Tsuneaki Yoshinaga

Adult or late-onset triple A syndrome: case report and literature review.

Triple A syndrome is caused by mutations in the gene encoding ALADIN, leading to achalasia, alacrima and addisonism. Neurologic manifestations of the disease include motor neuron disease-like presentations, motor-sensory or autonomic neuropathy, optic atrophy, cerebellar ataxia, Parkinsonism, and mild dementia. We report a 60-year-old Japanese man with triple A syndrome. He was born to non-consanguineous parents. He underwent a surgical operation for achalasia at age 40, and thereafter, he developed a slowly progressive gait disturbance. Neurological examinations at age 60 revealed limb muscle wasting and weakness with pyramidal tract signs, distal-dominant sensory disturbance, optic atrophy, and autonomic dysfunction. Alacrima was detected using Schirmer test. All of these features were consistent with typical triple A syndrome. He lacked adrenal insufficiency that is frequently observed in patients with the classic phenotype of triple A syndrome. His sural nerve biopsy showed a moderate loss of myelinated fibers and hypomyelination. He was homozygous for a missense mutation, p.R155H, in the disease-causing gene, AAAS. Seven patients with genetically-confirmed, adult or late-onset triple A syndrome, including ours, have been reported to date. All the patients showed upper and lower motor neuron signs (100%), while sensory disturbance (29%) and autonomic dysfunction (57%) were less frequent. Careful assessment for alacrima followed by molecular genetic analysis of AAAS should be considered in patients who show a combined phenotype of motor neuron disease and sensory/autonomic disturbance, even in elderly patients.

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

Abstract 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.

Cerebral amyloid angiopathy in posttransplant patients with hereditary ATTR amyloidosis

Objective: To investigate the prevalence and clinical features of posttransplant CNS symptoms in patients with hereditary ATTR amyloidosis and their Pittsburgh compound B (PiB)–PET imaging correlates. Methods: We monitored prevalence and type of CNS symptoms in 53 consecutive posttransplant patients with hereditary ATTR amyloidosis. 11C-PiB-PET was performed in 15 patients with various disease durations. We also analyzed pathologic and biochemical characteristics of ATTR amyloid deposition in the brain of a posttransplant patient. Results: Transient focal neurologic episodes (TFNEs) attributed to ATTR-type cerebral amyloid angiopathy (CAA) were found in 11.3% of posttransplant hereditary ATTR amyloidosis patients. TFNE occurred on average 16.8 years after onset of the disease. Patients with longer duration of illness (≥10 years) showed increased 11C-PiB retention in the brain. The 11C-PiB accumulation pattern in hereditary ATTR amyloidosis was unique and different from those in Alzheimer disease or Aβ-type CAA. In the autopsy case, ATTR amyloid deposition was mainly localized to leptomeningeal vessels and leptomeninges of the brain. Amyloid fibrils in the brain were almost completely composed of variant transthyretin (TTR). Conclusions: TFNE due to ATTR-type CAA occurred frequently in posttransplant patients with long disease durations. 11C-PiB-PET is a useful diagnostic tool for ATTR-type CAA. ATTR amyloid deposition in the CNS, as measured by PiB-PET, was detected approximately 10 years before onset of TFNE.

Short communicationAdult or late-onset triple A syndrome: Case report and literature review

Triple A syndrome is caused by mutations in the gene encoding ALADIN, leading to achalasia, alacrima and addisonism. Neurologic manifestations of the disease include motor neuron disease-like presentations, motor-sensory or autonomic neuropathy, optic atrophy, cerebellar ataxia, Parkinsonism, and mild dementia. We report a 60-year-old Japanese man with triple A syndrome. He was born to non-consanguineous parents. He underwent a surgical operation for achalasia at age 40, and thereafter, he developed a slowly progressive gait disturbance. Neurological examinations at age 60 revealed limb muscle wasting and weakness with pyramidal tract signs, distal-dominant sensory disturbance, optic atrophy, and autonomic dysfunction. Alacrima was detected using Schirmer test. All of these features were consistent with typical triple A syndrome. He lacked adrenal insufficiency that is frequently observed in patients with the classic phenotype of triple A syndrome. His sural nerve biopsy showed a moderate loss of myelinated fibers and hypomyelination. He was homozygous for a missense mutation, p.R155H, in the disease-causing gene, AAAS. Seven patients with genetically-confirmed, adult or late-onset triple A syndrome, including ours, have been reported to date. All the patients showed upper and lower motor neuron signs (100%), while sensory disturbance (29%) and autonomic dysfunction (57%) were less frequent. Careful assessment for alacrima followed by molecular genetic analysis of AAAS should be considered in patients who show a combined phenotype of motor neuron disease and sensory/autonomic disturbance, even in elderly patients.

