Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy.

Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing on SOD1, fused in sarcoma (FUS), and transacting response DNA-binding protein. The frequency of the C9ORF72 mutation is low in Japan, unlike in Europe and the United States, while SOD1 and FUS are more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.

Videofluoroscopic Dysphagia Scale as an Additional Indicator of Gastrostomy in Patients with Amyotrophic Lateral Sclerosis with Dysphagia.

Pseudobulbar palsy and bulbar palsy cause dysphagia in patients with amyotrophic lateral sclerosis (ALS). Dysphagia in patients with ALS not only increases the risk of aspiration and pneumonia but also leads to malnutrition and weight loss, which are poor prognostic factors. Gastrostomy is the preferred route of feeding and nutritional support in patients with dysphagia. However, there are no established standards to determine the ideal timing of gastrostomy for patients with ALS. Therefore, we used the videofluoroscopic dysphagia scale (VDS), which objectively quantifies swallowing function, in videofluoroscopic swallowing study (VFSS) to investigate whether this scale at diagnosis can be a useful predictor for the timing of gastrostomy. We retrospectively evaluated 22 patients with ALS who were diagnosed at our hospital. We assessed the VDS scores in all patients within 3 months of diagnosis. A decline in the ALS functional rating scale revised (ALSFRS-R) scores was used as an indicator of disease progression. As a result, we found that the VDS score of the pharyngeal phase and the total VDS score were significantly correlated with the ΔALSFRS-R scores. These scores were also associated with the existing indicators for the timing of gastrostomy, i.e., decreased body weight and percent-predicted forced vital capacity. We demonstrated the noninferiority of the VDS scores relative to the existing indicators. In addition, the VDS score of the pharyngeal phase was significantly correlated with the time from diagnosis to gastrostomy. The VDS score could estimate the timing of gastrostomy in patients with ALS with dysphagia at diagnosis.

Long-term outcomes after surgery to prevent aspiration for patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons selectively. In particular, weakness in respiratory and swallowing muscles occasionally causes aspiration pneumonia and choking, which can be lethal. Surgery to prevent aspiration, which separates the trachea and esophagus, can reduce the associated risks. Central-part laryngectomy (CPL) is a relatively minimally invasive surgery to prevent aspiration. No studies have been conducted on the long-term outcomes of surgery to prevent aspiration in patients with ALS. This case series aimed to determine the long-term outcomes of surgery to prevent aspiration and the use of a continuous low-pressure aspirator in patients with ALS by evaluating the frequency of intratracheal sputum suctions performed per day, intra- and postoperative complications, oral intake data, and satisfaction of patients and their primary caregiver to predict improvement in patients' quality of life (QOL). METHODS: We report a case series of six patients with ALS who underwent CPL along with tracheostomy to prevent aspiration between January 2015 and November 2018. We evaluated their pre- and postoperative status and administered questionnaires at the time of last admission to the patients and their primary caregivers. RESULTS: The mean follow-up period after CPL was 33.5 months. Aerophagia was a common postoperative complication. The use of a continuous low-pressure aspirator resulted in reduced frequency of intratracheal sputum suctions. All cases avoided aspiration pneumonia. Oral intake was continued for 2-4 years after the tracheostomy and CPL. The satisfaction levels of the patient and primary caregiver were high. CONCLUSION: Our case series suggests that the use of a continuous low-pressure aspirator in patients undergoing CPL improves oral intake and reduces the frequency of intratracheal sputum suctions, which improves the QOL of patients with ALS and their families and caregivers. CPL and continuous low-pressure aspiration should be considered as a management option for ALS with significant bulbar and respiratory muscle weakness/dysfunction.

A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy.

Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.

Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases.

Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy.

Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype-phenotype relationship and a hotspot on the inner DysF domain.

Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study.

BACKGROUND: Riluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events. METHODS: Patients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded. RESULTS: A total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment. CONCLUSION: Riluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.

Aberrant astrocytic expression of chondroitin sulfate proteoglycan receptors in a rat model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive and systemic loss of motor neurons with gliosis in the central nervous system (CNS) is a neuropathological hallmark of ALS. Chondroitin sulfate proteoglycans (CSPGs) are the major components of the extracellular matrix of the mammalian CNS, and they inhibit axonal regeneration physically by participating to form the glial scar. Recently, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related protein were discovered as CSPG receptors that play roles in inhibiting regeneration. Here we examined the expression of CSPG receptors in transgenic female rats overexpressing an ALS-linked mutant cytosolic Cu/Zn superoxide dismutase gene (SOD1). In contrast to controls, multiple immunofluorescence analyses revealed aberrant expression of CSPG receptors dominantly in reactive astrocytes, while PTPσ expression in neurons decreased in the spinal ventral horns of ALS transgenic rats. The aberrant and progressive astrocytic expression of CSPG receptors and reactive astrocytes themselves may be therapeutic targets for reconstructing a regeneration-supportive microenvironment under neurodegenerative conditions such as ALS.

[Therapeutic development for GNE myopathy.]

