Acute Hemichorea in an Elderly Patient With Positive Anti-centromere Antibodies and Lung Tumor.

Though rare, autoimmune paraneoplastic and non-paraneoplastic chorea can be leading causes of adult-onset acute/subacute chorea. Here, we report a case of acute-onset chorea with suspected autoimmune-mediated mechanisms in a 79-year-old female who exhibited acute-onset choreiform movements on the right side of her body. She tested positive for anti-centromere antibodies (ACAs) without displaying symptoms of scleroderma. Blood sugar levels, genetic testing for Huntington's disease, and an antibody panel related to paraneoplastic neurological syndrome were unremarkable. Brain magnetic resonance imaging revealed no significant abnormalities. Computed tomography (CT) identified an irregularly shaped nodule in the middle lobe of the right lung. An 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)-CT scan showed an accumulation of radioactivity in the nodule and slight hypermetabolism in the striatum of both hemispheres. Her choreiform movements almost disappeared with a low dose of tiapride alone, without the need for anti-tumor therapy or immunotherapy. In cases of adult-onset acute/subacute chorea, investigating neoplasms and autoimmune diseases as underlying conditions is recommended. Tiapride, due to its good tolerability, is a valuable symptomatic therapy for elderly patients presenting with chorea, even in cases driven by autoimmune mechanisms.

18q21.1q21.32 Deletion in a Patient With Juvenile Cerebral Infarction.

The chromosome 18q deletion syndrome is a well-recognized chromosomal aberration characterized by intellectual disability, facial dysmorphism, short stature, microcephaly, cardiac anomalies, such as atrial and ventricular septal defect, and hypotonia; however, the phenotype is highly variable depending on the combination of genes within the chromosomal aberration regions. Thus far, no association was found between 18q deletion and cerebral infarction. Herein, we report a case of 18q deletion syndrome that caused juvenile cerebral infarction. A 32-year-old woman with an intellectual disability and facial dysmorphism presented with sudden-onset left-sided weakness. Brain magnetic resonance imaging revealed a striatocapsular infarction. Abnormalities in thrombotic profiles and embolic sources could not be identified. Microarray-based comparative genomic hybridization analysis detected a microdeletion in chromosome 18 encompassing the cytoregion 18q21.1q21.32. The deletion region contains the TCF4 and SMAD4 genes, whose haploinsufficiency causes the causative genes of Pitt-Hopkins syndrome (PTHS) and juvenile polyposis/hereditary hemorrhagic telangiectasia (JPHT or JPHHT), respectively. The patient's facial features were characteristic of PTHS, including a broad, beaked nasal bridge and a wide mouth with a bow-shaped upper lip. On the contrary, the patient did not show breathing abnormalities, which is one of the hallmarks of PTHS. We could not elucidate the relationship between cerebral infarction and genes included in the deleted region of 18q. However, if patients with chromosomal aberrations have cerebral infarctions, investigating the genes included within the chromosomal aberration regions may increase our knowledge of the genes involved in juvenile cerebral infarction.

Severe Pressure Ulcers in Two Patients With Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare X-linked disease that affects the metabolism of very long-chain fatty acids (VLCFAs), leading to cognitive deterioration, progressive spastic paraplegia, sensory disturbance, adrenocortical insufficiency, and bladder and bowel abnormalities. Although the symptoms of ALD correspond to the risk of developing pressure ulcers, a pressure ulcer has never been listed as a complication of ALD. We present two cases of ALD with severe pressure ulcers in the pelvic region and feet. The first case was a 27-year-old male patient with adolescent cerebral-type ALD who had pressure ulcers with bone exposure on the sacral and bilateral greater trochanter region. The second case was a 64-year-old male patient with adrenomyeloneuropathy (AMN) phenotype who had pressure ulcers on the sacral region and both feet. Both patients had VLCFA accumulation and a likely pathogenic variant in the ABCD1 gene, the causative gene of ALD. These cases indicate that ALD patients with immobility and incontinence have a higher risk of developing severe pressure ulcers, which requires the proactive identification of ALD patients and early multidisciplinary intervention for patients and their families to prevent the development of pressure ulcers.

Cerebellar Hypoperfusion in Two Patients with Cornelia de Lange Syndrome with Novel NIPBL Variants.

