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The TARDBP gene variant is a known major cause of amyotrophic lateral sclerosis (ALS), with limited reports of Korean patients with ALS harboring the variants in TARDBP. This large cohort study introduces four ALS patients who share the p.M337V variant of the TARDBP, allowing for an investigation of clinical characteristics and prognosis by analyzing previously reported cases with the same variant. From November 2014 to August 2022, participants were recruited from two tertiary hospitals in Seoul, Korea. Clinical characteristics of patients diagnosed with ALS carrying the variant in TARDBP were evaluated. Previous articles demonstrating subjects' characteristics were reviewed. Four patients were identified with the pathogenic missense variant (c.1009A>G; p.M337V) in the TARDBP. The mean age of onset was 55 years old, and none of the patients showed severe cognitive impairment. Sixty-three patients carrying the p.M337V variant in TARDBP from this study and previous reports delineated young age of onset (51.6 years), high frequency of bulbar onset patients (61.9%), and low comorbidity of frontotemporal dementia. This study reveals the presence of pathogenic variant of TARDBP in Korea and emphasizes the importance of genetic screening of the TARDBP gene, in diagnosing ALS and evaluating prognosis among familial and simplex ALS patients in Korea., (© 2023. The Author(s).)

Microglia plays a key role in determining the progression of amyotrophic lateral sclerosis (ALS), yet their precise role in ALS has not been identified in humans. This study aimed to identify a key factor related to the functional characteristics of microglia in rapidly progressing sporadic ALS patients using the induced microglia model, although it is not identical to brain resident microglia. After confirming that microglia-like cells (iMGs) induced by human monocytes could recapitulate the main signatures of brain microglia, step-by-step comparative studies were conducted to delineate functional differences using iMGs from patients with slowly progressive ALS [ALS(S), n = 14] versus rapidly progressive ALS [ALS(R), n = 15]. Despite an absence of significant differences in the expression of microglial homeostatic genes, ALS(R)-iMGs preferentially showed defective phagocytosis and an exaggerated pro-inflammatory response to LPS stimuli compared to ALS(S)-iMGs. Transcriptome analysis revealed that the perturbed phagocytosis seen in ALS(R)-iMGs was closely associated with decreased NCKAP1 (NCK-associated protein 1)-mediated abnormal actin polymerization. NCKAP1 overexpression was sufficient to rescue impaired phagocytosis in ALS(R)-iMGs. Post-hoc analysis indicated that decreased NCKAP1 expression in iMGs was correlated with the progression of ALS. Our data suggest that microglial NCKAP1 may be an alternative therapeutic target in rapidly progressive sporadic ALS., (© 2023. The Author(s).)

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS., Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature., Results: We identified four sporadic ALS cases with de novo mutations in SOD1 . They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1 . We also encountered familial cases where de novo mutational events in recent generations may have been involved., Conclusions: De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy., Competing Interests: Competing interests: PMA serves on the scientific advisory boards of Biogen, Regeneron and Orphazyme A/S., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Dysregulation of calcium ion homeostasis and abnormal protein aggregation have been proposed as major pathogenic hallmarks underpinning selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Recently, mutations in annexin A11 ( ANXA11 ), a gene encoding a Ca 2+ -dependent phospholipid-binding protein, have been identified in familial and sporadic ALS. However, the physiological and pathophysiological roles of ANXA11 remain unknown. Here, we report functions of ANXA11 related to intracellular Ca 2+ homeostasis and stress granule dynamics. We analyzed the exome sequences of 500 Korean patients with sALS and identified nine ANXA11 variants in 13 patients. The amino-terminal variants p.G38R and p.D40G within the low-complexity domain of ANXA11 enhanced aggregation propensity, whereas the carboxyl-terminal ANX domain variants p.H390P and p.R456H altered Ca 2+ responses. Furthermore, all four variants in ANXA11 underwent abnormal phase separation to form droplets with aggregates and led to the alteration of the biophysical properties of ANXA11. These functional defects caused by ALS-linked variants induced alterations in both intracellular Ca 2+ homeostasis and stress granule disassembly. We also revealed that p.G228Lfs*29 reduced ANXA11 expression and impaired Ca 2+ homeostasis, as caused by missense variants. Ca 2+ -dependent interaction and coaggregation between ANXA11 and ALS-causative RNA-binding proteins, FUS and hnRNPA1, were observed in motor neuron cells and brain from a patient with ALS-FUS. The expression of ALS-linked ANXA11 variants in motor neuron cells caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis. Together, our findings suggest that disease-associated ANXA11 mutations can contribute to ALS pathogenesis through toxic gain-of-function mechanisms involving abnormal protein aggregation., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

