Biomedical subjects

Már Tulinius

Publications and source records attributed to Már Tulinius.

7 recordsLinked to original sources

PubMed2007

Orofacial dysfunction in children and adolescents with myotonic dystrophy.

Myotonic dystrophy (DM) is a neuromuscular disorder caused by an expansion of a CTG repeat sequence on chromosome 19q13. The aim of the present study was to describe the characteristics and prevalence of oral motor dysfunction in a cohort of children and adolescents with DM and to correlate different aspects of oral motor function with the type of DM and sex. Fifty-six individuals with DM (30 males, 26 females; median age 13y 2mo; range 2y 6mo-21y 5mo) were compared with healthy controls. They were divided into four subgroups: severe congenital DM (n=18); mild congenital DM (n=18); childhood DM (n=18); and classical DM (n=2). A speech-language pathologist assessed different variables of oral motor function, intelligibility, and lip force. The families used a questionnaire to report on eating difficulties and drooling. All individuals with DM had impaired facial expression. Intelligibility was moderately or severely reduced in 30 patients (60%), excluding six patients without speech. Most had a moderate or severe impairment of lip motility (76.0%), tongue motility (52.2%), and lip force (69.2%), causing deviant production of bilabial and dental consonants. The families reported problems with eating (51.9%) and drooling (37.0%). Oral motor dysfunction was most prominent in congenital DM, and males were more affected than females.

Adolescent↗

PubMed2006

POLG1 mutations associated with progressive encephalopathy in childhood.

We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.

Adolescent↗

PubMed2005

Novel mutations in the thymidine kinase 2 gene (TK2) associated with fatal mitochondrial myopathy and mitochondrial DNA depletion.

We describe the clinical, morphological and genetic findings in two siblings with the myopathic form of mitochondrial DNA depletion syndrome (MIM 251880). Sequencing of the thymidine kinase-2 gene revealed two heterozygous missense mutations, a C-->T mutation at nucleotide 191 resulting in a change of threonine to methionine at residue 64 in exon 3, and a C-->T mutation at nucleotide 547 resulting in an arginine to tryptophan amino acid change at residue 183 in exon 8. Both mutations changed highly conserved residues in the gene and neither one has been described previously. This report extends the phenotypic expression of mutations in the thymidine kinase-2 gene.

Amino Acid Sequence↗

PubMed2005

Myotonic dystrophy: muscle involvement in relation to disease type and size of expanded CTG-repeat sequence.

This study aimed to: classify a cohort of children and adolescents with myotonic dystrophy (dystrophia myotonica: DM) into congenital and childhood onset forms; estimate CTG expansion size; and quantify muscle strength, contractures, and motor function in children with DM and compare results with those of controls. Participants were clinically examined, medical records were reviewed, and isometric muscle strength, contractures, and motor function were measured. Participants were: 42 children with DM (18 females, 24 males; mean age 8y 9mo [SD 4y 7mo], range 10mo to 17y) and 42 age- and sex-matched, healthy controls. Children with DM were divided into three groups: severe congenital (n=13), mild congenital (n=15), and childhood (n=14). Children with childhood DM were significantly weaker than controls (wrist and ankle dorsiflexors [p=0.0044, p=0.0044 respectively]; hip abductors and flexors [p=0.0464, p=0.0217]; and knee flexors and extensors: [p=0.0382, p=0.0033]). Children with mild congenital DM were significantly weaker than controls in all assessed muscle groups. Contractures and skeletal deformities were more frequent at time of investigation than at birth, suggesting that foot and spine deformities in particular increase over time. Motor function score was significantly lower for children with DM than for controls. Children with severe congenital DM had the lowest motor function, with correlation between motor function and size of CTG repeat (p=-0.743). Children found jumping, heel standing, and head lifting the most difficult items to perform but few had difficulty walking, running, or stair climbing. DM in children is a heterogeneous disorder with a wide spectrum of muscle involvement, and owing to increased risk of contractures and skeletal deformities, regular follow-ups are recommended.

