Copper-histidine therapy in an infant with novel splice-site variant in the ATP7A gene of Menkes disease: the first experience in South East Asia and literature review

  1. Ekkarit Panichsillaphakit 1,
  2. Tanisa Kwanbunbumpen 1,
  3. Sirinuch Chomtho 2 and
  4. Chonnikant Visuthranukul 2
  1. 1 Division of Nutrition, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
  2. 2 Pediatric Nutrition Research Unit, Division of Nutrition, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, The Thai Red Cross Society, Bangkok, Thailand
  1. Correspondence to Dr Chonnikant Visuthranukul; chonnikant.v@chula.ac.th

Publication history

Accepted:24 Mar 2022
First published:07 Apr 2022
Online issue publication:07 Apr 2022

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Menkes disease (MD) is an X linked recessive multi-systemic disorder of copper metabolism, resulting from an ATP7A gene mutation. We report a male infant aged 4 months who presented with kinky hair, hypopigmented skin, epilepsy and delayed development. Magnetic resonance imaging (MRI) of brain demonstrated multiple tortuosities of intracranial vessels and brain atrophy. Investigation had showed markedly decreased serum copper and ceruloplasmin. The novel c.2172+1G>T splice-site mutation in the ATP7A gene confirmed MD. He was treated with subcutaneous administration of locally prepared copper-histidine (Cu-His). Following the therapy, hair manifestation was restored and serum ceruloplasmin was normalised 1 month later. Despite the treatment, epilepsy, neurodevelopment and osteoporosis still progressed. He died from severe respiratory tract infection at the age of 9.5 months. These findings suggest that the benefit of Cu-His in our case is limited which might be related to severe presentations and degree of ATP7A mutation.

Background

Menkes kinky hair disease or Menkes disease (MD) (MIM# 309400), formerly known as trichopoliodystrophy, is an X linked recessive disorder of copper metabolism. MD is a rare genetic disease, first described by John Hans Menkes in 1962,1 caused by a defect in the ATPase 7A gene (ATP7A) on chromosome Xq13.3-q21.1, 23 exons and 150 kb.2 3 The ATP7A gene produces proteins that are localised at the trans-Golgi network, which involves intracellular copper transport and are found in several organs, except the liver.4 The mutations cause copper trafficking in cells and a decrease in cuproenzyme activity. The systemic manifestations include hypopigmentation, growth and mental retardation, cerebral and cerebellar degeneration, connective tissue abnormalities and almost all patients die before the age of 3 years.5–7 Clinical presentation of this disease ranges from occipital horn syndrome (MIM# 304150), in its mildest form, to severe classic form (90%–95% of case).8 At present, a syndrome restricted to progressive distal neuropathy without overt signs of systemic copper deficiency (MIM# 300489) has also been identified to associate with ATP7A mutation.9

The incidence of this disease is between 1:100 000 and 1:300 000 live births.10 In Thailand, the incidence of this disease is still not known but there have been four reported cases since 1993. All patients were diagnosed at ages between 3 and 8 months with delayed development and seizure. The infants from Bangkok in 200311 and in 200512 were treated with copper sulfate and copper chloride injection, respectively. However, both did not respond to treatment and the other two infants received supportive treatment13 14 (table 1 shows a summary of case reports with various clinical presentations).

Table 1

Summary of case reports in Thailand with various clinical presentations compared with our case10–13

