Menkes Disease and the ATP7A Spectrum

X-linked copper transport disorders caused by pathogenic ATP7A variants: classical and atypical Menkes disease, occipital horn syndrome and X-linked distal motor neuropathy (SMAX3).

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and recognition of copper deficiency

In 1962, John H. Menkes and colleagues described in Pediatrics a sex-linked recessive disease characterised by growth retardation, unusual hair and focal cerebral and cerebellar degeneration, observed in five related male infants [15, 16]. The same author had described maple syrup urine disease in 1954, an eponymous coincidence that should not cause confusion when reading older literature [17]. Ten years later, David M. Danks and colleagues demonstrated that the disorder results from an inherited copper absorption defect with widespread effects, and all manifestations arise from deficiency of this trace element [18, 19]. This change in perspective transformed a descriptive syndrome into a metabolic disease with a therapeutic target, and the first attempts at parenteral copper replacement date from the 1970s [20].

1.2. Gene discovery

In January 1993, three groups simultaneously published gene isolation in Nature Genetics. Vulpe and colleagues identified a candidate gene with qualitative or quantitative mRNA abnormalities in 16 of 21 patients, four without detectable mRNA because of rearrangements, and showed that it encodes an approximately 1500-amino-acid protein resembling bacterial P-type copper-transporting ATPases, with six N-terminal metal-binding motifs, transcribed in all cell types except hepatocytes [21]. Chelly and colleagues started from chromosomal breakpoints at Xq13.3, described an 8 kb message present in all tissues, found deletions in 16% of 100 unrelated patients and identified the GMTCXXC metal-binding motif [22]. Mercer and colleagues reached the same gene by positional cloning from a translocation in an affected woman, less than 300 kb from PGK1, and documented an 8 kb transcript reduced or absent in patients [23]. The cytogenetic location Xq13.3 in the 1993 literature, still reproduced in reference works as Xq13.3 or Xq13.2–q13.3, has been replaced by the current annotation Xq21.1 [1, 5, 16, 24].

1.3. Expansion of the allelic spectrum

In 1994, Kaler and colleagues showed that occipital horn syndrome and mild Menkes are allelic to classical disease: in a family with four affected males aged 2 to 36 years they found a variant at position +3 of a splicing donor site and, in a 15-year-old boy with typical OHS, a variant at exonic position −2 of another donor site causing exon skipping and cryptic acceptor activation; some normal splicing persisted in both [25]. OHS had been classified as “X-linked cutis laxa”, a designation that persists in variant databases [1, 26]. In 2010, Kennerson and colleagues established the third allelic entity by demonstrating, in two families with X-linked distal hereditary motor neuropathy linked to Xq13.1–q21, the missense variants p.(Pro1386Ser) and p.(Thr994Ile) in the protein's carboxyl half, outside known functional domains [27]. The 2023 systematic review by De Feyter, Beyens and Callewaert brought together 162 published molecularly diagnosed patients and proposed operational definitions for classical Menkes, atypical Menkes, OHS and SMAX3 [9].

1.4. Therapeutic milestones

The National Institute of Child Health and Human Development (NICHD) trial begun in 1990 (NCT00001262) and published by Kaler and colleagues in 2008 in the New England Journal of Medicine demonstrated that neonatal diagnosis using plasma catechols enables copper histidinate initiation in the first weeks of life, with survival of 92% versus 13% in a historical comparison group [10, 28]. In 2019, a Brazilian group published the first diagnosis and treatment guideline for the disease based on GRADE (Grading of Recommendations Assessment, Development and Evaluation) [20]. In December 2024, the HAS published the French National Diagnosis and Care Protocol for Menkes disease and the other copper metabolism disorders, excluding Wilson disease, coordinated by the Nancy reference centre for inherited metabolic diseases [3]. On 12 January 2026, following a 30 September 2025 complete response letter (CRL) prompted by manufacturing issues, the FDA approved copper histidinate (Zycubo®) as the first authorised treatment for Menkes disease [12, 29, 30].

1.5. Definition of the entities covered

Classical Menkes disease is the severe form, with neurodegeneration beginning between 6 and 12 weeks, connective tissue abnormalities and low serum copper, usually lethal within the first 3 years without treatment [1]. Atypical or mild Menkes encompasses patients with better motor and cognitive development, who may walk and acquire language, with ataxia, tremor and head bobbing, and accounts, with OHS, for approximately 10% of patients [1, 31]. Occipital horn syndrome is the predominantly connective tissue and autonomic form, with mild or absent cognitive impairment and occipital exostoses at the trapezius and sternocleidomastoid insertions [1]. ATP7A-related distal motor neuropathy (SMAX3) is an axonal motor neuropathy beginning in adolescence or adulthood, without the systemic clinical and biochemical abnormalities of Menkes disease and OHS [1]. Autosomal dominant or recessive cutis laxa and CTR1 deficiency caused by biallelic SLC31A1 variants are addressed only as differential diagnoses [9, 32]. The 2024 French PNDS (French National Diagnosis and Care Protocol) groups under the heading of copper metabolism disorders, in addition to the three ATP7A-related forms, CTR1 deficiency, aceruloplasminaemia, MEDNIK and MEDNIK-like syndromes and Huppke–Brendel syndrome, which share low plasma copper and ceruloplasmin and have prevalences below 1 in 300,000 births; these autosomal recessive entities enter the differential diagnosis (section 6.3) [3].

2. Molecular Genetics and Pathophysiology

2.1. Copper metabolism and the role of ATP7A

An adult absorbs approximately 2 mg of copper daily; copper enters enterocytes and hepatocytes through the CTR1 membrane transporter, is removed from the portal circulation by the liver and eliminated exclusively through bile, which under physiological conditions matches absorption [31]. Within the cell, copper is always bound to chaperones that direct it to specific proteins such as superoxide dismutase, and more than 90% of plasma copper circulates bound to ceruloplasmin [31]. Two homologous ATPases export copper: ATP7A, expressed in all tissues except the liver, transfers it from enterocytes to the blood; hepatic ATP7B excretes it into bile, and its deficiency causes Wilson disease [31]. Both are synthesised in the endoplasmic reticulum and reside in the trans-Golgi network; when intracellular copper rises, they relocate to the cell periphery and, in the case of ATP7A, to the plasma membrane [31]. According to the PNDS (French National Diagnosis and Care Protocol), an adult's daily requirement is 1 to 1.6 mg of copper, derived mainly from offal, shellfish, dark chocolate, mushrooms and nuts, and total body content is about 50 to 120 mg; CTR1, the high-affinity transporter that takes up Cu⁺ after reduction of Cu²⁺ by STEAP metalloreductases, accounts for about 70% of absorption, and the chaperones ATOX1, CCS and COX17 route copper, respectively, to the trans-Golgi network ATPases and the nucleus, to superoxide dismutase and to cytochrome c oxidase [3]. ATP7A is expressed mainly in the intestine and at the blood–brain barrier, but also in the placenta and fetal endothelial cells, and interacts at the basolateral surface of cells with the PDZD11 protein [3].

ATP7A is an ATP-dependent Cu⁺ pump with dual functions. With low cytosolic copper it remains in the trans-Golgi network and loads copper into secretory pathway cuproenzymes; with high copper it moves to the plasma membrane and exports excess [4]. Intracellular ATP7A trafficking depends on the AP-1 adaptor complex, explaining phenotypic overlap with MEDNIK syndrome, and Menkes is also classified among “Golgipathies” [31, 33].

2.2. From loss of function to clinical manifestations

In Menkes disease, cellular copper uptake is normal but copper cannot be exported: enterocyte efflux into the circulation is greatly reduced and approximately twenty cuproenzymes receive insufficient cofactor [31]. This creates a biochemical paradox, with copper accumulation in the intestinal mucosa and kidney, where it is not exported, and deficiency throughout the rest of the body, particularly the brain [4]. When copper is given parenterally, the deficient ATP7A in the Golgi complex prevents its incorporation into proteins, and copper is stored in cytoplasmic vesicles, documented by electron microscopy; this accumulation in the kidney explains the nephrotoxicity of treatment, and ATP7A deficiency at the blood–brain barrier explains its limited neurological efficacy [3]. Table 2.1 summarises the relationship between deficient enzymes and clinical signs.

Table 2.1. Deficient cuproenzymes and corresponding manifestations [4, 16, 31].

Arterial tortuosity is attributed to deficient copper-dependent cross-linking in the internal elastic membrane, and partial DBH deficiency underlies the diagnostic catechol profile [4, 16]. Copper histidinate corrects peripheral deficiency but does not normalise neurochemical abnormalities, because DBH metallation in the secretory pathway requires ATP7A itself; treated survivors therefore retain dysautonomia [34]. The FDA label describes three deficits in Menkes disease: impaired intestinal copper absorption, impaired transport across the blood–brain barrier and dysregulation of copper-dependent enzymes [11]. In distal motor neuropathy, the mechanism is uncertain: motor neurons appear particularly sensitive to minor disturbances of copper homeostasis that take years to manifest and reproduce acquired copper deficiency after bariatric surgery [1, 31].

2.3. Gene and protein

The ATP7A gene lies at Xq21.1 and has MANE Select reference transcript NM_000052.7, encoding protein NP_000043.4 (identifiers HGNC:869, Entrez 538, Ensembl ENSG00000165240, UniProt Q04656) [4, 5]. The protein contains approximately 1500 amino acids, six N-terminal copper-binding domains with the GMTCXXC motif and P-type ATPase architecture; the cDNA is approximately 4.5 kb [21, 22, 35]. The gene has 23 exons and spans about 140 kb, and the protein shares about 55% homology with ATP7B [3].

2.4. Variant spectrum

The mutational spectrum is broad: single-nucleotide substitutions (nonsense, missense and splicing), small insertions and deletions, intragenic deletions of one or more exons, duplications and chromosomal abnormalities, particularly X–autosome translocations [1, 31]. Screening of 383 unrelated patients identified 57 large deletions, and larger deletions account for approximately 15% of cases [31]. The great majority of alterations predict a non-functional truncated protein [31]. The PNDS distributes known variants into small insertions or deletions (35%), nonsense (20%), splicing alterations (15%), missense (10%) and large deletions or rearrangements (20%); the sum of the first four categories (80%) approximates the approximately 75% of point alterations that the same protocol gives in its section on genetic diagnosis [3]. Most variants are private; the exon 1 deletion and the substitutions p.(Gly666Arg) and p.(Gly727Arg) recur in more than one family [1]. For p.(Gly666Arg), ClinVar records NM_000052.7:c.1996G>C as pathogenic, with multiple submitters without conflict (VCV000210411), and c.1996G>A as likely pathogenic (VCV000210410); for p.(Gly727Arg), it records c.2179G>A as pathogenic/likely pathogenic (VCV000210418), associated with X-linked cutis laxa and SMAX3 [26]. The exon 1 deletion has no published coordinates in the consulted sources.

Some variant types escape conventional pipelines. Deep intronic variants may not be detected by commercial laboratories, and insertion of an approximately 500 bp retropseudogene into exon 3 was described in a 3-year-old boy with classical Menkes, with hallmarks of target-primed reverse transcription, identified by exome sequencing supplemented with PCR and RNA sequencing [1, 36, 37].

Table 2.2. ATP7A variants cited in the article, normalised using VariantValidator (GRCh38, NM_000052.7) and consulted in ClinVar on 9 October 2026 [5, 26, 27, 38–41].

The substitution at position 1386 is proline to serine, p.(Pro1386Ser), as in the original article and ClinVar; “Phe1386Ser” in some secondary tables is a transcription error [26, 27]. Historical one-letter designations (p.T994I, p.P1386S, p.A991D, p.Q990P) correspond to the three-letter forms above [41]. Variant p.(Gln990Pro), described in 2026 as a new motor neuropathy cause, has no c. notation stated in the consulted abstract [41].