To identify pathogenic variants in 107 Korean patients with sporadic frontotemporal dementia (FTD), 46 genes related to FTD, amyotrophic lateral sclerosis, and other dementias were screened by next-generation sequencing. Hexanucleotide repeats in C9orf72 gene were also tested by repeat-primed polymerase chain reaction. Next-generation sequencing revealed one known pathogenic variant (c.708+1G>A) in the GRN gene in a patient with behavioral variant FTD (bvFTD). In addition, a novel in-frame deletion (c.2675_2683del) in the CSF1R gene was identified in a patient with bvFTD who had severe bifrontal atrophy with frontal subcortical white matter changes. Novel compound heterozygous variants in the AARS2 gene, c.1040+1G>A and c.636G>A (p.Met212Ile), were found in a patient with bvFTD. Forty-six variants of uncertain significance were detected in other patients. None of the patients had expanded hexanucleotide repeats in C9orf72. These results show that pathogenic variants of known FTD genes are rare in Korean FTD patients but the CSF1R and AARS2 genes should be screened for a genetic diagnosis of FTD or other dementias., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the safety and efficacy of 2 repeated intrathecal injections of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in amyotrophic lateral sclerosis (ALS)., Methods: In a phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with 2 BM-MSC injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events. The primary efficacy outcome was changes in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to 4 and 6 months postinjection. Post hoc analysis includes investigation of cerebrospinal fluid biomarkers and long-term survival analysis., Results: Safety rating showed no groupwise difference with absence of serious treatment-related adverse events. Mean changes in ALSFRS-R scores from baseline to 4 and 6 months postinjection were reduced in the MSC group compared with the control group (4 months: 2.98, 95% confidence interval [CI] = 1.48-4.47, p < 0.001; 6 months: 3.38, 95% CI = 1.23-5.54, p = 0.003). The MSC group showed decreased proinflammatory and increased anti-inflammatory cytokines. In good responders, transforming growth factor β1 significantly showed inverse correlation with monocyte chemoattractant protein-1. There was no significant difference in long-term survival between groups., Interpretation: Repeated intrathecal injections of BM-MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety, in ALS patients. A plausible action mechanism is that BM-MSCs mediate switching from pro- to anti-inflammatory conditions. A future randomized, double-blind, large-scale phase 3 clinical trial with additional BM-MSC treatments is required to evaluate long-term efficacy and safety. Ann Neurol 2018;84:361-373., (© 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

