Cu(e) the balancing act: Copper homeostasis explored in 5 siblings Poster with variable clinical course 595 Sonia A Varghese MD MPH MBA and Yael Shiloh-Malawsky MD

Objective Methods Case Presentation Discussion v Present a unique variation of v Review literature describing v The graph below depicts the phenotypic spectrum seen in the 5 brothers v ATP7A mutations produce a clinical spectrum phenotype and course in siblings copper transport disorders v Mom is a known carrier of ATP7A mutation v Siblings 1, 2, and 5 follow a more classic with Menkes Disease (MD) v Apply findings to our case of five v There is limited information on the siblings who were not seen at UNC Menke’s course, while siblings 3 and 4 exhibit affected siblings v The 6th sibling is the youngest and is a healthy female infant (not included here) a phenotypic variation

Sibling: v This variation is suggestive of a milder form of Background Treatment birth Presentation Exam Diagnostic testing Outcomes Copper Histidine Menkes such as occipital horn syndrome with v Mutations in ATP7A: copper deficiency order D: 16mos residual copper transport function (Menkes disease) O/AD: 1 Infancy/12mos N/A N/A No Brain v Siblings 3 and 4 had improvement with copper v Mutations in ATP7B: copper overload FTT, Seizures, DD hemorrhage supplementation, however declined when off (Wilson disease) O/AD: Infancy/NA D: 13mos supplementation -suggesting residual ATP7A v The amount of residual functioning 2 N/A N/A No FTT, FTT copper transport function copper transport influences disease Meningitis v In comparison, sibling 5 received Cu(His) severity as well as treatment response - Macrocephaly O/AD: 6yo/Birth - Frontal bossing twice daily since birth and had limited benefit FTT, DD, Ataxia and Ceruloplasmin 7.1mg/dL (L) v Phenotypes are influenced by the - Mild dysmorphic L: motor motor regression, Copper 0.20mcg/mL (L) Yes -suggesting that he had minimal to no resulting deficient activity of features regression Urogenital Vit C <0.1mg/dL (L) - infancy to 3y functioning transporters cuproenzymes - Pectus - Unable to 3 complications, CT head (2015): Unusually - 1 repeat carinatum ambulate Syncopal events, prominent CSF space course (not v Early Cu(His) - Ataxia (Speech, unassisted Conclusions supplementation Food aversion 2/2 ventral to brainstem and responsive) choking fear, Pyloric gait, hands) cerebellar hemispheres vRecognizing the unique clinical course in our appears to lower stenosis - Low muscle tone patients is important in guiding management risk of severe - Normal reflexes and providing appropriate genetic counseling. O/AD: 4yo/not neuro- tested - Dysmorphic vImportance of cuproenzymes should not be MRI brain (2017): Non- degeneration in FTT, Ataxia and features: angular overlooked when treating Menkes enhancing lesion within the L: motor motor regression, face, wide set eyes Yes: infancy- some patients left neck, possibly a regression vFuture research is indicated to clarify the Urogenital - Muscle wasting 3yo, 1 repeat v Treatment 4 lymphatic malformation affected common pathways and resulting complications, - Ataxia (Speech, course - Unable to CT head (2017): Torturous phenotypic similarities. efficacy varies Syncopal events, gait, hands) (responsive) ambulate intracranial vessels Chronic b/l radial - Low muscle tone unassisted vSufficient copper delivery to the brain is however, and Normal EKG, ECHO, EEG depends on dislocations, - Normal reflexes essential for proper neurodevelopment. amount of Behavioral concerns Therefore, early copper supplementation MRI brain: Foci of T2 should be considered if concerned for Menkes functioning Cu O/AD: Infancy/Birth - Occipital hyperintensity in b/l frontal, Yes: Neonatal D: 19 mos 1 flattening parietal, temporal lobes transporters FTT, Seizures period onward Severe References 5 (Infantile spasms), - Hypotonia EEG: infantile spasms - NIH Menkes malnutrition 1. Stephen G. Kaler. Nat Rev Neurol. 2011 January ; 7(1): 15–29. ATP7A-related copper Developmental - No contractures Microarrary: Hemizygous transport diseases—emerging concepts and future trends study . 2. Kaler SG. Metabolic and Molecular Bases of Menkes Disease and Occipital Horn regression - Malnourished deletion of the entire exon 1 Syndrome. Pediatric and Developmental Pathology. 1998;1(1):85-98. within ATP7A gene 3. Borm B, Møller LB, Hausser I, Emeis M, Baerlocher K, Horn N, Rossi R. Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/occipital horn syndrome in three affected males in a single family. J Pediatr. 2004 Jul;145(1):119-21.. O = Symptom Onset, AD = Age of Diagnosis, FTT: Failure to thrive DD = Developmental delay, D =Deceased, L =living Urogenital complications: Bladder diverticula, recurrent UTIs, VUR