2.5. Genotype–phenotype correlation

Residual ATPase activity correlates with phenotype and partly with response to early copper: variants abolishing transport are associated with classical Menkes, variants leaving little residual activity with atypical Menkes and OHS, and a small set of missense variants with still greater residual activity with DMN [1, 31]. Milder Menkes and OHS are frequently associated with “leaky” splicing variants, which alter but do not eliminate correct splicing, described in almost 50% of OHS patients [1, 31]. In De Feyter's review, splicing variants represented 31.3% (10/32) and intronic variants 9.4% (3/32) in OHS, versus 10.9% (10/92) and 0% in classical Menkes; truncating variants were 60.4% (55/91) in classical Menkes, 28.6% (4/14) in atypical disease and 29.0% (9/31) in OHS; SMAX3 had only missense variants in or near transmembrane helices [9]. Residual function of 2 to 5% has been proposed as sufficient for milder phenotypes, and beyond these trends there is no convincing correlation [9].

In DMN, variants lie at or near the protein's luminal surface and alter intracellular trafficking. Proteins p.(Pro1386Ser) and p.(Thr994Ile) preferentially localise abnormally to the plasma membrane; p.(Thr994Ile) exposes a concealed UBX domain avidly interacting with p97/VCP, associated with endosomal cargo sorting [1]. p.(Pro1386Ser) has normal mRNA and protein abundance, with a trafficking defect and only partial rescue in yeast [27]. In patient fibroblasts with p.(Thr994Ile), p.(Pro1386Ser) and p.(Ala991Asp), ATP7A localises less to the trans-Golgi network under low-copper conditions and cells retain less copper; of five variants of uncertain significance (VUS) tested in this functional model, p.(Arg703His), p.(Tyr760Cys), p.(Ala768Gly), p.(Gln990Pro) and p.(Met1311Val), only p.(Gln990Pro) was identified as a new cause of progressive peripheral motor neuropathy [41].

Intrafamilial variability occurs occasionally in Menkes, with the same variant producing Menkes and OHS in three boys from one family, and differences in weakness, atrophy and sensory loss have been described in two DMN families [1]. Survival and intellectual and motor development during treatment are better with some residual ATP7A activity [31]. Smith states that early treatment response occurs only in children with residual transport; GeneReviews is more nuanced (“in part”), the GRADE guideline recommends that treatment indication not be genotype-driven, and the FDA label demonstrated survival benefit precisely in a population restricted to severe variants [1, 11, 16, 20].

2.6. Inheritance, penetrance and heterozygous females

Inheritance is X-linked recessive, with complete male penetrance for Menkes disease [1, 42]. Heterozygous females are typically asymptomatic, in some cases because of favourably skewed X-inactivation; approximately 50% of obligate heterozygotes have areas of pili torti, and some have brittle hair lighter than expected in their family [1, 16]. Menkes disease in females is rare and occurs mainly with X–autosome translocations disrupting the Xq21.1 locus or unfavourably skewed X-inactivation; copper, ceruloplasmin and clinical findings vary [1, 16]. In De Feyter's review, 13.0% (21/162) of published patients were female, reflecting publication bias [9]. In one DMN family, heterozygous females had normal neurological examination and motor conduction [1]. ClinGen indicates overall penetrance at or above 40%, aggregating males and heterozygous females [42].

2.7. Allelic disorders and related entities

The three entities covered are allelic and form a severity continuum from classical Menkes to isolated DMN; six patients with OHS/DMN overlap have been described [1, 38]. Orphanet associates ATP7A with Hirschsprung disease (ORPHA:388), an association unsupported in the consulted sources and therefore not addressed in this article.

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what they measure

Natural history described in reference books and GeneReviews derives mainly from the NICHD series and clinical reports accumulated since the 1960s [1, 16]. The systematic review by De Feyter and colleagues, published in 2023, assembled 162 molecularly diagnosed patients described in 143 articles: 62.3% (101) with classical Menkes, 11.1% (18) atypical Menkes, 22.6% (37) OHS and 3.7% (6) SMAX3 [9]. These percentages reflect publication rather than true phenotype distribution; patients were mostly observed untreated or with late-started treatment, and denominators vary between signs because reports do not all describe the same parameters [9].

3.2. Classical Menkes disease

Neonatal period. Pregnancy and delivery are usually normal, and neonates appear healthy [1]. However, nonspecific signs may be present from birth: prematurity, large cephalohaematomas, transient hypoglycaemia, prolonged physiological jaundice, thermal instability or persistent hypothermia, skin laxity and uneven pigmentation, particularly in dark-skinned children [1, 16, 31]. Hair is normal at birth and begins losing pigment around 6 weeks [16]. In the systematic review, 14.9% (15/101) of classical Menkes patients had cardiovascular or respiratory complications at birth [9].

Disease onset. Between 6 and 12 weeks (1.5 to 3 months), after apparent normality, loss of skills, hypotonia, seizures and growth retardation develop; feeding difficulties or a seizure are the usual initial presentations [1]. In the systematic review, mean presentation age was 5 months (median 3 months) and more than half presented with seizures [9]. Without family history, investigation may take months, and usual diagnostic age is 4 to 8 months, when hypotonia and delay are already marked [1].

Central nervous system. The substrate is a severe degenerative process of the cortex with gliosis and atrophy [16]. Initial hypotonia is gradually replaced by spasticity, with painful pyramidal hypertonia and opisthotonus, irritability and intracranial haemorrhage [16, 31, 43]. Seizures occurred in 85.1% (86/101) of patients with classical Menkes disease, with mean onset at 0.4 years, and hypotonia in 79.2%; electroencephalography (EEG) shows slow background activity with multifocal waves [9, 43]. Seizures usually begin at 2–3 months, with focal clonic seizures and status epilepticus, and rare cases begin between 15 and 20 days of life; the epilepsy is drug-resistant and accompanied by episodes of hypothermia [3]. Developmental delay was described in 98.6% (73/74), moderate to severe in 95.0% (38/40), and intellectual disability in 91.3% (21/23) [9]. Subdural haematomas and strokes are not rare; in the review, 7.7% (7/91) of patients had a stroke, five of them with classical Menkes disease [1, 9]. Thermal instability is the dominant autonomic manifestation in classical Menkes disease (82.4%, 14/17), and patients who attain walking report dizziness and syncope [1, 9].

Neuroimaging. Magnetic resonance imaging (MRI) shows cerebral and cerebellar atrophy with ventriculomegaly, delayed myelination and vascular tortuosity, and MR angiography reveals “corkscrew” cerebral vessels [1]. Intracranial tortuosity was documented in 85.1% (74/87) across all subtypes, whereas delayed myelination or white matter abnormalities, present in approximately one-third, were described only in Menkes disease; basal ganglia abnormalities occurred in 15% of classical Menkes patients [9].

Hair and skin. Scalp and usually eyebrow hair is short, sparse, coarse, twisted and frequently white, silver or grey, shorter and finer at the sides and nape, resembling steel wool; it feels like sandpaper and breaks at pressure points when lying down [1, 31]. Light microscopy shows pili torti (180° twisting around the axis), trichoclasis (transverse fracture) and trichoptilosis (longitudinal splitting); because of shaft flattening, twist periodicity differs from naturally curly hair [1]. Pili torti occurs in all cases and was found in 94.3% (50/53) examined by trichoscopy [9, 31]. Skin is lax at the nape, axillae and trunk, sometimes thick and dry [1, 16]. Scalp haematomas were described in 23.7% (23/97) [9].

Face. The face has progressively more evident sagging (jowly) cheeks and little expression; the systematic review recorded sagging cheeks in 18.6% and a high palate in 10.3% [1, 9, 16, 31].

Connective tissue, vessels and bladder. Lax skin, vascular tortuosity and bladder diverticula are present in virtually all patients according to Saudubray, and the diverticula, which may obstruct the bladder neck, are a frequent source of infection [1, 31]. Arteriography and autopsy show diffuse arterial elongation and tortuosity [16]. Neck masses usually correspond to internal jugular phlebectasia [1]. In the systematic review, bladder diverticula were documented in 29.7% (30/101) of patients with classical Menkes disease and urinary infections in 4.0%, lower than reference-book figures because not all reports included urological investigation [9]. Umbilical and inguinal hernias and pectus excavatum are frequent [31]. The PNDS (French National Diagnosis and Care Protocol) reports hernias, mainly inguinal, in 80% of cases, and describes vesicoureteric reflux, hydronephrosis with a risk of infection and urolithiasis, aneurysms, particularly aortic, dilatation of the jugular veins and cases of pulmonary emphysema [3]. Smith also describes congenital heart disease at increased frequency [16].

Gastrointestinal system and nutrition. Feeding difficulties, vomiting and chronic diarrhoea are frequent; weight gain is insufficient, with relatively preserved linear growth [31]. Gastric polyps with gastrointestinal bleeding, pyloric stenosis and sliding hiatus hernia have been described [16]. Gastrointestinal bleeding occurred in 8.9% and feeding difficulties in 31.7% of classical Menkes patients in the review [9].

Skeleton. Skull radiographs show Wormian bones; long bones and ribs have metaphyseal widening with lateral spurs that frequently fracture [1, 16]. Cervical spine abnormalities, osteopenia and fractures have been described [1, 9]. Osteoporosis may warrant bisphosphonates [3]. Metaphyseal spurs and rib fractures may raise suspicion of maltreatment (section 4) [1].

Eyes and teeth. Visual acuity is very poor, with myopia and strabismus; gingival hypertrophy and delayed deciduous tooth eruption occur [16].

Death. Without early daily subcutaneous copper injections, and sometimes despite them, neurodegeneration is severe and death typically occurs between 7 months and 3.5 years; cardiorespiratory failure, frequently precipitated by pneumonia, is a common cause [1]. In the systematic review, 40.6% (41/101) of classical Menkes patients had died at publication, at a mean age of 2.3 years, and infection was the most frequent cause (31.8%, 7/22 with a stated cause) [9]. Saudubray notes that with current care, particularly feeding techniques, longer survival is not rare [31].

3.3. Atypical or mild Menkes

A small number have better motor and cognitive development, attaining independent walking and formal language [1]. Weakness, ataxia, tremor and head bobbing are characteristic; seizures, when present, begin in middle or late childhood, intellectual disability is mild, connective tissue problems may be more prominent and pili torti is present [1]. In the systematic review, mean presentation age was 7 months (median 4 months), ataxia affected 27.8% (versus 5.0% in classical Menkes, making it a subtype marker), seizures 27.8% (5/18), developmental delay 72.2% (13/18), moderate to severe in only 33.3%, intellectual disability 80.0% (12/15), moderate to severe in 22.2%, and bladder diverticula 38.9% (7/18) [9]. Published mortality was 11.1% (2/18), and mean age at last assessment 14.3 years [9].

3.4. Occipital horn syndrome

“Occipital horns” are wedge-shaped calcifications at the trapezius and sternocleidomastoid insertions into the occipital bone, palpable or visible on lateral skull radiography [1]. Saudubray describes them as exostoses mainly at the occipital insertions of the paraspinal muscles [31]. Associated findings are skin and joint laxity, bladder diverticula with recurrent urinary infections, vascular tortuosity, dysautonomia with chronic diarrhoea and orthostatic hypotension, and mild cognitive deficits, with normal or slightly reduced intellect [1, 31]. OHS presents in infancy or early childhood but is usually recognised only in late childhood or adolescence; in the review, age at presentation ranged from birth to 50 years, with a mean of 5 years and 8 months and a median of 5 months [1, 9]. The PNDS, drawing on an earlier review of 34 patients (Beyens and colleagues, 2019), gives a mean age at presentation of 17 years (1 to 50 years); the difference from the 2023 review probably reflects different series and different definitions of “presentation” [3].

In the systematic review, approximately one-third of OHS patients presented with dysautonomia, which was documented in 48.6% (18/37): diarrhoea in 72.2%, thermal instability in 44.4%, orthostatic hypotension in 38.9% and nausea or vomiting in 22.2% of those with dysautonomia [9]. Bladder diverticula were found in 70.3% (26/37) and urinary infections in 24.3%; joint dislocations in 40.5% (15/37), involving the radial head in 11 of these 15 (73.3%); hypermobility in 45.9%; contractures, exclusive to OHS, in 13.5%; dental abnormalities in 29.7%; and pyloric stenosis, also exclusive, in 10.8% (4/37) [9]. Downslanting palpebral fissures (13.5%) and a long face (29.7%) were more frequent in OHS than in classical Menkes disease (2.0% and 4.0%), and the hair is coarse rather than hypopigmented and twisted [9]. Developmental delay affected 61.3% (19/31) and intellectual disability 53.1% (17/32), with seizures in 16.2% (mean onset at 2.8 years) and hypotonia in 32.4% [9]. Elbow dislocations are not rare and scoliosis develops with age [1]. The PNDS describes cutis laxa in OHS as more frequent than in Menkes disease, inguinal hernias in more than 80% of cases and bladder diverticula in 70%, and regards dental abnormalities, present in one-third of patients, as strongly suggestive; it reports hypopigmented, brittle and sparse hair, with pili torti in more than 92% of patients examined by trichoscopy and scalp haematomas in 25%, figures close to those recorded by the systematic review across all subtypes (94.3% and 23.7%) [3, 9]. The description of hypopigmented hair differs from the coarse hair reported in the 2023 review, so hair appearance does not exclude OHS [3, 9]. The same protocol describes exostoses without osteopenia or fractures, but includes bone densitometry in surveillance (section 11.3), and considers cardiocirculatory or respiratory complications at birth exceptional [3].

