Menkes disease - An important cause of early onset refractory seizures.

CONTEXT: Menkes disease is an X-linked multisystem disorder characterized by early onset of cerebral and cerebellar neurodegeneration, fair skin, hypopigmented sparse hair and connective tissue abnormalities. AIMS: We aimed to evaluate the clinical, electrophysiological and radiological features of children with Menkes disease seen at our institute. SETTING/
DESIGN: The medical records of children diagnosed with Menkes disease admitted in the pediatric neurology ward or attending the special pediatric neurology clinic at a tertiary care and a referral hospital in North India, from January 2010 to December 2012, were retrospectively reviewed. The clinical data of each case was subsequently summarized and reported. STATISTICAL ANALYSIS USED: Descriptive statistics were used.
RESULTS: During the study period, 1174 children were seen. Out of these, 6 cases were diagnosed as Menkes disease on the basis of clinical phenotype, low serum copper and ceruloplasmin and supportive neuroimaging. All the children were males and had disease onset within 3 months of age, with 4 children presenting in the neonatal period. Global developmental delay and refractory seizures were the predominant clinical symptoms. Two children had symptomatic West syndrome. Other seizure semiologies included tonic-clonic (4), myoclonic (2) and tonic seizures (1). The electroencephalographic abnormalities included hypsarrythmia (2) and multifocal epileptiform discharges (3). The salient radiological features included white matter changes, temporal lobe abnormalities, global atrophy, subdural hygromas and tortuous cerebral blood vessels.
CONCLUSIONS: Menkes disease should be suspected in a case of refractory early onset seizures especially in the presence of subtle clinical clues. The neuroimaging findings may further support the diagnosis.

Introduction

Menkes disease is a rare, lethal, X-linked recessive, multisystem disorder caused by ATP7A mutations.[1] The majority of the reported cases are males. However, few females with a milder phenotype have been described.[2] ATP7A-related disorders have a variable phenotype ranging from mild occipital horn syndrome to the severe classic Menkes disease. It has been rarely reported in India.[345678] We describe six cases of Menkes disease managed at our institute over a period of 3 years. We also emphasize Menkes disease as an important cause of refractory neonatal seizures.

Subjects and Methods

The medical records of children diagnosed with Menkes disease admitted in the pediatric neurology ward or attending the special pediatric neurology clinic at a tertiary care and a referral hospital in North India, from January 2010 to December 2012, were retrospectively reviewed. The diagnosis of Menkes disease was based on the clinical phenotype, low serum copper and serum ceruloplasmin and neuro-imaging findings with exclusion of other causes.

All children underwent baseline hematological and biochemical investigations, neuroimaging, electroencepalography, serum copper and ceruloplasmin, hair microscopy, skeletal survey, ultrasonography of the abdomen, fundosopy and metabolic panel (random blood sugar, blood gas analysis, arterial lacate, serum ammonia, acylcarnitine profile, urinary gas chromatography-mass spectroscopy, serum biotinidase levels). Mutational analysis could not be done in any of the children. The ethical approval was taken from the ethics committee of the institute. The clinical data of each case was subsequently summarized and reported.

Results

During the study period, 1174 children were seen. Out of these, 6 cases were diagnosed as Menkes disease. Patient 1 has been previously reported.[5] The summarized clinical data of these 6 children are detailed below.

Clinical phenotype

The salient clinical features have been summarized in Table 1. All the children were males and had disease onset within 3 months of age, with 4 children presenting in the neonatal period. Global developmental delay and refractory seizures were the predominant clinical symptoms. The psychomotor retardation was severe in all cases with no gain of milestones. Patient 2 had global regression following onset of epileptic spasms.

Table 1

Salient clinical features of the children with Menkes disease

Two children had symptomatic West syndrome. Other seizure semiologies included tonic-clonic (4), myoclonic (2) and tonic seizures (1). The onset of seizures was within 3 months in all cases. The onset of seizures and semiology is depicted in Figure 1. These children were refractory to all the standard anti-epileptic drugs. Patient 2 had partial response (50-75%) to oral pyridoxine. Patient 5 became seizure-free after 10 days of oral prednisolone, but subsequently lost to follow up. The rest of the patients had multiple daily seizures. The electroencephalographic features are shown in Table 2 and Figure 2.

Figure 1

The onset of seizures and semiology in 6 children with Menkes disease

Table 2

Inter-ictal electro-encephalography in children with Menkes disease

Figure 2

Electroencephalographic findings in children with Menkes disease with epileptic spasms: Patient 2: There were frequent bursts of asynchronous high voltage slow waves intermixed with spikes lasting for around 2 seconds followed by suppression lasting for 2– 2.5 seconds suggestive of burst suppression variant of hypsarrhythmia. Patient 5: The background is chaotic and asynchronous with random high voltage slow waves and spikes suggestive of classical hypsarrhythmia

All the affected children were strikingly fair skinned with sparse hyopigmented ‘kinky’ hair [Figure 3]. The hair microscopy revealed pili torti in 2 children, normal in 3 children and could not be done in one child. Three children had macrocephaly. All the children had central hypotonia. The skeletal survey showed diffuse osteopenia (2), metaphyseal flaring (1), wormian bones in the skull (1) and was normal in 3 children. The ultrasonography of the abdomen was normal in all the children. Other findings included bilateral congenital talipes equinovarus (1), inguinal hernia (1) and delayed eruption of teeth (1). The family history was unremarkable in all the children.