GNE myopathy is rare muscle disease which affect distal muscles. GNE gene, which encodes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in the homozygote or compound heterozygote in the disease. The lack of sialic acid in skeletal muscle is the critical pathological process in GNE myopathy. GNE myopathy model mouse was established and supplementation of sialic acid improves the phenotype of model mouse. Phase Ⅰ clinical trial was conducted at Tohoku University Hospital using aceneuramic acid, followed by the trials using slow release product of sialic acid. Phase Ⅱ/Ⅲ study is ongoing.

Proteasome dysfunction induces muscle growth defects and protein aggregation.

The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes of protein and organelle clearance. The role of the proteasome pathway in mammalian muscle has not been examined in vivo. In this study, we report that the muscle-specific deletion of a crucial proteasomal gene, Rpt3 (also known as Psmc4), resulted in profound muscle growth defects and a decrease in force production in mice. Specifically, developing muscles in conditional Rpt3-knockout animals showed dysregulated proteasomal activity. The autophagy pathway was upregulated, but the process of autophagosome formation was impaired. A microscopic analysis revealed the accumulation of basophilic inclusions and disorganization of the sarcomeres in young adult mice. Our results suggest that appropriate proteasomal activity is important for muscle growth and for maintaining myofiber integrity in collaboration with autophagy pathways. The deletion of a component of the proteasome complex contributed to myofiber degeneration and weakness in muscle disorders that are characterized by the accumulation of abnormal inclusions.

Genotype-phenotype relationships in familial amyotrophic lateral sclerosis with FUS/TLS mutations in Japan.

INTRODUCTION: We investigated possible genotype-phenotype correlations in Japanese patients with familial amyotrophic lateral sclerosis (FALS) carrying fused in sarcoma/translated in liposarcoma (FUS/TLS) gene mutations. METHODS: A consecutive series of 111 Japanese FALS pedigrees were screened for copper/zinc superoxide dismutase 1 (SOD1) and FUS/TLS gene mutations. Clinical data, including onset age, onset site, disease duration, and extramotor symptoms, were collected. RESULTS: Nine different FUS/TLS mutations were found in 12 pedigrees. Most of the patients with FUS/TLS-linked FALS demonstrated early onset in the brainstem/upper cervical region, and relatively short disease duration. A few mutations exhibited phenotypes that were distinct from typical cases. Frontotemporal dementia was present in 1 patient. CONCLUSIONS: This study revealed a characteristic phenotype in FUS/TLS-linked FALS patients in Japan. FUS/TLS screening is recommended in patients with FALS with this phenotype. Muscle Nerve 54: 398-404, 2016.

Immunolocalization of corticotropin-releasing hormone (CRH) and its receptors (CRHR1 and CRHR2) in human endometrial carcinoma: CRHR1 as a potent prognostic factor.

OBJECTIVE: Corticotropin-releasing hormone (CRH), a major regulator of the stress response, regulates various biological functions through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2). CRH, CRHR1, and CRHR2 have recently been reported in several types of carcinoma, but the significance of these proteins has remained largely unknown in human endometrial carcinoma. MATERIALS AND METHODS: A total of 87 endometrial carcinoma specimens were obtained from Japanese female patients who underwent surgical treatment, fixed in 10% formalin, and embedded in paraffin wax. Immunohistochemistry for CRH, CRHR1, and CRHR2 was performed, and clinical data were obtained from the medical records. RESULTS: Immunopositivity of CRH, CRHR1, and CRHR2 in the specimens was 26%, 15%, and 10%, respectively. Univariate analysis revealed that immunohistochemical CRH status was positively associated with CRHR1 and CRHR2 status and that CRHR1 status was significantly associated with the risk of recurrence and poorer clinical outcome, whereas CRHR2 status was marginally associated with better prognosis for overall survival. Multivariate analysis demonstrated CRHR1 status as an independent prognostic factor for both disease-free and overall survival. CONCLUSIONS: These results suggest that intratumoral CRH-CRHR1 signaling plays an important role in the progression of endometrial carcinoma and that CRHR1 is a potent prognostic factor in patients with this disease.

Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy.

OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3. METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues. RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs. INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.

Nationwide survey of patients with multisystem proteinopathy in Japan.

OBJECTIVE: Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA-binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. METHODS: We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. RESULTS: In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single-photon emission computed tomography. INTERPRETATION: The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice.

The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.

Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure.

Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c.90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.

Spinal Cord Infarction in an Adolescent with Protein S Deficiency: A Case Report and Literature Review.

Protein S deficiency causes spinal cord infarction in rare cases. We herein report the first case of severe cervicothoracic cord infarction in an adolescent with protein S deficiency. A 16-year-old boy presented with neck pain, four-limb paralysis, and numbness. Magnetic resonance imaging revealed spinal artery infarction in the C4 to Th4 area. Protein S antigen and activity were decreased. The patient was diagnosed with protein S deficiency-associated cervicothoracic cord infarction, which was treated with anticoagulation. Protein S deficiency should be considered as a potential cause of spinal cord infarction in young healthy patients and should be appropriately treated with anticoagulation.