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Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertion‒deletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.

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BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844). METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing. RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping. CONCLUSION: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.

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INTRODUCTION: Spastic paraplegia (SPG) is a heterogenous group of neurodegenerative disorders, that may include ocular involvement. Here we report the clinical data of a patient with late-onset Kjellin syndrome, a peculiar form of hereditary SPG with macular dystrophy. MATERIALS AND METHODS: Clinical, functional and multimodal retinal imaging data were collected. Genetic testing was performed by Whole Exome Sequencing (WES). RESULTS: A 52-year-old female patient with SPG of unknown origin was referred for a progressive visual acuity loss. Multimodal fundus imaging revealed a peculiar macular dystrophy. Given the specific association of macular dystrophy and SPG, a Kjellin syndrome was suspected and genetic testing performed. WES revealed biallelic pathogenic variants in SPG11, co-segregating with disease in the family. CONCLUSION: Careful ophthalmological examination prompted the diagnosis and guided molecular testing. This case underlines the importance of a neuro-ophthalmologic assessment in patients with SPG.

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Background: To analyze the clinical phenotype of hereditary spastic paraplegia (HSP) caused by SPG11 mutations (SPG11-HSP). Methods: Among the 17 patients with sporadic HSP who performed whole exome sequencing analysis, six were diagnosed with SPG11-HSP. The clinical and radiologic findings and the results of the electrodiagnostic and neuropsychologic tests were reviewed retrospectively. Results: The median age at onset was 16.5 years (range, 13-38 years). Progressive spastic paraparesis was a core feature, and the median spastic paraplegia rating scale score was 24/52 (range, 16-31 points). Additional major symptoms were pseudobulbar dysarthria, intellectual disability, bladder dysfunction, and being overweight. Minor symptoms included upper limbs rigidity and sensory axonopathy. The median body mass index was 26.2 kg/m2 (range, 25.2-32.3 kg/m2). The thin corpus callosum (TCC) was predominant at the rostral body or anterior midbody, and the ears of the lynx sign was seen in all. The follow-up MRI showed the worsening of periventricular white matter (PVWM) signal abnormalities with ventricular widening or the extension of the TCC. Motor evoked potentials (MEP) to the lower limbs showed an absent central motor conduction time (CMCT) in all subjects. The upper limb CMCT was initially absent in three subjects, although it became abnormal in all at the follow-up. The mini-mental state examination median score was 27/30 (range, 26-28) with selective impairment of the attention/calculation domain. The median score of the full-scale intelligence quotient was 48 (range, 42-72) on the Wechsler Adult Intelligence Scale test. Conclusion: Attention/calculation deficits and being overweight as well as pseudobulbar dysarthria were common additional symptoms in patients with SPG11-HSP. The rostral body and anterior midbody of the corpus callosum were preferentially thinned, especially in the early stage of the disease. The TCC, PVWM signal changes, and MEP abnormality worsened as the disease progressed.

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A 24-year-old man presented with insidious onset progressive gait disturbance and was finally diagnosed with autosomal recessive hereditary spastic paraplegia. Two novel mutations, including a frameshift mutation (c.5687_5691del) and a non-sense mutation (c.751C>T), were identified in the SPG11 gene of the patient through whole genome sequencing. The frameshift mutation of c.5687_5691del leads to a change in amino acid synthesis beginning with amino acid No. 1896 arginine and terminating at the 8th amino acid after the change (p. Arg1896MetfsTer8). The non-sense mutation (c.751C>T) causes the conversion of codon 251st encoding the amino acid Gln into a stop codon (p. Gln251Ter), resulting in premature termination of peptide synthesis. Although confirmation of compound-heterozygosity could not be performed, our findings enriched the phenotypic spectrum of SPG11 mutations related to hereditary spastic paraplegia.

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BACKGROUND: Pathogenic variants in SPG11 cause the most common autosomal recessive complicated hereditary spastic paraplegia. Besides the prototypical combination of spastic paraplegia with a thin corpus callosum, obesity has increasingly been reported in this multisystem neurodegenerative disease. However, a detailed analysis of the metabolic state is lacking. METHODS: In order to characterize metabolic alterations, a cross-sectional analysis was performed comparing SPG11 patients (n = 16) and matched healthy controls (n = 16). We quantified anthropometric parameters, body composition as determined by bioimpedance spectroscopy, and serum metabolic biomarkers, and we measured hypothalamic volume by high-field MRI. RESULTS: Compared to healthy controls, SPG11 patients exhibited profound changes in body composition, characterized by increased fat tissue index, decreased lean tissue index, and decreased muscle mass. The presence of lymphedema correlated with increased extracellular fluid. The serum levels of the adipokines leptin, resistin, and progranulin were significantly altered in SPG11 while adiponectin and C1q/TNF-related protein 3 (CTRP-3) were unchanged. MRI volumetry revealed a decreased hypothalamic volume in SPG11 patients. CONCLUSIONS: Body composition, adipokine levels, and hypothalamic volume are altered in SPG11. Our data indicate a link between obesity and hypothalamic neurodegeneration in SPG11 and imply that specific metabolic interventions may prevent obesity despite severely impaired mobility in SPG11.

