Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis.

BACKGROUND: Systemic wild-type ATTR (ATTRwt) amyloidosis is a prevalent aging-related disorder. However, a limited number of systemic ATTRwt amyloidosis patients have been diagnosed antemortem, and therefore, the prevalence of ATTRwt is underestimated. Here, we investigated clinical findings of a series of systemic ATTRwt amyloidosis patients with antemortem diagnosis. METHODS: Thirty-one consecutive patients diagnosed with systemic ATTRwt amyloidosis at Shinshu University Hospital were included in this study. Systemic ATTRwt amyloidosis was diagnosed based on proven ATTR amyloid deposition in biopsy specimens and confirmation of wild-type TTR genotype. RESULTS: The systemic ATTRwt amyloidosis patients consisted of 24 men and seven women, and mean age of onset was 69.8 ± 9.0 years. The most common initial symptom was carpal tunnel syndrome (CTS, 17 patients), followed by heart failure symptoms (14 patients). The mean age at diagnosis was 74.5 ± 8.3 years and the duration of illness from onset to diagnosis was 5.4 ± 4.4 years. Cardiogenic embolism and renal dysfunction are also frequently seen during the course of the disease. CONCLUSIONS: CTS is the most common initial symptom of systemic ATTRwt amyloidosis. Our results suggest the possibility of systemic ATTRwt amyloidosis diagnosis at an early stage by carefully examining patients with CTS.

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

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 500 mg/day to 40 Japanese hereditary ATTR amyloidosis patents who were not candidates for liver transplantation. The observation period ranged from 2 to 116 months (mean ± SD: 38.0 ± 31.2 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 (p = 0.001) 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.

Effect of synovial transthyretin amyloid deposition on preoperative symptoms and postoperative recovery of median nerve function among patients with idiopathic carpal tunnel syndrome.

BACKGROUND: The clinical characteristics of wild-type transthyretin amyloid deposition among patients with carpal tunnel syndrome (CTS) have not been well investigated. METHODS: One-hundred and seven patients with idiopathic CTS who underwent carpal tunnel release were enrolled. They underwent physical examination of the hand, nerve-conduction study, and magnetic resonance imaging (MRI) study of the wrist, and completed a patient-oriented questionnaire. The tests, except for MRI, were repeated 1, 3, and 6 months postoperatively. Synovial tissue was obtained during surgery and analyzed by Congo red and immunohistochemical staining. Ordinal logistic regression analysis was used to evaluate the significance of different clinical and subjective findings between patients with and without amyloid deposition. Postoperative improvements were also compared. RESULTS: Wild-type transthyretin amyloid deposition was observed for 38 patients. Greater symptom severity and 2-point discrimination scores, and larger cross-sectional areas of the carpal tunnel, were significantly correlated with a larger amount of preoperative amyloid deposition. However, the presence and amount of preoperative amyloid deposition did not affect postoperative improvements in physical findings and nerve-conduction studies. CONCLUSIONS: Although transthyretin amyloid deposition can worsen CTS symptoms, postoperative improvements were similar for patients with and without this deposition.

High prevalence of ATTR amyloidosis in endomyocardial biopsy-proven cardiac amyloidosis patients.

BACKGROUND: Cardiac amyloidosis had been considered to be an incurable disease; however, new disease-modifying therapeutic approaches have succeeded in ameliorating the disease. Therefore, early and precise diagnosis based on the amyloid precursor protein is extremely important. OBJECTIVE: To determine the prevalence rates of systemic amyloidoses underlying cardiac amyloidosis. METHODS: The types of amyloidosis in 53 consecutive patients with endomyocardial biopsy-proven cardiac amyloidosis were analyzed by Congo red and immunohistochemical staining. If staining for TTR was positive, direct DNA sequencing of the entire TTR gene was performed. RESULTS: ATTR amyloidosis was the most common (32/53 patients, 60.4%). The ATTR amyloidosis subtypes were senile systemic amyloidosis (SSA) 11, familial ATTR 10, and genotype unknown 11. AL amyloidosis was the next most frequent (19/53, 35.8%). CONCLUSIONS: ATTR amyloidosis, especially SSA, might be much more common than previously thought. With the development of new drugs targeting the ATTR amyloidosis, major efforts should be made to increase awareness of senile systemic amyloidosis among cardiologists.

Arterial thromboembolism in senile systemic amyloidosis: report of two cases.

We describe a rare complication, systemic arterial thromboembolism, seen in two patients with senile systemic amyloidosis (SSA). Case 1 was a 73-year-old man who was tentatively diagnosed as having cardiac amyloidosis. Five months later, he was afflicted by severe left flank pain. CT disclosed renal infarction and then he received endomyocardial biopsy and the transthyretin (TTR) gene analysis, leading to the final diagnosis of SSA. Case 2 was an 88-year-old woman who had been definitively diagnosed as having SSA-related heart failure with atrial fibrillation two years before. She was transferred to the emergency room in our hospital and enhanced CT revealed complete occlusions of the left internal carotid and left vertebral arteries, both subclavian arteries, and the left renal and left internal iliac arteries. Paying much attention to intracardiac thrombosis might be necessary in taking care of SSA patients.

