- Email: [email protected]
PP6.5 – 1922 Incidental findings in array CGH
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E U R O P E A N JO U R N A L O F PAEDIATRIC N E U R O L O G Y
leukoencephalopathy aspect, calcifications and severe atrophy. Laboratory results (blood and urinary phosphorus and calcium, serum total parathormone, lactate, pyruvate, amino and organic acid chromatography) permitted to exclude common and rare causes of basal ganglia calcifications. TORCH serology was negative. Analysis of the CSF was performed searching increased levels of INF-alpha. AGS is a genetic disease with a severe clinical picture. It can be misdiagnosed as a congenital infection or, unless a brain CT scan is performed, as a leukoencephalopathy of unknown origin. Current studies aiming to clarify the molecular mechanisms underlying the pathogenesis of AGS could lead to the development of new therapeutic strategies.
PP6.5 - 1922 Incidental findings in array CGH Keymolen K, De Rademaeker M, Van Den Bogaert A. Center for Medical Genetics, UZ Brussel, VUB, Belgium – [email protected] Array Comparative Genomic Hybridization (array CGH) is nowadays widely used in the diagnostic work-up of intellectual disability, congenital anomalies and psychiatric disorders. In contrast with the standard karyotype, it allows us to pick up microdeletions - and duplications, thus increasing the number of patients for which the etiology of their problem can be demonstrated. In few cases, the array CGH result also uncovers susceptibility to serious late(r)-onset disorders, such as hereditary cancer syndromes. Although the risk for such an incidental finding is low, the physician who prescribes the analysis should be aware of this possibility and should inform the patient and/or the parents before the test is undertaken. In case of a parentally inherited aberration, the carrier parent is equally at risk for the concerned disorder and pretesting counseling should address this item too. We will illustrate the possibility of incidental findings on array CGH with two cases. The first patient is an infant with congenital anomalies and severe hypotonia. Array CGH analysis reveals a 23Mb deletion of 5q22.1q23.1. This region includes the APC gene, responsible for Familial Adenomatous Polyposis. This child will thus require close gastrointestinal follow-up from the age of 10 years on. Since the deletion is de novo, the parents are not at increased risk. The second patient is a girl with bilateral aniridia. She has a 15 Mb deletion on 11p14.1p11.2, encompassing the PAX 6 gene, which explains the ocular phenotype. However, the deletion also includes the WT1 gene, involved in renal neoplasia. Close monitoring allowed the early detection and treatment of a kidney tumor in the child. Conclusion: we want to draw the attention of the prescriber of array CGH to the small but existing risk of incidental findings with important consequences for the patient. Pretest information is therefore mandatory.
PP6.6 - 1797 Isolated complex I deficiency and atypical clinical courses in three patients due to novel mutations in NDUFS1 and NDUFV1 Björkman K, Sofou K, Darin N, Kollberg G, Holme E, Tulinius M, Oldfors A, Moslemi AR. The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Göteborg, Sweden – [email protected] Objectives: To report three patients with atypical clinical course, to add to our understanding of genotype-phenotype correlations in genes encoding complex I electron input module subunits. Material and methods: Three patients with isolated complex I deficiency. One girl, patient 1, who presented at birth with hypotonia and feeding difficulties, and died at 5 weeks of age. Two sisters, patients 2 and 3, who presented at 6–7 months of age with progressive muscle weakness and delayed motor development, and have since showed a mild clinical course with long life
17s (2013) S1 – S149
span and normal mental development. Results: Metabolic findings indicated isolated complex I deficiency. Molecular genetic analysis showed compound heterozygosity for two novel point mutations in NDUFS1 for patient 1 and compound heterozygosity for two novel point mutations in NDUFV1 for patients 2 and 3. A literature review of all reported cases of mutations in the affected genes (NDUFS1, 12 patients; NDUFV1, 14 patients) showed that the clinical course of these three patients was atypical with regard to other patients described with mutations in corresponding genes. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a shorter life span than patients with NDUFV1 mutation. Even considering this, the reported patients show that atypical clinical courses occur. Identifying the mutations is of importance for accurate genetic counseling. Compund heterozygosity due to the combination of a null mutation and a milder missense mutation may predict a more severe phenotype compared to the combination of two milder missense mutations.