ATXN2 intermediate-length trinucleotide repeat expansions have been reported as a risk factor for amyotrophic lateral sclerosis (ALS) in various ethnicities. We tried to confirm this finding in Korean patients with ALS by screening ATXN2 cytosine-adenine-guanine nucleotide sequences (CAG) repeat lengths in 464 unrelated ALS patients and 703 controls. The most common and the highest CAG repeat lengths in the controls were 22 and 28, respectively, whereas those in ALS patients were 22 and 33, respectively. The frequency of CAG repeat lengths of 30 or more was significantly different between the 2 groups after Bonferroni correction (1.5% in ALS vs. 0% in controls, corrected p = 0.0075). There were no significant differences in gender, age at onset, site of onset, functional rating scale-revised score at initial visit, calculated progression rate, or survival between patients with CAG repeat lengths of 30-33 and patients with CAG repeat lengths <30. These findings support the notion that intermediate-length ATXN2 repeat expansions might be a risk factor in Korean patients with ALS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The TANK-binding kinase 1 (TBK1) gene has recently been identified as a novel causative gene of amyotrophic lateral sclerosis (ALS). This study aims to determine the frequency and spectrum of TBK1 variants and their functional implications in Korean patients with sporadic ALS (sALS). TBK1 sequences were analyzed in 129 consecutive patients with sALS using either multigene panel or exome sequencing. One frameshift (c.1414delA) and 3 missense variants of uncertain significance in TBK1 were found in 4 patients each. In vitro functional studies revealed that the c.1414delA (p.Ile472Serfs*8) variant was associated with reduced mRNA expression of TBK1. Moreover, protein expression of this variant in patient-derived fibroblasts disrupted binding to autophagy adapter proteins and inhibited the function of TBK1 in HEK293T cells. In contrast, the 3 other missense variants of uncertain significance showed normal mRNA expression and no abnormalities in protein function. Based on these findings, the frequency of pathogenic TBK1 variants in Korean sALS patients was estimated to be 0.8% (1/129). In conclusion, pathogenic variants in TBK1 are rare but could be responsible for sALS in a small number of Korean patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The type II C-type lectin CLEC4C is a transmembrane protein selectively expressed on plasmacytoid dendritic cells (PDCs). Although its mechanism of action remains unclear, triggering of the extracellular C-terminal C-type carbohydrate recognition region of CLEC4C regulates the secretion of proinflammatory cytokines and type I IFNs in PDCs. Applying whole-exome sequencing in a patient with juvenile amyotrophic lateral sclerosis (ALS) and both healthy parents, we identified a de novo CLEC4C variant (c.629&#95;631delAGA; p.Lys210del). In this study, we report that the deletion of a lysine residue at the extracellular region of CLEC4C yields a C-terminal dilysine motif that results in endoplasmic reticulum (ER) retention of the protein in transfected HeLa and Jurkat T lymphoma cell models. As a consequence, a decrease in the surface expression of CLEC4C and the ER localization of the mutant construct were observed. Furthermore, depletion of the cell surface CLEC4C level was also observed in the patient PDCs, further suggesting that the variant p.Lys210del CLEC4C may contribute to juvenile ALS susceptibility., Competing Interests: The authors declare that there are no conflicts of interest to disclose.

