Association between underweight, serum albumin levels, and height loss in the Japanese male population: a retrospective study.

BACKGROUND: Previous study has shown that height loss (defined as the highest quartile of height loss per year) was inversely associated with serum albumin levels. Furthermore, comparatively healthy hyponutrition has been linked with being underweight; as such, underweight might be inversely associated with serum albumin levels and positively associated with height loss. METHODS: To clarify the associations between serum albumin level, underweight status, and height loss, we conducted a retrospective study of 8,096 men over 4.0 years (median). RESULTS: Serum albumin level at baseline was inversely associated with being underweight (body mass index [BMI]: < 18.5 kg/m2) at baseline and height loss. The known cardiovascular risk factor adjusted odds ratio (OR) and 95% confidence interval (CI) of underweight at baseline and of height loss for 1 standard deviation increment of serum albumin (0.28 g/dL) was 0.79 (0.70, 0.90) and 0.84 (0.80, 0.88). Underweight was also shown to be positively associated with height loss: with the reference of normal-low weight (BMI: 18.5-22.9 kg/m2), the adjusted OR (95% CI) was 1.60 (1.21, 2.10). CONCLUSION: Comparative healthy hyponutrition, which is related to low serum albumin levels and being underweight, is a significant risk factor for height loss among Japanese men. These results help to clarify the mechanisms underlying height loss.

Alexander disease with a novel GFAP insertion-deletion mutation mimicking progressive supranuclear palsy.

This report presents a case of Alexander disease showing clinical characteristics mimicking progressive supranuclear palsy (PSP). A 67-year-old woman complaining of motor disturbance exhibited severe atrophy of medulla, spinal cord, and midbrain tegmentum, as well as periventricular hyperintensity on cerebral MRI. Genetic analysis identified a novel in-frame deletion/insertion mutation in the exon 3 of the GFAP gene. Interestingly, neurological findings and decreased striatal uptake in dopamine transporter SPECT were suggestive of PSP. A novel GFAP gene mutation found in the present case may cause the unique clinical phenotype, which should be differentiated from PSP.

Substitution of Glu to Lys at Codon 332 on the GFAP Gene Alone Is Causative for Adult-onset Alexander Disease.

A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.

Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease.

BACKGROUND AND OBJECTIVE: Alexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation. METHODS: Genetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed. RESULTS: The patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5' end of the exon 4. DISCUSSION: GFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

Clinical and radiological characteristics of older-adult-onset Alexander disease.

BACKGROUND: Alexander disease (ALXDRD) affects a wide range of ages from infancy to adulthood. However, only a few cases involving patients with older-adult onset over 65 years of age have been reported. In contrast, regarding in-house data, 10.6% of 85 cases with the identification of GFAP mutations demonstrated older-adult onset. This discrepancy may be due to poor awareness of such cases. METHODS: The subjects included 9 older-adult-onset cases, with an onset age of 65 years or older. We characterized older-adult-onset ALXDRD by assessing neurological findings and several magnetic resonance imaging (MRI) parameters. RESULTS: The age at onset, mean age at diagnosis, and mean period from onset to diagnosis were 68.2 years, 70.4 years, and 2.2 years, respectively. The main neurological features at diagnosis included pyramidal signs with muscle weakness and/or cerebellar ataxia. Two-thirds of cases were dependent, and the dependence was significantly correlated with a longer period from onset to diagnosis. Quantitative MRI evaluation for brainstem atrophy demonstrated distinctive morphological features of bulbospinal ALXDRD. The corpus callosum index tended to be negatively correlated with the period from onset to diagnosis. CONCLUSIONS: Although neurological and MRI findings of older-adult-onset ALXDRD patients showed typical features of bulbospinal ALXDRD, their disease progression was more severe than that in younger-adult-onset ALXDRD, and patients developed dependence within 2 years from onset. Cerebral white matter damage tended to progress in proportion to the duration of illness. Our case study may help to advance understanding of the clinical spectrum of ALXDRD.

Social Factors for Leading to Life Satisfaction among Residents with Developmental Disorders in Fukushima Prefecture.

A developmental disorder is condition in which a person has deficiency in either physical, learning, language, or behavior, and people with developmental disorders often experience difficulties in their social lives. In Japan, no systematic surveys of developmental disorders targeting local residents have been reported, including working-age. Hence, we aimed to estimate the prevalence and determine the psychosocial factors associated with life satisfaction and psychological distress in the Fukushima prefecture. We conducted an Internet questionnaire survey among 4,030 residents (2,136 men and 1,894 women) aged 16-65 years who either had a job or were willing to work. Developmental disorders were defined based on participants' self-reported history diagnosed by a psychiatrist or their responses to screening questionnaires. The prevalence of developmental disorders was 9.6% (n = 386). Subsequently, a secondary survey (on a first-come, first-served basis) was conducted to assess psychosocial factors among those with developmental disorders, and responses were received from 121 men and 79 women aged 16-65. Being a regular employee and disclosing diagnosis at the workplace was associated with higher job satisfaction. The participants living with a spouse and/or their children tended to feel satisfied with their life (multivariable-adjusted odds ratio (OR): 3.55), job (OR: 3.20), and income (OR: 4.68), whereas those living with parents tended to not feel satisfied with their life, job, or income. Working as a regular employee, having co-workers who understand developmental disorders, and living with a spouse or children are important social factors that increase life satisfaction among people with developmental disorders.