PP6.7 - 1623 Acute liver failure in patients with POLG1 mutations after valproate exposure and their prognosis after liver transplantation Hynynen J, Komulainen T, Tukiainen E, Nordin A, Arola J, Kälviäinen R, Jutila L, Röyttä M, HInttala R, Suomalainen A, Majamaa K, Mäkisalo H, Uusimaa J. University of Oulu, Oulu University Hospital, Finland – johanna.uusimaa@oulu.fi Objectives: Patients with mutations in POLG1 gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma have an increased risk for valproate- induced liver failure. The role of liver transplantation for patients with mitochondrial diseases has been controversial. We studied the development of valproateinduced liver failure in patients with POLG1 mutations and the prognosis after possible liver transplantation. Methods: Patients with severe valproate-induced liver failure were retrospectively identified from the register at the Department of Transplantation and Liver Surgery, Helsinki University Hospital, Finland (880 liver transplantations since 1988). Liver transplantation and clinical follow-up had been conducted according to routine procedure. POLG1 was analyzed in blood DNA and the mtDNA content in patient and control liver samples was quantified by using real-time quantitative PCR. Results: Five out of six patients with valproateinduced liver failure (at 13–34 years) were identified (one patient with reversible liver failure was not studied). Four patients had mtDNA depletion in liver associated with homozygous POLG1 p. W748S and p. E1143G mutations; one being also heterozygous for p. Q497H mutation. One patient had died due to intractable status epilepticus and liver failure without transplantation. Three patients with liver transplant are alive and have survived 4–19 years. One patient has chronic pancreatic insufficiency. Neurological manifestations include ataxia, peripheral neuropathy and occasional epileptic seizures; one patient has been seizure free for 11 years. Furthermore, one patient with a heterozygous POLG1 p. Q1236H mutation without mtDNA depletion in liver died suddenly two years after the liver transplantation. Conclusions: Consistent with the recent finding a heterozygous POLG1 p. Q1236H mutation was related to valproate-induced liver failure without mtDNA depletion whereas patients homozygous for POLG1 p. W748S and p. E1143G mutations have mtDNA depletion. We emphasize that POLG1 gene analysis should be performed for all patients with acute liver failure following valproate treatment.
E U R O P E A N JO U R N A L O F PAEDIATRIC N E U R O L O G Y
leukoencephalopathy aspect, calcifications and severe atrophy. Laboratory results (blood and urinary phosphorus and calcium, serum total parathormone, lactate, pyruvate, amino and organic acid chromatography) permitted to exclude common and rare causes of basal ganglia calcifications. TORCH serology was negative. Analysis of the CSF was performed searching increased levels of INF-alpha. AGS is a genetic disease with a severe clinical picture. It can be misdiagnosed as a congenital infection or, unless a brain CT scan is performed, as a leukoencephalopathy of unknown origin. Current studies aiming to clarify the molecular mechanisms underlying the pathogenesis of AGS could lead to the development of new therapeutic strategies.
PP6.5 - 1922 Incidental findings in array CGH Keymolen K, De Rademaeker M, Van Den Bogaert A. Center for Medical Genetics, UZ Brussel, VUB, Belgium – [email protected] Array Comparative Genomic Hybridization (array CGH) is nowadays widely used in the diagnostic work-up of intellectual disability, congenital anomalies and psychiatric disorders. In contrast with the standard karyotype, it allows us to pick up microdeletions - and duplications, thus increasing the number of patients for which the etiology of their problem can be demonstrated. In few cases, the array CGH result also uncovers susceptibility to serious late(r)-onset disorders, such as hereditary cancer syndromes. Although the risk for such an incidental finding is low, the physician who prescribes the analysis should be aware of this possibility and should inform the patient and/or the parents before the test is undertaken. In case of a parentally inherited aberration, the carrier parent is equally at risk for the concerned disorder and pretesting counseling should address this item too. We will illustrate the possibility of incidental findings on array CGH with two cases. The first patient is an infant with congenital anomalies and severe hypotonia. Array CGH analysis reveals a 23Mb deletion of 5q22.1q23.1. This region includes the APC gene, responsible for Familial Adenomatous Polyposis. This child will thus require close gastrointestinal follow-up from the age of 10 years on. Since the deletion is de novo, the parents are not at increased risk. The second patient is a girl with bilateral aniridia. She has a 15 Mb deletion on 11p14.1p11.2, encompassing the PAX 6 gene, which explains the ocular phenotype. However, the deletion also includes the WT1 gene, involved in renal neoplasia. Close monitoring allowed the early detection and treatment of a kidney tumor in the child. Conclusion: we want to draw the attention of the prescriber of array CGH to the small but existing risk of incidental findings with important consequences for the patient. Pretest information is therefore mandatory.