Case no.
(place)		 Case 1
(Songkla, Southern Thailand)		 Case 2*
(Ramathibodi, Bangkok, Thailand)		 Case 3
(Siriraj, Bangkok, Thailand)		 Case 4
(Phramongkutklao,
Bangkok, Thailand)		 Case 5
(Khonkaen, Northeast Thailand)		 Case 6 (our case)
(KCMH,
Bangkok, Thailand)
Year 1993 1998 2003 2005 2016 2018
Birth weight (g) 2850 2550 3500 2560 2605 2690
Head size (percentile) 25 % NA 10%–25% 25%–50% 25 % 10 %
Onset of delayed development 4 months NA 3 months 3 months 3 months 2 months
Onset of seizure – NA 3 months 5 months 3 months 1.5 months
Skin Smooth Loose Loose Loose Loose Loose
Serum copper (µg/dL) 34.9 32.3 0 24.8 2.3 8.3
Serum ceruloplasmin (mg/dL) 2.3 5.5 0 5.33 5.0 7.9
Bony X-ray Wormian bone NA Wormian bone Wormian bone Wormian bone Wormian bone
CT brain Cerebral/Cerebellar atrophy Cerebral/Cerebellar atrophy Cerebral/Cerebellar atrophy Cerebral/Cerebellar atrophy Cerebral/Cerebellar atrophy Cerebral/Cerebellar atrophy
MRI/MRA – – – – Tortuosity and dilatation of circle of
Willis, internal iliac artery aneurysm		 Tortuosity of multiple intracranial artery, internal carotid arteries
Family history Negative Negative Negative Negative Negative Negative
Treatment Supportive Supportive Copper sulfate Copper chloride Supportive Copper histidine
Complication Pneumonia/Sepsis NA Urinary tract infection Pneumonia Pneumonia Pneumonia
Death at age NA NA NA 2 years 6 months 1 year 6 months 9.5 months

  • *Unpublished case.

  • MRA, magnetic resonance angiography; NA, not available.

Currently, the accepted therapy of MD is subcutaneous copper-histidine (Cu-His) injection, offering better bioavailability than copper salts into the cells.15 The aim of treatment is to bypass the normal route of copper absorption through the gastrointestinal tract by directly delivering copper to brain cells. Currently, a clinical trial for copper histidinate treatment in patients with MD is now available by the manufacturer.16 As there are no reported cases of MD in children who were treated with Cu-His in South East Asia, we present this rare genetic disease in addition to the biochemical and clinical benefits of subcutaneous Cu-His therapy.

Case presentation

A male infant with non-consanguineous parents presented with a generalised tonic seizure and nystagmus treated with phenobarbital since the age of 1.5 months, was referred to our centre with hypopigmented skin, kinky hair (figure 1A) and subtle flexor spasm at the age of 4 months. Light microscope of scalp hair revealed trichorrehexis nodosa (figure 1B). His anthropometry revealed a severe protein energy malnutrition. Ophthalmological examination showed brownish iris, clear cornea, sharp disc, flat retina and he did not blink to bright light on visual acuity. Neurological examination showed a lethargic infant with limb hypertonia and truncal hypotonia with equal movement, normoreflexia and myoclonic seizure. He could turn to voice and stared at face for a short period; nevertheless, his head was still lagging and he could not roll over. Other systems were unremarkable.

Figure 1

Skin and hair appearance of patient. (A) Hypopigmented skin with short, sparse, coarse lightly pigmented and kinky hair. (B) The arrows show ‘trichorrhexis nodosa’ (nodes along the hair shaft) (created by the authors).

Investigations

At the time of referral to our centre, the paediatric neurologist at the local hospital had already investigated to confirm the MD. Blood tests showed low plasma Cu 8.3 µg/dL (20–70 µg/dL in newborn)17 and low plasma ceruloplasmin 7.9 mg/dL (15–50 mg/dL in newborn).17 MRI and magnetic resonance angiography (MRA) of brain (figure 2) revealed severe cerebellar atrophy with chronic subdural effusion in posterior fossa (figure 2A), cystic changes in both temporal lobes and lateral inferior part of frontal lobes (figure 2B), abnormal tortuosity of intracranial arteries, basilar artery, V4 (intradural or intracranial) part of both vertebral arteries and cervical part of both internal carotid arteries (figure 2C). Echocardiography and ultrasound of the entire abdomen revealed normal internal organs.

Figure 2

MRI of the brain (A and B) and MRA (C) from the patient. (A) Mild diffuse cerebral atrophy, cystic changes in both temporal lobes and lateral inferior part of frontal lobes (arrows), (B) severe cerebellar atrophy (arrow), (C) tortuosity of cervical part of internal carotid artery (arrows) (created by the authors).