The X-linked cutis laxa description in the Brazilian genetic syndrome compendium includes a large anterior fontanelle, long neck, tortuous elongated carotid arteries, hydronephrosis and ureteric obstruction, soft redundant easily injured skin, bladder carcinoma, and musculoskeletal findings of narrow shoulders and chest, short broad clavicles, pectus excavatum or carinatum, short broad ribs, osteoporosis, kyphosis, coxa valga, pelvic exostoses, short humeri, genu valgum, limited elbow and knee extension, capitohamate fusion and flat feet [44]. Occipital exostoses with cutis laxa distinguish OHS from other multiple exostosis causes [45].

GeneReviews lists inguinal hernias among suggestive findings but notes elsewhere that frequency does not appear increased in OHS [1]. The systematic review found inguinal hernias in 85.7% (30/35) of the overall group in whom this was described, with hiatus (6/35), umbilical (4/35) and femoral hernias (3/35) [9]. The divergence probably reflects different denominators. Life expectancy appears essentially normal, but full natural-history and fertility information is scarce; in the review, 13.5% (5/37) had died, at mean age 25.3 years, from postoperative respiratory failure, perforated gastric ulcer or ruptured bladder diverticulum [1, 9].

3.5. ATP7A-related distal motor neuropathy (SMAX3)

Onset is between 5 and 60 years, typically in the second or third decade, with progressive distal atrophy and weakness of the hands and feet, foot drop with steppage gait, proximal lower-limb weakness, normal reflexes or absent ankle jerks, normal sensation or slight loss in the digits, and pes cavus [1]. Electrophysiology shows reduced compound motor action potential amplitudes with generally normal conduction velocities, and electromyography (EMG) shows positive waves and fibrillations [1]. The index case of the largest family progressed slowly over 25 years and required ankle–foot orthoses at 38 years [1]. DMN does not share the clinical and biochemical abnormalities of Menkes disease and OHS, and serum copper is normal [1, 38]. The PNDS places onset usually in the first decade, with slow progression, preserved walking and unaffected life expectancy, without pyramidal signs, without loss of pain and temperature sensation and without tongue fasciculations; the age at onset differs from that in GeneReviews (second or third decade), and the protocol considers heterozygous females asymptomatic [1, 3]. In the systematic review, the six patients from four families were male; weakness began in the feet with absent ankle jerks, progressed to the upper limbs with ataxic or steppage gait, and two had dysautonomia with diarrhoea, hyperhidrosis or retrograde ejaculation [9].

3.6. OHS and DMN overlap

Writzl and colleagues described in 2025 two Slovenian brothers with NM_000052.7:c.1544-2A>T and a mixed presentation: chronic diarrhoea from childhood, occipital horns on MRI and computed tomography (CT), slightly low copper and ceruloplasmin and adult distal motor neuropathy [38]. In the review of six patients with this overlap, chronic diarrhoea was the first symptom in five and diagnosis was delayed by decades; one patient's neuropathy worsened during copper replacement and another died suddenly at 46 years [38]. The case is described in detail in section 10.

3.7. Heterozygous females

Heterozygous females are generally asymptomatic, with pili torti areas in approximately half of obligate heterozygotes, and symptomatic female forms are rare (section 2.6) [1, 16].

3.8. Natural history and treated disease

Sections 3.2 to 3.5 mainly describe untreated or late-treated disease. In the NICHD trial, classical Menkes patients treated within the first month attained mean developmental ages at 36 months of 13.7 months for gross motor skills, 16.2 for fine motor skills, 17.7 for personal–social skills and 15.8 for language, versus 2.4 to 3.4 months in late-treated patients, and some had normal neurodevelopment and myelination [10, 28]. Treatment does not correct connective tissue abnormalities or dysautonomia: treated survivors retain vascular tortuosity, bladder diverticula and orthostatic hypotension, and the FDA label's most frequent adverse reactions during treatment were pneumonia, infections and respiratory failure, largely reflecting underlying disease [11, 34, 46]. Section 7 analyses these data.

4. Clinical Recognition and Warning Signs

4.1. Neonate with family history

The setting with greatest therapeutic impact is a male neonate born to a known carrier or with an affected brother or maternal uncle. GeneReviews recommends testing at-risk boys for the familial variant before 10 days of life so copper can begin promptly, and the therapeutic window described in screening studies is the first 4 to 6 weeks [1, 47]. When the familial variant is unknown, plasma catechols are the biochemical test of choice at this age, because copper and ceruloplasmin are physiologically low in healthy neonates (section 5) [4, 10].

4.2. Infant without family history

Disease should be suspected in a boy developing hypotonia, growth retardation and seizures between 6 and 12 weeks, particularly with short, sparse, coarse, twisted, poorly pigmented hair and sagging-cheek facies [1]. Nonspecific neonatal signs (persistent hypothermia, transient hypoglycaemia, prolonged jaundice, large cephalohaematomas) acquire significance only retrospectively or with abnormal hair [1, 31]. In metabolic assessment of infants, Menkes enters the differential of first-year seizures with low plasma copper, epilepsy with slow background activity and multifocal waves accompanied by pyramidal signs, hypotonia and kinky hair, regression with painful pyramidal hypertonia and opisthotonus, hypomyelination, and neonatal encephalopathy with abnormal hair and hypothermia; among X-linked diseases with seizures and delay, it combines sparse brittle hair with pili torti, an abnormal skeletal survey, joint hypermobility and inguinal hernias [43, 48, 49]. It also enters the differential of abnormal hair, generalised hypopigmentation and inverted nipples [50–52].

4.3. Subdural haematoma and suspected maltreatment

In an infant with subdural haematoma, Menkes disease should be excluded in boys with developmental delay or seizures, as should glutaric aciduria type 1; investigation includes copper and ceruloplasmin measurement, hair examination and a skeletal survey reviewed by a paediatric radiologist [24]. Subarachnoid haemorrhage, subdural collections and vascular tortuosity in an infant with encephalopathy or epilepsy should prompt copper and ceruloplasmin measurement [43]. Wormian bones, metaphyseal spurs and rib fractures may suggest maltreatment, and children with non-traumatic subdural haematomas have been misdiagnosed as victims of abuse; child protection services should be told that these findings are compatible with the natural history of the disease [1, 16].

4.4. Child, adolescent and adult

OHS should be considered in a child or adolescent with cutis laxa, joint hypermobility, radial head dislocation, bladder diverticula with recurrent urinary infections, hernias, chronic diarrhoea or orthostatic hypotension and mild cognitive impairment; occipital horns may be palpable [1, 9]. Childhood-onset chronic diarrhoea without a gastroenterological explanation was the first symptom in most OHS/DMN overlap patients [38]. DMN should be considered in an adolescent or adult with progressive distal motor neuropathy, preserved sensation and a transmission pattern compatible with X-linked inheritance [1].

4.5. Emergency signs

Emergencies include an untested at-risk neonate (treatment benefit depends on initiation within the first weeks), status epilepticus, intracranial haemorrhage, aspiration pneumonia or respiratory failure, urinary retention or infection of a bladder diverticulum, gastrointestinal bleeding, and abdominal pain or shock that may represent rupture of an aneurysm or diverticulum [1, 9, 39]. Because these children tend towards hypothermia, the French emergency protocol regards any temperature above 38 °C as fever, and acute pain should prompt a search for fracture, urolithiasis and urinary retention; management on admission is summarised in section 7.10 [3].

4.6. Newborn screening

The consulted sources describe no routine population newborn screening for Menkes disease: biochemical markers are incompatible with current dried blood spot mass spectrometry platforms [1]. Targeted ATP7A sequencing in dried blood spots correctly identified 21 of 22 samples with known pathogenic variants (95.5%), and whole-genome sequencing in dried blood spots, restricting analysis to 55 genes, detected variants in 24 individuals with known ATP7A variants [36, 47]. Menkes disease is included in genomic newborn screening research programmes BabyDetect in Belgium (6824 neonates between 2022 and 2025) and Early Check in North Carolina (30,000 planned between 2018 and 2026), without published disease-specific results in the consulted records [53, 54]. Inclusion in the US Recommended Uniform Screening Panel (RUSP) was not documented in the consulted sources.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

An ATP7A-related disorder is diagnosed in a boy with suggestive findings and a hemizygous pathogenic or likely pathogenic variant, or a female with suggestive findings and a heterozygous variant; ambiguous molecular results require additional biochemical studies [1]. A VUS neither establishes nor excludes diagnosis [1]. The 2019 GRADE guideline rated early neonatal plasma catechol diagnosis as high-quality evidence and prenatal diagnostic evidence as very low quality, although feasible in families with a previous case [20].

De Feyter's review proposed operational criteria distinguishing subtypes, summarised in Table 5.1 [9].

Table 5.1. Proposed criteria for clinical subtypes of ATP7A-related disease [9].

5.2. Biochemistry: copper and ceruloplasmin

Serum copper and ceruloplasmin are low in classical Menkes and, less markedly, atypical Menkes and OHS; they are normal or near-normal in DMN [1]. Both are physiologically low in healthy infants and progressively rise during the first months, whereas they remain low in untreated Menkes; diagnostic value in boys younger than 8 weeks is therefore problematic, and they are unreliable before 2 to 3 months [1, 20, 31].

Table 5.2. Approximate serum concentrations in boys, according to GeneReviews [1].

Saudubray considers serum copper below 11 µmol/L and ceruloplasmin below 200 mg/L supportive, without specificity in the first 3 months [31]. In the systematic review, serum copper was normal in 16.7% (26/105), without subtype differences, while ceruloplasmin was low in 89.9% (116/129): 96.6% (85/88) in classical Menkes, 63.6% (7/11) in atypical disease and 80.0% (24/30) in OHS, making ceruloplasmin more sensitive than copper [9]. Any cause of low ceruloplasmin reduces serum copper, so isolated low copper has multiple causes (section 6) [31].

The French PNDS (French National Diagnosis and Care Protocol) expresses the same ranges in mg/L and g/L: serum copper below 0.40 mg/L in Menkes disease, 0.40 to 0.75 mg/L in OHS and 0.80 to 1.00 mg/L in SMAX3 (reference range outside the neonatal period 0.75 to 1.50 mg/L), and ceruloplasmin below 0.10 g/L, 0.12 to 0.22 g/L and 0.23 to 0.30 g/L (reference range 0.20 to 0.45 g/L) [3]. According to the protocol, the fall in copper and ceruloplasmin is absent in about 15 to 25% of patients with Menkes disease or OHS; in OHS, copper and ceruloplasmin are low, without being collapsed, in 70% and 80% of patients, and mild biochemical abnormalities do not preclude genetic testing when clinical suspicion is strong [3]. Below 3 months of age, serum copper in healthy infants lies between 3 and 11 µmol/L and ceruloplasmin between 0.05 and 0.20 g/L [3]. Urinary copper, preferably in a 24-hour collection, is normal or low in ATP7A-related disorders (the protocol text describes it as collapsed in classical Menkes disease), in contrast to the normal or increased urinary copper of Huppke–Brendel and MEDNIK syndromes and the elevated urinary copper of Wilson disease [3]. Secondary mitochondrial deficiency may raise lactate in blood and CSF, and copper in cultured fibroblasts is increased [3].

Table 5.3. Reference values for copper studies according to the French PNDS (annex 5) [3].