Figure 3

Children with Menkes disease. Note the sparse hypopigmented hair and fair skin. Also note the global hypotonia in patient 1

Neuroimaging

The detailed description of neuroimaging findings of patient 1 has already been described.[5] The salient neuroimaging findings have been summarized in Table 3 and Figures 4 and 5. Varying degrees of cerebral atrophy were seen in all children. It was marked in patients 1 and 5 with large bilateral subdural collections. Prominent white matter signal changes were seen on T2-weighted and Fluid-Attenuated Inversion Recovery sequences in 4 children. They were marked in patient 1 simulating a leukodystrophy.[5] Both deep and subcortical white matter was involved. There was no involvement of cerebellar white matter or brainstem tracts. Prominent temporal lobe white matter changes were seen in patient 3. Temporal cysts were seen in patient 1. Tortuous cerebral arteries were seen in all the children. The cerebral angiography could not be done in patient 2.

Table 3

Neuroimaging findings in children with Menkes disease

Figure 4

Magnetic Resonance images of patients with Menkes disease showing the spectrum of imaging findings: Axial T2-Weighted images of the patient 1 at initial presentation (a) and at 5 months follow-up (b) shows tortuous vessels with diffuse white matter signal changes initially progressing to severe brain atrophy with gross bilateral subdural hemorrhages at followup. Patient 6 images (c and d) show marked brain atrophy with bilateral subdural collections

Figure 5

Magnetic Resonance images of patients with Menkes disease showing the spectrum of imaging findings: Axial T2-Weighted images of patient 3 (a and b) show the tortuosity of vessels with hyperintense signal changes of white matter with tendency to cyst formation at temporal poles and marked cerebral and cerebellar atrophy. The images of the patient 5 (c and d) shows marked tortuosity of intracranial vascular flow voids with mild white matter signal changes and brain atrophy

Follow-up neuroimaging was only available in patient 1. The prominent white matter changes with temporal cysts visible on neuroimaging done at 5 months of age progressed to marked cerebral atrophy with large subdural collections at 10 months of age.[5]

All the children were initiated with physical and nutritional rehabilitation with family counseling. The anti-epileptic therapy was further optimized. Copper treatment was not started in view of non-availability.

Discussion

The clinical phenotype of Menkes disease was first described by Menkes et al., in 1962[9] and subsequently, in 1972, Danks et al.,[10] established copper deficiency as the cause of the observed abnormal neurodevelopment. ATP7A gene on X-chromosome was shown to be responsible for Menkes disease.[1112] Other phenotypes associated with ATP7A mutations are Occipital Horn Syndrome and adult-onset distal motor neuropathy.[13] ATP7A plays a critical role in axonal outgrowth, synapse integrity and neuronal activation.[14]

The affected newborns with Menkes disease may have subtle clinical clues including hypopigmented hair, loose and redundant skin and episodic autonomic dysfunction. Low serum copper may not be a reliable indicator of the disease at this stage. The plasma neurochemical measurements based on deficient dopamine β-hydroxylase, have been suggested for neonatal diagnosis.[15] The classical Menkes disease manifests at 2-3 months of age. Seizures are often the presenting feature.

The clinical stages in the evolution of epilepsy in Menkes disease have been proposed.[16] The first stage of focal seizures is described at the mean age of 3 months. In the present case series, 4 children had seizure onset in the neonatal period. Tonic-clonic seizures were the predominant semiology in the neonatal-onset seizures. The earliest seizure onset in a previous Indian cohort was 4 months.[4] Two children presented with epileptic spasms (proposed second stage) without a preceding stage of focal seizures.

The epileptogenesis in Menkes disease has been attributed to deficits in neurotransmitter function, energy metabolism and excitotoxicity secondary to the copper deficiency in the brain.[17] More severe mutations in ATP7A gene causing marked reduction in copper transport across the blood–cerebrospinal fluid barrier and the blood–brain barrier may be responsible for early epileptogenesis in these children.

The other metabolic causes of seizures in the neonatal period are presented in Table 4. Fair complexion, hypopigmented sparse hair, loose and redundant skin may be subtle markers towards a diagnosis of Menkes disease. Early diagnosis, ideally within 2 weeks of birth, is critical as early treatment may confer protection against epilepsy in some individuals with certain ATP7A mutations.[315]

Table 4

Inborn errors of metabolism presenting as neonatal seizures

The radiological features of Menkes disease have been well described.[18] The salient features include white matter changes, transient temporal lobe abnormalities, global atrophy, subdural hygromas, tortuous cerebral blood vessels and rarely basal ganglia changes. The white matter changes can be very prominent and may mimic a leukodystrophy. Especially with macrocephaly and temporal cysts, it may closely mimic Canavan disease.[5] The presence of tortuous blood vessels visible on routine sequences or angiography may point towards the diagnosis of Menkes disease in this scenario. The white matter changes with temporal lobe cysts may also be seen in intra-uterine neuro-infections and subacute sclerosing panencephalitis[19] besides Menkes disease and Canavan disease.

The presence of large subdural hygromas/hematomas may also be a useful marker of Menkes disease. The differentials of this finding include non-accidental head trauma, glutaric aciduria type 1 and type 1 osteogenesis imperfect.[20]

The long term outcome of Menkes disease is uniformly poor with most children succumbing to the relentless cerebro-cerebellar neurodegeneration by 2-3 years of age. Future probabilities of neonatal diagnosis, early initiation of copper therapy and gene therapy may provide some hope.[14]

Thus, one needs to suspect Menkes disease in a case of refractory early onset seizures especially in the presence of subtle clinical clues as described. The neuroimaging findings may further support the diagnosis. Early copper treatment and gene therapy coupled with supportive management may be beneficial.