RARE DISEASE
Menkes disease
Menkes disease
Menkes disease
Synonyms: MD, Menkes kinky hair disease, Menkes syndrome
Synonyms: MD, Menkes kinky hair disease, Menkes syndrome
Synonyms: MD, Menkes kinky hair disease, Menkes syndrome
Drug discovery
9
drugs
With orphan designations
Overview
Menkes Disease Overview
Menkes disease is a rare X-linked recessive disorder caused by ATP7A gene mutations, impairing copper transport and leading to systemic copper deficiency. Characterized by kinky hair, neurodevelopmental regression, hypotonia, seizures, and failure to thrive, it primarily affects males. Early copper replacement (e.g., subcutaneous copper histidinate) within 28 days of birth may improve outcomes, but untreated cases typically result in severe neurodegeneration and death by age 3 [1][4][5].
Burden
Therapies
Copper supplementation: Subcutaneous copper histidinate initiated neonatally (≤28 days) improves survival and neurodevelopment [1][3][11].
Supportive care: Antiseizure medications, nutritional support, and physical therapy [4][10].
Emerging therapies: Investigational approaches include adeno-associated virus gene therapy and elesclomol-copper complexes [7][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare skin diseases
Research Papers
254 drug discovery papers about Menkes disease, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
254 drug discovery papers about Menkes disease, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-18 | Balancing copper: From redox biology to disease and therapy
Copper is an essential transition metal that plays a central role in biological redox chemistry due to its ability to cycle between the Cu(I) and Cu (II) oxidation states. This redox flexibility enables copper to function as a catalytic cofactor in a wide range of enzymes involved in fundamental processes such as cellular respiration, antioxidant defence, connective tissue formation, and neurotransmitter biosynthesis. However, the same redox activity also poses a risk, as unregulated copper catalyse the formation of harmful free radicals. Copper-mediated oxidative stress, in classical terms, is based on the involvement of copper in Fenton-like reactions. However, copper inside the cell is not free; rather, it is primarily controlled as redox-inactive Cu(I) species, coordinated by thiol-rich buffering system and copper chaperones. Dysregulation of copper homeostasis contributes to pathological conditions, including Wilson disease, Menkes disease and neurodegenerative disorders. In this review, we use copper as a model redox-active metal to examine how coordination control, kinetic regulation, and redox buffering govern cellular homeostasis and signalling and how their misregulation leads to disease, redox imbalance, and disruptions in metallostasis. We propose that metal toxicity arises primarily from failures in coordination and redox control rather than simple metal overload, offering new therapeutic perspectives focused on restoring metal-redox homeostasis rather than indiscriminate metal depletion.
2026-05-29 | Successful Treatment of Epileptic Spasms with Perampanel in a Patient with Menkes Disease Caused by a Novel Splice Variant in Intron of ATP7A.
Genetic variants in ATP7A are associated with a spectrum of X-linked copper metabolism disorders. Menkes disease (MD) is the most severe form of ATP7A-related disorders, characterized by severe central nervous system degeneration and connective tissue abnormalities. Intractable epilepsy is a hallmark of MD, typically progressing through epileptic spasms resistant to antiseizure drugs. Here, we report a severe case of MD with a novel splice variant (c.2782-3T > G) that was successfully treated with perampanel. The patient developed epileptic spasms during early infancy and his initial electroencephalography revealed hypsarrhythmia. As his seizures were refractory to many antiseizure drugs and thyrotropin-releasing hormone therapy, he underwent adrenocorticotropic hormone therapy; however, this treatment was ineffective and caused various side effects. Eventually, perampanel was initiated, resulting in the cessation of seizures and improvement in electroencephalography findings. This is the first reported case of MD successfully treated with perampanel, suggesting that perampanel may be a potential therapeutic option for intractable epilepsy with MD. Splice-site and intronic variants reportedly are more prevalent in milder forms of ATP7A-related disorders. The novel splice variant identified in the present case expands the understanding of intronic variation in ATP7A-related disorders.