REC (relative exchangeable copper) is the ratio of exchangeable copper to total copper. Values vary slightly between laboratories; serum copper increases with age, is higher in women and rises with inflammation, pregnancy and contraceptives; minimal blood contamination of CSF falsely increases measured copper, and a raised CSF protein suggests such contamination [3].

5.3. Plasma catechols

Partial DBH deficiency produces an abnormal plasma catechol profile at all ages in classical Menkes disease and OHS, and a normal profile in DMN [1]. In the NICHD study, conducted between May 1997 and July 2005, plasma dopamine, noradrenaline, DOPAC and DHPG were measured in 81 at-risk neonates; 46 had an abnormal profile, and longitudinal follow-up confirmed high sensitivity and specificity [10]. Catechols are the confirmatory biochemical test of choice in neonates and young infants, while low copper and ceruloplasmin support the diagnosis in older children [4]. Thresholds cited in recent literature are a dopamine/noradrenaline ratio above 0.2 or a DOPAC/DHPG ratio above 5; the authors of the Bahrain case attribute these to an earlier publication and note that urinary homovanillic acid may provide an indirect clue in the absence of inotropic dopamine [39]. Catechols can also be measured in cerebrospinal fluid (CSF) [1]. The PNDS adds an increased urinary homovanillic acid/vanillylmandelic acid ratio, attributes good diagnostic sensitivity at all ages, including the neonatal period, to catechol studies in plasma, urine and CSF, and considers that the clinical picture, copper profile and catechols are usually sufficient for diagnosis, subsequently confirmed by genetic testing [3].

5.4. Hair examination

Hair light microscopy shows pili torti, trichoclasis and trichoptilosis; trichoscopy identified pili torti in 94.3% (50/53) examined [1, 9]. Examination is simple and useful in clinical suspicion, but pili torti also occurs in other diseases (section 6) and may be absent in the first weeks [31, 43].

5.5. Imaging and neurophysiology

Brain MRI and MR angiography document atrophy, delayed myelination and vascular tortuosity; skull radiography shows Wormian bones and, in OHS, occipital horns; long-bone radiography shows metaphyseal spurs [1]. In suspected DMN, conduction studies and EMG demonstrate the motor axonal pattern (section 3.5) [1, 9].

5.6. Molecular testing

The single-gene strategy begins with ATP7A sequencing; if no variant or only a variant of uncertain interpretation is found, targeted deletion and duplication analysis follows, using quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA) or targeted microarray [1]. A multigene panel including the differential diagnosis genes is an alternative, with a greater likelihood of VUS [1]. The PNDS accepts targeted ATP7A testing when the clinical picture and biochemistry are typical, a copper metabolism panel (ATP7A, ATP7B, CP, AP1S1, AP1B1, SLC33A1 and, in one of the reference laboratories, SLC31A1) or first-line untargeted testing by phenotype-driven panel, exome or genome (in France, through the G2M network pre-indications in the Plan France Médecine Génomique), with biochemistry performed afterwards for confirmation [3]. When exome sequencing is used for clinical suspicion, the protocol recommends a targeted reanalysis of ATP7A and a technique able to detect exonic deletions and duplications, to avoid false negatives [3].

Table 5.4. Yield of molecular methods [1, 36, 37, 47].

The 80% and 20% figures describe the proportion of known variants detected by each technique, and 95.5% represents analytical sensitivity in a small enriched sample; none equals clinical sensitivity in a screened population [1, 36].

5.7. Test limitations

A negative test does not exclude diagnosis. Exon sequencing misses deep intronic variants, also missed by commercial laboratories; large deletions, approximately 15% of cases, may escape routine sequencing without copy-number analysis; mobile element insertions such as the exon 3 retropseudogene are not identified by conventional pipelines; and X–autosome translocations require karyotyping or breakpoint techniques [1, 31, 36, 37]. Maternal somatic or germline mosaicism may explain absence of the variant from the blood of a simplex case's mother [1]. With a typical biochemical phenotype and negative molecular investigation, RNA analysis for splicing variants, genome sequencing and differential reassessment are justified; RNA sequencing clarified the effect of c.1544-2A>T [37, 38]. Copper transport studies in cultured fibroblasts or amniocytes using radiolabelled copper pulse-chase demonstrate increased retention, but are reserved for research or urgent prenatal diagnosis without a known variant, now exceptional [1].

5.8. Molecular report and interpretation

The report should state the gene, versioned transcript (NM_000052.7), HGVS c. and p. notation, genomic coordinate with genome version, zygosity (hemizygous in males, heterozygous in females), ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) classification and copy-number variation (CNV) detection method [1, 5]. VUS may be clarified by familial segregation, catechol and ceruloplasmin profiles, RNA analysis and, for DMN-associated missense variants, functional fibroblast trafficking assays [1, 41]. ClinVar classification may conflict even for founder variants, as with c.2981C>T (Table 2.2) [26].

5.9. Prenatal diagnosis and preimplantation testing

With the familial variant identified, prenatal diagnosis on a fetal sample and preimplantation genetic testing are possible; prenatal diagnosis should preferably be molecular [1, 31]. The historical method of measuring excessive copper uptake in cultured amniocytes, used since 1981, has lost its place [1, 16]. The PNDS retains copper quantification in amniocytes as an alternative to molecular testing [3]. Section 8 details reproductive options.

5.10. Algorithm

Table 5.5. Context-specific diagnostic algorithm [1, 4, 9, 10, 20].

6. Differential Diagnosis

6.1. Principles

The differential changes with phenotype. Classical Menkes is confused with other infantile encephalopathies; OHS with cutis laxa and connective tissue diseases; DMN with other hereditary motor neuropathies [1]. A third differential axis is biochemical: low copper and ceruloplasmin are not exclusive to Menkes disease [31].

6.2. Infantile encephalopathies and intracranial haemorrhage

GeneReviews includes biotinidase deficiency, organic acidurias, aminoacidurias and mitochondrial myopathies in the classical Menkes differential [1]. Glutaric aciduria type 1 shares subarachnoid haemorrhage, subdural haematomas and cephalohaematomas, but not abnormal hair or low copper [24, 43]. Osteogenesis imperfecta shares Wormian bones and fractures, and maltreatment is the most consequential differential because of the implications of error (section 4.3) [16, 24].

For neonatal epilepsy, the PNDS (French National Diagnosis and Care Protocol) points out that 75% of cases have an acquired cause (hypoxia–ischaemia, infection, stroke, hypoglycaemia), 12.5% result from brain malformations and only 5% are metabolic [3]. Seizures in Menkes disease may begin at 15–20 days and be confused with vitamin-responsive epilepsies, which usually begin in the first week, may show sequential seizures with myoclonus, clonic jerks and a tonic phase and burst-suppression on EEG, and respond to a therapeutic trial of pyridoxine, folinic acid, pyridoxal phosphate and biotin, which should be offered in any drug-resistant epilepsy of the neonate and infant; measurement of serum copper, urinary copper and ceruloplasmin is recommended as second-line investigation for neonatal epilepsy [3]. Deficiencies of respiratory chain complex IV, which includes several cuproproteins, enter the differential diagnosis of a neurodegenerative picture with elevated plasma or CSF lactate, with a spectrum ranging from benign infantile muscular forms to rapidly lethal Leigh syndrome [3].

6.3. Other causes of low copper and ceruloplasmin

MEDNIK syndrome (mental retardation, enteropathy, deafness, neuropathy, ichthyosis and keratoderma), caused by biallelic AP1S1 variants encoding the σ1A subunit of the AP-1 complex required for ATP7A trafficking, combines low copper and ceruloplasmin with intellectual disability, variable intestinal pseudo-obstruction, deafness, ichthyosis and elevated transaminases, with features of both Menkes and Wilson disease; zinc acetate may improve it, and biallelic AP1B1 loss of function produces a similar phenotype [31]. Deficiency of the acetyl-CoA transporter AT-1 (Huppke–Brendel syndrome, SLC33A1, autosomal recessive and lethal in its severe forms) causes severe psychomotor delay, cerebral and cerebellar atrophy, deafness and congenital cataracts, with hypoceruloplasminaemia secondary to hypoacetylation [31, 33]. Aceruloplasminaemia has very low ceruloplasmin and copper but is principally an iron disorder, and some congenital disorders of glycosylation (CDG) have low ceruloplasmin with abnormal transaminases [31]. CTR1 deficiency, a newly defined autosomal recessive disease caused by biallelic SLC31A1 variants, was described in identical twins homozygous for NM_001859.4:c.284G>A p.(Arg95His), with infantile seizures and neurodegeneration due to copper deficiency in the central nervous system; copper histidinate normalised cytochrome c oxidase activity in vitro and was associated with modest clinical improvement [32]. Nutritional or acquired copper deficiency, such as after bariatric surgery, reproduces the neurological picture of DMN [31].

The 2024 PNDS details these entities. In CTR1 deficiency, with few published cases, the absence of the transporter at the blood–brain barrier as well explains a neurological picture close to that of Menkes disease: the monozygotic twins described in 2022 were well until 10 weeks, had complex focal seizures and thermal instability at 17 weeks and progressed to axial hypotonia and peripheral hypertonia, and a neonate from another family died at 1 month with refractory epilepsy, cerebral haemorrhages, tortuous cerebral arteries and pulmonary hypoplasia [3, 32]. Plasma copper and ceruloplasmin may be normal or low, CSF copper is low and lactate rises more in CSF than in plasma; the PNDS considers that copper histidinate, tried in two patients, has not shown efficacy, a more reserved assessment than the modest clinical improvement described by the authors of the report [3, 32]. Huppke–Brendel syndrome (OMIM 614482), with seven patients described at the time of the protocol, combines bilateral congenital cataracts with nystagmus, sensorineural deafness with absent otoacoustic emissions and auditory evoked potentials, axial hypotonia and severe delay without acquisition of sitting, cerebellar hypoplasia and defective myelination, with plasma copper at 10–20% of normal, collapsed ceruloplasmin and normal urinary copper in the only patient studied; a moderate form in a 29-year-old woman, treated for 25 years as Wilson disease without ATP7B variants, was resolved by exome sequencing, and copper histidinate partially improved a severely affected patient who died at 4 years [3]. MEDNIK syndrome improved with zinc acetate in a single report, and aceruloplasminaemia, with undetectable ceruloplasmin, elevated ferritin, microcytic anaemia, diabetes and iron accumulation in the brain, liver and pancreas, is treated with iron chelators [3].

The protocol also summarises the other contexts of low copper. In Wilson disease, relative exchangeable copper (REC) is above 15% and urinary copper is elevated; heterozygotes for a pathogenic ATP7B variant may have moderate abnormalities without clinical consequence (REC 9 to 14%, slightly low copper and ceruloplasmin, slightly increased urinary copper); some CDG, particularly type II forms, CCDC115-CDG (IIo), TMEM199-CDG (IIp) and ATP6AP1-CDG, combine low serum copper with hepatic copper accumulation; and copper abnormalities have been described in some patients with Niemann–Pick disease type C [3]. Acquired copper deficiencies, with low or collapsed urinary copper, occur in coeliac disease and malabsorption syndromes (never as an isolated deficiency), after bariatric surgery without nutritional follow-up, in major burns, with artificial nutrition, particularly with biliary diversion, with renal replacement therapy in intensive care and with zinc excess (supplements or denture creams), which combines anaemia with leuconeutropenia and later a myelopathy resembling subacute combined degeneration of the cord; in myelopathy with anaemia and neutropenia without an evident acquired cause, the protocol recommends genetic testing for copper disorders, not forgetting Wilson disease [3]. The myelopathy regresses only if treatment is early [3]. Table 6.1 compares the biochemical profiles.

Table 6.1. Usual biochemical profiles of copper metabolism disorders, according to the French PNDS [3].

In infants, copper and ceruloplasmin are physiologically low, which limits the interpretation of any of these profiles before 3 months of age [3].