Complete blood count (CBC) showed a total white blood cell count of 16 740 cells/µL (N 27.4%, L 58%, M 8.8%), haemoglobin (Hb) 11.3 (12.0±1.0) g/dL, haematocrit (Hct) 35.6% and platelet count of 4 36 000 cells/µL. Liver function test (LFT) revealed total protein of 6.2 (4.4–7.1), globulin 2.0, albumin 4.2 (2.8–4.7) g/dL, total bilirulin 0.13 (0.05–0.68), directed bilirubin 0.08 (0.05–0.30) mg/dL, aspartate transaminase 49 (20–67), alanine transaminase 55 (5–33), alkaline phosphatase 226 (134–518) and gamma-glutamyl transferase 175 (8–127) U/L. Iron studies showed serum iron at 44 (16–128) µg/dL, serum ferritin 135.5 (14–647) ng/mL, total iron binding capacity at 281 (250–400) µg/dL and transferrin saturation of 15% (<16%). Serum copper was 0.016 µg/dL (20–70 µg/dL in newborn)17 and serum ceruloplasmin was 7.0 mg/dL (20–70 mg/dL in newborn).17

In addition, wormian bones on skull radiography were also seen (figure 3). Sleep electroencephalography (figure 4) suggested a multifocal epileptic disorder arising from bilateral parieto-occipital area with mild-to-moderate encephalopathy. Thirteen rhythmic run of spike and wave complexes occurred more independently in the right than left hemisphere and were markedly at the parieto-occipital area (figure 4A), while low amplitude intervals followed rhythmic runs (figure 4B).

Figure 3

Lateral skull radiography shows wormian bones (arrows) (created by the authors).

Figure 4

Electroencephalography segments from patient with MD in this report. (A) Thirteen runs of spike and wave complexes were more in right hemisphere than in left hemisphere, markedly at parieto-occipital areas. (B) Low amplitude intervals followed rhythmic runs (created by the authors).

A blood sample from the patient was collected for genetic testing. A hemizygous splice site variant (NM_000052.6:c.2172+1G>T, chrX:77 267 172 G>T) in the ATP7A gene was identified in the patient by singleton whole exome sequencing analysis. This variant has not been identified in the gnomAD (https://gnomad.broadinstitute.org/) and the in-house Thai Exome databases. A splice-site mutation at the same genomic location has been previously reported in patients with X linked recessive MD.18 19 The variant is classified as pathogenic according to the American College of Medical Genetics and Genomics classification.20

Treatment

We prepared the Cu-His drug following the instruction of Sheela et al.21 CuCl2 dihydrate (Merck, 134.5 mg) and L-histidine (Merck, 245 mg) were separately dissolved in 40 mL NaCl solution at room temperature. The solution was mixed together and then blue colour appeared [CuCl2+2(L-histidine) ↔ Cu(L-histidine)2+2H++2Cl−] (figure 5A).22 The initial pH of aqueous solution was approximately 3.7. Thus, 0.1% NaOH was added to the solution until the pH reached 7.38–7.40. For physiological pH, >99% are Cu(L-His)2 structure.15 The solution was transferred to volumetric flask and final concentration was 500 µg/mL. The portion size 0.5 mL/ampoule were stored at 4°C in light protective bags with shelf-life of 56 days21 (figure 5B,C). Pyrogen detection test by kinetic turbidimetric method and sterility were tested before use.

Figure 5

Copper-histidine (Cu-His) preparation. (A) Blue colour of solution after mixing CuCl2 and L-histidine together. (B) Ready-to-use prefill sterile Cu-His ampoule (250 µg/0.5 mL). (C) The ampoules were stored at 4°C in light protective bags (created by the authors).

Before Cu-His replacement at the age of 6 months, the decision to start treatment was jointly conducted by medical professionals and his parents. Written informed consent was obtained. He was injected with 250 µg of Cu-His subcutaneously given two times per day.23 A mitochondrial cocktail of vitamins, cofactors and antioxidants were also given once daily following the report from Prasad et al.24 His parents were also taught how to clean his skin and drug injection technique before hospital discharge.

Outcome and follow-up

One month later, his hair manifestations were restored to normal appearance (figure 6). Blood investigation revealed serum copper increased to 0.132 µg/dL and ceruloplasmin was 32 mg/dL. CBC showed Hb 13.3 g/dL, Hct 40.6% and LFT was within normal range.