Background: Mutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients' fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures., Results: Here, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts., Conclusions: Thus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving motor neurons. Because a growing number of genes have been identified as the genetic etiology of ALS, simultaneous screening of mutations in multiple genes is likely to be more efficient than gene-by-gene testing. In this study, we performed a multigene panel testing by using targeted capture of 18 ALS-related genes followed by next-generation sequencing. Using this technique, we tried to identify mutations in 4 index patients with familial ALS and 148 sporadic ALS in Korean population and identified 4 known mutations in SOD1, ALS2, MAPT, and SQSTM1 genes, respectively, and 28 variants of uncertain significance in 9 genes. Among the 28 variants of uncertain significance, 6 missense variants were found in highly conserved residues and were consistently predicted to be deleterious by in silico analyses. These results suggest that multigene panel testing is an effective approach for mutation screening in ALS-related genes. Moreover, the relatively low frequency of mutations in known ALS genes implies marked genetic heterogeneity at least in Korean patients with ALS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder. Approximately 5% of ALS patients are familial (fALS) cases, and the remaining 95% are apparently sporadic (sALS) cases. To date, a number of genes have been discovered as associated with ALS, but the genetic background of sALS is not yet fully understood. The occurrence of de novo mutations in ALS genes might be an explanation for sALS, but reduced penetrance could be an alternative theory. Previously, we screened mutations in 5 ALS genes including SOD1 and FUS in 9 fALS and 249 sALS patients and found a total of 15 patients with either SOD1 (7 fALS and 3 sALS) or FUS (1 fALS and 4 sALS) mutations. Interestingly, only 1 fALS patient had the FUS mutation, whereas 4 sALS patients had mutations in this gene. To determine if the FUS mutations in sALS were de novo, we performed genetic analysis on 2 sALS patients with living parents. Genetic analysis confirmed that 2 FUS mutations, including the c.1483C>T (p.Arg495*) and the c.1509&#95;1510delAG (p.Gly504Trpfs*12) mutations, were found only in the patients and not in their parents, confirming the de novo occurrence of these mutations. These findings support the notion that de novo mutations are responsible for a certain proportion of sALS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mutations in the UBQLN2 and SIGMAR1 genes were recently identified in X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS and/or FTD) and FTD and/or motor neuron disease, respectively. Subsequent studies, however, found that UBQLN2 mutations were rare, and the pathogenicity of SIGMAR1 mutation in FTD and/or motor neuron disease was controversial. In the present study, we analyzed mutations in the UBQLN2 and SIGMAR1 genes in a Korean cohort of 258 patients with familial ALS (n = 9) or sporadic (sALS; n = 258) ALS. One novel UBQLN2 variant (p.D314E) was observed in 2 patients with sALS and 5 of 727 controls indicating that this variant might be a rare polymorphism rather than a disease-causing mutation. A novel SIGMAR1 gene variant in the 3'-untranslated region (c.*58T>C) was found in 1 sALS and was absent in 727 control samples. Taken together, our data suggest that causative mutations in the UBQLN2 and SIGMAR1 genes are rare in Korean patients with either familial or sporadic ALS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Cognitive impairment is associated with a negative prognosis in amyotrophic lateral sclerosis (ALS), as well as with clinical specificity. We investigate neuropsychological function in ALS patients without known genetic mutations in a Korean tertiary clinic., Methods: Three hundred and eighteen patients were enrolled in a prospective longitudinal cohort from September 2008 to February 2012. At the time of diagnosis of sporadic ALS, we carried out genetic and comprehensive neuropsychological tests on all patients, and collected demographic and clinical characteristics. Six cognitive domains, namely executive function, attention, language, calculation, visuospatial function and memory were evaluated. ANOVA and t-tests were used to assess differences in clinical characteristics and neuropsychological parameters between sporadic ALS patients. The Kaplan-Meier method and Cox proportional hazard model were used for survival analysis., Results: One hundred and sixty-six patients were categorized into five subtypes: normal cognition (ALS pure), cognitive impairment (ALSci), behavioral impairment (ALSbi), frontotemporal dementia (ALS-FTD), and other types of dementia. Seventy patients (70/166, 42.2%) were cognitively or behaviorally impaired. Among the impaired patients, eight (8/166, 4.8%) had FTD-type dementia and one (1/166, 0.6%) was Alzheimer's disease-type. The ALS patients with cognitive impairment (ALSci) and with FTD (ALS-FTD) were more severely impaired in executive function, attention, language and memory than the cognitively intact ALS patients (ALS pure). In a survival analysis, ALSci (β = 1.925, p = 0.025) and ALS-FTD groups (β = 4.150, p = 0.019) tended to have shorter survival than the ALS pure group., Conclusions: About half of ALS patients without known genetic variation have cognitive or behavioral impairment. ALS patients with cognitive abnormalities, especially FTD, have a poorer prognosis than those without cognitive impairment. In neuropsychological profiling, executive tasks were effective in identifying cognitive impairment in the ALS patients. It would be useful for clinicians to classify ALS according to neuropsychological profiles, and screen for subtle cognitive impairment.