2026-05-26 | Unraveling Menkes kinky hair disease: a rare but telltale disorder in infancy
Menkes kinky hair disease also known as “trichopoliodystrophy” resulting from a mutation in the ATP7A gene, which disrupts copper distribution across various tissues. Herein this report presents a case of a 4-month-old boy who presented with unprovoked seizures in status and developmental delay. He was evaluated for refractory seizures and developmental delay, and his serum copper and serum ceruloplasmin levels were found to be low and was later genetically diagnosed as Menkes kinky hair disease. Despite copper histidine therapy and multiple antiepileptics, seizures persisted until initiation of adjunctive cannabinoid therapy, after which the child became seizure-free. This case underscores the diagnostic and therapeutic challenges of Menkes disease and highlights the potential role of cannabinoids in seizure management.
2026-04-22 | Safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease and occipital horn syndrome in the USA: a randomised phase 1/2a crossover trial.
Menkes disease is an X-linked recessive disorder of human copper metabolism. Droxidopa is a synthetic amino acid effective in reversing neurogenic orthostatic hypotension and correcting neurochemical abnormalities in congenital absence of dopamine-beta-hydroxylase (DBH), a copper-dependent enzyme that influences autonomic function. Individuals with disorders associated with variants in the copper transport gene ATP7A may manifest symptoms of dysautonomia, due to deficient DBH activity. We aimed to evaluate the safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease or with occipital horn syndrome (an ATP7A allelic variant). We conducted a phase 1/2a, randomised, double-blind, placebo-controlled, crossover trial at one academic medical centre in Columbus, OH, USA. We compared placebo versus droxidopa treatment in adults with Menkes disease or occipital horn syndrome who manifested symptoms of dysautonomia (including orthostatic hypotension). Participants were recruited by invitation, screened, and randomly assigned to receive droxidopa or placebo for 6 weeks (Arm 1). Following a 7-10 day washout period, participants received the opposite treatment for 6 weeks (Arm 2/Crossover treatment). An open-label dose titration was utilised in advance to determine each participant's maximally tolerated dose (100, 200, or 300 mg) of droxidopa. The primary outcome of this trial was safety and tolerability assessed at 6 weeks, as reflected in the type and incidence of adverse events in the droxidopa treatment versus placebo groups. This trial is registered with ClinicalTrials.gov, NCT04977388. Between July 12, 2021 and Oct 30, 2023, three male participants were enrolled: two individuals with Menkes disease (19 and 26 years old) and one individual with occipital horn syndrome (age 35). We found significant improvements in norepinephrine levels (P < 0.01) and in a critical parameter of orthostatic hypotension, diastolic blood pressure drop during tilt table testing, while receiving droxidopa (-8.6, 95% CI -15.5 to -1.7; P = 0.018). There was no substantial difference in adverse events between the droxidopa and placebo groups. In this early phase trial, droxidopa was well tolerated in adults with Menkes disease and occipital horn syndrome and was associated with correction of orthostatic hypotension. These preliminary findings suggest that droxidopa at doses adjusted for patient tolerance is likely to be efficacious for treatment of dysautonomia in adults with ATP7A-related disorders. Further research is required, including in younger individuals with these conditions. The Menkes Disease Foundation UK, Associazione Angeli Per La Vita, and the Abigail Wexner Research Institute at Nationwide Children's Hospital.
2026-03-13 | Zycubo (copper histidinate), the first treatment for pediatric Menkes disease.
Copper histidinate (marketed as ZYCUVO®, formerly known as CUTX-101) is a copper replacement product indicated for the treatment of Menkes disease in pediatric patients. The chemical name is copper, (L-histidinato-κN,κN3,κO)(L-histidinato-κN,κO)-, (SP-5–14-C)- or copper bis((2S)-2-amino-3-(1H-imidazol-5-yl)propanoate). Copper histidinate has a molecular formula of C12H16CuN6O4 and a molecular weight of 371.84 g/mol. The molecule consists of a central copper (II) ion coordinated by two L-histidine ligands through nitrogen and oxygen donor atoms, forming a stable chelated complex that facilitates systemic copper delivery following subcutaneous administration. Copper histidinate is fully soluble in water, forming a blue solution. Reconstituted solutions must be used within 4 hours at room temperature (20°C to 25°C) or within 24 hours if refrigerated (2°C to 8°C).
