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P317 Cerebral creatine deficiency syndromes: clinical and laboratory follow-up in five patients with GAMT deficiency
Posters P315 Lipid peroxidative stress in SCAD deficiency (SCADD): clinical response to antioxidants Z. Zolkipli1 *, D. Lehotay2 , B.H. Robinson3 , I. Tein1,3 . 1 Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada; 2 University of Regina, Saskatchewan, Canada; 3 Genetic and Genomic Biology, Hospital for Sick Children, Toronto, Ontario, Canada Background: Given similarities of our SCADD case to Complex I deficient phenotype of cataracts, cardiomyopathy with excess superoxide radicals, we hypothesized that free radical production, arising from dysfunction of FAD-linked SCAD, may play a role in the pathogenesis of SCADD. We previously reported a 25 year old female who presented with congenital-onset myopathic facies, progressive severe limb girdle and axial multiminicore myopathy, lumbar lordosis, progressive external ophthalmoplegia, ptosis, cataracts, biatrial hypertrophy, and ethylmalonic aciduria. SCAD activity in fibroblasts was 0% with no detectable protein on Western blot. She was homozygous for c.319 C>T mutation. Independent 1 year trials of high carbohydrate/low fat diet + uncooked corn starch qhs, L-carnitine, and riboflavin did not improve strength. Objective: To assess oxidative stress in SCADD. Methods and Results: We measured 20 plasma aldehydes (lipid peroxidation products) in vivo by GC/MS and found a marked increase in our SCADD case, total of 2997.56 nM/L when compared to normal controls (total 2041.3±228.3, n = 12), p < 0.01 but comparable to elevations in Complex I deficient patients (3377.8±595.7, n = 14). We incubated our SCADD fibroblasts in vitro with 25 mM menadione, a free radical amplifier, and found 0% cell viability at 4 hrs in contrast to 100% viability at 48 hrs in controls. We instituted a 6 month clinical trial with antioxidants (Vitamin C & E) and documented a 6-fold increase in endurance on deltoid abduction from 15 to 90 seconds. Conclusion: Lipid peroxidative stress may contribute to SCADD pathology and warrants a clinical antioxidant trial. P316 Upregulation of OCTN transporter family in pregnant and lactating murine mammary gland: implications for suckling infant A.M. Lamhonwah1 , I. Tein1 *. 1 Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada Background: Organic cation/carnitine transporters transport carnitine, drugs, and xenobiotics, (e.g. choline, quinidine, verapamil) and are expressed in muscle, heart, blood vessels, brain, placenta, etc. The transport and provision of L-carnitine into breast milk is important for the normal growth and development of the suckling infant, particularly given the very low endogenous L-carnitine biosynthetic capabilities of the infant. Further, organic cationic drugs present in human breast milk may pose a significant exposure risk to the nursing infant. Methods: To characterize the expression patterns of mOctn1, -2 and -3 in murine mammary gland, we applied our transporter-specific antibodies to mOctn1, -2 and -3, followed by secondary antibody and the DAB peroxidase detection to murine breast sections at different stages of development counterstained with hematoxylin. Results: We demonstrated the differential expression of mOctn1, -2 and -3 in the epithelial ducts, muscle and lymphoid tissue of murine virginal non-lactating, pregnant, and lactating breast. There was a notable upregulation of expression of all three transporters in both the breast tissue of the pregnant mouse (18 days gestation) and lactating mouse (8 days after giving birth) compared to the virginal 8 week old mouse. There was also very strong expression of
S119 peroxisomal Octn3 in the specialized myoepithelial cells of the prelactating breast. Conclusions: The upregulation of the Octns is likely related to the increased metabolic energy demand of the actively lactating breast on plasmalemmal Octn2-, mitochondrial Octn1and peroxisomal Octn3-dependent fatty acid oxidation. This may also be related to an increased nutritional demand by the suckling infant for carnitine and other cationic homologues and xenobiotics from the nursing mother, which would be facilitated by an upregulation of mammary gland ductular epithelial Octn2 transporter. P317 Cerebral creatine deficiency syndromes: clinical and laboratory follow-up in five patients with GAMT deficiency G. Haliloglu1 *, K. Karlı Oguz2 , A. Dursun3 , A. Tokatlı3 , O. Bodamer4 , T. Coskun3 , M. Topcu1 . 1 Pediatric Neurology, Hacettepe Children’s Hospital, Ankara, Turkey; 2 Radiology, Hacettepe Children’s Hospital, Ankara, Turkey; 3 Pediatric Metabolism and Nutrition, Hacettepe Children’s Hospital, Ankara, Turkey; 4 University Children’s Hospital, Vienna, Austria Cerebral creatine deficiency syndromes (CCDS) are neurometabolic diseases that include two autosomal recessive creatine biosynthesis defects (arginine-glycine amidinotransferase: AGAT and guanidinoacetate methyl transferase: GAMT deficiencies) and an X-linked creatine transporter defect (SLC6A8 deficxiency). Clinical phenotype is characterized by intellectual disability, delay in language, autistic behaviour, epileptic seizures and movement disorder. We would like to present five patients (4 boys, 1 girl) from four different families with GAMT deficiency. There is firstdegree consanguinity in all. There is a family history of motor and mental retardation in two of the