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Mutations in SPG11, encoding spatacsin, constitute the major cause of autosomal recessive Hereditary Spastic Paraplegia (HSP) with thinning of the corpus callosum. Previous studies showed that spatacsin orchestrates cellular traffic events through the formation of a coat-like complex and its loss of function results in lysosomal and axonal transport impairments. However, the upstream mechanisms that regulate spatacsin trafficking are unknown. Here, using proteomics and CRISPR/Cas9-mediated tagging of endogenous spatacsin, we identified a subset of 14-3-3 proteins as physiological interactors of spatacsin. The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation of spatacsin at Ser1955, which initiates spatacsin trafficking from the plasma membrane to the intracellular space. Our study provides novel insight in understanding spatacsin physio-pathological roles with mechanistic dissection of its associated pathways.

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BACKGROUND: SPG11-linked hereditary spastic paraplegia is characterized by multisystem neurodegeneration leading to a complex clinical and yet incurable phenotype of progressive spasticity and weakness. Severe cognitive symptoms are present in the majority of SPG11 patients, but a systematic and multidimensional analysis of the neuropsychological phenotype in a larger cohort is lacking. While thinning of the corpus callosum is a well-known structural hallmark observed in SPG11 patients, the neuroanatomical pattern of cortical degeneration is less understood. We here aimed to integrate neuropsychological and brain morphometric measures in SPG11. METHODS: We examined the neuropsychological profile in 16 SPG11 patients using a defined neuropsychological testing battery. Long-term follow up testing was performed in 7 patients. Cortical and subcortical degeneration was analyzed using an approved, artificial intelligence based magnetic resonance imaging brain morphometry, comparing patients to established reference values and to matched controls. RESULTS: In SPG11 patients, verbal fluency and memory as well as frontal-executive functions were severely impaired. Later disease stages were associated with a global pattern of impairments. Interestingly, reaction times correlated significantly with disease progression. Brain morphometry showed a significant reduction of cortical and subcortical parenchymal volume following a rostro-caudal gradient in SPG11. Whereas performance in memory tasks correlated with white matter damage, verbal fluency measures showed strong associations with frontal and parietal cortical volumes. CONCLUSIONS: The present data will help define neuropsychological and imaging read out parameters in early as well as in advanced clinical stages for future interventional trials in SPG11.

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This is a unique case of SPG11 mutation presenting as childhood onset dystonic tremor without weakness or spastic paraplegia. Hereditary spastic paraplegia is the most common phenotype of SPG11 mutation though there are reports of an extended phenotype of SPG11 including dopa-responsive dystonia and tremor.

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SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.

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BACKGROUND: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts, and more than 80 HSP loci have been mapped to cause HSP. In this study, we aim to perform a genetic and clinical study of ten (6 male, 4 female) sporadic Chinese HSP patients. METHODS: Next-generation sequencing (NGS) gene panels combined with multiplex ligation-dependent probe amplification assay (MLPA) analysis and the trinucleotide repeat dynamic mutation detection are available for the ten patients. RESULTS: Among the 10 patients, one SPG7 patient, one SPG11 patient, and one pure SPG31 patient were detected. Two variants (deletion of exon 3-9 of SPG7 gene and the heterozygous mutation c.1861C > T/p.Q621* of SPG11 gene) were novel and three (c.1150_1150 + 1insCTAC/p.G384Afs*13 in SPG7 gene, c.3075dupA/p.E1026Rfs*4 in SPG11 gene, and c.478delA/p.R160Gfs*63 of REEP1 gene/SPG31) were previously reported. The SPG11 patient presented mild intellectual with peripheral neuropathy and thin corpus callosum (TCC) with no white matter abnormalities (WMA). The SPG7 patient detected in this study is the third SPG7 family reported in China; he manifested peripheral neuropathy, scoliosis, and polydactyly which expand the phenotype spectrum of SPG7. CONCLUSIONS: The AAO overlapped among each HSP subtype, which limited the ability to predict the subtype of HSP from AAO. Compared with non-Asian patients, the mutation frequency of SPG7 is relatively low in Asian populations. Considering the varieties of mutation types of HSP, we suggested targeted sequencing gene panels should be combined with MLPA for diagnosis of HSP.

