Prolonged survival in Menkes disease with a novel ATP7A variant: A case report

Abstract

BACKGROUND

Menkes disease (MD) is an uncommon, X-linked recessive neurodegenerative disorder caused by mutations in the copper-transporting ATP7A gene, leading to defective copper metabolism. Progressive neurological dysfunction, connective tissue abnormalities, characteristic skeletal and hair findings are defining features of the disease. The prognosis of the classical variant is poor since the majority of patients expire by the age of 3 years. This report presents the first documented case of MD in the Kingdom of Bahrain with a novel ATP7A variant.

CASE SUMMARY

We report a 45-day old male infant presenting with focal seizures and hypotonia. Fair, redundant skin and abnormal hair pigmentation was noted. Neuroimaging revealed classical MD findings like subdural hematoma and arterial tortuosity. In addition, cortical laminar necrosis and craniosynostosis were observed. Diagnostic work-up revealed low serum copper and ceruloplasmin levels with high dopamine levels. Eventually, a novel splice-site mutation in the ATP7A gene was identified using Sanger gene sequencing. A trial of copper-histidine therapy started at the age of 4 months was largely unsuccessful in controlling the disease, with minimal dermatological benefits. Later, the patient developed a large bladder diverticulum at the age of 4 years followed by multiple vascular aneurysms and pseudoaneurysms at 6 years. The patient passed away by the age of 6 years and 9 months most likely due to an aneurysmal rupture.

CONCLUSION

This case illustrates an intermediate phenotype which could be influenced by the new ATP7A variant and demonstrates the phenotypic continuum spectrum in Menkes disease.

Key Words: Copper; Menkes disease; ATP7A gene; Seizures; Connective tissue; Bladder diverticula; Pseudoaneurysm; Case report

Core Tip: This case report presents the first documented instance of Menkes disease (MD) in Bahrain, caused by a novel splice-site variant in the ATP7A copper-transport gene. The patient demonstrated an intermediate phenotype bridging classical MD and occipital horn syndrome, with atypical early neuroimaging findings and prolonged survival to 6 years and 9 months. Despite copper-histidine therapy, progressive neurological and connective tissue complications, including a giant bladder diverticulum and multiple vascular pseudoaneurysms, developed. This case highlights the expanding phenotypic spectrum of ATP7A-related disorders and underscores the need for early diagnosis and vigilant surveillance.

INTRODUCTION

Menkes disease (MD) (OMIM#309400) also known as “kinky hair disease” is a lethal infantile neurodegenerative disorder with X-linked recessive inheritance[1]. It results from pathogenic variants in the ATP7A gene, which encodes a transmembrane copper-transporting P-type ATPase (ATP7A)[1]. Defects in the ATPase gene lead to impaired intestinal absorption of copper leading to decreased activity of copper-dependent enzymes, such as dopamine-β-hydroxylase, cytochrome C oxidase, lysyl oxidase, among others[1]. Other phenotypes related to ATP7A variants include occipital horn syndrome (OHS) (OMIM#304150), and X-linked distal spinal muscular atrophy-3 (OMIM#300489)[2].

Geographical variability is evident in the prevalence of the disease. Roughly 1 in 35000 live male births in the United States are affected by the disease, though a recent genomic study suggests it is 1 in 8000[3]. In contrast, Europe and Japan report much lower rates, at 1 in 300000 and 1 in 4900000, respectively[4,5].

Classical MD (CMD) typically presents by the age of 6 weeks to 12 weeks, with early-onset neurodegeneration and connective tissue disorders. As the disease progresses, infants suffer from seizures, developmental delay and characteristic coarse, sparse, and hypopigmented kinky hair[6]. Skeletal abnormalities of the disease include wormian bones and metaphyseal spurring, which mimics non-accidental trauma[7]. Connective tissue manifestations include joint hypermobility, diaphragmatic hernia, bladder diverticula, and skin laxity[8]. Additionally, affected patients are at risk of aneurysmal disease and its potential rupture[8]. These connective tissue features arise from deficient lysyl oxidase activity, an essential enzyme for elastin and collagen cross-linking[1].

On the other hand, OHS presents with more pronounced connective tissue features, accompanied by mild intellectual disability and dysautonomia. Individuals with overlapping features of CMD and OHS are described as having atypical MD (AMD)[9]. De Feyter et al[9], in a systematic review of ATP7A gene-related disorders, analyzed data from 162 patients aged 27 days to 57 years. Of these, 101 (62.3%) were classified as having CMD, 7 (22.6%) as OHS, and 18 (11%) as AMD, based on survival beyond 10 years and severity of neurological features.

