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1.
Clin Neuropathol ; 31(3): 127-34, 2012.
Article in English | MEDLINE | ID: mdl-22551916

ABSTRACT

We report a case of iatrogenic Creutzfeldt-Jakob disease(iCJD) in a child with a neonatal growth hormone (GH) deficiency that was treated with native human growth hormone (hGH) between the ages of 9 months and 7 years. Three years after the end of treatment a progressive neurological syndrome consistent with Creutzfeldt-Jakob disease (CJD) developed, leading to death within a year, at age 11. Neuropathological examination showed an unusual widespread form of CJD, notably characterized by (i) involvement of the cerebellar white matter, (ii) cortico-spinal degeneration and (iii) ballooned neurons. A transitional form of the disease between common iatrogenic and panencephalopathic CJD is suggested.


Subject(s)
Brain/pathology , Creutzfeldt-Jakob Syndrome/pathology , Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , Child , Creutzfeldt-Jakob Syndrome/drug therapy , Fatal Outcome , Humans , Male
2.
Am J Hum Genet ; 81(4): 713-25, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17846997

ABSTRACT

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.


Subject(s)
Basal Ganglia Diseases/genetics , Adolescent , Adult , Basal Ganglia Diseases/cerebrospinal fluid , Basal Ganglia Diseases/pathology , Brain/pathology , Calcinosis/genetics , Calcinosis/pathology , Chilblains/genetics , Chilblains/pathology , Child , Child, Preschool , DNA Mutational Analysis , Exodeoxyribonucleases/genetics , Female , Humans , Infant , Infant, Newborn , Lymphocytosis/cerebrospinal fluid , Lymphocytosis/genetics , Male , Molecular Sequence Data , Mutation , Phenotype , Phosphoproteins/genetics , Ribonuclease H/genetics , Syndrome
3.
Eur J Hum Genet ; 15(4): 463-72, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17264864

ABSTRACT

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.


Subject(s)
Calcium Channels, T-Type/genetics , Calcium Channels/genetics , Chromosome Mapping , Chromosomes, Human, Pair 16/genetics , Epilepsy, Absence/genetics , Genetic Predisposition to Disease , Linkage Disequilibrium/genetics , Female , Genetic Markers/genetics , Humans , Male , Microsatellite Repeats/genetics , Pedigree , Polymorphism, Single Nucleotide , Seizures
4.
Am J Med Genet A ; 138A(3): 288-93, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-16158442

ABSTRACT

Intrachromosomal insertions are uncommon rearrangements, in which a chromosomal segment is intercalated into another part of the same chromosome. The insertion may occur in the same arm (paracentric) or in the other arm (pericentric). The cytogenetic recognition of these structurally rearranged chromosomes can be difficult, and intrachromosomal insertions can be easily mistaken for inversions. We describe a case of a familial pericentric insertion of chromosome 20, initially misdiagnosed as a pericentric inversion in the healthy carrier and then reinterpreted as insertion in an abnormal child with a recombinant chromosome. Fluorescence in situ hybridization (FISH) allowed us to confirm the mechanism of recombinant formation and to locate the three breakpoints precisely. Our cytogenetically unbalanced epileptic patient carried a 20q deletion and 20p duplication, and the genes, CHRNA4 and KCNQ2 that have been implicated in autosomal dominant epilepsy, were deleted. The haplo-insufficiency of these two genes may contribute to the cause of epilepsy in patients with ring chromosome 20.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Breakage , Chromosomes, Human, Pair 20/genetics , Epilepsy/genetics , Abnormalities, Multiple/diagnosis , Child , Child, Preschool , Chromosome Inversion , Cryptorchidism/diagnosis , Cryptorchidism/genetics , Diagnosis, Differential , Epilepsy/diagnosis , Genetic Markers , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Male , Microcephaly/diagnosis , Microcephaly/genetics , Recombination, Genetic
5.
Brain Dev ; 27(3): 201-6, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15737701

ABSTRACT

Aicardi-Goutieres syndrome is a familial progressive early onset encephalopathy with basal ganglia calcifications, chronic CSF lymphocytosis and high level of interferon-alpha in CSF. Cutaneous necrotic lesions and the neuropathological aspect of microangiopathy and microinfarctions suggest a vascular process in relation to elevated interferon-alpha. A genetic defect in the regulation of its synthesis may be the causal factor of the disorder.


Subject(s)
Basal Ganglia Diseases , Calcinosis , Interferon-alpha/cerebrospinal fluid , Lymphocytosis , Basal Ganglia Diseases/cerebrospinal fluid , Basal Ganglia Diseases/genetics , Basal Ganglia Diseases/pathology , Brain/pathology , Calcinosis/cerebrospinal fluid , Calcinosis/genetics , Calcinosis/pathology , Diagnosis, Differential , Humans , Infant , Infant, Newborn , Lymphocytosis/cerebrospinal fluid , Lymphocytosis/genetics , Lymphocytosis/pathology , Necrosis/pathology , Skin Diseases/cerebrospinal fluid , Skin Diseases/pathology
6.
Epilepsy Res ; 48(3): 169-79, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11904235

ABSTRACT

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by onset of typical absence seizures in otherwise normal children of school age. A genetic component to aetiology is well established but the mechanism of inheritance and the genes involved are unknown. Available evidence suggests that mutations in genes encoding GABA receptors or brain expressed voltage-dependent calcium channels (VDCCs) may underlie CAE. The aim of this work was to test this hypothesis by linkage analysis using microsatellite loci spanning theses genes in 33 nuclear families each with two or more individuals with CAE. Seventeen VDCC subunit genes, ten GABA(A)R subunit genes, two GABA(B) receptor genes and the ECA1 locus on 8q24 were investigated using 35 microsatellite loci. Assuming locus homogeneity, all loci gave statistically significant negative LOD scores, excluding these genes as major loci in the majority of these families. Positive HLOD scores assuming locus heterogeneity were observed for CACNG3 on chromosome 16p12-p13.1 and the GABRA5, GABRB3, GABRG3 cluster on chromosome 15q11-q13. Association studies are required to determine whether these loci are the site of susceptibility alleles in a subset of patients with CAE.


Subject(s)
Calcium Channels/genetics , Chromosomes, Human, Pair 8/genetics , Epilepsy, Absence/genetics , Genetic Linkage/genetics , Receptors, GABA-A/genetics , Receptors, GABA-B/genetics , Female , Genetic Markers/genetics , Humans , Lod Score , Male , Microsatellite Repeats/genetics , Pedigree
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