gene therapies
2025-11-27 | Supplementary file 4_Retropseudogene insertion generated through retrotransposition in the ATP7A gene results in premature stop codons and a case of Menkes disease.docx
Pathogenic variants in the ATP7A gene, which encodes a transmembrane copper-transporting P-type ATPase, underlie Menkes disease, a rare X-linked recessive disorder of copper metabolism. We report a 3-year-old boy presenting with progressive neurodegeneration, refractory epilepsy, connective tissue abnormalities, and characteristic kinky hair. Whole-exome sequencing and confirmatory analysis identified a retropseudogene insertion (~500 bp) in exon 3 of ATP7A, displaying the hallmarks of target-primed reverse transcription. PCR and RNA-seq revealed a marked reduction in ATP7A transcript levels in the patient. This case underscores the diagnostic relevance of retropseudogene insertions in disease genes and highlights their role in human pathology.
2025-11-14 | CRISPR prime editing as a promising therapeutic avenue for menkes disease: the next step in correcting ATP7A mutations
Menkes disease is a life-threatening X-linked disease caused by mutations in ATP7A, an ATPase that mediates copper transport and is vital for copper homeostasis in the nervous system and the whole body. Existing therapies such as copper histidinate injections have limited neurological effects because of inefficient brain copper uptake. CRISPR prime editing (PE) provides a very powerful alternative since it can accurately correct single base substitutions or small errors efficiently without inducing double-strand breaks. Compared to conventional gene therapy, PE also overcomes vector size restrictions and reduces off-target concerns. In this letter we will discuss ATP7A variants that may be prime-editable and suggest an ex vivo approach for correction in iPSCs generated from Menkes patients with validation of function to follow. There is currently no literature that demonstrates PE for Menkes disease to the best of our knowledge, and therefore represents a unique approach for a novel gene level intervention for this fatal disease.
2025-09-27 | Novel ATP7A Splice-Site Variant Causing Distal Motor Neuropathy and Occipital Horn Syndrome: Two Siblings and Literature Review.
Background: Pathogenic hemizygous variants in ATP7A most commonly cause Menkes disease or occipital horn syndrome (OHS), whereas ATP7A-related distal hereditary motor neuropathy (dHMN) is rarely reported. Here, we describe two adult brothers with an overlapping dHMN/OHS phenotype caused by a novel ATP7A splice-site variant and review the clinical and genetic features of previously published patients with ATP7A-related dHMN. Methods: We performed detailed clinical, electrophysiological, and genetic evaluations of both siblings, including exome sequencing and RNA analysis. Additionally, we reviewed the clinical, electrophysiological, and genetic data of previously reported patients with ATP7A-related dHMN. Results: We identified a novel hemizygous ATP7A splice-site variant (NM_000052.7:c.1544-2A>T) in both brothers. The younger brother, who exhibited a more severe phenotype, presented in early childhood with mild global developmental delay, intellectual disability, and chronic diarrhea, while the older brother had childhood-onset chronic diarrhea without cognitive impairment. Both developed distal hereditary motor neuropathy later in life, and imaging revealed occipital horns. Serum copper and ceruloplasmin levels were mildly reduced. RNA sequencing revealed two aberrant transcript isoforms resulting from the splice-site variant, one of which may produce a partially functional protein. Review of previously reported patients shows that ATP7A-related dHMN may occur isolated or with overlapping features of OHS. In patients with the overlapping phenotype, chronic diarrhea was often the first symptom, followed by slowly progressive dHMN. Conclusions: Previously reported ATP7A-related dHMN has been mostly associated with missense variants. Our findings expand the mutational spectrum by identifying a splice-site variant. In patients with an overlapping OHS/dHMN phenotype, diagnosis was typically delayed for decades, suggesting this presentation remains underdiagnosed.