Early diagnosis of MD based on clinical suspicion and biochemical testing alone is challenging. Serum copper and ceruloplasmin levels are physiologically low in neonates[10]. More specific biochemical markers include decreased plasma catecholamines[7]. Formal diagnosis is confirmed by detecting a pathogenic variant of the ATP7A gene, with most variants being private[2,10]. Management is complex and requires a multidisciplinary approach with copper-histidine supplements being the mainstay of treatment[6]. Unfortunately, overall prognosis remains poor, with most patients not surviving beyond 4 years[6].

This case report marks the first reported case of MD in Bahrain with a novel variant and an unexpectedly prolonged life expectancy.

CASE PRESENTATION

Chief complaints

A 45-day-old male infant presented with a 24-hour seizure episode characterized by left-sided twitching of the eye and hemiface.

History of present illness

At 45 days of life, the infant was admitted following a prolonged focal seizure lasting 24 hours. Electroencephalography demonstrated dysrhythmia over the right temporal and parietal regions. Seizures were partially controlled using three anticonvulsant medications.

The patient was readmitted at three months of age for daily focal seizures, poor feeding, failure to thrive, and diarrhea. By 8 months of age, seizures evolved into myoclonic jerks, requiring multiple anti-epileptic drugs with only partial control.

At 4 years and 8 months, he presented with abdominal distension and urinary retention. At 6 years and 7 months, he was readmitted with urinary tract infection and acute kidney injury, during which an abdominal mass was palpated.

History of past illness

There was no significant illness reported during the immediate neonatal period.

Personal and family history

The mother was 30 years old (G9P2A7) during the pregnancy, with a history of seven previous miscarriages. She was maintained on aspirin and anticoagulant therapy during pregnancy. No family history of similar conditions was reported.

The patient was a male neonate born at 37 weeks and 4 days of gestation via cesarean section, with a normal Apgar score and a birth weight of 3 kg. The immediate postnatal course was unremarkable, except for the mother noting light-colored hair during the first week of life.

Physical examination

On examination at 45 days of life, the infant exhibited coarse facial features including frontal bossing, overlapping temporoparietal bones, brachycephaly, and plagiocephaly. Neurological examination revealed generalized hypotonia and absent primitive reflexes.

At three months of age, examination showed sagging cheeks, absent eye contact, loose skin (Figure 1A), sparse, coarse, wiry hypopigmented hair (Figure 1B), and an umbilical hernia. The patient later developed spastic quadriparesis, blindness, and severe growth failure.

Figure 1 Physical examination findings of the child. A: Clinical examination revealing loose skin around the neck; B: Coarse, sparse, kinky and hypopigmented hair.

Laboratory examinations

A comprehensive metabolic and genetic work-up was performed, including plasma amino acids, urine organic acids, very long-chain fatty acids, biotinidase activity, and karyotyping. Due to clinical suspicion of MD, serum copper and ceruloplasmin levels were measured and found to be markedly reduced (copper: 30 µg/L; reference range 794-2023 µg/L; ceruloplasmin: < 0.03 g/L; reference range 0.15-0.3 g/L). Furthermore, catecholamine analysis showed elevated dopamine (DA) at 281 ng/L (normal ≤ 85 ng/L) with normal norepinephrine (NE) levels, yielding a dopamine-to-norepinephrine (DA/NE) ratio of 2. Cerebrospinal fluid amino acid analysis uncovered elevated lactate, taurine, serine, and citrulline with reduced lysine levels. Urinary organic acid testing detected thiodiglycolic acid and homovanillic acid (HVA), despite the absence of inotropic support.

Moreover, histopathological hair examination unveiled typical pili torti appearance (Figure 2). Genetic testing using Sanger sequencing, identified a novel splice mutation in ATP7A, c.2781+2T>C in intron 13, which has not reported in ClinVar and LOVD.

Figure 2 Microscopic image taken of the patient’s hair depicting the twisted appearance of the hair strand (pili torti).

Imaging examinations

Initial brain magnetic resonance imaging (MRI) showed sulcal hyperintensity with prominent leptomeningeal enhancement over the right parieto-occipital lobe and perirolandic region, consistent with the “ivy sign” (Figure 3A). The MRI report was later revised to include diffuse tortuosity of intracranial arteries (Figure 3B), a right-sided frontal subdural hematoma (Figure 3C), and contrast enhancement within the tabula of the right parietal bone (Figure 3D). The cerebellum, white matter, and basal ganglia were unaffected. Repeat brain MRI revealed persistent arterial tortuosity, resolution of the hemorrhage, and new hyperintense laminar cortical necrosis in the right occipital lobe (Figure 3E). Additionally, skull radiography illustrated bilateral fusion of the coronal and lambdoid sutures with marked sclerotic changes. Radiography of the lower limbs demonstrated small metaphyseal hooks on the right femur and subcortical resorption of the medial metaphysis of the left femur (Figure 4).