Spinal form cerebrotendinous xanthomatosis patient with long spinal cord lesion

Context: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited lipid storage disease caused by mutation in the CYP27A1 gene. Spinal form CTX is a rare clinical subgroup of CTX and only 14 patients from 11 families have been reported to date. Here, we report the first Asian patient with spinal form CTX showing characteristic radiological findings. Findings: The patient, a 46-year-old Japanese male, developed sensory disturbance of the lower legs at 39 and spastic gait at 46 years of age. Spinal cord magnetic resonance imaging (MRI) revealed a long hyperintense lesion involving lateral corticospinal tracts and gracile tracts in the cervical and thoracic cord on T2-weighted images. Gallium-67 (67Ga) scintigraphy revealed abnormal uptake in the Achilles tendons and the serum cholestanol level was elevated. CYP27A1 gene analysis identified homozygous missense mutation, c.1214G>A (p.R405Q). The patient was treated with atorvastatin monotherapy, which reduced serum cholestanol to less than 50% of the pretreatment level. Conclusion: Spinal form CTX should be considered in the differential diagnosis of cryptogenic myelopathy, especially in patients with a long spinal cord lesion, as treatment with chenodeoxycholic acid and/or competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase reverse the metabolic derangement and prevent the neurologiccal dysfunction.

A Case Report of WEBINO Syndrome with Convergence Impairment

A 73-year-old man suddenly presented with alternating exotropia, bilateral medial longitudinal fasciculus (MLF) syndrome, and impaired convergence. This symptom has been known as wall-eyed bilateral internuclear ophthalmoplegia (WEBINO syndrome). Diffusion-weighted images on magnetic resonance imaging showed a smalllocalized lesion in his pontine tegmentum. Based on he had some ischemic risk factors; he was diagnosed as having an ischemic stroke and started an antiplatelet therapy. His convergence impairment was improved, but abduction impairment of the right eye remained even 3 months later. The causing lesion of WEBINO syndrome has been reported to be either midbrain or pons mainly due to ischemic strokes or demyelinating diseases. In some cases, this syndrome was accompanied by convergence impairment; however, the pathophysiologic mechanism has not yet been elucidated. The neural circuit of vergence is discharges to the medial rectus subnucleus located in the abducens nerve nucleus. The mesencephalic reticular formation and nucleus reticularis tegmenti pontis (NRTP) are important regions in making signals of the supranuclear pathway, and NRTP impairment can induce the slow and fast vergence impairment. Thus, an involvement of near region of NRTP might be associated with WEBINO syndrome with convergence impairment.

Visualization of multiple organ amyloid involvement in systemic amyloidosis using 11 C-PiB PET imaging

PurposeTo investigate the utility of Pittsburgh compound B (PiB) positron emission tomography (PET) imaging for evaluating whole-body amyloid involvement in patients with systemic amyloidosis.MethodsWhole-body 11C-PiB PET was performed in seven patients with systemic immunoglobulin light-chain (AL) amyloidosis, seven patients with hereditary transthyretin (ATTRm) amyloidosis, one asymptomatic TTR mutation carrier and three healthy controls. The correlations between clinical organ involvement, radiological 11C-PiB uptake and histopathological findings were analysed for each organ.ResultsOrgan involvement on 11C-PiB PET imaging showed good correlations with the clinical findings for the heart and stomach. Abnormal tracer uptake was also observed in the spleen, lachrymal gland, submandibular gland, sublingual gland, lymph node, brain, scalp, extraocular muscles, nasal mucosa, pharynx, tongue and nuchal muscles, most of which were asymptomatic. Physiological tracer uptake was universally observed in the urinary tract (kidney, renal pelvis, ureter and bladder) and enterohepatic circulatory system (liver, gallbladder, bile duct and small intestine) in all participants. Most of the patients and one healthy control subject showed asymptomatic tracer uptake in the lung and parotid gland. The peripheral nervous system did not show any tracer uptake even in patients with apparent peripheral neuropathy. Histological amyloid deposition was confirmed in biopsied myocardium and gastric mucosa where abnormal 11C-PiB retention was observed.Conclusions11C-PiB PET imaging can be used clinically in the systemic evaluation of amyloid distribution in patients with AL and ATTRm amyloidosis. Quantitative analysis of 11C-PiB PET images may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response.