Figure 6

Hair manifestation after 1 month of copper-histidine treatment (created by the authors).

In terms of psychomotor development, he still could not roll over and was bed ridden. His skin appearance was still hypopigmented and epileptic pattern progressed to infantile spasm. The paediatric neurologist added topiramate and clobazam for seizure control. Furthermore, osteoporosis still progressed despite Cu-His treatment (figure 7). At 8 months, the patient suffered from aspiration pneumonia which developed into severe respiratory distress syndrome. High frequency oscillator was used, for 1 month, with respiratory support at a local hospital. However, the disease did not respond well to empirical antibiotics and the patient died at the age of 9.5 months.

Figure 7

X-ray long bone (left humerus) of the patient at 1, 4 and 9 months of age shows progression of osteoporosis despite treatment (created by the authors).

Discussion

MD is a fatal disorder that causes death in most patients before the third year of life from oropharyngeal incoordination with aspiration, progressive neurological symptoms and respiratory tract infection.25 The prenatal history of premature rupture of membrane is commonly found in MD26; furthermore, other symptoms such as hypothermia, prolonged jaundice, sparse and kinky hair and loose skin have also been reported.23 27 However, in the neonatal period, clinical presentations are usually subtle or normal. Thus, the diagnosis is often delayed until the patient develops seizure, hypotonia and delayed development at around 3–6 months.6

Skin and hair abnormalities are the most striking signs in MD. In our case, light microscope of scalp hair revealed trichorrehexis nodosa, a condition that has also been documented in previous report,28 while pili torti (hair shaft twisted 1800) is more commonly found in patients.29 Low serum levels of copper and ceruloplasmin are usually seen in this disease. Recently, additional biochemical markers have also been suggested by Kaler27 for diagnosis of MD. The genetic analysis in our case revealed a novel c.2172+1G>T splice-site mutation in the ATP7A gene that confirmed MD.

Neurological features include myoclonic or multifocal seizure, infantile spasm and status epilepticus, which are observed in over 90% of patients who are untreated between the age of 6 and 8 weeks.6 24 In the classic form of MD, three stages of epilepsy progression are identified.24 The early stage usually shows generalised hypotonia and clonic seizure, evolving towards status epilepticus which is consistent with our case. This stage can be treated with phenobarbital or benzodiazepine as a monotherapy, while intermediate and late stages are usually drug-resistant refractory epilepsy.30 31 The neuropathogenesis of disease is caused by copper deficiency in neuron cells, which involves cuproenzyme activity, for example, cytochrome c oxidase, dopamine β-hydroxylase and peptidyl α-amidating monooxygenase, leading to consequent alterations of neurotransmitters and cellular energy metabolism.24 27 Furthermore, MRI of brain of our case revealed a generalised cerebral and cerebellar atrophy. MRA of the brain also showed tortuosity of intracranial and cervical blood vessels, consistent with previous reports.6 24 30

Specific treatment of MD is to provide exogenous copper to the cells and cuproenzymes. Subcutaneous copper administration is the main method to modify disease progression.10 Previously, several copper salts (copper chloride, copper sulfate, copper EDTA, copper acetate and copper albumin) were used to treat MD.32 However, the administration of copper salts induces copper-albumin complex, which is not bioavailable to the cells.15 32 Recently, subcutaneous Cu-His injection is the most effective treatment and early administration of this drug can reverse the progression of disease, as well as serum copper and ceruloplasmin levels.32 33 Nevertheless, the treatment outcomes are likely to be effective in cases with early initiation, before onset of symptoms, and residual ATP7A activity.3 24 34 The immature blood-brain barrier (BBB) in infant, which allows copper transport across astrocytes to neuron cells, plays a critical role for therapy.33 35 Additionally, ATP7A is highly expressed in neonatal brain, which controls the copper transport across the BBB,7 indicating an age-dependent period of increased copper influx. Thus, the more mature BBB, the greater reduction of copper across the brain. However, Kinebuchi et al 36 reported that blood-cerebrospinal fluid barrier is an alternative pathway of copper from blood transport into cerebrospinal fluid (CSF). According to this mechanism, further studies focusing on biochemical and neurological outcomes of given Cu-His after critical period of BBB maturation are needed.

