Clinical description.

Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders caused by pathogenic variants in the ATP7A, the X-linked gene that encodes a copper-transporting ATPase. Classic Menkes disease typically presents after a six- to 12-week period of good health following a normal pregnancy and birth. Feeding difficulties and/or a seizure event are the usual initial presenting features. In the absence of a known or suspected positive family history, these issues prompt a diagnostic evaluation that may consume months, by which time hypotonia and significant neurodevelopmental delays are evident. OHS is milder neurologically and is not recognized until late childhood or adolescence. Both phenotypes involve subnormal serum copper levels and other manifestations of perturbed copper metabolism, including connective tissue weakness. In contrast, ATP7A-related DMN typically presents in early adulthood with isolated muscle weakness and atrophy, in the absence of overt copper metabolism abnormalities.

• While nonspecific temperature instability and hypoglycemia in the neonatal period may be noted retrospectively, infants with classic Menkes disease appear healthy until age 1.5 to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit neurologic findings and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, and often lightly pigmented). Without treatment, premature death is typical, often by age three years.
• OHS is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Intellect is normal or slightly reduced.
• ATP7A-related DMN, an adult-onset disorder resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or OHS.

Diagnosis/testing.

Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine-beta-hydroxylase (DBH) and lysyl oxidase. While serum copper concentration and serum ceruloplasmin concentration are low in Menkes disease and OHS, they are normal in ATP7A-related DMN. Notably, serum copper and ceruloplasmin levels are low in healthy newborns for the first several months of life; thus, these are not reliable diagnostic biomarkers in infants younger than age two months.

The diagnosis of ATP7A-related copper transport disorders is most often confirmed in a proband by detection of either a hemizygous ATP7A pathogenic variant in a male or a heterozygous ATP7A pathogenic variant in a female with skewed X inactivation, or with a X-autosome translocation; the latter scenarios are quite rare.

Management.

Prevention of primary manifestations (and treatment): Subcutaneous injections of copper histidinate beginning by age 28 days (corrected for prematurity/gestational age) enhances survival and improves neurodevelopmental outcomes.

Treatment of manifestations:

• Classic Menkes disease. Seizure management per neurologist; early intervention and individualized education plan per developmental pediatrician, feeding therapy and gastrostomy tube placement to enhance caloric intake; antibiotic prophylaxis to prevent bladder infection and surgery for bladder diverticula; RSV, influenza and COVID vaccinations due to risk of recurrent pneumonia; social work support.
• Occipital horn syndrome. Possible droxidopa treatment for dysautonomia; early academic support and individualized education plan as indicated per developmental pediatrician; surgical treatment of bladder diverticula and antibiotic prophylaxis as necessary; physical therapy; joint splints per orthopedist or rheumatologist for joint laxity.
• ATP7A-related distal motor neuropathy. Special shoes with good ankle support; ankle-foot orthoses; physical therapy; occupational therapy; orthopedic surgery for severe pes cavus deformity; mobility devices; and exercise as tolerated.

Surveillance:

• Menkes disease. At each visit assess seizures, developmental progress, educational needs, growth and nutrition, therapy needs, mobility, self-help skills, frequency of pulmonary infections, and family needs.
• Occipital horn syndrome. At each visit assess orthostatic blood pressures, development, and educational needs. Annual pelvic ultrasound for bladder diverticula.
• ATP7A-related distal motor neuropathy. Annual neurologic exam, electroneurography of peripheral nerves, electromyography/electroneurography, physical therapy assessment, occupational therapy assessment, foot examination for pressure sores or poorly fitting footwear.

Genetic counseling.