6.4. Cutis laxa and connective tissue diseases

The OHS differential includes cutis laxa caused by FBLN5 (autosomal recessive or, less frequently, dominant), ELN (autosomal dominant) and EFEMP2 variants [1]. Cutis laxa with a metabolic component includes P5CS deficiency (ALDH18A1, De Barsy syndrome), PYCR1 deficiency, ATP6V0A2-CDG (autosomal recessive cutis laxa type 2A), COG7-CDG, GLUT10 deficiency (arterial tortuosity syndrome), geroderma osteodysplasticum (GORAB) and PI4K2A deficiency [33, 43]. Among cutis laxa disorders with osteoporosis, ARCL IIA (ATP6V0A2), ARCL IIB (PYCR1), autosomal dominant cutis laxa and De Barsy syndrome do not have osteopenia, fractures or hip dislocation [55]. These entities belong to the hereditary cutis laxa disorders; OHS is distinguished by low copper and ceruloplasmin, occipital horns and dysautonomia [1, 44]. The joint hypermobility and skin changes of OHS, formerly termed Ehlers–Danlos syndrome type IX, also place it in the differential diagnosis of the Ehlers–Danlos syndromes.

6.5. Abnormal hair and pili torti

Pili torti and brittle hair also occur in trichothiodystrophy (ERCC2/XPD, with photosensitivity), argininosuccinic aciduria (with trichorrhexis nodosa), CDG, mitochondrial diseases and Björnstad syndrome (BCS1L, pili torti with deafness) [43]. Trichorhinophalangeal syndrome appears in the sparse-hair differential [50].

6.6. Hereditary motor neuropathies

DMN differs from other Charcot–Marie–Tooth disease (CMT) and distal hereditary motor neuropathies through X-linked inheritance and sensory preservation; diagnosis is molecular, through a neuropathy panel including ATP7A [1, 9]. Acquired copper deficiency should be excluded [31].

6.7. Comparative table

Table 6.2. Principal differential diagnosis [1, 3, 24, 31–33, 43, 55].

Table abbreviations are XL, X-linked; AR, autosomal recessive; AD, autosomal dominant; OI, osteogenesis imperfecta.

7. Treatments and Risk Management Strategies

7.1. Recommendation sources and divergences

At the last GeneReviews update (April 2021), no formal clinical practice guidelines had been published; GeneReviews still described copper histidinate as investigational, superseded by FDA approval in January 2026 [1, 12]. The only GRADE-based guideline is Vairo and colleagues' 2019 guideline, developed within the Brazilian Unified Health System rare disease care programme with the Comissão Nacional de Incorporação de Tecnologias (CONITEC), from 13 articles, involving experts, methodologists and patient representatives [20]. The published abstract formulates four conclusions: prenatal genetic diagnosis is feasible in families with a previous case; plasma catechols accurately diagnose neonates; copper histidinate increases survival and reduces neurological burden if started neonatally; and treatment indication should not be genotype-driven [20]. Evidence quality was rated high for neonatal diagnosis, very low for prenatal diagnosis and moderate for treatment efficacy, upgraded by effect magnitude and the early–late treatment gradient; individual recommendation strength appears only in the inaccessible full text [20].

The ClinGen paediatric actionability report (AC013, 2022) classifies Menkes disease as moderately actionable and recommends subcutaneous copper histidinate before 30 days in asymptomatic boys, continued indefinitely, but not in symptomatic boys or after 30 days [4, 42]. The subsequent FDA label indicates the medicine for paediatric Menkes disease without an initiation age limit, and its data show survival benefit also in the late-start group (section 7.5) [11]. GRADE, ClinGen and GeneReviews agree that maximum benefit depends on starting in the first weeks; they diverge on late initiation, which ClinGen does not recommend and the label allows [1, 11, 20, 42]. De Feyter's review adds surveillance and urological management proposals without specific evidence, and considers copper benefit more modest in published cases subject to reporting bias [9]. For OHS, the label explicitly excludes the indication, whereas GeneReviews authors consider it reasonable to expect copper histidinate benefit if started within the first 3 years, an opinion unsupported by evidence [1, 11].

The 2024 French PNDS (National Diagnosis and Care Protocol), developed using the HAS rare disease methodology by the reference centres for inherited metabolic diseases and for Wilson disease, describes aetiological treatment of Menkes disease as, so far, very disappointing: copper histidinate improves non-neurological manifestations, particularly skin and hair, and normalises copper and ceruloplasmin, but has not improved long-term neurological prognosis in the patients in whom it was tried, because copper is retained at the blood–brain barrier; the protocol acknowledges that uncertain neurological efficacy may prompt ethical discussions about prescribing [3]. Table 7.1 summarises divergences between the PNDS and the other sources; the reference dose remains that of the guidelines and trials (250 µg elemental copper), shared by the PNDS, and the wider French range describes titration practice [1, 3, 11].

Table 7.1. Divergences between the French PNDS (2024, with the AGEPS information sheet of 16 February 2023) and the other recommendation sources [1, 3, 9–11, 42].

The French protocol gives the bilirubin threshold in mmol/L, a unit incompatible with physiological values; the coherent value is 140 µmol/L [3].

7.2. Copper histidinate (Zycubo®)

Mechanism. Copper histidinate is a bioavailable copper formulation administered subcutaneously, bypassing blocked intestinal absorption and restoring copper available for cuproenzymes [11, 31]. The label also describes impaired copper transport across the blood–brain barrier, helping explain variable neurological response; treatment does not correct secretory-pathway DBH metallation, so dysautonomia persists [11, 34].

Formulation. Blue preservative-free lyophilised powder in a single-dose vial containing 2.9 mg copper histidinate, equivalent to 0.5 mg elemental copper (NDC 42358-329-01) [11].

Correspondence between labelled and classical doses. The label expresses dosage as copper histidinate mass: 1.45 mg, namely half a vial (0.5 mL after reconstitution with 1 mL). Because 2.9 mg copper histidinate equals 0.5 mg elemental copper, 1.45 mg equals 0.25 mg, namely 250 µg elemental copper, the same dose GeneReviews and Saudubray express as copper (250 µg in 0.5 mL) [1, 11, 58]. Both notations describe the same regimen; error arises if “1.45 mg” is transcribed as copper mass, almost six times the dose.

Table 7.2. Copper histidinate dosage [1, 11, 42, 58].

Preparation and administration. Remove the vial from refrigeration approximately 30 minutes beforehand; reconstitute with 1 mL 0.9% sodium chloride injected slowly against the wall using a 3 mL syringe and 16–22 G needle, gently swirl without shaking, and ensure a blue clear solution, rejecting particles, turbidity or another colour [11]. Withdraw 0.5 mL with a 1 mL syringe and 23–27 G needle and inject into subcutaneous abdominal tissue (5 cm from the umbilicus), buttocks, outer arm or thigh, rotating sites to reduce lipodystrophy risk and avoiding scarred, tender, bruised, red or indurated skin; discard the remainder and use each vial for a single dose [11]. A trained caregiver may administer it [11]. Do not mix with other medicines [11]. Store vials at 2–8 °C in the original packaging; reconstituted solution may be stored for up to 24 hours refrigerated or 4 hours at 20–25 °C [11]. Give a missed dose as soon as possible, with at least 6 hours until the next [11].

Baseline assessment and monitoring. Before starting, the label requires serum copper and ceruloplasmin, electrolytes, kidney and liver function and a full blood count [11]. Repeat every 6 weeks in the first 6 months, every 3 months for the next 18 months and every 6 months thereafter throughout treatment; abnormalities warrant consideration of reduced administration frequency, temporary withholding or permanent discontinuation [11]. GeneReviews recommends copper and ceruloplasmin monitoring to avoid supranormal values, without specifying an interval [1].

Warnings. Exogenous copper may accumulate and cause kidney injury, liver dysfunction and haematological abnormalities, particularly in the first 2 years because of renal and hepatic immaturity [11]. New or worsening non-anion-gap metabolic acidosis may indicate renal tubular acidosis; increased urinary β2-microglobulin and new hypophosphataemia, hyponatraemia or hypokalaemia may indicate proximal tubular toxicity, treated by electrolyte replacement; declining kidney function or new proteinuria suggests glomerular injury [11]. Transaminase elevations were observed in patients and, in juvenile rats treated for 13 weeks, single-cell necrosis, liver inflammation and fibrosis with increased transaminases and bilirubin; haematological toxicity may result from splenic or marrow dysfunction and interference with iron metabolism, with reported anaemia [11]. The label lists no contraindications [11].

Adverse reactions. In pooled analysis of two open-label single-arm trials (129 patients aged 0 to 48 months, median exposure 24 months, range 1 to 39), serious adverse reactions in 5% or more were pneumonia, dehydration, seizure, respiratory distress, respiratory syncytial virus (RSV) infection, cardiopulmonary failure, upper respiratory infection, respiratory failure and vomiting [11]. Without a control group, many reactions correspond to the disease itself.

Table 7.3. Adverse reactions in 7% or more of treated patients (N = 129) [11].

Pharmacokinetics and interactions. In healthy adults, a single 3 mg subcutaneous dose (approximately twice the approved daily dose from 1 year) produced Cmax 67 ng/mL (coefficient of variation 36%), AUC0–24h 186 ng·h/mL, median Tmax 0.75 h, apparent volume 1034 L, apparent clearance 10.3 L/h and mean terminal half-life 75 hours, with biliary copper elimination and undetermined absolute bioavailability [11]. In treated patients, mean serum copper increased from 30 µg/dL at baseline to 114 µg/dL at 12 months and 63 µg/dL at 36 months (with reduction to a single daily dose after 1 year), and ceruloplasmin from 12 to 33 and 20 mg/dL [11]. In vitro, copper histidinate weakly inhibits several cytochrome P450 enzymes and inhibits the bile salt export pump (BSEP) and MATE1 transporter, without clinical interaction studies; exposure–response is uncharacterised [11]. There are no carcinogenicity or fertility studies, and genotoxicity tests were negative [11].

Special populations. No pregnancy or lactation data or animal reproduction studies exist, and the medicine has not been studied in older people [11]. Juvenile rats with normal copper treated twice daily between postnatal days 10 and 100 developed liver and kidney abnormalities from 1 mg/kg (exposure similar to humans), without an established no-observed-adverse-effect level [11]. In premature infants, the 28-day window uses corrected age [1].

Availability outside the USA. Without marketing authorisation in the European Union, access depends on compassionate or named-patient use programmes, and compounded preparations have been used in several countries; in 2025 an Argentine group published a copper histidinate formulation stabilised with a copper:histidine ratio of 1:3 (the 1:2 ratio degrades above 8 °C) and quality-control methods accessible to hospital pharmacies [4, 59]. In France, copper histidinate is the only available form and is a hospital preparation of the AGEPS of the AP-HP (CIPH code 77772737), dispensed in kits of five sets of two glass ampoules: a 1 mL ampoule containing 6 mg copper as chloride (pH 3.6–4.2) and a 3 mL ampoule containing 117.20 mg histidine (39.07 mg/mL), whose mixture is hypotonic (260 mOsm/L) with a pH of 6.3 to 6.7; the ampoules are kept in the outer carton, protected from light [3]. The uses declared to the French medicines agency (ANSM) are Menkes disease and copper supplementation in depleted patients (major burns, some cases of upper gastrointestinal surgery, prolonged parenteral nutrition, prolonged renal replacement therapy, severe impairment of intestinal absorption or chronic excessive zinc intake), and prescribing arrangements are available on the AGEPS website [3]. The sheet lists as undesirable effects nephrotoxicity with prolonged administration, with cases of tubulopathy, injection-site pain, lipodystrophy and inflammatory reaction; it recommends caution in hepatic impairment, which reduces biliary copper excretion and favours accumulation, and in renal impairment, and, in case of overdose, discontinuation of treatment with measurement of serum copper; interactions have not been assessed by the ANSM thesaurus [3]. The consulted sources do not describe access in Portugal or Brazil.

7.3. Cupric chloride

Cupric chloride exists as a parenteral nutrition additive (200 µg in 0.5 mL, intravenous) and has been used subcutaneously in neonates as an emergency when copper histidinate was unavailable [1]. Its pH of 2.1 causes substantial local irritation and scarring, making prolonged subcutaneous use unsuitable; this is off-label use whose role should disappear following copper histidinate approval [1, 16].

