Clinical expression of Menkes disease in females with normal karyotype

Møller, Lisbeth Birk; Lenartowicz, Małgorzata; Zabot, M. T.; Arnaud, Josiane; Bürglen, Lydie; Bennett, Chris; Riconda, Daniel; Fisher, Richard; Janssens, Sandra; Mohammed, Shehla; Ausems, Margreet G. E. M.; Tümer, Zeynep; Horn, Nina; Jensen, Thomas G.

doi:10.1186/1750-1172-7-6

Cited by 39 publications

(42 citation statements)

References 19 publications

(28 reference statements)

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“…However, the literature reports few affected female patients, with most of them having an X-autosome translocation with a breakpoint at Xq21.1, truncating ATPA7, which results in clinical manifestations and is attributed to random X inactivation 4,11. In addition, there are few reports of females with milder symptoms who carry exon deletions (exon 6, 6–9, 1) or base-pair substitutions 12–14…”

Section: Epidemiologymentioning

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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Section: Epidemiologymentioning

confidence: 99%

Menkes disease: what a multidisciplinary approach can do

Ojha¹,

Prasad²

2016

JMDH

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“…Subtle neurochemical abnormalities consistent with deficiency of DBH were previously reported in Mo-br heterozygous females [6, 25]. Similarly, human Menkes female carriers occasionally develop neurological symptoms such as epilepsy and learning disability, as reported by Moller et al [26]. In a cohort consisting of 517 families, nine neurologically affected carriers with normal karyotypes were identified.…”

Section: Discussionmentioning

confidence: 53%

“…The clinical symptoms of affected females were generally milder than those of affected males in the families with the same mutations. X-inactivation analyses in affected female carriers suggested a correlation with the degree of mental retardation [26]. …”

Section: Discussionmentioning

confidence: 99%

Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model

Haddad

Patel

Sullivan

et al. 2014

Molecular Genetics and Metabolism

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Mottled-dappled (Mo-dp) is a mouse model of Menkes disease caused by a large, previously uncharacterized deletion in the 5' region of Atp7a, the mouse ortholog of ATP7A. Affected mutants die in utero at embryonic day 17, and show bending and thickening of the ribs and distortion of the pectoral and pelvic girdles and limbs. To characterize this allele, we designed a custom 4×180K microarray on the mouse X chromosome and performed comparative genomic hybridization using extracted DNA from normal and carrier Mo-dp females, and identified an approximately 9 kb deletion. We used PCR to fine-map the breakpoints and amplify a junction fragment of 630 bp. Sequencing of the junction fragment disclosed the exact breakpoint locations and that the Mo-dp deletion is precisely 8,990 bp, including approximately 2 kb in the promoter region of Atp7a. Western blot analysis of Mo-dp heterozygotes brains showed diminished amounts of Atp7a protein, consistent with reduced expression due to the promoter region deletion on one allele. In heterozygous females, brain copper levels tended to be lower compared to wild type whereas neurochemical analyses revealed higher dihydroxyphenylacetic acid: dihydroxyphenylglycol (DOPAC: DHPG) and dopamine: norepinephrine (DA:NE) ratios compared to normal (p=0.002 and 0.029, respectively), consistent with partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. Heterozygous females showed no significant differences in body weight compared to wild type females. Our results delineate the molecular details of the Mo-dp mutation for the first time and define novel biochemical findings in heterozygous female carriers of this allele.

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“…3 Most patients are males for the Xlinked recessive inheritance, though some female patients have been reported. 4 The location of ATP7A gene is on the long arm of the X chromosome between positions q13.2 and q13.3. It encodes a copper-transporting P-type ATPase.…”

Section: Discussionmentioning

confidence: 99%

A Truncating De Novo Point Mutation in a Young Infant with Severe Menkes Disease

Lin

Hsu

et al. 2017

Pediatrics & Neonatology

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Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair appearance, neurodegeneration, developmental delay, seizures, failure to thrive and other connective tissue or organ abnormalities. Other than biochemical tests, DNA-based diagnosis is now playing an important role. More than two hundred mutations in ATP7A gene were identified. Early copper supplementation can help improve neurological symptoms, but not non-neurological problems. Further molecular studies are needed to identify additional mutation types and to understand the mechanism of pathogenesis. This may help in discovering the possible treatment measures to cure the disease. We present a case with the clinical features and biochemical findings, abnormal brain magnetic resonance imaging as well as the effects of treatment with copper-histidine. Direct sequencing of ATP7A gene revealed a de novo point mutation which resulted in an early stop codon with truncated protein.

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Clinical expression of Menkes disease in females with normal karyotype

Cited by 39 publications

References 19 publications

Menkes disease: what a multidisciplinary approach can do

Menkes disease: what a multidisciplinary approach can do

Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model

A Truncating De Novo Point Mutation in a Young Infant with Severe Menkes Disease

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