The expansion of a noncoding hexanucleotide repeat (GGGGCC) in the chromosome 9 open reading frame (C9orf72) gene has been identified as the most common cause of familial and sporadic amyotrophic lateral sclerosis (ALS) in Caucasian populations. The role of the C9orf72 repeat expansion in Korean ALS patients, however, has not been reported. We therefore investigated the frequency of the C9orf72 repeat expansion in 254 Korean patients with familial (n = 8) and sporadic (n = 246) ALS and found that none of the patients had the expansion. The number of hexanucleotide repeats ranged from 2 to 11 in the 254 ALS patients without the expansion. Our results suggest that the C9orf72 repeat expansion is not the main cause of ALS in the Korean population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

About 5% of amyotrophic lateral sclerosis (ALS) cases are known to be familial (fALS) and mutations in SOD1 and other genes are found in more than 20% of fALS patients and in 2%-4% of apparently sporadic ALS (sALS) cases. However, there are few reports on the proportion of fALS and the frequency of mutations in Korean patients with ALS. We screened mutations in the SOD1, FUS, TARDBP, ANG, and OPTN genes in 258 consecutively enrolled Korean patients with ALS from October 2006 to November 2010. The frequency of fALS was estimated to be 3.5% (9/258), and mutations were identified in 88.9% (8/9) of fALS patients but only in 2.8% (7/249) of sALS patients. Seven fALS and 3 sALS patients had mutations in SOD1 gene while all the others had FUS gene. The proportion of fALS was lower than that reported in Caucasian populations but the frequency of SOD1 gene mutations in Korean fALS patients (77.8%, 7/9) was much higher than that reported in other ethnic groups. These findings might suggest that there is an ethnic difference in the proportion of fALS and the genetic background of ALS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) can present with heterogeneous symptoms resulting from the involvement of multiple brain systems including extramotor cortical areas. Involvement of other brain areas can cause diverse clinical symptoms including cognitive impairment and extrapyramidal symptoms. We report the case of a 50-year-old woman with bulbar onset ALS and frontotemporal lobar degeneration (FTLD), confirmed as cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient and her first-degree relatives harbored a mutation (R75P) in the NOTCH3 gene, indicative of vascular deficits. The details of this case add plausibility to the idea that ALS, FTLD, and CADASIL are different aspects of a spectrum of disorders with overlapping pathologic mechanisms.

We identified a novel missense mutation in the Cu/Zn superoxide dismutase (SOD1) gene in a 47-year-old woman with familial amyotrophic lateral sclerosis (ALS). The heterozygous mutation, in exon 1 of the SOD1 gene, is a GC to TT transversion in nucleotide positions 13 and 14 leading to an alanine 4 to phenylalanine (A4F) amino acid substitution. It was found in six family members. The effect of the A4F mutation was of similar severity to that of the A4V mutation. We discuss structural instability as a possible pathogenic mechanism in the case of this SOD1 mutation. The proband displayed upper motor neuron signs not observed in individuals with other codon 4 mutations. This could be because longer survival allows UMN dysfunction to become evident. We also provide a literature review., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Familial ALS (FALS) is mostly inherited as an age-dependent autosomal dominant trait. Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), testing for SOD1 gene mutations has become a routine part of the investigation into ALS patients with a family history. This study reports the results of mutation evaluation and clinical features examination in a Korean family with ALS. The clinical symptoms, signs and neurological findings of a four-generation pedigree with 34 members were collected. Five exons of the Cu/Zn SOD gene were analyzed by polymerase chain reaction. The clinical signs and symptoms of ALS patients began in the lower extremities and spread to the upper extremities and bulbar muscles. The mode of transmission was determined to be autosomal dominant, and low penetrance was seen in females. The age at onset varied from 37 to 77 years. ALSFRS-R testing showed variability in the clinical progression of the disease. A point mutation in exon 1 of the SOD1 gene, resulting in an amino acid change from phenylalanine 20 to cysteine (F20C), was identified. This is the first report of clinical features resulting from the Phe20Cys mutation in the SOD1 gene.

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.Results: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.Conclusions: De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy. [ABSTRACT FROM AUTHOR]