Resting muscle pain as the first clinical symptom in children carrying the MTTK A8344G mutation
Child; Female; Humans; Adult; Mutation; adolescent; Q3 Literature Search; DNA Mutational Analysis; Pedigree; DNA; Mitochondrial/genetics; MERRF Syndrome/complications/genetics/physiopathology; Muscular Diseases/etiology/genetics/physiopathology; Pain/etiology/genetics/physiopathology; Polymerase Chain Reaction
The characteristic clinical presentation, especially the appearance of muscle symptoms, is quite unique in children carrying the mtA8344G mutation. The diagnosis of MERRF syndrome is seldom made in the pediatric age. Fatigue is a common finding in children of pubertal age. Fatigue in combination with recurrent resting muscle pain occurs frequently in the initial phase of various hereditary muscle disorders and in several autoimmune, endocrine and metabolic syndromes. In the absence of obvious biochemical/metabolic abnormalities and in the lack of neurological symptoms the complaints are frequently labelled as fibromyalgia or chronic fatigue syndrome. In patients with behavioural or psychiatric abnormalities one might even start to question the organic etiology of the complaints. We describe a family carrying the classic MTTK mutation with a variable degree of heteroplasmy, presenting in childhood as isolated recurrent muscle pain as the first symptom of the disease.
2007
van de Glind G; de Vries M; Rodenburg R; Hol F; Smeitink JA; Morava E
European Journal Of Paediatric Neurology
2007
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Journal Article
<a href="http://doi.org/10.1016/j.ejpn.2007.01.004" target="_blank" rel="noreferrer">10.1016/j.ejpn.2007.01.004</a>
Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands
Child; Female; Humans; Male; Adult; Middle Aged; Mutation; Netherlands; Phenotype; adolescent; Preschool; infant; Models; Q3 Literature Search; Age of Onset; DNA Mutational Analysis; Acetyltransferases/chemistry/deficiency/genetics; DNA/genetics; Genotype; Missense; Molecular; Mucopolysaccharidosis III/classification/enzymology/genetics/physiopathology
Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene. Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between 1 and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alleles for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles. This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype.
2008
Ruijter GJ; Valstar MJ; van de Kamp JM; van der Helm RM; Durand S; van Diggelen OP; Wevers RA; Poorthuis BJ; Pshezhetsky AV; Wijburg FA
Molecular Genetics And Metabolism
2008
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1016/j.ymgme.2007.09.011" target="_blank" rel="noreferrer">10.1016/j.ymgme.2007.09.011</a>
Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations
Female; Humans; Male; Mutation; DNA Mutational Analysis; Pedigree; Chromosomes; Human; Genetics; Population; Chromosome Mapping; Haplotypes; Pair 2/genetics; Codon; Congenital/genetics; Founder Effect; Frameshift Mutation; Nonsense; Pain Insensitivity; Sequence Deletion; Sodium Channels/genetics
Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.
2007
Goldberg YP; MacFarlane J; MacDonald ML; Thompson J; Dube MP; Mattice M; Fraser R; Young C; Hossain S; Pape T; Payne B; Radomski C; Donaldson G; Ives E; Cox J; Younghusband HB; Green R; Duff A; Boltshauser E; Grinspan GA; Dimon JH; Sibley BG; Andria G; Toscano E; Kerdraon J; Bowsher D; Pimstone SN; Samuels ME; Sherrington R; Hayden MR
Clinical Genetics
2007
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Journal Article
<a href="http://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank" rel="noreferrer">10.1111/j.1399-0004.2007.00790.x</a>
Pyruvate dehydrogenase E3 binding protein (protein X) deficiency
Child; Female; Humans; Male; Severity of Illness Index; Preschool; infant; Q3 Literature Search; DNA Mutational Analysis; Protein Subunits/deficiency/genetics; Pyruvate Dehydrogenase Complex Deficiency Disease/diagnosis/genetics/metabolism; Pyruvate Dehydrogenase Complex/genetics/metabolism
Pyruvate dehydrogenase (PDH) deficiency is a major cause of neurological dysfunction and lactic acidosis in infancy and early childhood. The great majority of cases (>80%) result from mutations in the X-linked gene for the E1alpha subunit of the complex (PDHA1). Mutations in the genes for the other subunits have all been described, but only dihydrolipoamide dehydrogenase (E3) and E3 binding protein (E3BP) defects contribute significantly to the total number of patients with PDH deficiency. Although previously considered rare, with only 13 reported cases, we have found that mutations in PDX1, the gene for the E3 binding protein, are in fact relatively common. Clinical, biochemical, and genetic features of six new patients (four males, two females; age range 15mo-6y) with mutations in this gene are compared with previously reported cases. All patients with E3BP deficiency identified to date have mutations which completely prevent synthesis of the protein product. However, they are generally less severely affected than patients with PDHA1 mutations, although there is considerable overlap in clinical and neuroradiological features.