Introduction: Cornelia de Lange syndrome (CdLS) is a rare congenital malformation characterized by distinctive facial features, short stature, and limb defects. In addition, half of the patients with CdLS exhibit repetitive self-injurious behaviors (SIBs) related to intellectual disability with autistic traits. CdLS is caused by pathogenic variants of genes encoding the cohesin complex pathway, with 70% of these variants identified in the nipped-B-like (NIPBL) gene. Case Presentation: We report 2 patients with CdLS who exhibited repetitive SIBs. Patient 1, a 40-year-old male, carried a novel heterozygous duplication variant, c.1458dup, p.(Glu487*), in exon 9 of the NIPBL gene. Patient 2, a 49-year-old female, carried a novel heterozygous insertion variant, c.1751_1752ins[A;1652_1751], p.(Asp584Glufs*8), in exon 10 of the NIPBL gene. These variants were predicted to confer loss of function to the protein because of a premature stop codon. In both patients, single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed diffuse hypoperfusion in the cerebellum. Discussion: This report identified 2 novel pathogenic variants in the NIPBL gene and the relationship between SIBs and cerebellar hypoperfusion in patients with CdLS. The cerebellar hypoperfusion might have been caused by the dysfunction of the cohesin complex via the downregulation of the NIPBL gene products. Further studies should be conducted to elucidate the contribution of the NIPBL gene to the development of the cerebello-cerebral cortical circuits associated with behavioral disorders.

Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7.

Intellectual developmental disorder, autosomal dominant 7 (MRD7; OMIM 614104) is a rare disease characterized by microcephaly, intellectual disability, speech delay, feeding difficulties, and facial dysmorphisms. This disorder is caused by pathogenic/likely pathogenic variants of the DYRK1A gene, which encodes dual-specificity tyrosine-phosphorylation-regulated kinase 1A. Here, we report a case of MRD7 that was diagnosed using Face2Gene and whole-exome sequencing (WES). A 22-year-old man presented with microcephaly, intellectual disability, slender body, long slender fingers, and facial dysmorphisms. He was previously diagnosed with Cornelia de Lange syndrome (CdLS) at four years of age. However, his CdLS clinical diagnostic score was low at 22 years of age. The Face2Gene application introduced several candidate diseases including MRD7. Finally, by utilizing WES and Sanger sequencing analysis of cloned cDNA, we identified a novel heterozygous duplication variant (c.848dup, p.(Asn283LysfsTer6)) in the DYRK1A gene, which introduces a premature stop codon. This report provides more information about the phenotypic spectrum of a young adult patient with MRD7. Face2Gene helped us introduce candidate diseases of the patient. Registering further genetically confirmed cases with MRD7 will improve the accuracy of the diagnostic recommendations in Face2Gene. Moreover, WES is a powerful tool for diagnosing rare genetic diseases, such as MRD7.

Band-Like Brainstem Lesion in a Patient With a History of Lung Adenocarcinoma.

Leptomeningeal metastasis (LM) is a severe complication of primary malignancy that has spread to the leptomeninges and cerebrospinal fluid (CSF). Here, we report a patient whose magnetic resonance imaging (MRI) showed a unique brainstem lesion suspicious of LM. A 72-year-old man presented with dizziness, gait instability, and cognitive decline, primarily object naming. He had a history of lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. Brain MRI revealed a band-like lesion surrounding the ventral brainstem with T2 weighted-image/fluid attenuation inversion recovery (FLAIR) imaging and diffusion-weighted imaging (DWI) hyperintensity without gadolinium enhancement. No malignant cells were detected in the CSF. He underwent ventriculoperitoneal shunt two months after the onset, and his gait improved, but his cognitive function declined further. Recent reports suggest similar brainstem lesions as a unique LM pattern, which occurs almost exclusively in patients with lung adenocarcinoma with EGFR mutation. Therefore, if MRI shows this brainstem finding, repeated and appropriate CSF cytology is needed to detect tumor cells. Furthermore, if a patient with lung adenocarcinoma shows a cognitive decline, cerebral LM and auto-antibodies that mainly target neuronal surface antigens should be considered.

Dyggve-Melchior-Clausen Syndrome Caused by a Novel Frameshift Variant in a Japanese Patient.

Introduction: Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal recessive spondyloepimetaphyseal dysplasia characterized by short stature, microcephaly, intellectual disability, and coarse face. This disorder is caused by pathogenic/likely pathogenic variants of the DYM gene which encodes dymeclin. Case Presentation: Herein, we report a 60-year-old Japanese man who was born to consanguineous parents. He presented with abdominal distention and rectal prolapse in addition to the common features of DMC. We identified a novel homozygous frameshift variant [c.1670delT, p.(Leu557Argfs*20)] in the DYM gene, which introduces a premature stop codon. Histological analysis revealed disarrangement of actin filaments in cultured fibroblasts. Discussion: To the best of our knowledge, this is the first Japanese case of DMC with a confirmed variant in the DYM gene. This report provides more information about the geographic distribution and phenotypic spectrum of DMC. Moreover, it presents a novel DYM variant and insights about DMC pathology that may be associated with the disarrangement of actin filaments.

