Epilepsy in Menkes disease

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Epilepsy in Menkes disease: analysis of clinical stages.
Epilepsia. 2006 Feb;47(2):380-6.
Bahi-Buisson N et al.

12 patients with Menkes disease are studied. Their epilepsy is characterized by three successive periods:
early focal status
infantile spasms
myoclonic and multifocal epilepsy

For more information on Menkes disease, please see chapter 126

Thank you very much in advance for your contributions to this blog.
Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

One Response to “Epilepsy in Menkes disease”

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    Chapter 126: Disorders of Copper Transport


    Clinical Features.

    The distinct clinical features of Menkes disease are present by 3 months of age and are often brought to attention in affected infants by the loss of developmental milestones and failure to thrive.9,162,186-188 The typical-appearing infant has a cherubic face with pudgy cheeks, sagging jowls, and scant eyebrows (Fig. 126-8A). The hair is sparse, resembling steel wool, and on microscopy reveals twisting of the hair shaft (pili torti) as well as fractures and longitudinal splitting (Fig. 126-8B). The absence of tyrosinase activity leaves the hair lacking in pigment and appearing white or gray. Loss of lysyl oxidase activity results in connective tissue abnormalities, including wormian skull bones as well as radiographic evidence of osteoporosis and metaphyseal dysplasia, including anterior flaring and fracture of the ribs. As a result of connective tissue weakening, diverticula of the bladder, uterus, and other organs may be present. Vascular complications including aortic aneurysms are commonly present, and neuroimaging techniques reveal tortuosity of the intracranial blood vessels.189 Histologic examination of these blood vessels reveals thinning of the connective tissue with disruption of the elastic lamina (Fig. 126-8C).

    Fig. 126-8

    Fig. 126-8: A. Clinical features observed in a newborn infant with Menkes disease. B. Pili torti demonstrated by microscopic imaging of hair shaft from an affected patient. C. Microscopic analysis of a cross-section of a large artery from a patient with Menkes disease, illustrating frayed and split elastic lamina. D. Microscopic analysis of Purkinje cells from the cerebellum of a child with Menkes disease, revealing classic axonal swelling. (Reprinted with permission from Menkes et al.188)

    Eventually cerebral degeneration ensues, at least in part due to the loss of activity of cytochrome c oxidase, peptidyl 0x0003b1-amidating monoxygenase, and dopamine 0x0003b2-hydroxylase in the central nervous system. Magnetic resonance imaging reveals abnormal myelination and cerebral and cerebellar atrophy, in some cases as early as 5 weeks of age.190,191 Autopsy of the brain demonstrates subdural hematomas with diffuse atrophy, focal degeneration of gray matter, and prominent neuronal loss in the cerebellum. Purkinje cells are frequently affected, showing abnormal arborization of dendrites and focal swelling of the axons (Fig. 126-8D). Not all of these neurologic problems can be explained by the loss of activity of the known copper enzymes, implying that additional cuproenzymes essential for brain development remain to be identified. Diagnosis may be difficult in the neonatal period until the more typical signs and symptoms appear. Premature delivery is common, and affected newborn infants frequently have hypothermia, hypoglycemia, hyperbilirubinemia, umbilical hernias, hypotonia, and seizures.9,186 Central nervous system abnormalities become more prominent with time and include truncal hypotonia, abnormal head control, and hyperactive reflexes.

    Although survival beyond childhood is rare, some children with profound neurologic deficits have survived for many years. In addition, several milder clinical variants have been described, including children who present somewhat later in infancy in whom ataxia and mild intellectual delay are the only neurologic features.186,192 In the occipital horn syndrome, also known as X-linked cutis laxa or type IX Ehrlers-Danlos syndrome, affected patients have exostoses secondary to calcifications at the insertion sites of muscles attaching to the occiput as well as marked connective tissue abnormalities but little or no neurologic disease. The somewhat atypical presentation of these milder phenotypes suggests that any male infant with connective tissue abnormalities and mental retardation should be evaluated for the possibility of Menkes disease. Reports have appeared in the literature of individuals with clinical features similar to Menkes disease yet displaying differences in biochemical markers of copper absorption and metabolism. At this time it remains unclear if these represent variants of Menkes disease or distinct disorders that have yet to be completely characterized.193-195

    Laboratory Findings.

    The marked copper deficiency in affected patients is reflected in very low serum ceruloplasmin and copper concentrations. However, these values are normally quite low in the neonatal period and are diagnostically useful in suspected cases only after the first several months of life. Copper deficiency results in a reduction in the activity of a number of copper-dependent enzymes as well as copper accumulation in tissues where copper export is impaired. The defect in copper export in Menkes disease can be detected by examining copper accumulation in cultured fibroblasts using radioactive copper.196,197 This technique shows clear differences between affected and unaffected male infants, but does not distinguish between mildly and severely affected patients. Analysis of placental copper concentration, which is increased in affected patients, is often useful if the diagnosis is suspected in the newborn period. Deficiency of dopamine 0x0003b2-hydroxylase activity results in increased plasma and cerebrospinal fluid catecholamines reflective of impaired norepinephrine biosynthesis. Measurement of these metabolites also may be useful in confirming the diagnosis.198,199 Prenatal diagnosis is possible by examining copper accumulation in cultured amniotic fluid cells, although the results of such studies are variable. First trimester diagnosis also may be made by determining the copper content of chorionic villi.200

    Molecular diagnosis of Menkes disease is complicated by the heterogeneity at this locus. The development of sensitive methods to rapidly screen for a multiplicity of different mutations will facilitate this diagnostic approach in any given patient. When the mutation in a given family is known, this analysis may be superior to biochemical information, especially in cases of prenatal diagnosis.201,202 Although carrier detection can be done by measuring copper accumulation in fibroblasts, random X inactivation makes negative results difficult to interpret.203 Carrier diagnosis is best done with mutation analysis and is readily accomplished when the specific mutation is known. In families where the mutation has not been identified, polymorphic markers and intragenic repeats have been used to facilitate carrier diagnosis.

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