Ketogenic Diet Therapy for Intractable Epilepsy in Infantile Alexander Disease: A Small Case Series and Analyses of Astroglial Chemokines and Proinflammatory Cytokines.

In infantile Alexander disease (iAxD), one of the serious symptoms is intractable epilepsy, and some reports have suggested that neuroinflammation may be involved in the pathophysiology of the disease. Drug-resistant seizures adversely affect not only the quality of life of the caregivers and patients, but also patients' lifespan. Thus, controlling epilepsy is clinically important. For intractable childhood epilepsy, ketogenic diet therapy (KDT) is well-established, but its effects on iAxD have not been characterized. Here, we describe the use of KDT in three iAxD patients experiencing drug-resistant seizures. In all three cases, the formerly intractable epilepsies were well controlled by KDT. However, the brain magnetic resonance imaging findings deteriorated even after the epilepsy was controlled. In addition, the concentrations of monocyte chemotactic protein-1 and proinflammatory cytokines in the cerebrospinal fluid of the patients remained still high. KDT is effective in controlling epilepsy in iAxD. Our results clinically support previous reports arguing the involvement of neuroinflammation in the pathophysiology of iAxD.　Although KDT cannot prevent disease progression, earlier initiation might contribute to a better prognosis.

[A case of Alexander disease presented with dystonia of lower limb and decreased dopaminergic uptake in dopamine transporter scintigraphy].

A 50-year-old woman developed gait disturbances and dysarthria since the past 2 years. She also presented with dystonia and hypokinesia of her left lower limb, and orthostatic hypotension. The dopamine transporter SPECT with 123I ioflupane showed abnormal scans in bilateral striatum. Cerebral MRI revealed atrophy and signal changes in the medulla and spinal cord, from which Alexander disease (AxD) was suspected. Consequently, we checked the Glial fibrillary acidic protein (GFAP) gene. The analysis of the gene detected a heterozygous c.219G>T mutation, which was the first mutation reported in Japan, and finally she was diagnosed with AxD. Dystonia is relatively rare in AxD patients, but this case demonstrated that AxD should be listed in the differential diagnosis of extrapyramidal syndromes with abnormalities of the medulla and spinal cord on MRI.

Clinical characteristics of Alexander disease.

Alexander disease (ALXDRD) is a primary astrocyte disease caused by GFAP gene mutation. The clinical features of ALXDRD vary from infantile-onset cerebral white matter involvement to adult-onset brainstem involvement. Several studies revealed that the level of GFAP overexpression is correlated with disease severity, and basic research on therapies to reduce abnormal GFAP accumulation has recently been published. Therefore, the accumulation of clinical data to advance understanding of the natural history is essential for clinical trials expected in the future. This review focuses on the clinical characteristics of ALXDRD including the clinical symptoms, imaging findings and genetics to provide diagnostic information useful in daily clinical practice.

[Clinical characteristics and diagnostic criteria on Alexander disease].

Alexander disease (ALXDRD) is a primary astrocyte disease caused by glial fibrillary acidic protein (GFAP) gene mutation. ALXDRD had been clinically regarded as a cerebral white matter disease that affects only children for about 50 years since the initial report in 1949; however, in the early part of the 21st century, case reports of adult-onset ALXDRD with medulla and spinal cord lesions increased. Basic research on therapies to reduce abnormal GFAP accumulation, such as drug-repositioning and antisense oligonucleotide suppression, has recently been published. The accumulation of clinical data to advance understanding of natural history is essential for clinical trials expected in the future. In this review, I classified ALXDRD into two subtypes: early-onset and late-onset, and detail the clinical symptoms, imaging findings, and genetic characteristics as well as the epidemiology and historical changes in the clinical classification described in the literature. The diagnostic criteria based on Japanese ALXDRD patients that are useful in daily clinical practice are also mentioned.

[A case of Alexander disease with repeated loss of consciousness and with rapid aggravation of dysbasia by falling].