A novel frameshift mutation of SYNE1 in a Japanese family with autosomal recessive cerebellar ataxia type 8

A Japanese family with autosomal recessive cerebellar ataxia type 8 (SCAR8, MIM 610743) is described. We identified a novel SYNE1 frameshift deletion (c.6843del, p.Q2282Sfs*3). This family shared similar clinical manifestations characterized by adult-onset, relatively pure cerebellar ataxia with mild eye movement abnormality. Intelligence and bulbar and respiratory functions were unaffected. This study suggests the clinical utility of using panel-based exome sequencing for genetic diagnosis in hereditary ataxias in a cost-efficient manner.

The pathological and biochemical identification of possible seed-lesions of transmitted transthyretin amyloidosis after domino liver transplantation

The most serious issue in domino liver transplantation (DLT) using liver grafts from patients with transthyretin (TTR)‐related familial amyloid polyneuropathy (FAP) is the development of iatrogenic transmitted amyloidosis (de novo amyloidosis) in DLT‐recipients. However, little is known regarding the mechanisms of the initial stage of amyloid formation in these recipients. We detected initial lesions (possible seed‐lesions) of this iatrogenic amyloidosis in two recipients following liver grafting from FAP patients. Patient 1 underwent DLT at age 65 from an FAP patient with a Val30Met TTR variant and patient 2 received DLT from an FAP patient with a Val30Leu TTR variant at age 32. Patient 2 was started on diflunisal administration from 4 years after DLT. While neither patient had symptoms of FAP, small amyloid deposits were detected on the gastroduodenal mucosae 14 months and 12 years after DLT in patient 1 and patient 2, respectively. The amyloid was analyzed using a laser microdissection system and tandem mass spectrometry. Biochemical analysis indicated that the amyloid was composed mostly of variant TTR produced from the transplanted liver in both patients. In patient 1, wild‐type TTR amyloid was detectable in the duodenal mucosa obtained 2 years after DLT. This is the first study to successfully capture the pathological and biochemical features of initial‐stage amyloid lesions in DLT recipients. The findings clearly indicate that amyloid deposition can start by deposition of variant TTR followed by deposition of wild‐type TTR, and blocking of amyloid seed formation from variant TTR may be a key to prevent or delay the development of DLT‐associated amyloidosis.

Primary AL amyloidosis presenting with systemic lymphadenopathy with calcification

tomography (Fig. 1a–d) revealed enlarged systemic lymph nodes, with conspicuous swelling of the obturator lymph nodes. In addition, diffuse and granular calcification was observed in these nodes. A biopsy specimen obtained from the right axillary lymph node revealed diffuse deposition of amorphous and acellular matter without abnormal cells (Fig. 2a). Apple-green birefringence was detected under polarized light, which was considered to be amyloid deposition (Fig. 2b). On immunohistochemistry, the biopsy was positive for λ-chain and negative for κ-chain (Fig. 2c,d). Biopsy of the rectal mucosa also revealed amyloid deposition. Based on the above findings, a diagnosis of primary AL amyloidosis was established. Primary AL amyloidosis shows a variety of symptoms, which may vary depending on the site of amyloid deposition, such as congestive heart failure, arrhythmia, hepatic dysfunction, or renal failure. Amyloid fibrils have affinity for calcium ions [1], and calcification associated with amyloidosis has been sporadically reported in cases presenting with mesenteric lymphadenopathy [2], pericardial thickening [3], or gastrointestinal amyloidosis [4]. However, systemic lymphadenopathy with calcification, as observed in this case, is extremely rare.