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| ID | Type | Description | Link |
|---|---|---|---|
| 90-CH-0149 |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Copper histidine | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Copper Histidine | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Gross Motor Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate gross motor development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | 36 months or death |
| Fine Motor Adaptive Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate fine motor development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | 36 months or death |
| Personal-Social Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate personal-social development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | 36 months or death |
| Language Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate language development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | 36 months or death |
| Measure | Description | Time Frame |
|---|---|---|
| Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Weight Percentile | 36 months or death | |
| Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Length Percentile | 36 months or death |
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Stephen G Kaler, M.D. | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8526465 | Result | 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. | |
| 18256395 | Result | 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. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Early | Classic Menkes disease: Copper histidine treatment beginning within 1 month of age |
| FG001 | Late | Classic Menkes disease: Copper histidine treatment beginning after 1 month of age and after onset of symptoms |
| FG002 | Mild | Milder variants of Menkes disease: Copper histidine treatment beginning late (L) and after onset of (milder) symptoms |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Early | Classic Menkes disease: Copper histidine treatment beginning within 1 month of age |
| BG001 | Late | Classic Menkes disease: Copper histidine treatment beginning after 1 month of age and after onset of symptoms |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Gross Motor Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate gross motor development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | Posted | Mean | Standard Deviation | Other - months | 36 months or death |
|
36 months or death
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Early | Classic Menkes disease: Copper histidine treatment beginning within 1 month of age |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | Nervous system disorders | Menkes disease |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kaler, Stephen G | National Institute of Child Health and Human Development | +1 301 451 6034 | kalers@mail.nih.gov |
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| ID | Term |
|---|---|
| D007706 | Menkes Kinky Hair Syndrome |
| D009410 | Nerve Degeneration |
| ID | Term |
|---|---|
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C098468 | copper histidine |
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| Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Head Circumference Percentile | 36 months or death |
| 8295415 | Result | 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. |
| 8419622 | Result | 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. |
| 16278898 | Result | 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. |
| 17482283 | Result | 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. |
| 22134099 | Result | 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. |
| 7842019 | Result | 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. |
| 15923132 | Result | 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. |
| 8812725 | Result | 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. |
| 18752978 | Result | 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. |
| 19194885 | Result | 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. |
| 20652413 | Result | 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. |
| 20497190 | Result | 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. |
| 25281031 | Result | 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. |
| BG002 | Mild | Milder variants of Menkes disease: Copper histidine treatment beginning late (L) and after onset of (milder) symptoms |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG002 | Mild | Milder variants of Menkes disease: Copper histidine treatment beginning late (L) and after onset of (milder) symptoms |
|
|
| Primary | Fine Motor Adaptive Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate fine motor development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | Posted | Mean | Standard Deviation | Other - Months | 36 months or death |
|
|
|
| Primary | Personal-Social Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate personal-social development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | Posted | Mean | Standard Deviation | Other - Months | 36 months or death |
|
|
|
| Primary | Language Development at 36 Mos of Age or at Death (Mos) | This was measured based on the Denver Developmental Screening Test (DDST) I or II for age-appropriate language development in apparently normal healthy subjects at specific ages (in months). The DDST employs a grid to assess expected developmental milestones in relation to chronologic age. | Posted | Mean | Standard Deviation | Other - Months | 36 months or death |
|
|
|
| Secondary | Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Weight Percentile | Posted | Mean | Standard Deviation | Other - Percentile | 36 months or death |
|
|
|
| Secondary | Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Length Percentile | Posted | Mean | Standard Deviation | Other - Percentile | 36 months or death |
|
|
|
| Secondary | Somatic Growth Percentiles at 3 Years of Age (or at Age of Death) - Head Circumference Percentile | Posted | Mean | Standard Deviation | Other - Percentile | 36 months or death |
|
|
|
| 10 |
| 35 |
| 0 |
| 35 |
| EG001 | Late | Classic Menkes disease: Copper histidine treatment beginning after 1 month of age and after onset of symptoms | 11 | 22 | 0 | 22 |
| EG002 | Mild | Milder variants of Menkes disease: Copper histidine treatment beginning late (L) and after onset of (milder) symptoms | 0 | 3 | 0 | 3 |
| Dehydration | Nervous system disorders |
|
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| D009422 | Nervous System Diseases |
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D008661 | Metabolism, Inborn Errors |
| D008664 | Metal Metabolism, Inborn Errors |
| D006201 | Hair Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |