Menkes disease: what a multidisciplinary approach can do

Figures & data

Figure 1 Multidisciplinary approach to MD.

Abbreviations: GI, gastrointestinal; MD, Menkes disease.

Figure 2 MD: (A) scalp shows “kinky hair”, (B) the inset shows “pili torti” and a normal hair strand under a high power microscope.

Abbreviation: MD, Menkes disease.

Table 1 Copper enzymes and their role in MD

Enzyme	Biological role	Associated symptoms of MD
Cytochrome oxidase	Cellular metabolism	CNS degeneration, ataxia Respiratory failure
Dopamine β-hydroxylase	Catecholamine production	Hypothermia Hypotension Diarrhea
Lysyl oxidase	Collagen and elastin cross-linking	Cephalohematomas Dysmorphic facial features Emphysema, petechial hemorrhage Arterial defects Skin, bone, and joint abnormalities
Sulfhydryl oxidase	Keratin cross-linking	Bladder diverticula, hernias Hair abnormalities
Super oxide dismutase	Free radical scavengers	CNS degeneration
Tyrosinase	Pigment formation	Hypopigmentation

Abbreviations: CNS, central nervous system; MD, Menkes disease.

Table 2 Functions of ATP7A: a multitasking protein in the nervous system

Function	Evidence	Reference
Maintenance of axonal outgrowth and synaptic integrity	Animal model	El Meskini et al^Citation31
ATP7A traffics to hippocampal glutamatergic neurons in response to NMDA receptor activation. Calcium entry following such activation is accompanied by copper efflux	Animal model	Schlief et al^Citation32
ATP7A participates in the provision of copper to dopamine β-hydroxylase to facilitate conversion of dopamine into NE	Based on CSF neurotransmitter profiles in affected individuals with MD	Kaler et al^Citation33
ATP7A participates in the maintenance of cholinergic neurons in the peripheral nervous system	Human and yeast models. Unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy which do not alter the transporters critical functions but impaired trafficking despite normal ATP7A protein and mRNA levels. Neuropathy occurs without overt signs of systemic copper deficiency	Kennerson et al^Citation34
Angiotensin-II-associated hypertension	Animal model suggests that angiotensin-II-induced hypertension is regulated through extracellular superoxide dismutase SOD3 activity through the increase in copper delivery via the ATP7A protein	Qin et al^Citation35
Cisplatin resistance	Cell line studies suggest enhancement of cisplatin toxicity in cells overexpressing ATP7A alone or on pretreatment with O(6)-benzylguanine	Rabik et al^Citation36
Bactericidal activity of macrophages	Animal model suggesting a role of ATP7A at the host pathogen interface	White et al^Citation37
Hepatic mobilization of copper in the event of a cardiac copper deficiency	Animal model suggesting a regulatory mechanism for copper mobilization from the liver to the heart in response to tissue demand that is mediated through ATP7A protein	Kim et al^Citation38

Abbreviations: CSF, cerebrospinal fluid; MD, Menkes disease; NE, norepinephrine; NMDA, N-methyl-d-aspartate.

Table 3 Manifestations of MD

Symptoms and laboratory findings in MD	Classical	Intermediate	OHS
Clinical
Facial dysmorphism	+	±	+
Neurological abnormalities
Intractable seizures	++	−	−
Dysarthria	−	++	±
Ataxia	−	++	+
Developmental delay	++	±	±
Hypotonia	++	+	±
Dermatological abnormalities
Hair abnormalities	++	+	±
Hypopigmented skin	+	+	−
Cutis laxa	+	+	++
Bony changes (osteoporosis, rib fracture, wormian bone in skull)	++	+	+
Hypothermia	+	±	±
Bladder diverticula	+	+	+
Recurrent UTI	+	+	+
Diarrhea	+	+	+
GORD, polyp, hiatus hernia	+	?	?
Retinal degeneration	+	?	?
Biochemical
Low serum copper and ceruloplasmin	+	+	+
Abnormal plasma/CSF catecholamines	+	?	?
Radiological
X-Ray skull: presence of wormian bones	++	−	−
CT/MRI changes in brain: global cerebral atrophy, cerebellar atrophy, focal changes in temporo-occipital, frontal parietal lobes, subdural effusion, leukoencephalopathy, and abnormal vasculature	++	±	±
Tortuosity of intracranial vessels	++	?	?

Notes: ++ is very much likely; + is likely; − is not likely; +/− may or may not be likely; ? is questionable.

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; GORD, gastro-oesophageal reflux disease; MD, Menkes disease; MRI, magnetic resonance imaging; OHS, occipital horn syndrome; UTI, urinary tract infection.