[Case report of transthyretin Val30Met familial amyloid polyneuropathy presenting hydrocephalus].

A 70-year-old man was admitted to our hospital with visual loss, dysesthesia, gait disturbance, and urinary retention. A pacemaker was implanted 1 year ago for atrioventricular conduction block. Neurologic examination revealed mild cognitive impairment, near blindness with vitreous opacity, diffuse muscle weakness, loss of all sensory modalities with areflexia, and orthostatic hypotension. Head CT showed hydrocephalus. The Congo red staining of vitrectomized specimen and the biopsied sural nerve showed amyloid depositions. Gene analysis disclosed Val30Met missense mutation of transthyretin, which is responsible for familial amyloid polyneuropathy. His bed-ridden brother also had severe urinary dysfunction and orthostatic hypotension with hydrocephalus on MRI. These two sibling cases suggest correlation of the transthyretin Val30Met mutation with hydrocephalus, a rare phenotype of this disease.

Two siblings diagnosed to have transthyretin-related familial amyloid cardiomyopathy around the same time at different hospitals.

Mutation in the transthyretin (TTR) gene may clinically manifest as cardiomyopathy. Here, we describe 69-year-old and 72-year-old brothers who were diagnosed as having TTR-related familial amyloid cardiomyopathy by endomyocardial biopsy at different hospitals at around the same time. They were not from an endemic area of familial amyloid polyneuropathy. Genetic analysis showed a base change in the TTR gene leading to a p.Val30Met mutation in both patients. Screening of family members, as well as detailed family history taking, is important for the diagnosis of cardiomyopathy of unknown etiology.

Diagnostic value of abdominal wall fat pad biopsy in senile systemic amyloidosis.

Senile systemic amyloidosis (SSA) is a main cause of intractable heart failure in elderly individuals. To demonstrate transthyretin (TTR)-derived amyloid deposition endomyocardial biopsy has been commonly carried out in the patients with SSA, but this invasive biopsy technique cannot always be performed in aged patients with severe cardiac dysfunction. During the past 3 years, 11 patients with SSA (6 males and 5 females; ages from 70 to 97 years) were examined. All underwent skin biopsy from the abdominal wall and 8 showed TTR-immunoreactive amyloid deposition (sensitivity: 73%): amyloid deposits were seen mainly in the deep layer of subcutaneous fat tissue and showed a patchy distribution. They were weakly Congophilic, but were strongly immunolabeled by an anti-TTR antibody. The severity and pattern of amyloid deposition in this biopsy of SSA patients were considerably different from those obtained from age-matched patients with TTR-related familial amyloid polyneuropathy. Surgical skin biopsy including the deep subcutaneous fat pad can be performed safely at the bedside and is useful for the histopathological diagnosis of SSA.

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.

Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

A Young Man with Anti-NMDAR Encephalitis following Guillain-Barré Syndrome.

A 19-year-old man developed rapidly progressive muscle weakness and dysesthesia in the extremities, and dyspnea after a flu-like episode. Nerve conduction studies showed reduced motor nerve conduction velocities with conduction block, and sensory nerve action potentials could not be evoked. The patient was diagnosed as having Guillain-Barré syndrome (GBS), and was treated with 2 cycles of intravenous immunoglobulin (IVIg) therapy and was assisted by mechanical ventilation. During the recovery course of the illness, he experienced several attacks of psychomotor agitation from the 37th hospital day, and generalized tonic convulsive seizures suddenly developed on the 42nd hospital day. Brain MRI showed high-intensity lesions in the bilateral thalamus and medial temporal lobes. The convulsions were controlled by continuous thiopental infusion (until the 50th hospital day) and mechanical ventilation (until the 84th hospital day). Intravenous methylprednisolone pulse therapy (1,000 mg/day) for 3 days followed by dexamethasone (16 mg/day) was added. After relief of convulsive seizures, prominent orolingual dyskinesia appeared, and on MRI marked atrophy of the bilateral medial temporal lobes was seen. Anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in serum and cerebrospinal fluid were positive on the 92nd hospital day. Anti-NMDAR encephalitis usually affects young females but a small number of male cases with this disease have been reported. Our male patient was unique in having GBS, a post-infectious autoimmune disease, as a preceding disease, suggesting that anti-NMDAR encephalitis itself is caused by a parainfectious autoimmune mechanism.

Pneumatosis cystoides intestinalis in neuropsychiatric systemic lupus erythematosus with diabetes mellitus: case report and literature review.

We report a patient with neuropsychiatric systemic lupus erythematosus (NPSLE) complicated by diabetes mellitus (DM) who showed pneumatosis cystoides intestinalis (PCI) while being treated with prednisolone (PSL) and an alpha-glucosidase inhibitor (αGI). The PCI was ameliorated with the cessation of the αGI and tapering of PSL in addition to transient fasting. Multiple factors, including NPSLE, DM, and medications, may have been involved in the pathogenesis of PCI in this patient.

Intestinal angina due to atherosclerosis in a 45-year-old systemic lupus erythematosus patient.