2006
Brown RM; Head RA; Morris AA; Raiman JA; Walter JH; Whitehouse WP; Brown GK
Developmental Medicine And Child Neurology
2006
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Journal Article
<a href="http://doi.org/10.1017/S0012162206001617" target="_blank" rel="noreferrer">10.1017/S0012162206001617</a>
Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey
Child; Female; Humans; Male; Outcome Assessment (Health Care); Heterozygote; adolescent; Preschool; Q3 Literature Search; Age of Onset; DNA Mutational Analysis; alpha-Galactosidase/metabolism/therapeutic use; Fabry Disease/diagnosis/drug therapy/physiopathology; Isoenzymes/therapeutic use
BACKGROUND: Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme alpha-galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. AIM: Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS--the Fabry Outcome Survey--a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). METHODS: Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. RESULTS: The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2-5 y later in girls than in boys. There was an approximately 3-y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed. CONCLUSION: Although the life-threatening complications of Fabry disease, such as stroke and renal and heart failure, are not seen in children, the present analysis shows that other symptoms are common and may have an impact on quality of life.
2006
Ramaswami U; Whybra C; Parini R; Pintos-Morell G; Mehta A; Sunder-Plassmann G; Widmer U; Beck M; FOS European Investigators
Acta Paediatrica
2006
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Journal Article
<a href="http://doi.org/10.1111/j.1651-2227.2006.tb02186.x" target="_blank" rel="noreferrer">10.1111/j.1651-2227.2006.tb02186.x</a>
Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations
Female; Humans; infant; Male; Phenotype; infant; Q3 Literature Search; Newborn; DNA Mutational Analysis; Muscle; Skeletal/pathology; Proteins/genetics; Frameshift Mutation; Cytochrome-c Oxidase Deficiency/complications/genetics/pathology; Kidney Diseases/etiology; Leigh Disease/complications/genetics/pathology; Membrane Proteins; Mitochondrial Proteins
Mutations in the SURF1 gene are the most frequent causes of Leigh disease with cytochrome c oxidase deficiency. We describe four children with novel SURF1 mutations and unusual features: three had prominent renal symptoms and one had ragged red fibers in the muscle biopsy. We identified five pathogenic mutations in SURF1: two mutations were novel, an in-frame nonsense mutation (834G-->A) and an out-of-frame duplication (820-824dupTACAT). Although renal manifestations have not been described in association with SURF1 mutations, they can be part of the clinical presentation. Likewise, mitochondrial proliferation in muscle (with ragged red fibers) is most unusual in Leigh disease but might be part of an emerging phenotype.
2005
Tay SK; Sacconi S; Akman HO; Morales JF; Morales A; De Vivo DC; Shanske S; Bonilla E; DiMauro S
Journal Of Child Neurology
2005
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Journal Article
<a href="http://doi.org/10.1177/08830738050200080701" target="_blank" rel="noreferrer">10.1177/08830738050200080701</a>
Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency
Humans; Male; Aged; Treatment Outcome; Disease Progression; Magnetic Resonance Imaging; Food; Q3 Literature Search; Brain Diseases; Age of Onset; DNA Mutational Analysis; Mutation/genetics; Metabolic; Atrophy/enzymology/genetics/physiopathology; Carnitine/therapeutic use; Cerebral Cortex/enzymology/pathology/physiopathology; Cognition Disorders/enzymology/genetics/physiopathology; Formulated; Glutaryl-CoA Dehydrogenase/deficiency; Inborn/enzymology/genetics/physiopathology; Lateral Ventricles/pathology; Movement Disorders/enzymology/genetics/physiopathology; Myelinated/pathology; Nerve Fibers
Neurologic disease in glutaryl-CoA dehydrogenase (GCDH) deficiency usually presents with acute encephalopathic crises before 2 years of age. The authors report two previously asymptomatic patients with macrocephaly presenting with progressive neurologic deterioration and a severe leukoencephalopathy during adolescence or adulthood.