2025-08-08 | Clinical Features of Copper Deficiency
Copper is an essential trace element that functions as an enzymatic cofactor in processes involving connective tissue formation, iron metabolism and hematopoiesis, and central nervous system function. The adult human body contains only about 50–120 mg of copper, which is significantly lower than other trace elements such as iron and zinc. The recommended safe and adequate dietary intake of copper for adults is 700–900 µg per day. Copper is primarily absorbed in the small intestine, with a small amount absorbed in the stomach, transported via the portal blood to the liver, and incorporated into ceruloplasmin. Ceruloplasmin is released into the blood and delivers copper to tissues throughout the body. Copper deficiency is less common in healthy individuals because copper is a ubiquitous element and is present in almost all foods. In the past, copper deficiency has been observed in preterm infants and patients with hereditary conditions, such as Menkes disease. Advances in medical techniques, and an increase in the aging population has led to increased copper deficiency. Copper deficiency causes a variety of symptoms, such as hematological disorders, neurological complications, bone abnormalities, and so on. Here we introduce the clinical features of copper deficiency including its causes and treatments.
2025-05-01 | Abstract 2535 Mitochondrial matrix Cu transport is required for cytoplasmic signaling and metabolic reprogramming
The transition metal copper (Cu) is an essential catalytic cofactor in the active sites of Cu-dependent enzymes responsible for a diverse range of biological functions including mitochondrial respiration and cellular proliferation. In the case of mitochondria, Cu import is facilitated by the dual Cu and phosphate carrier, SLC25A3, whose knockout causes loss in activity of Cu-dependent enzymes like the cytochrome c oxidase (COX) complex. Given that Cu homeostasis is integral to normal cell survival as evidenced by Menkes disease, surprisingly little is known about Cu-sensing mechanisms and their interaction with key signaling molecules that translates copper abundance to distinct cellular functions.
oligonucleotides
2025-01-25 | Restoration of Genetic Code in Macular Mouse Fibroblasts via APOBEC1-Mediated RNA Editing.
RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation into new candidate genes encoding other elements of the complex could reveal further details regarding APOBEC-mediated mRNA editing. Menkes disease is a recessive X-chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from a macular mouse model of Menkes disease withs T>C mutation. Around 35% of the mutated C nucleotide (nt) was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field.
2024-01-17 | Application of an artificial deaminase system for restoration of mutated mRNAs in the macular mouse caused by T>C mutation
Abstract RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in regulation of mammalian genetic diversity. The ability to define and limit access of the enzymatic machinery, to avoid modification of unintended targets, is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation of new candidate genes encoding other elements of the complex could reveal further details of APOBEC mediated mRNA editing. Menkes disease is a recessive X chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper-transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from the macular mouse model of Menkes disease having T > C mutation. Around 35% of the mutated C nucleotide was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field.
proteins
2026-06-24 | Adjunctive ACTH therapy for refractory infantile spasms in genetically confirmed Menkes disease: a case report
Background. Menkes disease is a rare X-linked recessive disorder caused by pathogenic variants in ATP7A, leading to systemic copper deficiency and severe neurological manifestations, including refractory seizures. Case report. We describe a 3-year-old boy with genetically confirmed Menkes disease who developed refractory epileptic spasms from 6 months of age despite six antiseizure medications and a ketogenic diet. Whole-exome sequencing identified a de novo hemizygous pathogenic ATP7A alteration involving exon 21: an approximately 310-base LINE-1 repeated-element insertion at chrX:77,298,856-77,298,867, affecting transcript NM_000052.6. Copper histidine therapy was unavailable. At approximately 3 years of age, intramuscular adrenocorticotropic hormone (ACTH; Synacthen 0.25 mg, three times weekly for nine doses) was added as adjunctive therapy while all existing treatments were continued. Parents reported a reduction in daily seizure frequency from 10–15 to 3–5 episodes and shortening of seizure duration from 30–45 to 10–15 seconds. Irritability was the only reported adverse effect. Conclusion. This case illustrates a partial clinical response to adjunctive ACTH therapy in refractory infantile spasms associated with Menkes disease. ACTH may represent a symptomatic option when disease-specific therapy is inaccessible, although causality cannot be established from a single uncontrolled observation.