The ATP7A-related copper transport disorders are inherited in an X-linked manner. Approximately one third of affected males have no family history of Menkes disease/OHS/DMN. If the mother is a heterozygote, the risk of transmitting the ATP7A pathogenic variant is 50% in each pregnancy: a male who inherits the pathogenic variant will be affected with the disorder present in his brother; females who inherit the pathogenic variant will be heterozygotes and generally will not be affected. Male Menkes disease survivors and males with OHS or ATP7A-related DMN theoretically could pass the pathogenic variant to all of their daughters and none of their sons. When a pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

An ATP7A-related copper transport disorder (Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy) should be suspected in individuals with the following clinical and laboratory findings.

Establishing the Diagnosis

The diagnosis of ATP7A-related copper transport disorders is most commonly established in a proband by detection of either a hemizygous ATP7A pathogenic (or likely pathogenic) variant in a male or a heterozygous ATP7A pathogenic (or likely pathogenic) variant in a female on molecular genetic testing (Table 2) or by additional biochemical studies (see Additional Biochemical Studies) if molecular genetic test results are ambiguous.

Note: (1) The clinical/laboratory findings necessary to establish this diagnosis in a female proband are the same as for males (see Table 1). In some instances, a symptomatic female has an X-autosome translocation involving Xq21.1. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of a hemizygous or heterozygous ATP7A variant of uncertain significance does not establish or rule out the diagnosis.

Clinical Description

The clinical spectrum of ATP7A-related copper transport disorders ranges from classic Menkes disease at the severe end, to occipital horn syndrome (OHS), to isolated distal motor neuropathy (DMN) [Kaler 2011]. Classic Menkes disease is characterized by neurodegeneration and failure to thrive commencing at age two to three months. The age at diagnosis is usually between four to eight months. In contrast, OHS presents in early-to-middle childhood and is characterized predominantly by connective tissue abnormalities. ATP7A-related DMN is an adult-onset disorder resembling Charcot-Marie-Tooth hereditary neuropathy; it shares none of the clinical abnormalities characteristic of classic Menkes disease or OHS.

Genotype-Phenotype Correlations

The amount of residual ATPase enzyme activity correlates with the phenotype in Menkes disease, OHS, and ATP7A-related distal motor neuropathy (DMN) and, in part, with response to early copper treatment in Menkes disease [Kaler et al 2008].

Milder variants of Menkes disease and OHS are often associated with splice junction pathogenic variants that alter but do not eliminate proper RNA splicing (i.e., "leaky" splice junction defects).

The pathogenic variants associated with ATP7A-related DMN involve unique missense variants within or near the luminal surface of the protein, which may be relevant to the abnormal intracellular trafficking shown for these defects and to the mechanism of this form of motor neuron disease [Kennerson et al 2010, Yi et al 2012, Yi & Kaler 2018]. Variants p.Phe1386Ser and p.Thr994Ile result in altered distribution of the protein, with preferential localization to the plasma membrane [Yi et al 2012]. The p.Thr994Ile variant exposes a hidden UBX domain that interacts avidly with vasolin-containing protein (p97/VCP) that has been linked to various membrane protein trafficking processes, including cargo sorting through the endosomal pathway [Yi & Kaler 2018].

Intrafamilial phenotypic variability is occasionally observed in Menkes disease [Kaler et al 1994, Borm et al 2004, Donsante et al 2007]. Differences noted among affected individuals from two families with ATP7A-related DMN included degree of weakness, atrophy, and sensory loss [Kennerson et al 2010].

Nomenclature

Menkes disease is also known as Menkes kinky hair syndrome, or trichopoliodystrophy.

Occipital horn syndrome was formerly known as X-linked cutis laxa.

ATP7A-related distal motor neuropathy is also known as X-linked distal spinal muscular atrophy 3.

Prevalence

Previous estimates of the prevalence of Menkes disease were based on confirmed clinical cases ascertained from specific populations and varied from 1:40,000 to 1:354,507.