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Individuals with hereditary spastic paraplegia (HSP) are known to present with a variety of symptoms, including intellectual disability, cognitive decline, parkinsonism, and epilepsy. We report here our experience of treating a family with consanguinity, including three patients with HSP-related symptoms. We performed whole-exome sequencing and identified a novel pathogenic nonsense variant, c.4544G > A, p.W1515*, in the SPG11 gene. Proband and her affected sister showed the same course of gait disturbance due to spastic paraplegia from childhood and progressive cognitive decline from early adulthood. Brain MRI depicted a thinning of the corpus callosum, severe atrophic changes in the frontotemporal lobes, and ears of the lynx sign. Patients with SPG11 variants clinically present with distinctive symptoms.

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OBJECTIVE: To retrospectively report prVEPs in SPG11 ARHSP-TCC. BACKGROUND: ARHSPTCC is characterized by a thin corpus callosum, progressive spastic paraparesis, cognitive decline,and axonal neuropathy by SPG11 mutations. Additionally, seizures, cerebellar ataxia, speech and swallowing problems, extrapyramidal signs, and skeletal deformities may occur. Neuroradiological findings include thinning of the anterior corpus callosum (TCC), periventricular white matter changes, and cortical atrophy. Electromyography and nerve conduction studies may reveal axonal neuropathy or anterior horn involvement. However, optic nerve involvement and prVEPs have not been well described. DESIGN/METHODS: Routine prVEPs were performed in 11 subjects with genetically confirmed (Athena Diagnostic USA) SPG11 ARHSPTCC. Independent stimulation of each eye with a full-field checkerboard pattern reverse stimulation technique was performed. Repetitive waveforms were averaged and the P-100 was recorded. RESULTS: Eleven subjects aged 20 to 37 years were studied, 5 were female. Nine were from consanguineous parents. Nine had a family history and 3 pairs were siblings. Nine had TCC, 8 had diffuse brain atrophy and 1 had cerebellum and brainstem atrophy. Additionally, 9 had bilaterally abnormal prVEPs. The mean P100 latency of the left eye was 129.45 ms±19.47, and a mean amplitude of 7 µV±2.33, while the right had a mean P100 of 127.72 ms±12.69, and mean amplitude of 6.74 µV±2.84. CONCLUSIONS: Abnormal prVEPs occurred in 81.82% of our subjects with significantly prolonged P100 bilateral responses. This indicates that the visual pathway is affected in patients with SPG11 ARHSPTCC. However, no specific mutation was predominant. prVEPs should be considered in the routine evaluation for spastic paraparesis.

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BACKGROUND: The detailed neuropathological features of patients with autosomal recessive hereditary spastic paraplegia with a thin corpus callosum (TCC) and SPG11 mutations are poorly understood, as only a few autopsies have been reported. Herein, we describe the clinicopathological findings of a patient with this disease who received long-term care at our medical facility. CASE PRESENTATION: A Japanese man exhibited a mild developmental delay in early childhood and intellectual disability, followed by the appearance of a spastic gait by age 13. At the age of 25 years, he became bedridden and needed a ventilator. Genetic analysis revealed a homozygous splice site variant in the SPG11 gene (c. 4162-2A > G) after the provision of genetic counselling and acquisition of informed consent from his parents. He died of pneumonia at the age of 44. His brain weighed 967 g and was characterized by a TCC, and his spinal cord was flattened. Microscopically, degeneration was observed in the posterior spinocerebellar tract, the gracile fasciculus, and the posterior column in addition to the corticospinal tract. Marked neuronal loss and gliosis were observed in the anterior horn, Clarke's column, and hypoglossal and facial nuclei. Various types of neurons, in addition to motor neurons, showed coarse eosinophilic granules that were immunoreactive for p62. The loss of pigmented neurons with gliosis was apparent in both the substantia nigra and locus coeruleus. Lateral geniculate body degeneration was a characteristic feature of this patient. Furthermore, peripheral Lewy body-related α-synucleinopathy and scattered α-synuclein-immunoreactive neurites in the locus coeruleus and reticular formation of the brainstem were observed. CONCLUSIONS: In patients with hereditary spastic paraplegia with SPG11 mutations, a variety of clinical phenotypes develop due to widespread lesions containing p62-immunoreactive neuronal cytoplasmic inclusions. We herein report the lateral geniculate body as another degenerative site related to SPG11-related pathologies that should be studied in future investigations.

