Shu-ichi Ikeda

Pathogenesis of and Therapeutic Strategies to Ameliorate the Transthyretin Amyloidoses

Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.

Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an inxa0vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders.

High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly

Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome. One hundred twenty-three patients with carpal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire transthyretin gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four patients (34.0%) with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabeling with antitransthyretin antibody. Direct DNA sequencing of the entire transthyretin gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio, 15.8; 95% confidence interval, 3.3-5.7), and age and male sex were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.

Marked regression of abdominal fat amyloid in patients with familial amyloid polyneuropathy during long-term follow-up after liver transplantation

To elucidate whether the amount of tissue‐deposited amyloid in familial amyloid polyneuropathy (FAP) patients decreases or increases over the long‐term course after liver transplantation (LT), we examined changes in histopathological and biochemical characteristics of abdominal fat amyloid in the transplanted patients with a postoperative history of more than 10 years. Using a series of aspirated abdominal fat tissues from 6 FAP patients with transthyretin (TTR) Val30Met variant, the severity of amyloid deposits was examined and the composition ratio of wild type‐to‐variant TTR in fat amyloid was assayed by liquid chromatography‐ion trap mass spectrometry (LC‐MS/MS). Histopathological examination of abdominal fat tissues demonstrated a significant decrease or disappearance of amyloid deposits in all 6 patients. On LC‐MS/MS analysis, the contribution of wild‐type TTR to the composition ratio in amyloid fibrils was markedly increased in all patients after LT. This is the first report showing pathological evidence that deposited amyloid in FAP patients with long posttransplantation courses can gradually regress or disappear. Liver Transpl 14:563–570, 2008.

Ten-year follow-up of peripheral nerve function in patients with familial amyloid polyneuropathy after liver transplantation

BackgroundThe electrophysiological long-term effects of liver transplantation on peripheral nerve function in patients with familial amyloid polyneuropathy (FAP) have not been evaluated.MethodsEight FAP patients with a proven ATTRVal30Met gene were observed for 10 years after liver transplantation. We performed repeated measurement of maximal motor nerve conduction velocity (MCV), distal latency, size of compound muscle action potential (CMAP) and maximal sensory nerve conduction velocity (SCV) in both the ulnar and tibial nerves. We also recorded the coefficients of variance in the R-R interval on the electrocardiogram (CVR-R).ResultsSome autonomic symptoms subsided but motor and sensory symptoms 10 years after transplantation were either slightly improved or almost the same as before surgery in 7 of 8 patients. These 7 have returned to their previous social lives including their jobs. The MCV of the tibial nerve slightly improved, and other parameters of motor and sensory nerve function and CVR-R did not show any deterioration during the 10-year observation period.ConclusionsLiver transplantation can halt the progression of peripheral neuropathy in FAP patients.

Clinical features of non‐hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy

Background and purpose: The present study aims to clarify the clinical features of non‐hypertensive cerebral amyloid angiopathy‐related lobar intracerebral hemorrhage (CAA‐L‐ICH).

Peripheral nerve involvement in primary systemic AL amyloidosis: a clinical and electrophysiological study

Background:u2002 Involvement of visceral organs usually dominates the clinical picture of primary systemic AL amyloidosis, but some patients suffer from serious peripheral neuropathy. The aim of this study is to clinically and electrophysiologically investigate peripheral nerve involvement in AL amyloidosis patients.

Neuronal activity in the globus pallidus in chorea caused by striatal lacunar infarction

Pallidotomy was performed in a patient with hemichorea caused by lacunar infarction in the striatum. Chorea in the lower limb was reduced after a neurosurgical lesion in the medial portion of the sensorimotor territory of the internal segment of the globus pallidus, and chorea in the upper limb disappeared after an additional lesion in the lateral portion of that same area. Intraoperative neuronal recording revealed that mean firing rates were low, and that firing was irregular in the globus pallidus compared with off‐state parkinsonian patients. These results suggest that chorea with striatal infarction is driven by phasic neuronal activity with a low firing rate in the globus pallidus and that the neural pathway of chorea has a functional somatotopical organization in the globus pallidus.

Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis

Abstract Background: A recent 2-year randomized controlled trial indicated that the transthyretin (TTR) tetramer stabilizer, diflunisal, inhibits polyneuropathy progression and preserves quality of life in hereditary ATTR amyloidosis. However, its long-term outcomes are unknown. Here, we report tolerance and efficacy of long-term diflunisal administration in hereditary ATTR amyloidosis. Methods: Diflunisal was administered orally at 500u2009mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (meanu2009±u2009SD: 38.0u2009±u200931.2 months). Results: Diflunisal-related adverse events included deterioration of renal function and thrombocytopenia resulting in discontinuation of the drug in three patients. Orally administered diflunisal significantly increased serum TTR concentration (pu2009=u20090.001) and stabilized TTR tetramer structure in each patient. Longitudinal analyses of data collected at baseline, 24 months, and after 24 months confirmed sustaining effects of diflunisal on both neurological and cardiac functions. Notably, ulnar compound muscle action potential amplitude, cardiac wall thickness, and ejection fraction were not deteriorated after 24 months of treatment. Conclusions: Diflunisal was tolerated well by most hereditary ATTR amyloidosis patients, although renal function and blood cell counts must be carefully monitored. Clinical effects of diflunisal were sustained after 2 years of treatment.

Lack of modulation of Ib inhibition during antagonist contraction in spasticity

Objective: To examine the modulation of non-reciprocal group I (Ib) inhibition during tonic contraction of antagonist muscles in patients with spasticity vs normal subjects. Methods: The authors studied 10 patients with spastic paraplegia due to cervical compression myelopathy and 16 age-matched normal subjects. Ib inhibition to soleus motoneurons was recorded as the change in size of the H-reflex of the soleus, evoked by conditioning stimulus to the nerve innervating the medial gastrocnemius muscle. The extent of inhibition was studied at rest and during tonic contraction of the pretibial muscles of variable strength. Results: In the resting state, the extent of inhibition in the patients did not differ from normal controls. During antagonist contraction, the extent of inhibition increased both in the normal subjects and patients. The increment was smaller in the patients, especially in those with severe spastic gait. The smaller increment in the inhibition was correlated with the time required to walk 10 m in the patients. Conclusion: The authors observed a lack of modulation of Ib inhibition during tonic antagonist contraction in patients with spasticity, especially those with gait disturbance. Disturbed central modulation of non-reciprocal (Ib) interneurons may be responsible for spasticity.