Figure 3 Brain magnetic resonance imaging depicting several abnormalities. A: Abnormal sulcal hyperintensity (‘ivy sign’) leptomeningeal enhancement over the right parieto-occipital lobe and peri-rolandic region (arrow); B: Diffuse tortuosity of the intracranial arteries on axial T2 image and post-contrast axial T1-weighted maximum intensity projection image; C: Hyperintense 3 mm subdural hematoma on the right frontal lobe on coronal fluid-attenuated inversion recovery image (arrow); D: Contrast-enhancement within the tabula of the right parietal bone (arrow); E: Hyperintense laminar cortical necrosis of right occipital lobe (arrow).

Figure 4 Lower limbs X-ray outlining small hooks of the corners of the metaphysis right femur, and subcortical resorption of the medial corner of the metaphysis left femur (arrows).

Meanwhile, electroencephalography demonstrated dysrhythmia over the right temporal and parietal regions.

At 4 years and 8 months, an ascending cystourethrogram demonstrated a large bladder diverticulum measuring 9 cm × 9 cm arising from the right lateral wall (Figure 5A). At 6 years and 7 months, computed tomography (CT) angiography of the abdomen identified a 6 cm × 5.5 cm × 4.5 cm porta hepatis pseudoaneurysm originating from the right proper hepatic artery, a smaller infrarenal lesion distal to the superior mesenteric artery, and multiple aneurysmal dilatations involving the external iliac, inferior mesenteric, and superior mesenteric arteries (Figure 5B).

Figure 5 Further complications detected in our patient later in life. A: Ascending cystourethrogram depicting the right-sided bladder diverticula measuring 9 cm × 9 cm (arrow); B: Computed tomography angiography: Pseudoaneurysm measuring 6 cm × 5.5 cm × 4.5 cm originating from the porta hepatis of the right proper hepatic artery (arrow).

MULTIDISCIPLINARY EXPERT CONSULTATION

The patient was evaluated by pediatric neurology, radiology, urology, and pediatric surgery teams. The vascular findings were deemed inoperable due to extensive arterial involvement and poor overall prognosis.

FINAL DIAGNOSIS

MD due to a novel ATP7A splice-site mutation (c.2781+2T>C), complicated by severe neurodevelopmental impairment, refractory epilepsy, autonomic dysfunction, bladder diverticulum, and widespread arterial aneurysms with pseudoaneurysm formation.

TREATMENT

Subcutaneous copper histidine therapy was initiated at 5 months of age at a dose of 250 µg twice daily and continued for four months. Multiple anticonvulsant medications were used with partial seizure control. Supportive management included gastrostomy feeding and intermittent bladder catheterization.

OUTCOME AND FOLLOW-UP

Copper histidine therapy resulted in improvement in hair growth and texture (Figure 6) and normalization of serum copper and ceruloplasmin levels. Despite treatment, the patient remained severely disabled with blindness, spastic quadriparesis, refractory epilepsy, chronic diarrhea, and growth failure.

Figure 6 The patient’s hair transformation after starting copper-histidine supplements after only 2 months.

The bladder diverticulum was managed conservatively. The extensive vascular aneurysms were considered inoperable. Two months after the last hospitalization, the patient collapsed at home, presumed secondary to aneurysmal rupture. No post-mortem examination was performed.

DISCUSSION

CMD is characterized by early-onset neurodegenerative disease associated with connective tissue abnormalities, arterial tortuosity and “kinky” hair. Our patient’s journey conveys the challenging diagnosis of MD in its earlier stages, as initial symptoms like temperature instability and prolonged physiological jaundice are often nonspecific[1]. Neonatal cardiocirculatory or respiratory complications were reported in 14.9% of infants, in a systemic review by De Feyter et al[9]. Furthermore, characteristic hair findings are often absent in the early phase of the disease and features are usually evident at 2 months to 3 months of age[1]. In our patient, wiry and blond hair was noted in the first week of life, but typical hair anomalies were not observed initially because of traditional shaving. Sparse, coarse, and lightly pigmented hair is a characteristic clue for MD, with pili torti identified in 94.3% of patients with CMD[6]. Among connective tissue anomalies, herniations, joints dislocation and laxity, dental abnormalities, and bladder diverticula occur more frequently in OHS compared to CMD, in a systematic review[6].

The infant remained well until 40 days of age, where he developed irritability, suggestive of early brain insult. In the subsequent days, he progressed to focal complex status epticus. Notably, focal clonic seizures are characteristic of the initial stage of epilepsy in MD[11]. In a systematic review by De Feyter et al[9], seizures and hypotonia were the most common presenting symptoms in patient with CMD, observed in 54% and 33%, respectively.