A 41-year-old woman presented with short-stepped gait from 20 years old and with repeated loss of consciousness from 21 years old. She had a deep cerebral white matter lesion on brain MRI at 34 years of age, but she did not reach a definitive diagnosis. At the age of 41, the gait disorder rapidly worsened after fall and fall-related head trauma. She had fixation nystagmus, dysphonia, speech disorder and exaggerated tendon reflexes. Her bilateral plantar reflex was positive, and she was not able to walk by herself. The brain and cervical MRI showed atrophy of the medulla and upper spinal cord and a deep cerebral white matter lesion. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. As a result, we identified a heterozygous p.R79H (c.250 G>A) missense mutation of the GFAP gene in the patient. This case suggests that loss of consciousness may be caused by autonomic disorder due to orthostatic hypotension and reflex syncope (vasovagal syncope), psychogenic non-epileptic seizures (PNES) by mental and physical stress. It is important to consider the pathophysiology and management of Alexander disease, in which the progression of gait disorder caused by pyramidal tract disorder is rapidly exacerbated by fall and head injury.

Inflammatory neuropathology of infantile Alexander disease: A case report.

BACKGROUND: Alexander disease (AxD) is a rare fatal leukodystrophy caused by a dominant missense mutation in the glial fibrillary acidic protein. In a mouse model of AxD, the pathological astrocyte causes a pronounced immune response. The inflammatory environment in the brain might play an important role in the neuronal dysfunction of AxD. CASE: A 3-month-old girl diagnosed with infantile AxD presented with severe intractable seizures and a deteriorated neurological state. Steroid pulse therapy was effective at preventing the epileptic activity and progressive white matter abnormalities on magnetic resonance images, but the effect was temporary. Levels of interleukin (IL)-6, IL-8, and macrophage chemotactic protein 1 (MCP-1) in the cerebrospinal fluid were high at onset and reduced transiently after steroid pulse therapy. DISCUSSION: These results suggest that inflammatory responses of astrocyte and microglia can contribute to the neuropathology of AxD. Robust immunomodulation that targets activated astrocytes and microglia may be a novel therapeutic strategy to improve neurological prognosis in AxD.

Towards genomic database of Alexander disease to identify variations modifying disease phenotype.

Alexander disease (AxD) is an extremely rare neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations. Compared with the cerebral type, which is characterized by infantile onset, the bulbospinal type and intermediate form are associated with a late onset, spanning from juveniles to the elderly, and more diverse clinical spectrum, suggesting the existence of factors contributing to phenotypic diversity. To build a foundation for future genetic studies of this rare disease, we obtained genomic data by whole exome-sequencing (WES) and DNA microarray derived from thirty-one AxD patients with the bulbospinal type and intermediate form. Using this data, we aimed to identify genetic variations determining the age at onset (AAO) of AxD. As a result, WES- or microarray-based association studies between younger (<45 years; n = 13)- and older (≥45 years; n = 18)-onset patients considering the predicted GFAP-mutation pathogenicity identified no genome-wide significant variant. The candidate gene approach identified several variants likely correlated with AAO (p < 0.05): GAN, SLC1A2, CASP3, HDACs, and PI3K. Although we need to replicate the results using an independent population, this is the first step towards constructing a database, which may serve as an important tool to advance our understanding of AxD.

[A case of Alexander disease with dropped head syndrome].

A 51-year-old woman presented with progressive weakness of the neck extensor muscles and gait disturbances since the past 6 years. In addition, she presented with symptoms such as dysarthria, dysphagia, bladder, and rectal disturbances. Bilateral plantar reflex was positive. Her gait was short-stepped-spastic. Brain and cervical MRI showed atrophy of the medulla and spinal cord. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. We identified a heterozygous c.368T>C missense mutation of the GFAP gene in the patient. This was the first case of the mutation in Japanese patients, and subsequently, she was diagnosed with AxD type 2. There are a few studies which reported that patients with AxD complained of dropped head syndrome. Dropped head syndrome can be the initial manifestation of AxD.

Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an Alexander disease model.

Alexander disease (AxD) is a rare neurodegenerative disorder caused by gain of function mutations in the glial fibrillary acidic protein (GFAP) gene. Accumulation of GFAP proteins and formation of Rosenthal fibers (RFs) in astrocytes are hallmarks of AxD. However, malfunction of astrocytes in the AxD brain is poorly understood. Here, we show aberrant Ca2+ responses in astrocytes as playing a causative role in AxD. Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca2+ homeostasis molecules. In situ AxD model astrocytes produced aberrant extra-large Ca2+ signals "AxCa signals", which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca2+ . Inhibition of AxCa signals by deletion of inositol 1,4,5-trisphosphate type 2 receptors (IP3R2) ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would contribute to AxD pathogenesis.

A novel three-base duplication, E243dup, of GFAP identified in a patient with Alexander disease.

Alexander disease (AxD) is a rare hereditary neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations, most of which are missense mutations. We present an AxD case with a novel de novo three-base duplication mutation in GFAP resulting in E243dup.