7.4. Regulatory status

NDA 211241 was submitted on 31 October 2024 under section 505(b) of the Federal Food, Drug, and Cosmetic Act [29]. The FDA issued a CRL on 30 September 2025 because of observations concerning manufacturing-site good manufacturing practice compliance, without other approvability objections according to the applicant; the 14 November 2025 resubmission was accepted as a class 1 response [29, 30, 60]. Approval dates from 12 January 2026 as a new molecular entity under priority review, with a rare paediatric disease priority review voucher; the medicine had Breakthrough Therapy, Fast Track, rare paediatric disease and orphan drug designations [12, 29, 30]. The holder's 13 January 2026 approval announcement presents it as the first and only US-approved Menkes treatment and states that the product was acquired from Cyprium Therapeutics in 2023; neither launch date nor price had then been announced [60, 61]. Postmarketing commitment 4866-1 requires a trial assessing serum copper and ceruloplasmin concentrations with approved doses, with final report expected April 2031 [29]. The company press release gave historical control median survival of 16.1 months, from preliminary results; the final label states 17.6 months, the figure used here [11, 30].

Table 7.4. Regulatory status of copper histidinate and other agents [4, 11–13, 29, 62].

The 2020 European orphan designation stated prevalence below 1 in 10,000 EU residents, the regulatory threshold rather than an epidemiological estimate, and recorded no authorised treatments, with injectable copper supplements sometimes administered [13]. In the EMA designation register, elesclomol–copper was updated in June 2025 with a code change, possibly because of sponsor transfer [13]. Absence of an authorisation application in consulted public databases does not exclude an undisclosed application.

7.5. Copper histidinate efficacy evidence

The NICHD neonatal study treated 12 newborns with copper by 22 days of life: survival was 92% at a median follow-up of 4.6 years, compared with 13% at a median follow-up of 1.8 years in a historical group of 15 patients diagnosed and treated late; two of the 12 had normal neurodevelopment and myelination, one with a variant retaining partial ATPase activity and the other with partial correct splicing [10]. Registered results of trial NCT00001262 (1990–2013, 60 patients) compared 35 patients with classical Menkes treated by 1 month, 22 treated late and 3 with mild variants; developmental ages at 36 months or at death are given in Table 7.5 [28]. ClinGen summarises the comparison of mortality at 3 years or at death as not significantly different (28.5% versus 50%), despite significant improvement in all four developmental domains [42].

FDA approval-supporting data derive from pooled NCT00001262 and NCT00811785 analysis restricted to patients with severe ATP7A variants (duplication or deletion, nonsense or canonical splicing variant) born after 1999: 83 patients, comprising 66 treated and 17 untreated contemporary external controls collected through an amendment to the second trial protocol; 81 were boys and most were born prematurely [11]. The early-treatment group (31 patients) began copper by 4 weeks corrected age, at median initiation age 0.4 months; the late group (35 patients) began at median age 7.1 months; median treatment duration was 34.1 and 20 months, respectively [11].

Table 7.5. Trials and studies of copper histidinate and other agents [10, 11, 28, 34, 46, 63–68].

In the label's two treated groups, 15 (48%) early-group patients survived beyond 6 years and 7 (23%) beyond 12 years, and 11 (31.4%) late-group patients beyond 6 years and 1 (2.9%) beyond 12 years; no external control survived beyond 6 years [11]. Hazard ratio 0.22 represents a 78% reduction in death risk in the early group and 0.27 a 73% reduction in the late group [11].

Evidence limitations. No study is randomised: comparison groups are historical or contemporary external controls, the late control group is a subset of the early control group, and deaths of unknown date were censored at the last known date [11]. Eligibility criteria differ between treated and control groups (early controls had to survive at least 4 weeks after diagnosis and be asymptomatic at 4 weeks), potentially introducing immortal-time survival bias in either direction [11]. The efficacy population excludes non-severe variants, patients born before 2000 and OHS and DMN, and the label does not establish neurodevelopmental benefit [11]. Survival medians should be read alongside absolute numbers: almost half (15/31) of the early group had died by follow-up end. NCT00811785 OHS results remain unpublished, and ClinGen describes the NICHD 3-year mortality difference as nonsignificant; comparison across studies with different populations and outcomes is invalid [42, 63]. The published-case review found frequent good biochemical response but neurodevelopmental improvement in only 8 of 38 classical Menkes patients (21%), 2 of 10 atypical Menkes and 2 of 8 OHS, subject to publication and late-initiation bias [9]. Some early-treated infants show no significant improvement over natural history [1].

7.6. Treatment of manifestations

Table 7.6. Treatment of manifestations in classical Menkes disease [1, 9, 40].

Table abbreviations denote thyrotropin-releasing hormone (TRH) and adrenocorticotrophic hormone (ACTH).

In OHS, dysautonomia may justify investigational droxidopa (section 7.7); academic support, surgical treatment of bladder diverticula with antibiotic prophylaxis when necessary, and physiotherapy and splinting for joint hypermobility complete management [1]. DMN recommendations include footwear with good ankle support, ankle–foot orthoses for foot drop, strengthening and stretching physiotherapy, occupational therapy, orthopaedic surgery for severe pes cavus, walking aids or wheelchair, and exercise within capacity, because many patients remain physically active [1]. Copper replacement has no demonstrated role in DMN, and worsening neuropathy during replacement has been reported [38].

The PNDS (French National Diagnosis and Care Protocol) adds pain management; nutritional support by nasogastric tube or gastrostomy in severe malnutrition or failure of oral feeding; periodic densitometry to detect bone fragility; early treatment of respiratory infections and respiratory failure, with chest physiotherapy for bronchial drainage; antibiotic prophylaxis of urinary tract infections and surgical treatment of diverticula when necessary; joint orthoses for hyperlaxity; and psychological support and therapeutic education for the patient and family [3]. The efficacy of antiseizure medicines in copper disorders is poorly documented: status epilepticus is treated as usual, with benzodiazepines followed by phenytoin, levetiracetam or phenobarbital, and topiramate, valproate, clobazam, levetiracetam and vigabatrin have been used for maintenance treatment, almost always as polytherapy because of drug resistance; copper histidinate does not appear to act on seizures [3]. The onset of epileptic spasms defines an infantile spasms syndrome, which favours vigabatrin and corticosteroids and requires withdrawal of aggravating drugs such as carbamazepine and phenytoin [3]. For motor neuropathy, the protocol provides thermoformed insoles for cavus or unstable feet, made-to-measure footwear in advanced cases, ankle–foot orthoses for balance and gait, upper limb positioning orthoses and thumb opposition orthoses, and physiotherapy to maintain muscle extensibility and joint mobility and to prevent neuro-orthopaedic deformities; it specifies 1 to 2 sessions weekly in SMAX3 and 2 to 3 sessions weekly when addressing peripheral rehabilitation across copper disorders as a whole, with therapeutic education for parents [3].

7.7. Droxidopa for dysautonomia

Droxidopa (Northera®) is a synthetic noradrenaline precursor converted by aromatic L-amino acid decarboxylase, bypassing deficient DBH; its half-life is approximately 2.5 hours, and use in Menkes disease and OHS is off-label and experimental [1, 34]. The single-centre US randomised, double-blind, placebo-controlled crossover phase 1/2a trial enrolled three men between July 2021 and October 2023, two Menkes survivors (19 and 26 years) and one with OHS (35 years) [34]. Following 4-day inpatient open-label titration to a maximum tolerated dose of 100, 200 or 300 mg twice daily (early morning and late afternoon), 6 weeks of droxidopa and 6 of placebo followed, with a 7- to 10-day washout; the dose was reduced for blood pressure above 140/90 mmHg or headache lasting more than 2 hours [34]. Assigned doses were 100 mg in one patient (vomiting at 200 mg), 200 mg in another (reduced from 300 mg for elevated blood pressure) and 300 mg in the third [34]. The primary safety endpoint showed no substantial difference (adverse events in 62.5% with droxidopa and 37.5% with placebo, including proteinuria of 30 mg/dL and creatinine of 1.43 mg/dL, without serious events or deaths); plasma noradrenaline increased (P <0.01) and the decline in diastolic pressure during the tilt test was attenuated by −8.6 mmHg (95% CI −15.5 to −1.7; P = 0.018) [34, 66]. The authors acknowledge that younger children will probably need doses below 100 mg and suggest an oral suspension [34]. A paediatric phase I/II trial (NCT07398508), in survivors aged 7 to 17 years treated early with copper histidinate, began recruitment in August 2026 [67]. With three patients, these data are preliminary and do not support recommending droxidopa routinely. The PNDS (French National Diagnosis and Care Protocol) allows a trial of droxidopa for dysautonomia in Menkes disease and OHS [3].

7.8. Developments in the past 12 months and research

Elesclomol–copper (case series; exceptional use). In 2025, a Spanish group described two children diagnosed in the first days through family history, with frameshift variants and absent protein, treated under an exceptional-use protocol authorised by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) with weekly subcutaneous elesclomol–copper adjunctive to daily copper histidinate [46]. In the first patient, started at 20 months with 4 µg (0.4 µg/kg) and escalated to 250 µg weekly, then reduced to 125 µg for tolerability, Bayley-III assessment moved from below the 5th percentile in almost all domains to normal cognitive, expressive language and fine motor domains after 10 months of treatment; at 57 months he walked, ran and conversed [46]. The second patient, started at 2 months corrected age with 6 µg to a maximum 140 µg, was normal in all domains except gross motor at 29 months [46]. Mild to moderate injection-site skin inflammation and fat necrosis on ultrasonography occurred, treated with topical corticosteroid and ibuprofen; noradrenaline and adrenaline remained low in the first patient, CSF copper remained below normal, and lung disease, vascular tortuosity and bladder diverticula persisted [46]. Kaler challenged the interpretation: elesclomol–copper represented 7.7% and 4.46% of weekly copper, outcomes resembled cohorts treated with copper histidinate alone, and adipocyte necrosis reactions had never occurred in more than 150 copper histidinate-treated patients [69]. The authors replied that the first patient acted as his own control, treated with copper histidinate from day five and below the 5th percentile at 20 months, and that elesclomol–copper delivers copper to cytochrome c oxidase 5000 times more potently in vitro; they acknowledge that results do not establish elesclomol–copper alone as responsible [70]. Both sides declare conflicts of interest (reduced ATP7A cDNA patent, consultancy for the sponsoring company) [69, 70]. Evidence is a two-case series with published controversy, without a clinical trial.

Gene therapy (preclinical). In mottled-brindled mice, which die by postnatal day 14, a single intravenous AAV9 dose carrying codon-optimised reduced human ATP7A (two rather than six copper-binding domains, 3.12 kb cDNA), combined with subcutaneous copper histidinate during the first month, produced 95% long-term survival across the treated groups as a whole, and 89% (32/36) with low or medium doses; medium-dose AAV alone had no survivors [35]. Growth reached approximately 70% of wild type, motor performance resembled wild type with combination treatment, brain copper normalised and the vector also reached liver, heart, kidney and lung [35]. Earlier AAV studies targeting the choroid plexus or CSF, combined with copper, had rescued 22 to 53% of mice [1, 62]. An approximately 4.1-million-dollar National Institute of Neurological Disorders and Stroke (NINDS) grant, announced in 2024, funds preclinical studies, manufacturing and preparation of the investigational new drug application (IND) for human trials [62]. No human gene therapy trial registration was found in the USA or Europe; the only record, in China (NCT05507996, one patient), terminated in 2022 by investigator decision, without results [68]. The 2024 PNDS (French National Diagnosis and Care Protocol) still presented this trial as ongoing, combined with parenteral copper histidinate [3, 68]. Absence of registration does not prove there is no pending application.

Copper nanoclusters (preclinical). In September 2026, a French group described daily subcutaneous copper nanoclusters in ATP7A-deficient mice that cross the blood–brain barrier, improved survival, normalised cuproprotein activity and restored cognitive and motor functions [71]. The 2024 PNDS described this approach, then in development, as nanoclusters smaller than 1 nm that cross physiological barriers by persorption, through membrane pores and intercellular spaces, without depending on transporters [3].

Genomic newborn screening. Whole-genome sequencing in dried blood spots, published in 2026, detected all known ATP7A variants in 24 individuals and is proposed as a route to treatment within the first 4 to 6 weeks (section 4.6) [47].

Ineffective therapies. Vitamin C proved ineffective [1].