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The dysregulation of circular RNA (circRNA) has been monitored in osteoarthritis (OA) cartilage, hinting that circRNA deregulation modulates OA progression. We thus aimed to unveil the role of circRNA spastic paraplegia 11 (circ_SPG11) in OA conditions. The upregulation of circ_SPG11 was observed in OA cartilage and IL-1ß-treated chondrocytes. Knockdown of circ_SPG11 restored IL-1ß-depleted cell proliferation and alleviated IL-1ß-induced cell apoptosis and ECM degradation. Circ_SPG11 bound to miR-665 and negatively regulated miR-665 expression. Inhibition of miR-665 reversed the inhibitory effect on IL-1ß-induced chondrocyte injury caused by circ_SPG11 knockdown. GREM1 was a target of miR-665, and circ_SPG11 knockdown depleted GREM1 expression by enriching miR-665. Overexpression of GREM1 also reversed the inhibitory effect on IL-1ß-induced chondrocyte injury caused by miR-665 enrichment. Circ_SPG11 might promote IL-1ß-induced chondrocyte apoptosis and ECM degradation via increasing GREM1 expression by decoying miR-665.

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Pathogenic variants in SPG11 are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs. To investigate whether mitochondrial pathology is present in SPG11, we differentiated MNs from induced pluripotent stem cells derived from SPG11 patients and controls. MN derived from human embryonic stem cells and an isogenic SPG11 knockout line were also included in the study. Morphological analysis of mitochondria in the MN soma versus neurites revealed specific alterations of mitochondrial morphology within SPG11 neurites, but not within the soma. In addition, impaired mitochondrial membrane potential was indicative of mitochondrial dysfunction. Moreover, we reveal neuritic aggregates further supporting neurite pathology in SPG11. Correspondingly, using a microfluidic-based MN culture system, we demonstrate that axonal mitochondrial transport was significantly impaired in SPG11. Overall, our data demonstrate that alterations in morphology, function, and transport of mitochondria are an important feature of axonal dysfunction in SPG11 MNs.

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BACKGROUND: Osteoarthritis (OA) is responsible for the impotent disability in old people. Circular RNA (circRNA) has been reported to be related to the development of diseases. The lack of research on the role of circRNA spastic paraplegia 11 (circ-SPG11) results in conducting this study. METHODS: The expression of circ-SPG11, microRNA-337-3p (miR-337-3p), and aggrecanases like a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used to measure the protein expression of extracellular matrix (ECM) degradation-related markers and ADAMTS5. Ribonuclease R (RNase R) was applied to test the stability of circ-SPG11 in CHON-001 cells. The viability, apoptosis, TNF-α and IL-6 production were determined by cell counting kit-8 (CCK-8) assay, flow cytometry assay, and enzyme-linked immunosorbent assay (ELISA), respectively. Meanwhile, the interaction between miR-337-3p and circ-SPG11 or ADAMTS5 was respectively predicted by Circinteractome or Starbase2.0, which was further verified by dual-luciferase reporter system and RNA binding protein immunoprecipitation (RIP) assay. RESULTS: Circ-SPG11 and ADAMTS5 were upregulated and miR-337-3p was downregulated in OA tissues and OA model cells. Circ-SPG11 knockdown allayed interleukin 1ß (IL-1ß)-induced restraint in viability and promotion in apoptosis, TNF-α, and IL-6 generation and ECM degradation in CHON-001 cells. Anti-miR-337-3p or ADAMTS5 overexpression correspondingly reversed si-circ-SPG11 or miR-337-3p overexpression-mediated facilitation in viability, and inhibition in apoptosis, TNF-α and IL-6 generation and ECM degradation in OA model cells. Moreover, anti-miR-337-3p ameliorated si-circ-SPG11-mediated inhibition in ADAMTS5 mRNA and protein expression in OA model cells. CONCLUSION: Circ-SPG11 facilitated OA development via regulating miR-337-3p/ADAMTS5 axis. This finding might contribute to the improvement of OA therapy.

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Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype of autosomal recessive hereditary spastic paraplegia (HSP), to date, there are more than 181 different KIAA1840 gene mutations detected, and yet the genetic landscape of SPG11 is far from complete. To find the clinical and genetic characteristics of SPG11, we performed a reanalysis of the clinical features and genotype-phenotype correlations in all reported studies exhibiting SPG11 mutations. A total of 339 patients were collected, their mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and mental retardation (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%). The most common brain MRI abnormality is thinning of the corpus callosum (TCC) (173/190, 91.05%), followed by periventricular white matter changes (130/158, 82.28%), cerebral or cerebellar cortical atrophy (55/107, 51.40%). The mutational spectrum associated with KIAA1840 gene is wide, and frameshift mutations are the most common type followed by nonsense mutations. Our reanalysis demonstrated that SPG11 exhibited significant clinical and genetic heterogeneity, and no clear genotype-phenotype correlation was observed. There is no mutational hot spot in the KIAA1840 gene, which emphasizes the need to analyse the whole gene in clinical practice. In addition to conventional genetic testing methods, further mRNA analysis should be conducted on some cases to yield a definitive diagnosis.

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