Evidence map›Paper›PMID 42135902›Full record

ArticleAnnals of clinical and translational neurology2026

Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy.

Rotem Orbach, Sandra Donkervoort, Carola Hedberg-Oldfors, Giovanni Baranello, Dimah Saade, Precilla D'Souza, Ruchee Patel, Eva Michael, A Reghan Foley, Diana Bharucha-Goebel and 14 more

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Article in Annals of clinical and translational neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Rotem OrbachNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID https://orcid.org/0000-0002-1015-1529
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID https://orcid.org/0000-0001-6399-1444
Carola Hedberg-OldforsDepartment of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.ORCID https://orcid.org/0000-0002-7141-4185
Giovanni BaranelloDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, London, UK.
Dimah SaadeDepartment of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Precilla D'SouzaNIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Ruchee PatelNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Eva MichaelDepartment of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.ORCID https://orcid.org/0000-0002-8483-2028
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID https://orcid.org/0000-0003-2168-1119
Diana Bharucha-GoebelNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
S Jin HauglandNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Meghan McAnallyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Omer Abdul HamidDepartment of Pediatrics, Nemours Children's Health, Orlando, Florida, USA.
Katherine ChaoProgram in Medical and Population Genetics, Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Ellen F MacnamaraNIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Alan H BeggsDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.ORCID https://orcid.org/0000-0001-8818-0568
Anna SarkozyThe Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK.
Juliane MuellerThe Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK.ORCID https://orcid.org/0009-0005-9831-8926
Steven A MooreDepartment of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Richard S FinkelCenter for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Cynthia J TifftNIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Francesco MuntoniDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, London, UK.
Anders OldforsDepartment of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID https://orcid.org/0000-0002-5930-2324

Funding

Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
Muscular Dystrophy Specialized Research Center: Project 2P50NS053672 · NINDS · UNIVERSITY OF IOWA · PI KEVIN P. CAMPBELL · 2020 to 2026
$11.9M
A powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9M
NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NIH HHS P50NS053672NINDS NIH HHS P50 NS053672Vetenskapsrådet 2021-02109
6 · The paper itself

Abstract

objectiveSRPK3/TTN-digenic myopathy was recently established as a skeletal muscle myopathy caused by digenic inheritance. This study characterizes the early clinical presentation of SRPK3/TTN-digenic myopathy in one previously reported and seven newly identified pediatric patients.

methodsNext generation sequencing and deep clinical phenotyping provide detailed genetic, clinical, imaging, and histopathological characterization of SRPK3/TTN-digenic myopathy.

resultsFrom the cohort of eight male patients (5-19 years at last evaluation), five presented prenatally with reduced fetal movements. At the time of birth, five had hypotonia, two had contractures, and two had respiratory distress. All patients demonstrated motor delay and muscle weakness within the first 15 months of life. Independent ambulation was achieved in six patients (ages 1.5-4 years); three could run. Variable respiratory compromise was documented as early as 5 years of age, with one patient requiring non-invasive nocturnal ventilation support. Cardiac evaluation was normal in all except one patient who had left ventricular non-compaction cardiomyopathy. Muscle MRI demonstrated mild, slowly progressive fibroadipose replacement of muscle with striking early selective involvement of the semitendinosus muscle. Histopathologic and ultrastructural features mimicked TTN-related myopathy (titinopathy), showing abnormal fiber size variation, increased internally placed nuclei, type 1 fiber predominance, and cores/minicores.

interpretationThis work highlights the early clinical manifestations of SRPK3/TTN-digenic myopathy and demonstrates early muscle imaging patterns and histopathological features that are indistinct from those observed in monogenic biallelic titinopathy cases. These features could help with the potentially challenging interpretation of digenic SRPK3 and TTN variants to allow for a confident clinical diagnosis of this novel congenital myopathy.

Indexed as

congenital myopathydigenicmuscle MRImuscle‐specific protein kinasetitin

Identifiers

PMID42135902
PMCPMC13394633

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.