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Bjarne Udd

Publications and source records attributed to Bjarne Udd.

At least 19 recordsLinked to original sources
PubMed2025

The burden of TTN variants in the genomic era: Analysis of 18,462 individuals from the Solve-RD consortium and general recommendations.

PURPOSE: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. METHODS: We collected data from 11,072 individuals with suspected rare diseases and 7390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. RESULTS: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high cardiac percent spliced in exon (>80%), and 4 had an overt cardiomyopathy. CONCLUSION: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in individuals with skeletal myopathy with het TTNtv. Establishing consensus on percent spliced in-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.

Humans↗
PubMed2025

Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy.

PURPOSE: Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies. METHODS: Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants. Clinical data, electrophysiology, muscle computed tomography or magnetic resonance imaging, and muscle biopsy findings were collected and standardized. SPTAN1 protein, messenger RNA expression analysis and copy DNA sequencing was performed on muscle tissue from 2 participants. RESULTS: Five families showed autosomal dominant mode of inheritance, whereas in 9 patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In 2 families, further segregation analysis was not possible. All affected participants presented with early childhood-onset distal weakness and foot abnormalities. Muscle magnetic resonance imaging or computed tomography in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense-mediated decay in muscle tissue derived from 2 patients. CONCLUSION: We present evidence linking heterozygous SPTAN1 loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.

Humans↗
PubMed2024

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets.

PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.

Humans↗
PubMed2006

Molecular biology of distal muscular dystrophies--sarcomeric proteins on top.

During the last 10 years several muscular dystrophies within the group of distal myopathies have been clarified as to the molecular genetic cause of the disease. Currently, the next steps are carried out to identify the molecular pathogenesis downstream of the gene defects. Some early ideas on what is going on in the muscle cells based on the defect proteins are emerging. However, in no single distal muscular dystrophy these efforts have yet reached the point where direct trials for therapy would have been launched, and in many distal dystrophies the causative gene is still lacking. When comparing the gene defects in the distal dystrophies with the more common proximal muscular dystrophies such as dystrophinopathies or limb-girdle muscular dystrophies, there is a striking difference: the genes for distal dystrophies encode sarcomere proteins whereas the genes for proximal dystrophies more often encode sarcolemmal proteins.

Animals↗
PubMed2006

Constitutive upregulations of titin-based signalling proteins in KY deficient muscles.

An increase in the expression of stretch/stress response elements in fast and slow muscles has been previously described in a transcriptional profiling of KY deficient muscles. Here, we have characterized the induction of this titin-based family of signalling proteins in ky/ky muscles at the protein level. Changes in expression of MLP, MARP2 and Xin have been related to the onset of dystrophic and adaptive changes that operate in ky/ky muscles. Our results indicate that induction of this set of genes is an early consequence of the interference caused by the absence of the KY protein. A search of muscle profiles of mouse models revealed such molecular hallmark only in muscles subjected to a single bout of eccentric contractions and specific titin mutants. Based on the role of this family as titin-based stress response molecules, it is suggested that titin structural/signalling instability is common to ky and titin mouse mutants and eccentric contractions.

Adaptation, Physiological↗
PubMed2006

Myotilinopathy in a family with late onset myopathy.

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.

Age of Onset↗
PubMed2006

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

Adolescent↗
PubMed2006

[Not Available].

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Journal Article↗
PubMed2005

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone.

We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.

Endoplasmic Reticulum Chaperone BiP↗
PubMed2005

Myopathy is a prominent feature in Marinesco-Sjögren syndrome: A muscle computed tomography study.