Adolescent↗

PubMed2004

A family with pyruvate dehydrogenase complex deficiency due to a novel C>T substitution at nucleotide position 407 in exon 4 of the X-linked Epsilon1alpha gene.

UNLABELLED: The pyruvate dehydrogenase complex (PDHc; McKusick 312170), localised in the mitochondrial matrix, is a multienzyme complex which converts pyruvate to acetyl-CoA. A deficiency of PDHc leads to inadequate removal of pyruvate and lactate resulting in lactic acidaemia and insufficient energy production. The major cause of PDHc deficiency is a defect in the E1alpha component. The gene of this component is localised to Xp22.1. We describe two brothers with a relatively mild clinical phenotype of PDHc deficiency. Onset of disease was associated with muscle weakness and swallowing difficulties in both. At follow-up, the older brother developed encephalopathic features consistent with Leigh syndrome. Lactate to pyruvate ratios were low, consistent with a PDHc deficiency which was confirmed by measurements of PDHc activity in thrombocytes. A 407C>T change in exon 4 of the E1alpha gene was found in both brothers and their mother. This substitution predicts a replacement of a conserved alanine at position 136 by valine. CONCLUSION: Due to the X-linked inheritance pattern combined with the overall results of clinical investigations, molecular genetic findings and a corresponding functional deficiency of the gene product we believe that this substitution in the pyruvate dehydrogenase E1alpha gene is a mutation leading to pyruvate dehydrogenase complex deficiency in this family.

Amino Acid Substitution↗

PubMed2003

Mitochondrial encephalomyopathies.

Mitochondrial encephalomyopathies are diseases caused by defective oxidative phosphorylation (OXPHOS), and affect the nervous system and/or skeletal muscle. They have emerged as a major entity among the neurometabolic diseases of childhood with an incidence of 1 in 11,000 children, and also have a high prevalence in adults. The first pathogenic mutation of human mitochondrial DNA (mtDNA) was discovered in 1988. Since then more than 100 mutations of mtDNA have been reported, including point mutations of genes encoding transfer RNA, ribosomal RNA, and proteins, as well as large-scale deletions. The first nuclear-DNA gene mutation causing OXPHOS disease was described in 1995. Mutations in nuclear genes may affect the respiratory chain by various mechanisms. Pathogenic mutations of nuclear-DNA-encoded subunits of complex I and II have been demonstrated as have mutations of respiratory chain assembly proteins. Several nuclear genes associated with mtDNA maintenance have been found to be associated with mitochondrial disorders since mutations in these genes predispose to multiple mtDNA deletions and/or reduced copy number of mtDNA. The genotype-phenotype correlation is not yet entirely clear, but new animal models will enhance our ability to study the pathophysiology of OXPHOS disorders.

Animals↗

PubMed2002

Multiple congenital contractures: birth prevalence, etiology, and outcome.

OBJECTIVES: We wanted to estimate the birth prevalence of multiple congenital contractures (MCC), determine the cause of the MCC according to the primary level of involvement of the developing motor system, and compare the different groups in terms of inheritance, mortality, and morbidity. STUDY DESIGN: A retrospective epidemiologic study through the screening of registers, reviews of medical records, and clinical re-examinations was performed in western Sweden to identify all the children with MCC born between 1979 and 1994. RESULTS: The birth prevalence of MCC on the basis of 68 cases was 1 in 5100 live births. The majority of cases with cerebral involvement (n = 23), spinal involvement (n = 16), or mechanical restriction (n = 3) were sporadic, whereas most cases with neuromuscular (n = 12) or connective tissue involvement (n = 9) were inherited. The cerebral group was more severely affected compared with the other groups in terms of mortality, joint contractures at birth, feeding difficulties during infancy, and independent walking at follow-up. In 8 cases with myopathy, the joint contractures were normalized on follow-up. CONCLUSION: A search for a specific etiology in each case is important for genetic counseling, prognosis, and therapy because inheritance, mortality, and morbidity differ between the groups.

Contracture↗