small molecules
2026-07-18 | Balancing copper: From redox biology to disease and therapy
Copper is an essential transition metal that plays a central role in biological redox chemistry due to its ability to cycle between the Cu(I) and Cu (II) oxidation states. This redox flexibility enables copper to function as a catalytic cofactor in a wide range of enzymes involved in fundamental processes such as cellular respiration, antioxidant defence, connective tissue formation, and neurotransmitter biosynthesis. However, the same redox activity also poses a risk, as unregulated copper catalyse the formation of harmful free radicals. Copper-mediated oxidative stress, in classical terms, is based on the involvement of copper in Fenton-like reactions. However, copper inside the cell is not free; rather, it is primarily controlled as redox-inactive Cu(I) species, coordinated by thiol-rich buffering system and copper chaperones. Dysregulation of copper homeostasis contributes to pathological conditions, including Wilson disease, Menkes disease and neurodegenerative disorders. In this review, we use copper as a model redox-active metal to examine how coordination control, kinetic regulation, and redox buffering govern cellular homeostasis and signalling and how their misregulation leads to disease, redox imbalance, and disruptions in metallostasis. We propose that metal toxicity arises primarily from failures in coordination and redox control rather than simple metal overload, offering new therapeutic perspectives focused on restoring metal-redox homeostasis rather than indiscriminate metal depletion.
2026-05-29 | Successful Treatment of Epileptic Spasms with Perampanel in a Patient with Menkes Disease Caused by a Novel Splice Variant in Intron of ATP7A.
Genetic variants in ATP7A are associated with a spectrum of X-linked copper metabolism disorders. Menkes disease (MD) is the most severe form of ATP7A-related disorders, characterized by severe central nervous system degeneration and connective tissue abnormalities. Intractable epilepsy is a hallmark of MD, typically progressing through epileptic spasms resistant to antiseizure drugs. Here, we report a severe case of MD with a novel splice variant (c.2782-3T > G) that was successfully treated with perampanel. The patient developed epileptic spasms during early infancy and his initial electroencephalography revealed hypsarrhythmia. As his seizures were refractory to many antiseizure drugs and thyrotropin-releasing hormone therapy, he underwent adrenocorticotropic hormone therapy; however, this treatment was ineffective and caused various side effects. Eventually, perampanel was initiated, resulting in the cessation of seizures and improvement in electroencephalography findings. This is the first reported case of MD successfully treated with perampanel, suggesting that perampanel may be a potential therapeutic option for intractable epilepsy with MD. Splice-site and intronic variants reportedly are more prevalent in milder forms of ATP7A-related disorders. The novel splice variant identified in the present case expands the understanding of intronic variation in ATP7A-related disorders.
2026-05-26 | Unraveling Menkes kinky hair disease: a rare but telltale disorder in infancy
Menkes kinky hair disease also known as “trichopoliodystrophy” resulting from a mutation in the ATP7A gene, which disrupts copper distribution across various tissues. Herein this report presents a case of a 4-month-old boy who presented with unprovoked seizures in status and developmental delay. He was evaluated for refractory seizures and developmental delay, and his serum copper and serum ceruloplasmin levels were found to be low and was later genetically diagnosed as Menkes kinky hair disease. Despite copper histidine therapy and multiple antiepileptics, seizures persisted until initiation of adjunctive cannabinoid therapy, after which the child became seizure-free. This case underscores the diagnostic and therapeutic challenges of Menkes disease and highlights the potential role of cannabinoids in seizure management.
2026-04-22 | Safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease and occipital horn syndrome in the USA: a randomised phase 1/2a crossover trial.