PP6.6 - 1797 Isolated complex I deficiency and atypical clinical courses in three patients due to novel mutations in NDUFS1 and NDUFV1 Björkman K, Sofou K, Darin N, Kollberg G, Holme E, Tulinius M, Oldfors A, Moslemi AR. The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Göteborg, Sweden – [email protected] Objectives: To report three patients with atypical clinical course, to add to our understanding of genotype-phenotype correlations in genes encoding complex I electron input module subunits. Material and methods: Three patients with isolated complex I deficiency. One girl, patient 1, who presented at birth with hypotonia and feeding difficulties, and died at 5 weeks of age. Two sisters, patients 2 and 3, who presented at 6–7 months of age with progressive muscle weakness and delayed motor development, and have since showed a mild clinical course with long life
17s (2013) S1 – S149
span and normal mental development. Results: Metabolic findings indicated isolated complex I deficiency. Molecular genetic analysis showed compound heterozygosity for two novel point mutations in NDUFS1 for patient 1 and compound heterozygosity for two novel point mutations in NDUFV1 for patients 2 and 3. A literature review of all reported cases of mutations in the affected genes (NDUFS1, 12 patients; NDUFV1, 14 patients) showed that the clinical course of these three patients was atypical with regard to other patients described with mutations in corresponding genes. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a shorter life span than patients with NDUFV1 mutation. Even considering this, the reported patients show that atypical clinical courses occur. Identifying the mutations is of importance for accurate genetic counseling. Compund heterozygosity due to the combination of a null mutation and a milder missense mutation may predict a more severe phenotype compared to the combination of two milder missense mutations.
PP6.7 - 1623 Acute liver failure in patients with POLG1 mutations after valproate exposure and their prognosis after liver transplantation Hynynen J, Komulainen T, Tukiainen E, Nordin A, Arola J, Kälviäinen R, Jutila L, Röyttä M, HInttala R, Suomalainen A, Majamaa K, Mäkisalo H, Uusimaa J. University of Oulu, Oulu University Hospital, Finland – johanna.uusimaa@oulu.fi Objectives: Patients with mutations in POLG1 gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma have an increased risk for valproate- induced liver failure. The role of liver transplantation for patients with mitochondrial diseases has been controversial. We studied the development of valproateinduced liver failure in patients with POLG1 mutations and the prognosis after possible liver transplantation. Methods: Patients with severe valproate-induced liver failure were retrospectively identified from the register at the Department of Transplantation and Liver Surgery, Helsinki University Hospital, Finland (880 liver transplantations since 1988). Liver transplantation and clinical follow-up had been conducted according to routine procedure. POLG1 was analyzed in blood DNA and the mtDNA content in patient and control liver samples was quantified by using real-time quantitative PCR. Results: Five out of six patients with valproateinduced liver failure (at 13–34 years) were identified (one patient with reversible liver failure was not studied). Four patients had mtDNA depletion in liver associated with homozygous POLG1 p. W748S and p. E1143G mutations; one being also heterozygous for p. Q497H mutation. One patient had died due to intractable status epilepticus and liver failure without transplantation. Three patients with liver transplant are alive and have survived 4–19 years. One patient has chronic pancreatic insufficiency. Neurological manifestations include ataxia, peripheral neuropathy and occasional epileptic seizures; one patient has been seizure free for 11 years. Furthermore, one patient with a heterozygous POLG1 p. Q1236H mutation without mtDNA depletion in liver died suddenly two years after the liver transplantation. Conclusions: Consistent with the recent finding a heterozygous POLG1 p. Q1236H mutation was related to valproate-induced liver failure without mtDNA depletion whereas patients homozygous for POLG1 p. W748S and p. E1143G mutations have mtDNA depletion. We emphasize that POLG1 gene analysis should be performed for all patients with acute liver failure following valproate treatment.