2005
Kulkens S; Harting I; Sauer S; Zschocke J; Hoffmann GF; Gruber S; Bodamer OA; Kolker S
Neurology
2005
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Journal Article
<a href="http://doi.org/10.1212/01.WNL.0000167428.12417.B2" target="_blank" rel="noreferrer">10.1212/01.WNL.0000167428.12417.B2</a>
Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations
Mutation; Severity of Illness Index; Longitudinal Studies; DNA Mutational Analysis; DNA/chemistry/genetics; Endopeptidases; Neuronal Ceroid-Lipofuscinoses/genetics/pathology/physiopathology; Peptide Hydrolases/genetics/metabolism; Psychomotor Performance/physiology; Seizures/physiopathology; Vision/physiology
We examined 26 individuals with clinical and electron microscopic signs of late infantile neuronal ceroid lipofuscinosis (LINCL). In 22 cases, we found both pathogenic alleles. Sixteen patients exclusively carried either one or a combination of the two common mutations R208X and IVS5-1G > C. In the remaining cases, four missense mutations could be detected, of which R127Q, N286S, and T353P represent novel, previously not described alleles. A clinical performance score was developed by rating motor, visual, and verbal functions and the incidence of cerebral seizures in 3-month intervals during the course of the disease. A Total Disability Score was derived by summing up the single scores for motor, visual, and verbal functions. The 16 individuals with the two common mutations were grouped together (referred to as standard patients), and the 5th, 50th, and 95th centiles were calculated and graphically depicted over time. The scores for motor function and language ability dropped earliest and progressed very similarly in the standard patients. The performance curves of two children with the N286S mutation slightly diverged from the 95th centile. However, the performance curves of one patient with atypical LINCL carrying the R127Q mutation fell far beyond the 95th centile. The presented performance rating clearly and quantitatively delineates the disease course of the LINCL patients and hence offers a useful tool for clinical evaluation of future therapeutic interventions. In addition, the described performance score system can be applied to other types of neuronal ceroid lipofuscinoses and could be adapted to various other neurodegenerative diseases of childhood.
2002
Steinfeld R; Heim P; von Gregory H; Meyer K; Ullrich K; Goebel HH; Kohlschutter A
American Journal Of Medical Genetics
2002
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Journal Article
<a href="http://doi.org/10.1002/ajmg.10660" target="_blank" rel="noreferrer">10.1002/ajmg.10660</a>
A Genomewide Linkage-Disequilibrium Scan Localizes the Saguenay -Lac-Saint-Jean Cytochrome Oxidase Deficiency to 2p16
Female; Humans; Male; Mutation; Family Health; Gene Frequency; Molecular Sequence Data; DNA Mutational Analysis; DNA/chemistry/genetics; Pedigree; Chromosomes; Human; Base Sequence; Disease Specific; Chromosome Mapping; Cytochrome-c Oxidase Deficiency; Electron Transport Complex IV/genetics; Genes/genetics; Genome; Haplotypes; Leigh Disease/enzymology/genetics; Linkage Disequilibrium; Microsatellite Repeats; Pair 2/genetics; Polymorphism; Single Nucleotide
2001
Lee N; Daly MJ; Delmonte T; Lander ES; Xu F; Hudson TJ; Mitchell GA; Morin CC; Robinson BH; Rioux JD
American Journal Of Human Genetics
2001
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Journal Article
<a href="http://doi.org/10.1086/318197" target="_blank" rel="noreferrer">10.1086/318197</a>