Menkes disease: what a multidisciplinary approach can do

Abstract

Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with the recognition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, through to the description of infants suffering from a progressive neurodegenerative disorder characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair quality (giving the condition its distinctive label of "kinky hair disease"). In this review, we trace the historical background and describe the biochemistry and physiology of copper metabolism and transport, inheritance patterns, molecular genetics, and genotype-phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions.

Keywords: Menkes disease; ceruloplasmin; copper homeostasis; kinky hair; neurodegenerative.

Figure 1

Multidisciplinary approach to MD. Abbreviations: GI, gastrointestinal; MD, Menkes disease.

Figure 2

MD: (A) scalp shows “kinky hair”, (B) the inset shows “pili torti” and a normal hair strand under a high power microscope. Abbreviation: MD, Menkes disease.

Figure 3

EEG segments from patient with MD. Notes: (A) Anterior–posterior bipolar montage shows ictal rhythm corresponding to a focal seizure originating in the right mid to posterior temporal regions (15 mm/s, sensitivity at 15 μV/mm). (B) Ictal rhythms showing rhythmic generalized spike and slow waves (time base at 30 mm/s, sensitivity at 20 lV/mm). (C) Late stages – interictal background rhythms are slow for age, with multifocal independent spikes and spike and wave complexes (time base at 30 mm/s, sensitivity at 20 lV/mm). Abbreviations: EEG, electroencephalography; MD, Menkes disease.

Figure 4

MRI of the brain (A) and MRA (B) from the same patient. Notes: (A) Generalized fronto-temporal cerebral atrophy resulting in exposure of the insula, and thinning of the subcortical white matter (arrows). (B) Tortuosity of intracranial vertebral arteries (arrow). Abbreviations: L, left; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; R, right.