Ketogenic Diet for a Young Adult Patient With Chronic-Phase Febrile Infection-Related Epilepsy Syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is a rare disease, whereby refractory status epilepticus (a severe epileptic syndrome) occurs in previously healthy individuals following a febrile illness. Here, we report a patient with FIRES who received ketogenic diet (KD) therapy initiated in the chronic phase. A 21-year-old man presented with status epilepticus, following fever and headache. In the acute phase, his seizures were refractory to conventional antiepileptic drugs and were suppressed only by intravenous anesthetics. In the chronic phase, he showed frequent seizures with concurrent severe cognitive decline. Twenty-seven months after onset, the patient was started on KD. Consequently, his seizure frequency rapidly reduced while his cognitive function slowly improved, albeit incompletely. Recently, KD has been shown to both reduce seizures and improve cognitive prognoses in children with FIRES. Although early KD may help in both seizure control and cognitive prognosis, it is likely that KD can be applied to adult patients with chronic FIRES.

Visual illusions in Parkinson's disease: an interview survey of symptomatology.

BACKGROUND: Several types of visual illusions can occur in Parkinson's disease (PD). However, the prevalence and types of specific illusions experienced by patients with PD remain unclear. This study aimed to investigate the types of illusions. METHODS: A questionnaire of visual illusions was developed through a literature review in consultation with clinicians and neurologists. Based on the questionnaire, 40 consecutive patients with PD were asked a series of Yes/No questions regarding 20 types of visual illusions since the onset of PD. If participants answered 'Yes', they were then asked to detail their experience(s). RESULTS: In total, 30 patients with PD had experienced visual illusions since disease onset; among them, 25 were still experiencing them at the time of the study. The most commonly observed illusion types were dysmorphopsia, complex visual illusions, metachromatopsia, and diplopia. Other observed illusions included textural illusions, macropsia, micropsia, teleopsia, pelopsia, kinetopsia, akinetopsia, Zeitraffer/Zeitlupen phenomena, tilt illusion, upside-down illusion, and palinopsia. Additionally, aberrant perception of surface orientation (inclination) was reported, which is yet to be reported in association with any disease. Visual illusions had detrimental effects on the patients' daily lives in some cases. CONCLUSIONS: Systematic interviews regarding the incidence and details of visual illusions experienced by patients with PD could offer important information regarding their quality of life.

Prevention of Tracheo-Innominate Artery Fistula by Using an Adjustable Tracheostomy Tube.

Tracheo-innominate artery fistula (TIF) is a severe complication associated with a long-term tracheostomy, and TIF-associated bleeding has a high mortality rate. Here, we report two patients who were considered to be at high risk of developing TIF due to retrocollis after tracheostomy. The patients were an 82-year-old woman with Parkinson's disease (PD) and a 64-year-old man with multiple system atrophy (MSA). Both patients underwent tracheostomy at an advanced stage and later showed retrocollis. Colored and 3D-reconstructed computed tomography (CT) showed tracheal deformation into a C curve, with the tip of the tracheostomy tube attached to the anterior wall, where the innominate artery transverses. Since they were considered to be at high risk of developing TIF, we used an adjustable tracheostomy tube. Follow-up CT revealed that the tip of the new tracheostomy tube had separated from the tracheal anterior wall. Although retrocollis is rare in PD and MSA, it can develop at the end stage of these diseases. An adjustable tracheostomy tube may be an option for preventing TIF development in cases where surgical intervention would be difficult.

Frontal Hypoperfusion and the Effectiveness of Perampanel in Long-Lived Patient with Lafora Disease.

We report a long-lived patient with Lafora disease (LD). A 34-year-old woman experienced onset of seizures at the age of 11 years. She was bedridden in her early twenties due to frequent generalized tonic-clonic seizures, myoclonus, and progressive mental deterioration. Her seizures occurred all the time despite administration of multiple anticonvulsants at high doses. At the age of 31, she started perampanel, which resulted in reduction of anticonvulsants after her visible myoclonus and convulsions disappeared. Brain magnetic resonance imaging showed marked cerebral and cerebellar atrophy, and single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed significant hypoperfusion of the frontal lobe and cerebellum. We identified a W219R homozygous mutation in exon 1 of the NHLRC1 gene. Because perampanel may not only control seizures but also prevent mental deterioration in LD, we propose that perampanel should be administered from the early stage of LD.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Decrease in Blood Flow in Cerebellum.