We report a patient with systemic lupus erythematosus (SLE) who developed progressive emaciation and postprandial abdominal pain with a 27-year history of corticosteroid treatment. The patient was diagnosed as having intestinal angina based on computed tomography that showed severe stenosis of the superior mesenteric artery (SMA) in addition to complete occlusion of the celiac and inferior mesenteric arteries. Histopathology of the SMA and abdominal aorta showed atherosclerosis with no vasculitis or thrombus formation. Intestinal angina should actively be considered as a possible cause of recurrent abdominal pain in SLE patients, particularly in those with a long history of disease.

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy.

We report here two patients with amyloidogenic transthyretin (ATTR) Val30Met familial amyloid polyneuropathy (FAP) who developed numbness in both hands and were diagnosed as having bilateral carpal tunnel syndrome (CTS). In both patients systemic TTR amyloidosis consisting of polyneuropathy affecting both upper and lower limbs and/or autonomic dysfunction gradually appeared after surgery for CTS. Although CTS associated with TTR amyloidosis has been known as an initial symptom in some patients with ATTR non-Val30Met FAP and those with senile systemic amyloidosis, this is the first report of ATTR Val30Met FAP patients starting with upper limb neuropathy including CTS-like symptoms. It is also notable that both patients had no genealogical relationship with two Japanese endemic foci of this disease.

Significant deposition of wild type transthyretin-derived amyloid in the gastrointestinal tract of aged individuals.

Two male patients aged 72 and 77 were found to have transthyretin (TTR) immunoreactive amyloid deposits in their gastrointestinal tracts when they underwent surgery for gastric and sigmoid colon cancer, respectively. They had no cardiac symptoms and there was no mutation in their TTR gene. Amyloid deposits were seen mainly on vascular walls in submucosal layers of the stomach and colon, while the muscularis mucosae, which is invariably affected in familial amyloid polyneuropathy (FAP), was completely free of amyloid deposition. The pattern of TTR-derived amyloid deposition in the gastrointestinal tract in SSA and in FAP are quite different.

An unusual case of Klippel-Trénaunay-Weber syndrome presenting with portosystemic encephalopathy.

We report a unique male patient presenting with portosystemic encephalopathy (PSE) due to intrahepatic portohepatic venous (PHV) shunts. He was diagnosed as having Klippel-Trénaunay-Weber syndrome (KTWS) based on the findings of a hemitruncal port-wine stain with subcutaneous arteriovenous fistulae and varicose veins in the legs. However, limb-hypertrophy, which is one of the most cardinal manifestations of KTWS, was absent, and in KTWS, PSE is quite a rare clinical manifestation. Hence, the clinical picture of this patient was unusual. Our clinical observation suggests that KTWS can be one of the underlying disorders causing PSE.

Amyloidogenic transthyretin Val30Met homozygote showing unusually early-onset familial amyloid polyneuropathy.

We report an amyloidogenic transthyretin (ATTR) Val30Met homozygote showing extremely early-onset, severe familial amyloid polyneuropathy (FAP). Although homozygotes have been reported to show late-onset and mild clinical manifestations, detailed analyses of the present and previously reported families suggest that homozygotes have a slightly more severe clinical course than heterozygotes. This is the youngest reported patient with ATTR Val30Met FAP, a condition believed to be attributable to homozygosity of this mutation. The clinical severity is consistent with TTR protein instability.

Cortical petechial hemorrhage, subarachnoid hemorrhage and corticosteroid-responsive leukoencephalopathy in a patient with cerebral amyloid angiopathy.

We describe a 69-year-old woman who developed subacute onset cognitive decline after hitting the left side of her head. Cerebral spinal fluid showed yellowish discoloration with highly elevated protein content. FLAIR MRI revealed diffuse high signal intensity in all cortical sulci, and leptomeningeal enhancement in the left cerebral hemisphere was seen in the T1 image after contrast administration. She was treated with a corticosteroid. Consciousness disturbance was temporarily relieved but again worsened, resulting in an apathetic state due to communicating hydrocephalus. A shunt tube was placed in her right lateral ventricle. A brain biopsy disclosed multiple cortical microbleeds and heavy deposition of Abeta-immuoreactive amyloid on vascular walls. Inflammatory mononuclear cells surrounded a few leptomeningeal vessels. After the operation her condition further deteriorated and she fell into a coma. MRI showed diffuse swelling of the right cerebral white matter. She again received high-dose corticosteroid and gradually recovered during the following 2 months. On MRI the vast majority of abnormal signals in the right cerebral white matter disappeared. An initial manifestation of this patient was possibly caused by multiple microhemorrhages from fragile cortical and subarachnoid vessels with Abeta-amyloid deposition, which was triggered by head trauma. CAA-related inflammation possibly worsened this condition. Additionally, surgical intervention for communicating hydrocephalus might have induced cerebral amyloid angiopathy (CAA)-related leukoencephalopathy in her right cerebral hemisphere. These CAA-derived manifestations are unusual and high-dose corticosteroids seems to be useful for vascular events in CAA patients.