release surgery. The amyloid fibril deposits in the ATTR Y114H patient had an altered structure compared with that in wild-type ATTR patients, as determined by luminescent conjugated poly/oligo-thiophene fluorescence spectroscopy. Biophysical studies using recombinant protein showed that Y114H TTR was markedly destabilized both thermodynamically and kinetically and was highly amyloidogenic in vitro. These data suggest that extremely low serum variant Y114H TTR concentration, probably due to endoplasmic reticulum-associated degradation of unstable variant TTR protein, protected this patient from severe amyloidosis, as self-assembly of the amyloidogenic intermediate is a concentration-dependent process.

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