Table 4 Evolution and progression of epilepsy in MD

Epilepsy course (stage)	Type of seizure	Median age	EEG findings	Outcomes
Early	Focal clonic and status epilepticus	3 months	Ictal EEG showed slow spike wave and slow wave in posterior region; interictal EEG showed multifocal and polymorphic slow waves or mixed slow wave spikes	Partial seizure control in nine of the 12 patients
Intermediate	Intractable infantile spasm	10 months	Modified hypsarrhythmia; different irregular slow waves and spike waves	Six patients died at a median age of 15 months
Late	Multifocal, myoclonic seizure and tonic spasm	25 months	Multifocal high-amplitude activity; mixed irregular slow waves	The remaining six patients died at a median age of 3.6 years

Note: Data adapted from Bahi-Buisson et al.⁷⁸

Abbreviations: EEG, electroencephalography; MD, Menkes disease.

Figure 3 EEG segments from patient with MD.

Notes: (A) Anterior–posterior bipolar montage shows ictal rhythm corresponding to a focal seizure originating in the right mid to posterior temporal regions (15 mm/s, sensitivity at 15 μV/mm). (B) Ictal rhythms showing rhythmic generalized spike and slow waves (time base at 30 mm/s, sensitivity at 20 lV/mm). (C) Late stages – interictal background rhythms are slow for age, with multifocal independent spikes and spike and wave complexes (time base at 30 mm/s, sensitivity at 20 lV/mm).
Abbreviations: EEG, electroencephalography; MD, Menkes disease.

Figure 4 MRI of the brain (A) and MRA (B) from the same patient.

Notes: (A) Generalized fronto-temporal cerebral atrophy resulting in exposure of the insula, and thinning of the subcortical white matter (arrows). (B) Tortuosity of intracranial vertebral arteries (arrow).
Abbreviations: L, left; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; R, right.

Table 5 Multidisciplinary management in MD

Clinical care issues in MD by age and stage of disease	Multidisciplinary services
Neonatal period
• Early diagnosis, referral, and treatment  • Recognize early and subtle signs and symptoms (facial features, hypothermia, hair changes),investigate and confirm diagnosis so as to start treatment with copper as early as possible	• Neonatologist/pediatrician • Neonatal nurse • Geneticist • Biochemist • Dietitian
• Newborn care  • Maintaining temperature by increasing room temperature, keeping head covered, providing care with minimal skin exposure, limiting repeated blood sampling  • Optimizing feeds: feeding assessment: patients may need N/G feeding	• Nurse • Social worker
• Family education and emotional and financial support
Later care (supportive)
• Growth and nutrition  • Feeding assessment: providing option of N/G feeding or G-tube feeding  • Preventing aspiration: need for suction equipment and education	• Dietitian • Nutritionist • SLP • Gastroenterologist • Pediatrician
• Seizure optimization  • Safe environment, medications to alleviate symptoms. Education and anticipatory guidance	• Neurologist • Developmental pediatrician • Occupational therapist
• Developmental assessment  • Intellectual/cognitive assessment, range of movement assessment, preventing contractures, and bed sores	• Physiotherapist • Occupational therapist • Genetic counselor • Community nurse
• Other supportive care  • Home care and education  • Respite and other services  • Genetic counseling

Abbreviations: G-tube, gastric tube; MD, Menkes disease; N/G, nasogastric; SLP, speech and linguistic pathologist.

El MeskiniRCrabtreeKLClineLBMainsREEipperBARonnettGVATP7A (Menkes protein) functions in axonal targeting and synaptogenesisMol Cell Neurosci200734340942117215139

 PubMed Web of Science ®Google Scholar

SchliefMLWestTCraigAMHoltzmanDMGitlinJDRole of the Menkes copper- transporting ATPase in NMDA receptor-mediated neuronal toxicityProc Natl Acad Sci U S A200610340149191492417003121

 PubMed Web of Science ®Google Scholar

KalerSGGoldsteinDSHolmesCSalernoJAGahlWAPlasma and cerebrospinal fluid neurochemical pattern in Menkes diseaseAnn Neurol19933321711758434878

 PubMed Web of Science ®Google Scholar

KennersonMLNicholsonGAKalerSGMissense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathyAm J Hum Genet201086334335220170900

 PubMed Web of Science ®Google Scholar

QinZGongoraMCOzumiKRole of Menkes ATPase in angiotensin II-induced hypertension a key modulator for extracellular superoxide dismutase functionHypertension200852594595118768397

 PubMed Web of Science ®Google Scholar

RabikCAMaryonEBKaszaKShaferJTBartnikCMDolanMERole of copper transporters in resistance to platinating agentsCancer Chemother Pharmacol200964113314218998134

 PubMed Web of Science ®Google Scholar

WhiteCLeeJKambeTFritscheKPetrisMJA role for the ATP7A copper transporting ATPase in macrophage bactericidal activityJ Biol Chem200928449339493395619808669

 PubMed Web of Science ®Google Scholar

KimBETurskiMLNoseYCasadMRockmanHAThieleDJCardiac copper deficiency activates a systemic signaling mechanism that communicates with the copper acquisition and storage organsCell Metab201011535336320444417

 PubMed Web of Science ®Google Scholar

Bahi-BuissonNKaminskaANabboutREpilepsy in Menkes disease: analysis of clinical stagesEpilepsia200647238038616499764

 PubMed Web of Science ®Google Scholar