families with three more affected siblings. The age at referral was 11 months, 14 months, 3, 10 and 11 years. Clinical symptoms were developmental and speech delay (n = 5), autistic behavior (n = 5), seizures (n = 3), movement disorder (n = 1). Onset of symptoms was within the first year of life in all patients. MRI showed bilateral increased intensity in globus pallidi (n = 4). Diagnosis was done by biochemical features showing decreased serum creatinine levels, increased urinary guanidinoacetate excretion and absence of cerebral creatine levels by MRS. Interval between onset of symptoms and and diagnosis varies between 6 months to 10 years. All of the patients are on creatine supplementation. Follow-up period varies between 2 to 4 years. The patient with the longest follow-up period shows improvement of developmental milestones, is free of seizures and movement disorder, had normal creatine pool at the 6th month of treatment demonstrated by MRS. Molecular genetic tests showed GAMT mutations in all patients. In children with expressive delay in language and autistic behavior CCDS should be included in the differential diagnosis. Oral creatine substitution leads to almost normalization of creatine pool and improvement of epilepsy, movement disorder and abnormal signal intensities of the basal ganglia. P318 Unusual presentations in Niemann Pick disease type C: Clues for early diagnosis M. Topcu1 *, G. Haliloglu1 , U. Kaya1 , K. Karlı Oguz3 , F. Gurakan2 , A. Yuce2 . 1 Pediatric Neurology, Hacettepe Children’s Hospital, Ankara, Turkey; 2 Pediatric Gastroenterology, Hacettepe Children’s Hospital, Ankara, Turkey; 3 Radiology, Hacettepe Children’s Hospital, Ankara, Turkey Niemann Pick disease type C (NPC) is an autosomal recessive, progressive, lysosomal lipid storage disorder with variable symptoms. NPC arises from mutations in two genes, NPC1
S119 peroxisomal Octn3 in the specialized myoepithelial cells of the prelactating breast. Conclusions: The upregulation of the Octns is likely related to the increased metabolic energy demand of the actively lactating breast on plasmalemmal Octn2-, mitochondrial Octn1and peroxisomal Octn3-dependent fatty acid oxidation. This may also be related to an increased nutritional demand by the suckling infant for carnitine and other cationic homologues and xenobiotics from the nursing mother, which would be facilitated by an upregulation of mammary gland ductular epithelial Octn2 transporter. P317 Cerebral creatine deficiency syndromes: clinical and laboratory follow-up in five patients with GAMT deficiency G. Haliloglu1 *, K. Karlı Oguz2 , A. Dursun3 , A. Tokatlı3 , O. Bodamer4 , T. Coskun3 , M. Topcu1 . 1 Pediatric Neurology, Hacettepe Children’s Hospital, Ankara, Turkey; 2 Radiology, Hacettepe Children’s Hospital, Ankara, Turkey; 3 Pediatric Metabolism and Nutrition, Hacettepe Children’s Hospital, Ankara, Turkey; 4 University Children’s Hospital, Vienna, Austria Cerebral creatine deficiency syndromes (CCDS) are neurometabolic diseases that include two autosomal recessive creatine biosynthesis defects (arginine-glycine amidinotransferase: AGAT and guanidinoacetate methyl transferase: GAMT deficiencies) and an X-linked creatine transporter defect (SLC6A8 deficxiency). Clinical phenotype is characterized by intellectual disability, delay in language, autistic behaviour, epileptic seizures and movement disorder. We would like to present five patients (4 boys, 1 girl) from four different families with GAMT deficiency. There is firstdegree consanguinity in all. There is a family history of motor and mental retardation in two of the families with three more affected siblings. The age at referral was 11 months, 14 months, 3, 10 and 11 years. Clinical symptoms were developmental and speech delay (n = 5), autistic behavior (n = 5), seizures (n = 3), movement disorder (n = 1). Onset of symptoms was within the first year of life in all patients. MRI showed bilateral increased intensity in globus pallidi (n = 4). Diagnosis was done by biochemical features showing decreased serum creatinine levels, increased urinary guanidinoacetate excretion and absence of cerebral creatine levels by MRS. Interval between onset of symptoms and and diagnosis varies between 6 months to 10 years. All of the patients are on creatine supplementation. Follow-up period varies between 2 to 4 years. The patient with the longest follow-up period shows improvement of developmental milestones, is free of seizures and movement disorder, had normal creatine pool at the 6th month of treatment demonstrated by MRS. Molecular genetic tests showed GAMT mutations in all patients. In children with expressive delay in language and autistic behavior CCDS should be included in the differential diagnosis. Oral creatine substitution leads to almost normalization of creatine pool and improvement of epilepsy, movement disorder and abnormal signal intensities of the basal ganglia. P318 Unusual presentations in Niemann Pick disease type C: Clues for early diagnosis M. Topcu1 *, G. Haliloglu1 , U. Kaya1 , K. Karlı Oguz3 , F. Gurakan2 , A. Yuce2 . 1 Pediatric Neurology, Hacettepe Children’s Hospital, Ankara, Turkey; 2 Pediatric Gastroenterology, Hacettepe Children’s Hospital, Ankara, Turkey; 3 Radiology, Hacettepe Children’s Hospital, Ankara, Turkey Niemann Pick disease type C (NPC) is an autosomal recessive, progressive, lysosomal lipid storage disorder with variable symptoms. NPC arises from mutations in two genes, NPC1