The Mild Form of Menkes Disease: A 34 Year Progress Report on the Original Case

Tchan, Michel; Wilcken, Bridget; Christodoulou, John

doi:10.1007/8904_2012_183

Cited by 10 publications

(7 citation statements)

References 13 publications

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“…A milder form of MD is not lethal and exhibits weaker clinical symptoms. 37 The ATP7A gene mutations also lead to OHS, characterized by a connective tissue disorder and skeletal abnormalities often associated with mild mental retardation (OMIM: 304150), or to distal motor neuropathy, characterized by motor nerve degeneration in the anterior horn of the spinal cord and atrophy of lower and upper extremities (OMIM: 300489). Interestingly, the expression of ATP7A protein is inversely correlated with the severity of the disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

et al. 2015

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X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders.

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Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

et al. 2015

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“…Tchan et al108 reported a patient with MD at 34 years having received copper supplementation for >30 years and having only mild intellectual impairment. Another patient with MD receiving copper supplement was reported to have survived till the age of 13.5 years 109…”

Section: Managementmentioning

confidence: 99%

Menkes disease: what a multidisciplinary approach can do

Ojha¹,

Prasad²

2016

JMDH

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Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with the recognition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, through to the description of infants suffering from a progressive neurodegenerative disorder characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair quality (giving the condition its distinctive label of “kinky hair disease”). In this review, we trace the historical background and describe the biochemistry and physiology of copper metabolism and transport, inheritance patterns, molecular genetics, and genotype–phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions.

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“…In T.L.H., trafficking is affected but the protein has normal TGN localization at basal conditions. Notably, in another copper‐treated patient, without connective tissue disturbances and occipital horns and with a p.(Ala1362Val) mutation, a similar trafficking pattern was observed . It is suggestive that normal TGN‐localization is important for copper loading of LOX, even though trafficking is defective.…”

Section: Resultsmentioning

confidence: 64%

“…Variations which block phosphorylation of ATP7A prevent copper‐induced relocalization of the protein from TGN, whereas variations which block dephosphorylation prevent TGN localization . Pro852 resides on the surface of the A‐domain, which moves toward the P‐domain when ATP7A is loaded with copper, and hereby facilitates dephosphorylation during catalytic cycle. Due to this localization, Pro852Leu was expected to affect dephosphorylation: however, defective trafficking of ATP7A‐P852L to PM suggests that this substitution may instead block the phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

A 37‐year‐old Menkes disease patient—Residual ATP7A activity and early copper administration as key factors in beneficial treatment

et al. 2017

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Menkes disease (MD) is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving MD patient (37 years) receiving early-onset and long-term copper treatment. He has few neurological symptoms without connective tissue disturbances; and a missense ATP7A variant, p.(Pro852Leu), which results in impaired protein trafficking while the copper transport function is spared. These findings suggest that some cuproenzymes maintain their function when sufficient copper is provided to the cells; and underline the importance of early initiated copper treatment, efficiency of which is likely to be dependent on the mutant ATP7A function.

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The Mild Form of Menkes Disease: A 34 Year Progress Report on the Original Case

Abstract: Classical Menkes disease is a neurodegenerative disorder caused by mutations in the copper-transporting

Cited by 10 publications

References 13 publications

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

Menkes disease: what a multidisciplinary approach can do

A 37‐year‐old Menkes disease patient—Residual ATP7A activity and early copper administration as key factors in beneficial treatment

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