BACKGROUND: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multiorgan disorder showing clinical and genetic heterogeneity. The key features of MSS include cerebellar ataxia, early bilateral cataracts, delayed motor development, and varying degrees of mental retardation. Patients with a subtype of MSS with myoglobinuria and neuropathy have been linked to chromosome 18qter, and recently a locus for classical MSS has been localized on chromosome 5q31. OBJECTIVES: To determine the importance of myopathy in this disorder apart from the CNS based disability and to establish the pattern of muscle involvement and degree of its severity. METHODS: Muscle computed tomography (CT) investigations were carried out in nine Finnish MSS patients homozygous for markers around the MSS locus on chromosome 5q31. RESULTS: Patients with severe clinical disability showed severe and generalized muscle degeneration. Muscle CT findings in patients with relatively severe clinical picture were characterized by severe involvement of the posterior thoracic and pelvic muscles, and almost all thigh muscles. In the legs the peronei and posterior compartment muscles were severely degenerated. The group of patients with moderate severity of disease showed the same pattern of involved muscle, albeit with lower degree of muscle degeneration. CONCLUSIONS: Patients with MSS linked to chromosome 5q31 have a severe progressive myopathy, the extent of which may remain largely unrecognized because of the CNS involvement.

Adult↗
PubMed2005

Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin.

Mutations in the catalytic subunit of the mitochondrial DNA polymerase gamma (POLG) have been found to be an important cause of neurological disease. Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G. Here, we studied the frequency of this allele and found it to be among the most common genetic causes of inherited ataxia in Finland. We identified 27 patients with mitochondrial recessive ataxia syndrome (MIRAS) from 15 Finnish families, with a carrier frequency in the general population of 1 : 125. Since the mutation pair W748S+E1143G has also been described in European patients, we examined the haplotypes of 13 non-Finnish, European patients with the W748S mutation. Haplotype analysis revealed that all the chromosomes carrying these two changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common, northern haplotypes, outside the core haplotype, could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicate that this newly identified ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes.

Adult↗
PubMed2005

The kinase domain of titin controls muscle gene expression and protein turnover.

The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.

Amino Acid Sequence↗
PubMed2005

A quantitative method for the assessment of intraepidermal nerve fibers in small-fiber neuropathy.

OBJECTIVES: The purpose of this paper is to present an easy-to-use and reproducible morphometrical method of determining the density of intraepidermal nerve fibers (IENF) per epidermal area with the corresponding reference range of the IENF-counts. METHODS: Thirty patients and 22 controls were included in this study. The patients were divided into three groups: small-fiber (SFN), diabetic and demyelinating neuropathy. All subjects underwent punch skin biopsy. Specimens were fixed routinely in formalin and thereafter embedded in paraffin. Nerve fibers were revealed using immunoperoxidase staining with panaxonal antibody PGP 9.5. Using light microscopy, immunopositive nerves were counted morphometrically per epidermal area (NPEA) and, for comparison, per epidermal length (NPEL). RESULTS: Both the NPEA and NPEL estimates of SFN and diabetic neuropathy group differed significantly from those of control specimen (p < 0.001 and p < 0.001, Mann-Whitney test). Our method of counting, NPEA, shows a good correlation to NPEL (r = 0.945). CONCLUSIONS: IENF-counting by a new morphometric modification is reproducible and diagnostically sensitive and can easily be adopted in any laboratory familiar with the basic immunohistochemical methodology. The method is less dependent on costly technical support systems and seems to be less time consuming when compared with conventional methods for IENF-counting.

Biopsy, Needle↗
PubMed2005

Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T-->C mutation.

The 8993T-->C mutation in mitochondrial DNA (mtDNA) has been described previously to be associated with infantile- or childhood-onset phenotypes, ranging from Leigh's syndrome to neurogenic weakness, ataxia, and retinitis pigmentosa syndrome. We report a kindred with adult-onset slowly progressive ataxia and polyneuropathy and with the heteroplasmic 8993T-->C mutation. Our findings suggest that the 8993T-->C mtDNA mutation should be considered in the differential diagnosis of nondominant adult-onset ataxia and axonal neuropathy.

Adult↗
PubMed2004

Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3).

We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence.

Adult↗
PubMed2003

Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.

Base Sequence↗