However, recent analyses based on genomic ascertainment of pathogenic alleles and assuming Hardy-Weinberg equilibrium predict a birth prevalence of ATP7A-related disorders potentially as high as 1:8,664 live male births [Kaler et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a male diagnosed with an ATP7A-related copper transport disorder, the evaluations summarized in Table 3a, 3b, and 3c (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

Menkes disease. In classic Menkes disease, early treatment with subcutaneous injections of copper histidinate (CuHis), ideally within four weeks of birth (corrected for prematurity/gestational age) often enhances survival and improves quality of neurodevelopmental outcome [Kaler et al 2008; Kaler et al 2010; Kaler et al, unpublished data]. However, some infants may not show significant improvement relative to the natural history of untreated Menkes disease [Kaler et al 1995; Kaler et al 2008; Kaler et al, unpublished data]. The type and severity of the ATP7A pathogenic variant may partly influence response to early copper treatment [Kaler et al 2008].

To maintain serum copper concentration in the normal range (75-150 µg/dL), the suggested dose of copper histidinate (CuHis) is:

• For infants age <1 year: 250 µg administered subcutaneously (0.5 mL) 2x/day
• For infants age ≥1 year: 250 µg administered subcutaneously (0.5 mL) 1x/day

Cupric chloride (CuCl₂) is available commercially in a concentration of 200 µg/0.5 mL for intravenous administration as a total parenteral nutrition additive. CuCl₂ has been used for subcutaneous injections in urgent situations to raise circulating copper levels in affected newborns with Menkes disease for whom CuHis was not immediately available. However, the highly acidic pH (2.1) renders this formulation unsuitable for long-term subcutaneous use due to local skin irritation and considerable scarring.

Any role for subcutaneous CuCl₂ in Menkes disease should be eliminated when CuHis is approved by regulatory authorities in the US and other countries.

Occipital horn syndrome. Although there is no evidence that copper replacement therapy for OHS is clinically beneficial; in the authors' opinion it is reasonable to expect even better neurodevelopmental and neurocognitive outcomes if individuals with OHS were identified early and treated with CuHis during their first three years of life.

Surveillance

For infants being treated with CuHis (or temporarily with CuCl₂), monitor serum copper and ceruloplasmin levels to avoid supranormal levels.

Evaluation of Relatives at Risk

It is appropriate to test male relatives at risk for Menkes disease for the ATP7A pathogenic variant identified in the family before age ten days in order to promptly begin copper replacement treatment (see Prevention of Primary Manifestations).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

CuHis received FDA FastTrack (2018) and Breakthrough (2020) designations from the US Food and Drug Administration and the European Medicines Agency Committee for Orphan Medicinal Products issued a positive opinion for Orphan Drug Designation in 2020. An expanded access clinical trial that provides CuHis for individuals with Menkes disease in the US (NCT04074512) is currently in progress.

For updated preliminary results on subcutaneous CuHis treatment for Menkes disease, click here.

Adeno-associated viral (AAV) gene therapy in combination with copper has also been investigated in Menkes disease mouse models, with promising results [Donsante et al 2011, Haddad et al 2018].

Newborn screening is not currently available for Menkes disease because biochemical strategies may not be compatible with or practical for current newborn screening platforms. A pilot study to evaluate the potential of sequence analysis of ATP7A from dried blood spots demonstrated proof of principle for this approach [Parad et al 2020]. If successful, such testing would allow early diagnosis and treatment of Menkes disease and other ATP7A-related disorders.

A Phase I/II clinical trial of droxidopa (Northera^®) for dysautonomia in adult survivors of Menkes disease and adults with occipital horn syndrome is scheduled to open in Spring, 2021, using a double-blind placebo-controlled randomized crossover design.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Therapies proven to be ineffective include vitamin C.