Menkes disease is an X-linked recessive disorder of human copper metabolism. Droxidopa is a synthetic amino acid effective in reversing neurogenic orthostatic hypotension and correcting neurochemical abnormalities in congenital absence of dopamine-beta-hydroxylase (DBH), a copper-dependent enzyme that influences autonomic function. Individuals with disorders associated with variants in the copper transport gene ATP7A may manifest symptoms of dysautonomia, due to deficient DBH activity. We aimed to evaluate the safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease or with occipital horn syndrome (an ATP7A allelic variant). We conducted a phase 1/2a, randomised, double-blind, placebo-controlled, crossover trial at one academic medical centre in Columbus, OH, USA. We compared placebo versus droxidopa treatment in adults with Menkes disease or occipital horn syndrome who manifested symptoms of dysautonomia (including orthostatic hypotension). Participants were recruited by invitation, screened, and randomly assigned to receive droxidopa or placebo for 6 weeks (Arm 1). Following a 7-10 day washout period, participants received the opposite treatment for 6 weeks (Arm 2/Crossover treatment). An open-label dose titration was utilised in advance to determine each participant's maximally tolerated dose (100, 200, or 300 mg) of droxidopa. The primary outcome of this trial was safety and tolerability assessed at 6 weeks, as reflected in the type and incidence of adverse events in the droxidopa treatment versus placebo groups. This trial is registered with ClinicalTrials.gov, NCT04977388. Between July 12, 2021 and Oct 30, 2023, three male participants were enrolled: two individuals with Menkes disease (19 and 26 years old) and one individual with occipital horn syndrome (age 35). We found significant improvements in norepinephrine levels (P < 0.01) and in a critical parameter of orthostatic hypotension, diastolic blood pressure drop during tilt table testing, while receiving droxidopa (-8.6, 95% CI -15.5 to -1.7; P = 0.018). There was no substantial difference in adverse events between the droxidopa and placebo groups. In this early phase trial, droxidopa was well tolerated in adults with Menkes disease and occipital horn syndrome and was associated with correction of orthostatic hypotension. These preliminary findings suggest that droxidopa at doses adjusted for patient tolerance is likely to be efficacious for treatment of dysautonomia in adults with ATP7A-related disorders. Further research is required, including in younger individuals with these conditions. The Menkes Disease Foundation UK, Associazione Angeli Per La Vita, and the Abigail Wexner Research Institute at Nationwide Children's Hospital.
2026-03-13 | Zycubo (copper histidinate), the first treatment for pediatric Menkes disease.
Copper histidinate (marketed as ZYCUVO®, formerly known as CUTX-101) is a copper replacement product indicated for the treatment of Menkes disease in pediatric patients. The chemical name is copper, (L-histidinato-κN,κN3,κO)(L-histidinato-κN,κO)-, (SP-5–14-C)- or copper bis((2S)-2-amino-3-(1H-imidazol-5-yl)propanoate). Copper histidinate has a molecular formula of C12H16CuN6O4 and a molecular weight of 371.84 g/mol. The molecule consists of a central copper (II) ion coordinated by two L-histidine ligands through nitrogen and oxygen donor atoms, forming a stable chelated complex that facilitates systemic copper delivery following subcutaneous administration. Copper histidinate is fully soluble in water, forming a blue solution. Reconstituted solutions must be used within 4 hours at room temperature (20°C to 25°C) or within 24 hours if refrigerated (2°C to 8°C).
gene therapies
2025-11-27 | Supplementary file 4_Retropseudogene insertion generated through retrotransposition in the ATP7A gene results in premature stop codons and a case of Menkes disease.docx
Pathogenic variants in the ATP7A gene, which encodes a transmembrane copper-transporting P-type ATPase, underlie Menkes disease, a rare X-linked recessive disorder of copper metabolism. We report a 3-year-old boy presenting with progressive neurodegeneration, refractory epilepsy, connective tissue abnormalities, and characteristic kinky hair. Whole-exome sequencing and confirmatory analysis identified a retropseudogene insertion (~500 bp) in exon 3 of ATP7A, displaying the hallmarks of target-primed reverse transcription. PCR and RNA-seq revealed a marked reduction in ATP7A transcript levels in the patient. This case underscores the diagnostic relevance of retropseudogene insertions in disease genes and highlights their role in human pathology.
