Clinical trial NCT00001262: Copper Histidine Therapy for Menkes Diseases
Official title: Early Copper Histidine Therapy in Menkes Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Kinky Hair Syndrome
Keywords: Menkes
Copper
X-Linked
Neurodegeneration
ATP7A
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 1999-11-04
Enrollment: 60
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Menkes Disease is a genetic disorder affecting the metabolism of copper. Patient with this disease are both physically and mentally retarded. Menkes disease is usually first detected in the first 2-3 months of life. Infant males born with the disease fail to thrive, experience hypothermia, have delayed development, and experience seizures. These infants also have characteristic physical features such as changes of their hair and face. Females may also have changes in hair and skin color, but rarely have significant medical problems.

Appropriate treatment of Menkes Disease requires that the disease be diagnosed early and treatment started before irreversible brain damage occurs. The aim of treatment is to bypass the normal route of absorption of copper through the gastrointestinal tract. Copper must then be delivered to brain cells and be available for use by enzymes.

Copper histidine is a copper replacement that can be injected directly into the body to avoid absorption through the gastrointestinal tract. However, studies have shown the genetic abnormalities causing Menkes disease cannot simply be corrected by copper replacement injections.

The genetic abnormality causing Menkes disease can vary in its severity. Patients with a genetic abnormality that may still permit some production of the enzymes required to process copper may receive benefit from early treatment with copper replacement. However, patients with severe abnormalities of the genes responsible for copper metabolism may receive no benefit from copper replacement.

The purpose of this study is to continue to evaluate the effects of early copper histidine in Menkes disease patients and to correlate specific molecular defects with responses to treatment.

Detailed description: Menkes disease is an X-linked recessive neurodegenerative disorder caused by defects in a gene that encodes an evolutionarily conserved copper-transporting ATPase (ATP7A). Several issues must be addressed in configuring therapeutic strategies for this disorder: (a) affected infants must be identified and treatment commenced very early in life before irreparable neurodegeneration occurs, (b) the block in intestinal absorption of copper must be bypassed, (c) circulating copper must be delivered to the brain, and (d) copper must be available to enzymes within cells that require it as a cofactor.

Very early, pre-symptomatic therapy with copper injections has been associated with improved overall survival and, in some patients - based on their molecular defects, with vastly better neurological outcomes in comparison to the usual natural history of this disorder. The purpose of this study is to continue to provide early copper treatment to other newborn infants diagnosed as having Menkes disease.

Eligibility criteria: * INCLUSION CRITERIA:

Newborn infants in whom Menkes disease is confirmed on biochemical or molecular grounds and in whom no neurological symptoms are present are eligible for enrollment in this study.

EXCLUSION CRITERIA:

Newly identified patients classified as symptomatic at the time of diagnosis, and affected individuals with mild phenotypes are not currently eligible for this clinical trial.

Primary outcomes:
measure: Gross Motor Development at 36 Mos of Age or at Death (Mos)
timeFrame: 36 months or death
measure: Fine Motor Adaptive Development at 36 Mos of Age or at Death (Mos)
timeFrame: 36 months or death
measure: Personal-Social Development at 36 Mos of Age or at Death (Mos)
timeFrame: 36 months or death
measure: Language Development at 36 Mos of Age or at Death (Mos)
timeFrame: 36 months or death
Secondary outcomes:
measure: Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Weight Percentile
timeFrame: 36 months or death
measure: Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Length Percentile
timeFrame: 36 months or death
measure: Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Head Circumference Percentile
timeFrame: 36 months or death
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Stephen G Kaler, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kaler SG, Buist NR, Holmes CS, Goldstein DS, Miller RC, Gahl WA. Early copper therapy in classic Menkes disease patients with a novel splicing mutation. Ann Neurol. 1995 Dec;38(6):921-8. doi: 10.1002/ana.410380613.
citation: Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008 Feb 7;358(6):605-14. doi: 10.1056/NEJMoa070613.
citation: Kaler SG, Gahl WA, Berry SA, Holmes CS, Goldstein DS. Predictive value of plasma catecholamine levels in neonatal detection of Menkes disease. J Inherit Metab Dis. 1993;16(5):907-8. doi: 10.1007/BF00714295. No abstract available.
citation: Kaler SG, Westman JA, Bernes SM, Elsayed AM, Bowe CM, Freeman KL, Wu CD, Wallach MT. Gastrointestinal hemorrhage associated with gastric polyps in Menkes disease. J Pediatr. 1993 Jan;122(1):93-5. doi: 10.1016/s0022-3476(05)83496-1.
citation: Grange DK, Kaler SG, Albers GM, Petterchak JA, Thorpe CM, DeMello DE. Severe bilateral panlobular emphysema and pulmonary arterial hypoplasia: unusual manifestations of Menkes disease. Am J Med Genet A. 2005 Dec 1;139A(2):151-5. doi: 10.1002/ajmg.a.31001.
citation: Price DJ, Ravindranath T, Kaler SG. Internal jugular phlebectasia in Menkes disease. Int J Pediatr Otorhinolaryngol. 2007 Jul;71(7):1145-8. doi: 10.1016/j.ijporl.2007.02.021. Epub 2007 May 4.
citation: Hicks JD, Donsante A, Pierson TM, Gillespie MJ, Chou DE, Kaler SG. Increased frequency of congenital heart defects in Menkes disease. Clin Dysmorphol. 2012 Apr;21(2):59-63. doi: 10.1097/MCD.0b013e32834ea52b.
citation: Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA, Goldstein DS, Holmes CS, Gahl WA. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet. 1994 Oct;8(2):195-202. doi: 10.1038/ng1094-195.
citation: Liu PC, Chen YW, Centeno JA, Quezado M, Lem K, Kaler SG. Downregulation of myelination, energy, and translational genes in Menkes disease brain. Mol Genet Metab. 2005 Aug;85(4):291-300. doi: 10.1016/j.ymgme.2005.04.007.
citation: Kaler SG, Das S, Levinson B, Goldstein DS, Holmes CS, Patronas NJ, Packman S, Gahl WA. Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small In-frame deletion. Biochem Mol Med. 1996 Feb;57(1):37-46. doi: 10.1006/bmme.1996.0007.
citation: Tang J, Donsante A, Desai V, Patronas N, Kaler SG. Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R. Mol Genet Metab. 2008 Nov;95(3):174-81. doi: 10.1016/j.ymgme.2008.06.015. Epub 2008 Aug 26.
citation: Kaler SG, Tang J, Donsante A, Kaneski CR. Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease. Ann Neurol. 2009 Jan;65(1):108-13. doi: 10.1002/ana.21576.
citation: Kaler SG, Liew CJ, Donsante A, Hicks JD, Sato S, Greenfield JC. Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. J Inherit Metab Dis. 2010 Oct;33(5):583-9. doi: 10.1007/s10545-010-9118-2. Epub 2010 Jul 21.
citation: Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet. 2011 Feb;79(2):176-82. doi: 10.1111/j.1399-0004.2010.01451.x.
citation: Kaler SG. Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment. J Trace Elem Med Biol. 2014 Oct;28(4):427-30. doi: 10.1016/j.jtemb.2014.08.008. Epub 2014 Aug 28.