Radiological findings play a crucial role in the diagnosis of MD, as they unveil characteristic but often underrecognized abnormalities. The presence of intracranial tortuosity is highly suggestive of MD, though not pathognomonic. Approximately 85% of cases possess such vascular changes and can be detected within the first month of life, or even prenatally[6,7]. Also, brain magnetic resonance angiography serves as the best tool radiological tool to discover tortuous vessels, but was initially missed in our patient until MD was suspected. Other documented findings include cerebral and cerebellar atrophy and white matter lesions[11]. However, these were not evident in our patient during the first six months of life and follow-up imaging was not performed beyond that period. Up to 65% of cases develop subdural hematoma, often appearing after 6 months of age, and can be mistaken for non-accidental trauma. Interestingly, our patient encountered this complication early-on, at 45 days of life, opposing the usual age of occurrence. These findings highlight the critical importance of early neuroimaging in infants with suspected to MD for guiding diagnosis[12,13]

Unique to our case was the “ivy sign” which is a radiological marker of leptomeningeal collateralization in response to chronic cerebral hypoperfusion. This sign was initially attributed to post ictal hypoperfusion in our patient; however, it cannot result from vascular tortuosity alone. Other potentially novel or independent imaging findings were skull bone enhancement suggestive of potential bone marrow involvement, craniosynostosis, and cortical laminar necrosis. While cortical laminar necrosis has been occasionally reported in hypoxic events, craniosynostosis and skull bone enhancement have not been well-documented, making these findings noteworthy additions to the spectrum of MD manifestations[12,13].

Early diagnosis of MD remains complex as serum copper can be physiologically low in healthy infants. Therefore, current recommendations emphasize on the use of plasma catecholamine analysis, either the DA/NE ratio (> 0.2) or the dihydroxyphenylacetic acid-to-dihydroxyphenylglycol ratio (> 5). This provides greater diagnostic accuracy compared to serum copper and ceruloplasmin[14]. Moreover, the presence of urinary HVA may act as an indirect biochemical clue, especially in the absence of inotropic dopamine therapy. Identifying mutation in ATP7A remains the most definitive proof of MD, though most variants are family specific, and almost a third of cases exhibit de novo mutations[2,14]. However, due to the gene’s large size and allelic heterogeneity observed in different families, molecular diagnosis can be time-consuming and is not widely used in a neonatal setting[14].

Respiratory infections, vascular and connective tissue complications are the leading causes of death in individuals with MD, often due to missed or delayed diagnosis[15]. Fragility of the vascular walls predisposes individuals to several complications including arterial tortuosity, dissections, and aneurysmal rupture[15]. Furthermore, bladder diverticula and subsequent UTI are well-recognized complications, as portrayed in our patient. Management is typically conservative, involving intermittent catheterization; however, surgical repair may be required in select cases. The decision for surgical intervention remains controversial due to the generally poor prognosis, high recurrence rate, and limited life expectancy associated with MD[16].

Unfortunately, connective tissue complications persist even after copper therapy, which suggests that the function of lysyl-oxidase may not be corrected with copper histidine or the irreversibility of such complications[17]. Despite the prompt diagnosis and initiation of copper therapy, the efficacy of treatment is often limited once neurological and other systemic manifestations have developed. Although difficult to suspect early on, diagnosing and starting treatment within the neonatal period can prevent neurological symptoms and improve prognosis[1,14]. A study by Kaler et al[18] described a significant reduction in seizures following early treatment, where seizures were observed in 12.5% in the early treatment group compared to 87.5% in the late or no treatment group. However, in those described cases, early diagnosis was feasible due to a positive family history.

Although the oldest reported age of death in CMD was 9 years in a systematic review, our patient survived well beyond the mean age of 2.4 years described in the same study[6]. This suggests a possible phenotypic overlap between CMD and OHS, an emerging concept previously delineated in the literature[6]. The clinical spectrum of ATP7A-related disorders is closely influenced by the specific mutation and its effect on protein function and cellular localization; however, genotype-phenotype correlation remains incomplete[2,19]. Nevertheless, the novel splice-site mutation identified in our patient may enhance our current understanding of genotype-phenotype relationships in MD.

CONCLUSION

This case highlights the potential of vascular complications, especially aneurysmal rupture, as a cause of death. In diagnosed cases, particularly in underreported areas, it emphasizes the importance of early detection and treatment, including genetic testing and surveillance for connective tissue associated complications. Physician awareness of the disease should be emphasized in clinical practice and incorporating it as a differential diagnosis in early onset seizures.