Mode of Inheritance

ATP7A-related copper transport disorders (i.e., classic Menkes disease, occipital horn syndrome [OHS], and ATP7A-related distal motor neuropathy [DMN]) are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the ATP7A pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the ATP7A pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo ATP7A pathogenic variant (in which case the mother is not heterozygous), or the mother may have somatic/germline mosaicism.
  About one third of affected males represent simplex cases.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an ATP7A pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected. Intrafamilial phenotypic variability is occasionally observed in Menkes disease and may also be observed in ATP7A-related DMN (see Genotype-Phenotype Correlations).
  • Females who inherit the pathogenic variant will be heterozygotes. About 50% of females who are obligate heterozygotes for an ATP7A pathogenic variant demonstrate regions of pili torti but are otherwise generally asymptomatic (see Clinical Description, Heterozygous Females).
• If the proband represents a simplex case and if the ATP7A pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband

• Male Menkes disease survivors, and males with OHS, or ATP7A-related DMN transmit the ATP7A pathogenic variant to all of their daughters and none of their sons.
• Males with classic Menkes disease are not known to reproduce.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of being heterozygous for an ATP7A pathogenic variant.

Heterozygote Detection

Molecular genetic testing. Identification of female heterozygotes requires either prior identification of the ATP7A pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

About 50% of females who are obligate heterozygotes for an ATP7A pathogenic variant demonstrate regions of pili torti but are otherwise generally asymptomatic (see Clinical Description, Heterozygous Females).

Note: Biochemical testing is generally unreliable for carrier detection because of overlap with normal ranges.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous or affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ATP7A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The protein encoded by ATP7A, a P-type ATPase, transports copper across cellular membranes and is critical for copper homeostasis.

ATP7A pathogenic variants may result in a gene product with no copper transport capability (usually associated with a severe phenotype) or reduced quantity of normally functioning gene product (can be associated with a milder phenotype).

Most ATP7A pathogenic variants are family specific (unique), although certain variants have occurred in more than one family (e.g., exon 1 deletion, Gly666Arg, Gly727Arg). ATP7A variant types include: deletions and duplications; insertions; and nonsense, splice junction, and missense variants.

ATP7A-related distal motor neuropathy involves several unique pathogenic missense variants within or near the luminal surface of the protein [Kennerson et al 2010], which may be relevant to the abnormal intracellular trafficking shown for these defects and the mechanism of this form of motor neuron disease.

Mechanism of disease causation

• Menkes disease, OHS. Loss of copper transport function
• ATP7A-related isolated DMN. Uncertain

ATP7A-specific laboratory technical considerations. Deep intronic variants may be difficult to detect by commercial molecular diagnostic laboratories [Parad et al 2020].

Author Notes

www.nationwidechildrens.org/specialties/menkes-disease-clinic

Acknowledgments

We thank the following organizations for research support: NICHD, Cyprium Therapeutics, Inc, NINDS, NIH Clinical Center, NIH Pharmaceutical Development Section, Office of Rare Diseases/NCATS, NIH Bench-to-Bedside Program, NIH Office of Dietary Supplements, UK Menkes Foundation, The Menkes Foundation (USA), Nos Enfants Menkes, Angeli per la Vita; the many patients, living and deceased, and their devoted families, who participated in the clinical research described; and colleagues in the copper research, viral gene therapy, and newborn screening communities, as well as regulatory experts at FDA and EMA, for their collective wisdom and invaluable guidance.

Revision History

• 15 April 2021 (sw) Comprehensive update posted live
• 18 August 2016 (bp) Comprehensive update posted live
• 14 October 2010 (me) Comprehensive update posted live
• 13 July 2005 (me) Comprehensive update posted live
• 9 May 2003 (me) Review posted live
• 27 November 2002 (sk) Original submission