2025-11-14 | CRISPR prime editing as a promising therapeutic avenue for menkes disease: the next step in correcting ATP7A mutations
Menkes disease is a life-threatening X-linked disease caused by mutations in ATP7A, an ATPase that mediates copper transport and is vital for copper homeostasis in the nervous system and the whole body. Existing therapies such as copper histidinate injections have limited neurological effects because of inefficient brain copper uptake. CRISPR prime editing (PE) provides a very powerful alternative since it can accurately correct single base substitutions or small errors efficiently without inducing double-strand breaks. Compared to conventional gene therapy, PE also overcomes vector size restrictions and reduces off-target concerns. In this letter we will discuss ATP7A variants that may be prime-editable and suggest an ex vivo approach for correction in iPSCs generated from Menkes patients with validation of function to follow. There is currently no literature that demonstrates PE for Menkes disease to the best of our knowledge, and therefore represents a unique approach for a novel gene level intervention for this fatal disease.
2025-09-27 | Novel ATP7A Splice-Site Variant Causing Distal Motor Neuropathy and Occipital Horn Syndrome: Two Siblings and Literature Review.
Background: Pathogenic hemizygous variants in ATP7A most commonly cause Menkes disease or occipital horn syndrome (OHS), whereas ATP7A-related distal hereditary motor neuropathy (dHMN) is rarely reported. Here, we describe two adult brothers with an overlapping dHMN/OHS phenotype caused by a novel ATP7A splice-site variant and review the clinical and genetic features of previously published patients with ATP7A-related dHMN. Methods: We performed detailed clinical, electrophysiological, and genetic evaluations of both siblings, including exome sequencing and RNA analysis. Additionally, we reviewed the clinical, electrophysiological, and genetic data of previously reported patients with ATP7A-related dHMN. Results: We identified a novel hemizygous ATP7A splice-site variant (NM_000052.7:c.1544-2A>T) in both brothers. The younger brother, who exhibited a more severe phenotype, presented in early childhood with mild global developmental delay, intellectual disability, and chronic diarrhea, while the older brother had childhood-onset chronic diarrhea without cognitive impairment. Both developed distal hereditary motor neuropathy later in life, and imaging revealed occipital horns. Serum copper and ceruloplasmin levels were mildly reduced. RNA sequencing revealed two aberrant transcript isoforms resulting from the splice-site variant, one of which may produce a partially functional protein. Review of previously reported patients shows that ATP7A-related dHMN may occur isolated or with overlapping features of OHS. In patients with the overlapping phenotype, chronic diarrhea was often the first symptom, followed by slowly progressive dHMN. Conclusions: Previously reported ATP7A-related dHMN has been mostly associated with missense variants. Our findings expand the mutational spectrum by identifying a splice-site variant. In patients with an overlapping OHS/dHMN phenotype, diagnosis was typically delayed for decades, suggesting this presentation remains underdiagnosed.
2025-08-08 | Clinical Features of Copper Deficiency
Copper is an essential trace element that functions as an enzymatic cofactor in processes involving connective tissue formation, iron metabolism and hematopoiesis, and central nervous system function. The adult human body contains only about 50–120 mg of copper, which is significantly lower than other trace elements such as iron and zinc. The recommended safe and adequate dietary intake of copper for adults is 700–900 µg per day. Copper is primarily absorbed in the small intestine, with a small amount absorbed in the stomach, transported via the portal blood to the liver, and incorporated into ceruloplasmin. Ceruloplasmin is released into the blood and delivers copper to tissues throughout the body. Copper deficiency is less common in healthy individuals because copper is a ubiquitous element and is present in almost all foods. In the past, copper deficiency has been observed in preterm infants and patients with hereditary conditions, such as Menkes disease. Advances in medical techniques, and an increase in the aging population has led to increased copper deficiency. Copper deficiency causes a variety of symptoms, such as hematological disorders, neurological complications, bone abnormalities, and so on. Here we introduce the clinical features of copper deficiency including its causes and treatments.