In our case, we prepared Cu-His following the regimen by Sheela et al. 21 However, we could not perform the process of bubbling nitrogen gas into 0.9% NaCl solution due to a limitation of materials. It is well known that Cu-His solution is sensitive to oxygen and light33; nevertheless, direct absorption of ultraviolet or visible light by imidazole function of histidine (the maximum absorptive wavelength of Cu(His)2 is 645 nm)22 33 is not the major reaction.37 In an oxygen-enrich environment, histidine photooxidation mainly occurs via the type II mechanism. In this mechanism, the energy from light is transferred to the ground state oxygen molecule which turns into a singlet oxygen (1O2).38 The singlet oxygen is unstable endoperoxide and in turn, reacts with imidazole residue of histidine, which further degrades to aspartic acid, urea and asparagine derivatives via several intermediate compounds.37 39 Thus, in our opinion, light energy should be a primary factor to activate this process. If we can protect these drugs from light, they could be stored for nearly 56 days.21

Cu-His was given to the patient at the age of 6 months, which at that time, seizures had already developed. After initiation, serum ceruloplasmin was returned to normal value within 4 weeks which was consistent with a previous study.35 However, serum copper was slightly increased but it could not reach the normal value. The result of this observation might be caused by some limitation of our drug preparation method. In terms of seizure control and psychomotor development, the benefit of copper therapy in our case was limited. At older age, his seizure type turned into infantile spasm which was refractory to antiepileptic drugs. Recently, a systematic review has suggested that early treatment, especially before 30 days of life, is an effective way to achieve a good clinical outcome in patients with MD.40 Thus, not only the disease related to in utero metabolic change, but disease progression might also be from delayed initiation of copper therapy. In addition, osteoporosis still progressed despite treatment in our case, which was consistent with previous studies3 10 reporting that Cu-His could not prevent advance skeletal abnormalities.

To the best of our knowledge, this is the first case report to explore the effects of Cu-His replacement in a patient with MD in South East Asia. We used a self-prepared drug following the protocol of a previous study.21 Fortunately, Cu-His preparation was of low cost and did not pose an economic hardship on the parents and our centre. However, there were some limitations. First, the blood or CSF catecholamine analysis could not be tested prior/post treatment. Second, we could not analyse Cu-His complex species in our drug by using thin-layer chromatography before use. In conclusion, early recognition and diagnosis of MD for timely initiation of Cu-His therapy may be effective methods to improve neurological symptoms and some serious complications.

Patient’s perspective

Patient is deceased.

Learning points

  • Menkes disease is a rare inherited disorder of copper homeostasis.

  • Patients with classic clinical presentation almost always die in early childhood period.

  • Currently, subcutaneous copper-histidine therapy is the main method to bypass the gastrointestinal tract, directly delivering copper to brain cells.

  • Early recognition and prompt medical intervention has offered beneficial effects on restraining progression of disease.

Ethics statements

Patient consent for publication

Acknowledgments

The study was conducted by Pediatric Nutrition Research Unit in the Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. We are grateful to Nimitwongsin S (Department of Pharmacy, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand), Siritientong T (Assistant Professor, PhD from the Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand) and the National Blood Center, Thai Red Cross Society for preparing Cu-His injection following pharmaceutical methodology. We acknowledge Deesudchit T (MD, Division of Neurology, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand) for providing neuroclinical data and EEGs, Chantawarangul K (MD, Division of Dermatology, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand) for light microscope of hair manifestation. We would like to thank Boonsimma P (MD, Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand) and her colleagues for DNA extraction and genetic analyses, and Pongwatcharaporn K (MD, Pediatric Neurologist, Surin Hospital, Thailand) who made the diagnosis and shared this clinical experience with us.

Footnotes

  • Contributors EP reviewed articles, participated in generation of the tables and figures and drafted the initial manuscript. TK collected the data, CV and SC critically revised the content of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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