Literature Cited

• Borm B, Moller LB, Hausser I, Emeis M, Baerlocher K, Horn N, Rossi R. Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/occipital horn syndrome in three affected males in a single family. J Pediatr. 2004;145:119–21. [PubMed: 15238919]
• Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet. 2011;79:176–82. [PMC free article: PMC3099248] [PubMed: 20497190]
• Donsante A, Tang JR, Godwin SC, Holmes CS, Goldstein DS, Bassuk A, Kaler SG. Differences in ATP7A gene expression underlie intra-familial variability in Menkes disease/occipital horn syndrome. J Med Genet. 2007;44:492–7. [PMC free article: PMC2597922] [PubMed: 17496194]
• Donsante A, Yi L, Zerfas P, Brinster L, Sullivan P, Goldstein DS, Prohaska J, Centeno JA, Kaler SG. ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Mol Ther. 2011;19:2114–23. [PMC free article: PMC3242653] [PubMed: 21878905]
• Haddad MR, Choi EY, Zerfas PM, Yi L, Martinelli D, Sullivan P, Goldstein DS, Centeno J, Brinster L, Ralle M, Kaler SG. Cerebrospinal fluid-directed rAAV9-rsATP7A plus subcutaneous copper histidinate advance survival and outcomes in a Menkes disease mouse model. Mol Ther Methods Clin Dev. 2018;10:165–78. [PMC free article: PMC6080355] [PubMed: 30090842]
• Hill SC, Dwyer AJ, Kaler SG. Cervical spine anomalies in Menkes disease: a radiologic finding potentially confused with child abuse. Pediatr Radiol. 2012;42:1301–4. [PMC free article: PMC3482292] [PubMed: 22825777]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Kaler SG. The neurology of ATP7A copper transporter disease: emerging concepts and future trends. Nat Rev Neurol. 2011;7:15–29. [PMC free article: PMC4214867] [PubMed: 21221114]
• Kaler SG, Buist NR, Holmes CS, Goldstein DS, Miller RC, Gahl WA. Early copper therapy in classic Menkes disease patients with a novel splicing mutation. Ann Neurol. 1995;38:921–8. [PubMed: 8526465]
• Kaler SG, Ferreira CR, Yam LS. Estimated genetic prevalence of Menkes disease based on the Genome Aggregation Database (gnomAD). Mol Genet Metab Rep. 2020;24:100602. [PMC free article: PMC7283148] [PubMed: 32528851]
• Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA, Goldstein DS, Holmes CS, Gahl WA. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet. 1994;8:195–202. [PubMed: 7842019]
• Kaler SG, Holmes CS, Goldstein DS, Tang JR, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358:605–14. [PMC free article: PMC3477514] [PubMed: 18256395]
• Kaler SG, Liew CJ, Donsante A, Hicks JD, Sato S, Greenfield JC. Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. J Inher Metab Dis. 2010;33:583–9. [PMC free article: PMC3113468] [PubMed: 20652413]
• Kennerson M, Nicholson G, Kowalski B, Krajewski K, El-Khechen D, Feely S, Chu S, Shy M, Garbern J. X-linked distal hereditary motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology. 2009;72:246–52. [PubMed: 19153371]
• Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010;86:343–52. [PMC free article: PMC2833394] [PubMed: 20170900]
• Moore CM, Howell RR. Ectodermal manifestations in Menkes disease. Clin Genet. 1985;28:532–40. [PubMed: 4075564]
• Parad RB, Kaler SG, Mauceli E, Sokolsky T, Yi L, Bhattacharjee A. Targeted next generation sequencing for newborn screening of Menkes disease. Mol Genet Metab Rep. 2020;24:100625. [PMC free article: PMC7378272] [PubMed: 32714836]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Stevens KE, Price JE, Marko J, Kaler SG. Neck masses due to internal jugular vein phlebectasia: frequency in Menkes disease and literature review of 85 pediatric cases. Am J Med Genet Part A. 2020;182:1364–77. [PubMed: 32293788]
• Yi L, Donsante A, Kennerson ML, Mercer JFB, Garbern JY, Kaler SG. Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy. Hum Mol Genet. 2012;21:1794–807. [PMC free article: PMC3313796] [PubMed: 22210628]
• Yi L, Kaler SG. Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration. J Biol Chem. 2018;293:7606–17. [PMC free article: PMC5961040] [PubMed: 29599289]