2025-05-01 | Abstract 2535 Mitochondrial matrix Cu transport is required for cytoplasmic signaling and metabolic reprogramming
The transition metal copper (Cu) is an essential catalytic cofactor in the active sites of Cu-dependent enzymes responsible for a diverse range of biological functions including mitochondrial respiration and cellular proliferation. In the case of mitochondria, Cu import is facilitated by the dual Cu and phosphate carrier, SLC25A3, whose knockout causes loss in activity of Cu-dependent enzymes like the cytochrome c oxidase (COX) complex. Given that Cu homeostasis is integral to normal cell survival as evidenced by Menkes disease, surprisingly little is known about Cu-sensing mechanisms and their interaction with key signaling molecules that translates copper abundance to distinct cellular functions.
oligonucleotides
2025-01-25 | Restoration of Genetic Code in Macular Mouse Fibroblasts via APOBEC1-Mediated RNA Editing.
RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation into new candidate genes encoding other elements of the complex could reveal further details regarding APOBEC-mediated mRNA editing. Menkes disease is a recessive X-chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from a macular mouse model of Menkes disease withs T>C mutation. Around 35% of the mutated C nucleotide (nt) was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field.
2024-01-17 | Application of an artificial deaminase system for restoration of mutated mRNAs in the macular mouse caused by T>C mutation
Abstract RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in regulation of mammalian genetic diversity. The ability to define and limit access of the enzymatic machinery, to avoid modification of unintended targets, is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation of new candidate genes encoding other elements of the complex could reveal further details of APOBEC mediated mRNA editing. Menkes disease is a recessive X chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper-transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from the macular mouse model of Menkes disease having T > C mutation. Around 35% of the mutated C nucleotide was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field.
proteins
2026-06-24 | Adjunctive ACTH therapy for refractory infantile spasms in genetically confirmed Menkes disease: a case report
Background. Menkes disease is a rare X-linked recessive disorder caused by pathogenic variants in ATP7A, leading to systemic copper deficiency and severe neurological manifestations, including refractory seizures. Case report. We describe a 3-year-old boy with genetically confirmed Menkes disease who developed refractory epileptic spasms from 6 months of age despite six antiseizure medications and a ketogenic diet. Whole-exome sequencing identified a de novo hemizygous pathogenic ATP7A alteration involving exon 21: an approximately 310-base LINE-1 repeated-element insertion at chrX:77,298,856-77,298,867, affecting transcript NM_000052.6. Copper histidine therapy was unavailable. At approximately 3 years of age, intramuscular adrenocorticotropic hormone (ACTH; Synacthen 0.25 mg, three times weekly for nine doses) was added as adjunctive therapy while all existing treatments were continued. Parents reported a reduction in daily seizure frequency from 10–15 to 3–5 episodes and shortening of seizure duration from 30–45 to 10–15 seconds. Irritability was the only reported adverse effect. Conclusion. This case illustrates a partial clinical response to adjunctive ACTH therapy in refractory infantile spasms associated with Menkes disease. ACTH may represent a symptomatic option when disease-specific therapy is inaccessible, although causality cannot be established from a single uncontrolled observation.
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Drug Discovery Landscape
9 orphan drug designations for Menkes disease, including 1 approved therapy.
9 orphan drug designations for Menkes disease, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
elesclomol co-administered with Copper (II) (co-packaged) | small molecules | FDA | — | Engrail Therapeutics, Inc. |
recombinant adeno-associated virus vector serotype-9 carrying the human ATP7A transgene | gene therapies | FDA | — | Lantu Biopharma (Guangzhou) Co., Ltd. |
copper nanocluster conjugated to acetate, histidinate, and ascorbate | other | FDA | — | SATT Sayens |
Elesclomol-copper | small molecules | EMA | — | Propharma Group The Netherlands B.V. |
Elesclomol copper | small molecules | FDA | — | Engrail Therapeutics, Inc. |
Copper nanocluster conjugated to acetate, histidinate and ascorbate | small molecules | EMA | — | Satt Sayens |
Copper histidinate | small molecules | EMA | CambPharma Solutions (CY) Limited | |
rsATP7A cDNA | gene therapies | FDA | — | Cyprium Therapeutics, Inc. |
copper histidinate [Zycubo] | small molecules | FDA | Approved | Sentynl Therapeutics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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