7.9. Agents to avoid, pregnancy, perioperative period and transition

ClinGen identified no circumstances or agents to avoid [42]. The French emergency protocol likewise identifies no disease-specific drug contraindications, with the caveat, in the same document, of carbamazepine and phenytoin in infantile spasms syndrome [3]. Copper administration should avoid supranormal serum copper and requires renal, hepatic and haematological surveillance during the first 2 years (section 7.2) [1, 11]. There are no data on copper histidinate use in pregnancy or lactation [11]. Fertility in OHS is poorly known and no males with classical Menkes are recorded as having children; the consulted sources describe no pregnancies in symptomatic women [1]. In the perioperative period, OHS carries risk: in the systematic review, one death resulted from postoperative respiratory failure, and vascular tortuosity, described visceral aneurysms (section 10) and connective tissue fragility merit consideration in anaesthetic and surgical planning; the consulted sources describe no specific perioperative recommendations [9, 39]. Transition to adult care is increasingly relevant with improved survival of early-treated patients, and droxidopa trials already include adult survivors; the consulted sources describe no specific transition protocols [34]. For travel, the PNDS (French National Diagnosis and Care Protocol) recommends carrying an emergency medical certificate written by the reference physician, a certificate justifying carriage of medicines in the cabin, including liquids in primary packaging above 100 mL, all medicines needed for the stay in cabin baggage, and all prescriptions, and temporarily avoiding pill organisers that prevent identification of the drugs [3]. In advanced forms, the protocol recommends addressing progressively, within a relationship of trust between patient, carer and team, the advance directives and trusted person provided for by French law (the Leonetti law of 2005 and the Claeys-Leonetti law of 2016), with support from psychologists and palliative care teams when necessary [3].

7.10. Emergency management

The PNDS includes an emergency protocol for Menkes disease, intended for teams receiving the child, which lists the risks (developmental delay, seizures, neuropathic pain, dystonia, stroke and subdural haematomas; urinary tract infection, bladder diverticulum, lithiasis and urinary retention; sleep apnoea and emphysema; osteopenia and fractures; aneurysms) and the management on admission [3]. The protocol specifies the drugs and their sequence, but gives only the dose of oral clonazepam; the remaining doses in Table 7.7 come from the French and European summaries of product characteristics (SmPC) [3, 72–77].

Table 7.7. Management on emergency admission of a child with Menkes disease [3, 72–77].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Inheritance is X-linked. The father of an affected boy is neither affected nor hemizygous and does not need to be tested [1]. A woman with more than one affected son, or with one affected son and another affected relative in the maternal line, is an obligate heterozygote; if she has more than one affected son without other affected relatives and the variant is not detected in her leucocytes, germline mosaicism is the most likely explanation [1]. About one-third of affected boys are simplex cases, and Saudubray also estimates the proportion of de novo variants at about one-third [1, 31]. In a simplex case, the mother may be heterozygous, the variant may have arisen de novo in the proband, or the mother may have somatic or germline mosaicism; maternal molecular testing is recommended [1]. The PNDS (French National Diagnosis and Care Protocol) estimates de novo variant cases at about 30%, mentions rare cases of germline mosaicism and of women affected through an X-chromosome translocation, a possibility to consider in counselling, and considers testing the mother for the variant necessary to establish the mode of transmission [3].

Table 8.1. Scenario-specific recurrence risks [1].

8.2. Cascade testing and heterozygote detection

Identifying heterozygous females requires a known familial variant; without an affected individual available for testing, ATP7A sequencing followed by deletion and duplication analysis is performed in the at-risk woman [1]. Biochemical tests are unreliable for carrier identification because values overlap normal ranges [1]. Hair observation may show pili torti in approximately half of heterozygotes, but absence does not exclude carrier status [1]. In DMN, clinical screening of at-risk relatives forms part of initial assessment [1].

8.3. At-risk neonates

Every boy born to a known heterozygote should be tested for the familial variant before 10 days of life so that, if affected, copper histidinate can begin within the first 4-week window (section 4.1) [1]. Planning, including medicine and catechol laboratory access, should be organised before delivery [1, 10].

8.4. Prenatal diagnosis and preimplantation testing

Once the familial variant is identified, prenatal diagnosis and preimplantation genetic testing are possible, and prenatal diagnosis should preferably be molecular [1, 31]. The GRADE guideline considers it feasible in families with a previous case, with very low quality of evidence [20]. Prenatal diagnosis also allows immediate neonatal treatment to be planned [10, 20]. Perspectives on the use of prenatal diagnosis differ, especially when the aim is termination of pregnancy, and should be discussed non-directively [1]. In France, prenatal or preimplantation diagnosis by genetic testing may be offered, as this is an incurable disease of particular severity, within a multidisciplinary prenatal diagnosis centre (CPDPN), provided the index case variant has previously been identified [3]. Copper uptake studies in amniocytes, used historically, are justified only in exceptional situations without an identified variant [1, 16].

8.5. Counselling content

The optimal time to determine genetic risk and discuss prenatal and preimplantation diagnosis is before pregnancy, and counselling should be offered to affected, heterozygous or at-risk young adults [1]. When the molecular diagnosis is not confirmed, DNA banking from the affected individual is recommended [1]. The PNDS (French National Diagnosis and Care Protocol) recommends that genetic counselling take place in a dedicated genetics clinic [3]. Counselling should explain the dependence of therapeutic benefit on timing of initiation, the availability of the medicine in the country of residence and the persistence of connective tissue and autonomic manifestations under treatment [11, 34, 46]. In minors, the situation is asymmetric: testing of at-risk boys is urgent because of the benefit of early treatment, whereas for girls at risk of being heterozygous, usually asymptomatic, the consulted sources set no age for testing, and carrier status information is mainly relevant to future reproductive decisions [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each estimate measures

Frequency estimates for Menkes disease measure different things and should not be compared directly. Older clinical estimates, based on confirmed cases in specific populations, range from 1:40,000 to 1:354,507 [1]. Saudubray cites an approximate incidence of 1:250,000 [31]. The GRADE guideline cites 1 in 300,000 live births in Europe and up to 1 in 40,000 in Australia [20]. ClinGen cites birth incidences of 1/300,000 in Europe, 1/360,000 in Japan and 1/40,000 to 1/100,000 in Australia, with a possible founder effect in the latter, and a prevalence below 1–2/100,000 [42]. The French PNDS (National Diagnosis and Care Protocol) adopts the incidence of 1 in 250,000 births [3].

Table 9.1. Frequency estimates and their nature [2–4, 6–8, 13, 47].

The genomic estimate starts with 1106 ATP7A variants in 205,523 gnomAD alleles, including 4 complete loss-of-function alleles (frequency 0.0000194), and adds 12 alleles of 9 missense variants classified deleterious by prediction tools; for comparison, the authors give 1:7246 for Duchenne muscular dystrophy [8]. The 1:8664 figure is approximately five times clinical estimates, suggesting underdiagnosis of mild phenotypes and infants dying before diagnosis; it encompasses all three phenotypes without separating them and has not been confirmed through screening [4, 8]. The 2026 neonatal genome sequencing study uses the minimum estimate of 1/34 810 [47].

9.2. Geography and populations

Sources describe higher frequency in Australia than Europe and Japan, interpreted as a possible founder effect [6, 42]. In the US approval-supporting trials, the efficacy population was 63% White, 13% Hispanic, 10% Black, 2% Asian or Pacific Islander and 12% unknown or other origin, and 98% male [11]. Skin presentation may vary with pigmentation: uneven pigmentation at birth is more evident in dark-skinned children [16]. The first documented Bahrain case was published in 2026 (section 10) [39]. The consulted sources include no Portuguese or Brazilian epidemiological data; the only GRADE guideline was produced by a Porto Alegre group within the Brazilian Unified Health System rare disease programme [20]. Absence of data in the consulted sources does not mean there are no published studies.

9.3. Special populations

Heterozygous girls and women are generally asymptomatic, but symptomatic forms should be considered with X–autosome translocation or skewed X-inactivation (section 2.6) [1]. In premature infants, the treatment window uses corrected age, and most trial patients were born prematurely (77% in the early group) [1, 11]. Copper toxicity risk is higher in the first two years [11]. Early-treated adult survivors form a new population with persistent dysautonomia and transition needs (section 7.9) [34].

9.4. Reference networks and patient associations

MetabERN, the European Reference Network for hereditary metabolic diseases, includes copper metabolism disorders, with copper alpha ATPase deficiency in its three forms (severe Menkes, OHS and SMAX3), and organised an early diagnosis webinar with the Menkes International Association [14]. Patient associations include the Málaga-based Menkes International Association, The Menkes Foundation in the USA, Menkes Disease Foundation UK, Associazione Angeli per la Vita in Italy and Nos Enfants Menkes in France [1, 34, 78, 79]. GeneReviews also lists MedlinePlus and NINDS information resources and a specialist clinic at Nationwide Children's Hospital in Columbus [1]. In France, the PNDS (French National Diagnosis and Care Protocol) identifies as reference structures the coordinating reference centre for inherited metabolic diseases (Marseille), eight constituent centres (Lyon, Lille, Nancy, Paris-Necker, Paris-Pitié-Salpêtrière, Toulouse and Tours) and twenty competence centres, the reference centre for Wilson disease and other rare copper-related diseases (Paris, Hôpital Fondation Adolphe de Rothschild, and Lyon) and the reference centre for haemochromatoses and other metabolic iron diseases (Rennes), coordinated within the G2M filière [3]. Serum and urinary copper, exchangeable copper, ceruloplasmin, ferroxidase activity, neurotransmitters and catechols are measured in reference laboratories (Lariboisière and Necker, in Paris, Lyon Sud, Rennes, Grenoble and Bordeaux), and testing of ATP7A and of the copper panel is performed in Tours and Lyon-Bron, with the updated list in Orphanet [3]. The Nos Enfants Menkes association was founded by families about a decade ago, and the protocol also lists the Maladies Rares Info Services forum and, for epilepsy, Epilepsie France [3].

9.5. Organisation of care and medico-social support in France

In the French system, Menkes disease and the other copper disorders fall under long-term condition (ALD) no. 17 (inherited metabolic diseases requiring prolonged specialised treatment), with 100% coverage of related costs; the care protocol is drawn up with the medical adviser and, when not completed in a reference or competence centre, is accompanied by the completion support form for inherited metabolic diseases [3]. Coordination is the responsibility of a physician from a reference or competence centre, with a metabolic specialist, neurologist or paediatric neurologist, geneticist, paediatrician, general practitioner, biologist, radiologist, surgeon, psychiatrist, physical medicine and rehabilitation physician, ophthalmologist and otorhinolaryngologist, and with nursing, physiotherapy, psychomotor therapy, occupational therapy, speech and language therapy, dietetics, social work, psychology and neuropsychology [3]. Before 6 years of age, follow-up takes place at the early medico-social action centre (CAMSP) in the area of residence; thereafter, rehabilitation continues on an outpatient basis, in special education and home care services (SESSAD), in medico-psychological centres or in medico-educational institutes (IME), with rehabilitation admissions for respite or after acute deterioration [3]. The application to the Maison départementale des personnes handicapées (MDPH) allows assessment of the degree of disability, award of the allocation d'éducation de l'enfant handicapé (AEEH) and its supplements or of the prestation de compensation du handicap (PCH), priority and disability cards, temporary respite care of up to 90 days per year and funding of home and vehicle adaptations and technical aids; the allocation journalière de présence parentale (AJPP) compensates for one parent's suspension of professional activity, and in adults the allocation aux adultes handicapés (AAH) and referrals to medico-social services and establishments and to sheltered employment are added [3]. At school, an individualised reception plan (PAI) written by a paediatric neurologist ensures emergency care for seizures and administration of medicines, and the personalised schooling plan (PPS), support from an assistant for pupils with disabilities (AESH) and adapted units and establishments (ULIS, SEGPA, IME, IEM, EEAP) adjust schooling to the degree of disability, with discussion of educational orientation starting from the middle year of pre-school [3]. The first medical certificate for the MDPH should preferably be written by a specialist physician and accompanied by reports documenting the impact of the disease on daily life [3].

