Menkes Disease-A Rare Neurodegenerative Disorder

Menkes Disease is a rare neurological disorder of impaired copper transport, characterized by progressive neurodegeneration, refractory epilepsy and characteristic hair abnormalities. Here, we report a 5 month old child with developmental delay, refractory seizures, and hypopigmented short, sparse hair with microscopic pili torti; low serum copper and ceruloplasmin and neuroimaging revealing white matter hyperintensities and tortuous vessels. J Nepal Paediatr Soc 2015;35(2):177-180


Introduction
M enkes Disease is a progressive neurodegenera ve disorder of copper metabolism with an X-linked recessive inheritance.The predominant clinical manifesta ons are neurodegenera on and short, sparse, kinky, lightly pigmented hair.Menkes Disease occurs due to muta ons in the copper transpor ng P type ATPase (ATP7A) 1 .We describe a 5 month old infant with Menkes Disease with characteris c clinical features, laboratory inves ga ons and neuroimaging.

The Case
A fi ve month old male infant was admi ed with history of generalized tonic clonic seizures star ng at the age of three months.He was second in birth order, born out of a non consanguineous marriage at 38 weeks' gesta on by a normal vaginal delivery with an uneven ul perinatal period.There was no history of any neonatal complica ons.The fi rst child of the couple had a similar history of seizures and died at the age of 4 months due to mul ple seizures, no records of hospitaliza on are available.On examina on, the infant was lethargic and malnourished.He weighed 5kg (-3SD), head and chest circumference were 39.5 cm (-2SD) and 37 cm respec vely; length was 61cms (-2SD).The hairs were short, sparse, hypopigmented, wooly and easily pluckable.(Figure 1) Neurologic examina on revealed hypotonia in all four limbs with poor head and trunk support.The deep tendon refl exes were brisk and plantars extensor bilaterally.The development of the infant was delayed.There was no head control or roll over.Occasional smile and babbling was present.He did not track the objects but blinked in response to light s mula on however fundoscopy was normal.Corneal opaci es and iris anomalies were absent.Rest of the systemic examina on was unremarkable.
The complete blood counts, liver enzymes, albumin, total protein, blood urea nitrogen and crea nine, serum calcium, phosphorous, alkaline phosphatase, electrolytes, thyroid profi le were within normal limits.CSF study was normal.Blood gas analysis, urine ketones, plasma lactate and ammonia levels were normal.Plasma acylcarni ne profi le and urine gas chromatography-mass spectrometry for organic acidurias were normal.Abdominal ultrasound did not reveal any abnormality.There were no metaphyseal changes in X-rays of limbs.Plasma catecholamine levels and DOPA/DHPG ra o could not be done due to non availability of the tests at our center and fi nancial constraints.
Serum copper was low 14.5 μg/dl (normal range for infants is 20-70 μg/dl) and serum ceruloplasmin was also low 8.1 mg/dl (normal 20-60 mg/dl).Microscopic analysis of hair showed hypopigmenta on and the pathognomonic pili tor i.e. 180 ̊ twis ng of the hair sha .(Figure 2) showed immature background ac vity with mul focal inter-ictal epilep c discharges.Magne c resonance imaging showed asymmetric white ma er hyperintensi es in bilateral frontal and temporal lobes and tortuosity of intracranial fl ow voids.(Figure 3) The diagnosis of Menkes Disease was suspected on the basis of typical clinical presenta on along with typical hair sha abnormali es, which was supported biochemically by low levels of serum copper and ceruloplasmin and MRI fi ndings, however diagnos c gene c tes ng for muta ons could not be performed due to non-availability of those tests.Gene c counseling of the parents was done and prognosis was explained.Parenteral copper could not be started due to non availability.Suppor ve treatment was started.The seizures were controlled on three an epilep c drugs.The pa ent was lost to follow up.

Discussion
Menkes Disease is a gene c disorder of copper metabolism with an X-linked recessive inheritance, fi rst described in 1962 2 .It is a rare condi on with an incidence of 1 in 298, 000 live births 3 .
Menkes Disease is caused by muta ons in ATP7A gene 1 encoding a transmembrane protein which is involved in the export of surplus copper from cells and in the delivery of copper to the secreted copper enzymes.Elimina on of copper from cells is the basic disturbance in Menkes Disease, resul ng in copper accumula on in almost all ssues except liver and brain 4 .Copper is a key cofactor of several enzymes and its defi ciency results in malfunc on of these cuproenzymes such as cytochrome C oxidase, superoxide-dismutase, tyrosinase and lysyl oxidase, which then leads to a mul system compromise, especially the central nervous system 4 .
The gene c disorders associated with muta ons in the ATP7A gene have variable phenotype and are clinically divided into three categories: classical Menkes Disease, mild Menkes Disease, and Occipital Horn Syndrome (OHS).OHS is considered to be the mildest form.
Menkes disease typically occurs in males with onset at 2-3 mo of age.There is loss of previously obtained developmental milestones, onset of seizures, and failure to thrive.The epileptogenesis in Menkes disease has been a ributed to defi cits in neurotransmi er func on, energy metabolism and excitotoxicity secondary to the copper defi ciency in the brain 5 .The characteris c hair fi ndings of short, sparse, depigmented, wooly hair, which on microscopy reveal pili tor , in conjunc on with typical neurologic fi ndings, o en suggest the ini al diagnosis.It is suggested that kinky hair forma on results from low ac vity of sul ydryl oxidase, a copper enzyme, in hair 6 .Vascular, urogenital and skeletal abnormali es may be seen.Low serum concentra on of copper and ceruloplasmin would support the diagnosis further.
The neuroimaging in Menkes Disease typically reveals global atrophy, subdural hygromas, transient temporal lobe abnormali es, excessive tortuosity of cerebral arteries and white ma er changes 7,8 .The ul mate diagnos c proof of Menkes Disease is the demonstra on of the molecular defect in ATP7A.However, because of the large size of the gene and the variety of the muta ons observed in diff erent families, detec on of the gene c defect in a given family may take me 4 .Pre-natal diagnosis of Menkes disease is made by gene analysis and measuring copper content in the culture of amnio c liquid cells and chorionic villi 9 .
The current management strategy for Menkes Disease is parenteral copper administra on and an convulsant therapy.Oral administra on of copper is ineff ec ve as copper is trapped in the intes nes.
Copper his dine normalizes plasma concentra ons of copper and ceruloplasmin and reduces epilep c discharges 10 .However, treatment with copperhis dine once neurological symptoms appear is too late to prevent neurodegenera on, possibly because the administered copper accumulates at the bloodbrain barrier and is not transported to neurons 11 .In the natural history of classic Menkes disease, death usually occurs by the age of 2-3 years.Neonatal diagnosis and early treatment with copper injec ons may enhance survival and improve clinical outcomes in individuals with certain ATP7A muta ons 12 .

Conclusion
We report the case due to its rarity and clinical presenta on.The suspicion of Menkes Disease in children with developmental delay and early onset refractory epilepsy is emphasized.

Fig 3 :
Fig 3: Magne c Resonance images of the pa ent: Axial T2-Weighted images showing the hyperintense signal changes of white ma er in bilateral temporal lobes(black arrows) and tortuosity of intracranial vascular fl ow voids (white arrow).