In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, progressive cerebellar atrophy potentially leads to severe sequelae. We encountered a patient with anti-NMDAR antibody encephalitis who showed a decrease of blood flow in the cerebellum. A 15-year-old girl presented with consciousness disturbance. Influenza encephalopathy was suspected, and she was treated with glucocorticoid pulse therapy, high-dose intravenous immunoglobulins, and plasma exchange sequentially. She subsequently underwent left oophorectomy due to the presence of anti-NMDAR antibodies and a left ovarian teratoma. In spite of the surgery, her neuropsychiatric symptoms persisted, and she recovered slowly after the introduction of oral methotrexate (MTX). Sequential cerebral blood flow monitoring with single-photon emission computed tomography showed marked cerebellar hypoperfusion. Although mild impairments including working memory and verbal fluency persisted, she eventually returned to high school 3 years after onset. Profound cerebellar hypoperfusion including lobules VI and VII may be the reason for her working memory impairment and speaking problems. Oral MTX may be a promising alternative treatment for some refractory cases of anti-NMDAR encephalitis.

The Effectiveness of Perampanel for Myoclonic Seizures in Down Syndrome with Isodicentric Chromosome 21.

Epileptic seizures are common in the elderly Down syndrome population. We encountered a patient with Down syndrome in whom karyotyping showed the rare isodicentric chromosome 21 and who suffered from myoclonic seizures. A 52-year-old woman with Down syndrome experienced sudden onset of drowsiness and frequent myoclonic jerks in the upper body. Video-EEG recordings demonstrated generalized polyspike-wave discharges consistent with myoclonic jerks, which were exacerbated by photo-stimulation. Her myoclonus completely resolved with perampanel administration. Perampanel was effective for myoclonic seizures in our patient. We suggest that perampanel is an option as first-line therapy for epilepsy and myoclonus in elderly Down syndrome patients.

A case of female adrenoleukodystrophy carrier with insidious neurogenic bladder.

A 65-year-old woman with mutation of the ABCD1 gene for adrenoleukodystrophy (ALD) was admitted to our hospital with a urinary tract infection. Abdominal computed tomography showed dilation of the urinary tract. Although she had noticed pollakisuria since her forties, she had not been followed up by any medical institutions until we diagnosed her as a female carrier with ALD. ALD is an X-linked pattern of inheritance that typically affects males, but many female carriers actually present slowly progressive myelopathy and neuropathy. Therefore, it is important to identify female carriers with ALD and treat them at the earliest stage possible.

A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans.

Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional ß subunits, expression of which is induced by IFN-γ, are substituted for their constitutively expressed counterparts, the structure is converted to an immunoproteasome. However, the underlying roles of immunoproteasomes in human diseases are poorly understood. Using exome analysis, we found a homozygous missense mutation (G197V) in immunoproteasome subunit, ß type 8 (PSMB8), which encodes one of the ß subunits induced by IFN-γ in patients from 2 consanguineous families. Patients bearing this mutation suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was highly expressed, and there was reduced expression of PSMB8. Downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. These findings identify PSMB8 as an essential component and regulator not only of inflammation, but also of adipocyte differentiation, and indicate that immunoproteasomes have pleiotropic functions in maintaining the homeostasis of a variety of cell types.

Long-term follow up of thymus in patients with myasthenia gravis.

We examined transversely the thymus of 33 myasthenia gravis (MG) patients followed up for more than 5 years and found three thymomas. One was found 21 years after thymoma resection (Masaoka I, WHO Type B2 thymoma) and extended thymectomy. The other two were non-thymomatous at onset, and they were not treated with extended thymectomy. Therapeutic guidelines should mention the importance of follow-up in MG thymus.

Acute encephalopathy associated with ingestion of a mushroom, Pleurocybella porrigens (angel's wing), in a patient with chronic renal failure.

The authors report an autopsy case of acute encephalopathy in which generalized convulsion and coma occurred after ingestion of Pleurocybella porrigens (angel's wing mushroom). The patient was a 65-year-old man who had undergone hemodialysis for 3 months due to chronic renal failure. Pathologic examination of the brain revealed extensive postinfarction-like cystic necrosis in the bilateral putamens and multiple spotty necroses in the deep cerebral and cerebellar cortices. In 2004, similar acute encephalopathy related to ingestion of the mushroom was endemic in Japan, the pathogenesis of which remains to be elucidated.

[The research of the pathogen responsible for Pleurocybella porrigens related encephalopathy: investigation of 3-nitropropionic acid hypothesis].

Pleurocybella porrigens related encephalopathy exhibits consciousness disturbance and convulsion in the patients after taking and patients show bilateral basal ganglia lesion resulted in high mortality rate. This encephalopathy is a very similar to the moldy sugarcane encephalopathy epidemic in China in the past. We investigated the relationship between Pleurocybella porrigens related encephalopathy and 3-nitropropionic acid which had caused the moldy sugarcane encephalopathy. We have tried to detect 3-NPA in the various specimens from patients and Pleurocybella porrigens, but failed. Further examinations for elucidating the causation of Pleurocybella porrigens related encephalopathy are needed.