10. Illustrative Clinical Case

10.1. Menkes with prolonged survival and vascular complications (Bahrain)

Hadi and colleagues described in 2026 the first documented Menkes disease case in Bahrain [39]. The patient was a boy born at 37 weeks and 4 days by caesarean section, with normal Apgar score and weight 3 kg; his 30-year-old mother had seven previous miscarriages and had received aspirin and an anticoagulant during pregnancy, without family disease history [39]. She noticed light hair in the first week, but traditional head shaving initially concealed hair abnormalities [39]. The infant was well until 40 days, when irritability and then complex focal status epilepticus developed; at 45 days he had focal seizures, generalised hypotonia, absent primitive reflexes, frontal bossing, brachycephaly, plagiocephaly and overlapping temporoparietal bones [39]. At 3 months he had sagging cheeks, no eye contact, lax skin (Figure 1A), sparse coarse rough hypopigmented hair (Figure 1B) and an umbilical hernia; subsequently he developed spastic tetraparesis, blindness and severe growth retardation [39].

Serum copper was 30 µg/L (reference 794–2023 µg/L) and ceruloplasmin below 0.03 g/L (0.15–0.3); plasma dopamine was elevated (281 ng/L; reference up to 85), with normal noradrenaline and dopamine/noradrenaline ratio 2; CSF lactate, taurine and serine were elevated [39]. Hair histology showed pili torti (Figure 2), and Sanger sequencing identified splicing variant c.2781+2T>C in intron 13, unreported in ClinVar or LOVD; the article specifies no transcript, and normalisation to NM_000052.7 corresponds to NC_000023.11:g.78020400T>C [5, 39]. Initial MRI showed sulcal hyperintensity with right parieto-occipital and perirolandic leptomeningeal enhancement (“ivy sign”, Figure 3A), diffuse intracranial arterial tortuosity (Figure 3B), a 3 mm right frontal subdural haematoma (Figure 3C) and enhancement of the right parietal table (Figure 3D), and later right occipital cortical laminar necrosis (Figure 3E) and craniosynostosis; lower-limb radiographs showed femoral metaphyseal spurs (Figure 4) [39].

Subcutaneous copper histidinate began at 5 months (the abstract states 4 months, an internal article discrepancy), at 250 µg twice daily for 4 months [39]. Hair improved within 2 months (Figure 6) and copper and ceruloplasmin normalised, but neurological benefit was absent: blindness, spastic tetraparesis, refractory epilepsy partially controlled despite multiple anticonvulsants, chronic diarrhoea and growth retardation persisted, requiring gastrostomy and intermittent bladder catheterisation [39]. At 4 years and 8 months, cystourethrography showed a right bladder diverticulum measuring 9 × 9 cm (Figure 5A), managed conservatively; at 6 years and 7 months, admitted with urinary infection and acute kidney injury, CT angiography revealed a 6 × 5.5 × 4.5 cm right proper hepatic artery pseudoaneurysm and infrarenal, external iliac and mesenteric aneurysmal dilatations (Figure 5B), considered inoperable [39]. Two months later, at 6 years and 9 months, he collapsed at home, presumably from aneurysm rupture, without autopsy [39]. The authors interpret the presentation as an intermediate classical Menkes–OHS phenotype [39].

The consulted figures are available at https://pmc.ncbi.nlm.nih.gov/articles/PMC13217188/figure/F1/ (skin and hair), https://pmc.ncbi.nlm.nih.gov/articles/PMC13217188/figure/F3/ (MRI), https://pmc.ncbi.nlm.nih.gov/articles/PMC13217188/figure/F5/ (bladder diverticulum and pseudoaneurysm) and https://pmc.ncbi.nlm.nih.gov/articles/PMC13217188/figure/F6/ (hair after treatment) [39].

Comment. The case illustrates the typical sequence (period of normality, seizures at 6 weeks, abnormal hair, very low copper and ceruloplasmin, vascular tortuosity and subdural haematoma) and three practice points. First, treatment started at 4–5 months, outside the window of the first 4 weeks, normalised biochemistry and hair without altering the neurological course, as predicted by trial data and by the ClinGen recommendation not to start after 30 days; the FDA label allows late initiation, with survival benefit in the population with severe variants (section 7) [10, 11, 42]. Second, stopping treatment after 4 months does not correspond to the label regimen or to duration recommendations (Table 7.2), and the article does not explain why [39]. Third, survival beyond early childhood exposes connective tissue complications, bladder diverticula and visceral aneurysms, which copper does not prevent, and abdominal angiography was not part of published surveillance protocols until the 2024 French PNDS (National Diagnosis and Care Protocol), which includes aortic and abdominal CT angiography in the initial assessment of Menkes disease and OHS [1, 3, 9].

10.2. OHS/DMN overlap in adult brothers (Slovenia)

Writzl and colleagues described two brothers with NM_000052.7:c.1544-2A>T [38]. The younger, aged 34, had mild global delay from 1–2 years (walking at 18 months, first words after 3 years), childhood regression, chronic diarrhoea and occasional urinary infections from the first year, attended special education and developed steppage gait; he had a long face, high palate, coarse hair and mild kyphoscoliosis, EMG compatible with axonal motor neuropathy, and MRI showed an occipital horn and cerebral and particularly cerebellar atrophy [38]. The elder, aged 42 without cognitive impairment, had diarrhoea and hyperhidrosis from 5 years, difficulty running at 16, cramps from 27, hand tremor and poor dexterity at 36, atrial fibrillation at 39 treated by ablation, and progressively worse gait from 40; examination showed distal atrophy and weakness, absent ankle jerks, peroneal gait, mild lower-limb ataxia, normal sensation and −6-dioptre myopia, and CT showed an occipital horn [38]. Serum copper was 65.5 and 54.2 µg/dL (reference 70–140) and ceruloplasmin 19 and 18 mg/dL (20–60) [38]. RNA sequencing showed two aberrant isoforms, one skipping exon 6 with frameshift and another truncating 42 nucleotides at the start of exon 6, producing an in-frame deletion of 14 amino acids possibly retaining partial function, explaining the attenuated phenotype [38]. Article figure 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12469850/figure/genes-16-01077-f001/), consulted, shows occipital horns on MRI in the younger brother and CT in the elder [38]. The case shows that unexplained childhood-onset chronic diarrhoea with adult motor neuropathy should prompt lateral skull radiography and ATP7A testing, and RNA analysis may clarify splicing variants [38].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Untreated classical Menkes usually causes death by 3 years, typically between 7 months and 3.5 years, from pneumonia and cardiorespiratory failure, other infections or vascular complications [1, 16, 31]. In the systematic review of published cases, mean classical Menkes death age was 2.3 years [9]. With copper histidinate started by 4 weeks, median survival in the label analysis was 177.1 months versus 17.6 months in external controls, with 48% alive at 6 years and 23% at 12 years; later initiation yielded a median of 62.4 versus 20.7 months [11]. In the 2008 neonatal study, survival was 92% with median follow-up 4.6 years [10]. Neurodevelopmental improvement is heterogeneous and partly dependent on residual ATP7A activity; dysautonomia and connective tissue manifestations persist [1, 31, 34]. Saudubray notes that even without early treatment, current care, particularly feeding techniques, makes longer survival not uncommon [31].

In atypical Menkes, mean age at last assessment in published patients was 14.3 years and mortality 11.1% [9]. In OHS, life expectancy appears essentially normal, although the systematic review records 13.5% published deaths at mean age 25.3 years from surgical, gastrointestinal or bladder complications [1, 9]. In DMN, progression is slow over decades and many remain active [1].

11.2. Assessment after diagnosis

In classical Menkes disease, the initial assessment includes neurological examination with MRI and MR angiography, EEG if there are seizures and screening for autonomic signs; assessment of motor, personal-social and language development with referral to early intervention; gastroenterological and nutritional assessment with evaluation of aspiration risk, hernias and gastric polyps; paediatric nephrological and urological assessment with pelvic ultrasonography; chest radiography if there are respiratory symptoms; genetic counselling; and assessment of family needs, with social work, home nursing and patient associations [1]. ClinGen includes development, feeding and nutrition and bladder function in the initial assessments [42]. Before starting copper histidinate, copper, ceruloplasmin, electrolytes, kidney and liver function and full blood count are obtained [11]. In OHS, the initial assessment includes MRI and MR angiography, autonomic assessment (orthostatic hypotension, chronic diarrhoea), cognitive and educational assessment, pelvic ultrasonography and rheumatological assessment of hyperlaxity [1]. In DMN, it includes neurological examination, nerve conduction studies and EMG, orthopaedic and physical medicine and rehabilitation assessment, physiotherapy and occupational therapy, and clinical screening of at-risk relatives [1]. De Feyter also proposes a lateral skull radiograph to look for occipital horns and EMG if SMAX3 is suspected [9]. The PNDS (French National Diagnosis and Care Protocol) proposes a system-based initial assessment, adapted to age and severity: in Menkes disease, brain MRI with a time-of-flight (TOF) sequence and MR angiography, EEG and screening for dysautonomia; developmental and language assessment; growth, vomiting and chronic diarrhoea, with nutritional support and possible gastrostomy; abdominopelvic ultrasonography to look for bladder diverticula; chest radiograph and overnight oximetry; bone densitometry; aortic and abdominal CT angiography to look for aneurysms; initiation of medico-social entitlements; and genetic counselling [3]. In OHS, it includes MRI with TOF and MR angiography, EEG, supine and standing blood pressure, developmental assessment with educational support, abdominopelvic ultrasonography, aortic and abdominal CT angiography and clinical assessment of joint laxity; in SMAX3, EMG and conduction velocities, motor and orthopaedic assessment and physiotherapy [3].

11.3. Surveillance

Table 11.1. Recommended surveillance [1, 3, 9, 11].

De Feyter's proposals are not based on specific evidence and should be read as expert opinion [9]. ClinGen identified no evidence-supported surveillance recommendations [42]. Abdominal vascular surveillance did not appear in earlier protocols; the 2024 French PNDS (National Diagnosis and Care Protocol) includes aortic and abdominal CT angiography in the initial assessment and abdominal CT in OHS follow-up, without a defined interval, and the case described in section 10 shows that visceral aneurysms may occur in survivors [3, 39]. The PNDS presents its follow-up framework as indicative, to be adapted case by case, and intended for patients whose treatment has already been adjusted [3].

12. Summary and Final Considerations

Pathogenic variants in ATP7A, an X-linked gene encoding a copper-transporting ATPase, produce a continuous disease spectrum from classical Menkes, a lethal infantile neurodegeneration with connective tissue abnormalities, through atypical Menkes and predominantly connective tissue and autonomic occipital horn syndrome, to adult distal motor neuropathy without systemic copper abnormalities. Severity broadly follows residual protein activity: truncating variants and large deletions are associated with classical disease, leaky splicing variants with attenuated forms, and a small group of trafficking-defective missense variants with neuropathy.

In classical Menkes, treatment initiation timing is the strongest determinant of outcome. Subcutaneous copper histidinate begun within the first 4 weeks prolongs survival and improves neurodevelopment in some; after symptoms begin, it normalises biochemistry and hair but has little neurological effect. This window requires presymptomatic diagnosis, currently possible only in families with a previous case, testing the neonate before 10 days, or in genomic newborn screening research programmes. In a symptomatic infant, regression at 6–12 weeks, seizures, pili torti, vascular tortuosity and low copper and ceruloplasmin should lead to diagnosis, remembering these markers are unreliable before 2–3 months and plasma catechols are the neonatal test of choice. Disease-related subdural haematomas and metaphyseal abnormalities should not be confused with maltreatment.

FDA copper histidinate approval in January 2026 changed the US regulatory framework, but evidence still rests on open-label trials with external controls, and the medicine has no EU authorisation or OHS or DMN indication. The labelled dose, 1.45 mg copper histidinate, corresponds to the 250 µg elemental copper in clinical literature. Treatment requires renal, hepatic and haematological surveillance, particularly during the first two years. Elesclomol–copper, droxidopa for dysautonomia, AAV9 gene therapy and copper nanoclusters represent distinct evidence levels, from a controversial two-case series and three-patient crossover trial to exclusively preclinical studies.

Survivors of early-treated Menkes disease and patients with OHS now live into adulthood with dysautonomia, bladder diverticula, connective tissue fragility and vascular risk, which copper does not correct. In France, the 2024 PNDS (National Diagnosis and Care Protocol) organises this care in reference centres, with copper histidinate as a hospital preparation, an emergency protocol and structured medico-social support, and extends surveillance to aortic and abdominal CT angiography. Multidisciplinary follow-up, genetic counselling with cascade testing of women in the maternal line, pregnancy planning with prenatal or preimplantation diagnosis, and links to European reference networks and patient associations complete the approach.

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