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Item does not contain fulltext, BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutieres syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.

Item does not contain fulltext, BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutieres syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.

Item does not contain fulltext, BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutieres syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.

Hintergrund: Ein Neugeborenen-Screening auf konnatale Cytomegalie-Infektionen (CMV) existiert bisher nicht. Zur Thematik CMV assoziierter sowie progredienter Hörstörungen von Neugeborenen soll der folgende Fall zur Diskussion gestellt werden.Material und Methoden: Wir berichten über ein Mädchen, bei welchem im Alter von zwei Wochen im Rahmen des Neugeborenenhörscreenings (NHS) die transitorisch evozierten Otoakustischen Emissionen (TEOAE) lediglich rechts nachweisbar waren. Eine Hirnstammaudiometrie (BERA) erfolgte im Alter von acht Wochen im Spontanschlaf sowie im Alter von sechs und zehn Monaten in Vollnarkose (ITN). Neben der humangenetischen Untersuchung auf Connexin 26 und 30 Genmutationen fanden serologische Untersuchungen hinsichtlich einer CMV-Infektion statt.Ergebnisse: Im Alter von acht Wochen konnte hirnstammaudiometrisch im Spontanschlaf rechts eine Hörschwelle bei 60 dB gesichert werden. Links waren bis 70 dB keine Antworten nachzuweisen. Im Alter von sechs Monaten wurden in ITN eine Adenotomie sowie beidseitige Paukendrainage bei Mukotympanon mit anschließender Hirnstammaudiometrie durchgeführt. Nun waren beidseits bis 90 dB keine Reizantworten mehr vorhanden. Im zehnten Lebensmonat wurde nach sicherer Abheilung der Ohren durch eine erneute BERA eine beidseitige Surditas in ITN bestätigt. Es fanden sich keine Hinweise auf Genmutationen jedoch ein erhöhter CMV-IgG-Titer beim Kind sowie bei der Mutter. Zudem erwies sich das Mädchen mit dem Nachweis von CMV-DNA im Urin, Speichel und Blut als Dauerausscheider. Eine Augenbeteiligung konnte ausgeschlossen werden. Nach einer initial probatorischen Hörgeräteversorgung wurde das Kind mit Cochleaimplantaten (CI) versorgt.Diskussion: Bei dem Mädchen stellt sich eine progrediente Hörstörung in den ersten Lebensmonaten unter hoher CMV-Last dar. Sowohl vor dem Hintergrund CMV assoziierter Hörstörungen als auch vor dem Hintergrund der möglichen Progredienz unter CMV-Last wäre die frühe Erkennung einer CMV-Infektion w

Hintergrund: Ein Neugeborenen-Screening auf konnatale Cytomegalie-Infektionen (CMV) existiert bisher nicht. Zur Thematik CMV assoziierter sowie progredienter Hörstörungen von Neugeborenen soll der folgende Fall zur Diskussion gestellt werden.Material und Methoden: Wir berichten über ein Mädchen, bei welchem im Alter von zwei Wochen im Rahmen des Neugeborenenhörscreenings (NHS) die transitorisch evozierten Otoakustischen Emissionen (TEOAE) lediglich rechts nachweisbar waren. Eine Hirnstammaudiometrie (BERA) erfolgte im Alter von acht Wochen im Spontanschlaf sowie im Alter von sechs und zehn Monaten in Vollnarkose (ITN). Neben der humangenetischen Untersuchung auf Connexin 26 und 30 Genmutationen fanden serologische Untersuchungen hinsichtlich einer CMV-Infektion statt.Ergebnisse: Im Alter von acht Wochen konnte hirnstammaudiometrisch im Spontanschlaf rechts eine Hörschwelle bei 60 dB gesichert werden. Links waren bis 70 dB keine Antworten nachzuweisen. Im Alter von sechs Monaten wurden in ITN eine Adenotomie sowie beidseitige Paukendrainage bei Mukotympanon mit anschließender Hirnstammaudiometrie durchgeführt. Nun waren beidseits bis 90 dB keine Reizantworten mehr vorhanden. Im zehnten Lebensmonat wurde nach sicherer Abheilung der Ohren durch eine erneute BERA eine beidseitige Surditas in ITN bestätigt. Es fanden sich keine Hinweise auf Genmutationen jedoch ein erhöhter CMV-IgG-Titer beim Kind sowie bei der Mutter. Zudem erwies sich das Mädchen mit dem Nachweis von CMV-DNA im Urin, Speichel und Blut als Dauerausscheider. Eine Augenbeteiligung konnte ausgeschlossen werden. Nach einer initial probatorischen Hörgeräteversorgung wurde das Kind mit Cochleaimplantaten (CI) versorgt.Diskussion: Bei dem Mädchen stellt sich eine progrediente Hörstörung in den ersten Lebensmonaten unter hoher CMV-Last dar. Sowohl vor dem Hintergrund CMV assoziierter Hörstörungen als auch vor dem Hintergrund der möglichen Progredienz unter CMV-Last wäre die frühe Erkennung einer CMV-Infektion w

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

1 juni 2010, Contains fulltext : 88083.pdf (publisher's version ) (Closed access), Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder.

01 juni 2010, Contains fulltext : 88083.pdf (publisher's version ) (Closed access), Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder.

01 juni 2010, Contains fulltext : 88083.pdf (publisher's version ) (Closed access), Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder.