Chapter 10

INHERITED METABOLIC DISORDERS

MISCELLANEOUS METABOLIC DISORDERS

MENKES DISEASE

Menkes disease is an X-linked metabolic disorder caused by mutations of the ATP7A gene, located on Xq21.1. This gene is expressed in the placenta, intestine, and brain. Its product is important for transport of copper across the placenta, absorption of copper in the small intestine, getting copper across the blood-brain barrier, and moving intracellular copper from the cytosol to several copper-dependent enzymes. ATP7A is also involved in eliminating excess copper from cells. Thus, mutations of ATP7A cause generalized copper deficiency resulting in severe progressive pathological changes. The clinical manifestations of Menkes disease are due to deficiency of copper-dependent enzymes that are involved in cellular respiration, antioxidant function, neurotransmitter synthesis, the structure and pigmentation of hair, collagen and elastin formation, and other processes.


Menkes disease

Menkes disease. Decolorized, "steely" hair.

Menkes disease is characterized by neurological and connective tissue abnormalities. Patients are normal in the first 2 or 3 months of life but then they develop failure to thrive, hypothermia, hypotonia, seizures, severe psychomotor retardation, and usually die before 2 years of age. Their hair is sparse, coarse, steely, and depigmented, and appears twisted (hence Menkes’ kinky hair disease) or broken. Their skin is lax, and their cheeks are redundant. X-rays reveal wormian cranial bones, osteoporosis, and metaphyseal dysplasia. The MRI shows defective myelination, cortical atrophy, ventricular enlargement, and vascular tortuosity. Subdural hematomas often develop as a result of brain atrophy. Serum copper and cerulopalsmin levels are low, and plasma and CSF catecholamines are also low (dopamine-beta-hydroxylase, which is important for catecholamine synthesis, is a copper-dependent enzyme). A milder form of the disease, the occipital horn syndrome (OHS), previously known as X-linked cutis laxa, is characterized mainly by connective tissue abnormalities (hyperelastic skin, loose joints, skeletal abnormalities) and minor neurological abnormalities. The phenotype of the OHS can be explained by deficiency of lysyl oxidase.


MD. Brain atrophy

Menkes disease. Brain atrophy.


MD. Cortical degeneration

Menkes disease. Laminar degeneration of the cerebral cortex.


MD. Subdurals

Menkes disease. Organized subdurals enveloping the whole brain.


MD. Cerebellar degeneration

Menkes disease, cerebellum. Granular neurons are lost but Purkinje cells are relatively spared. Note also the vascular proliferation in the subarachnoid space, a characteristic feature of MD.


MD. Cerebellar degeneration

Menkes disease, cerebellum. Purkinje cell dendrites branch in the molecular layer.

The brain in Menkes disease shows cerebral and cerebellar atrophy, bilateral chronic subdural hematomas, and tortuous, thin-walled arteries. The cortex shows neuronal loss, mineralized neurons, and gliosis. The white matter is reduced in volume, attenuated, and gliotic. Neuronal loss and gliosis is seen in the thalamus and other subcortical nuclei. The cerebellum shows severe depletion of granular neurons with relative preservation of Purkinje cells, a pattern opposite of that seen in other neurodegenerations. Purkinje cell dendrites branch in the molecular layer forming cactus-shaped expansions. The highest concentration of ATP7A is in the cerebellum and choroid plexus. The neuropathological changes can be attributed, in large part, to deficiency of cytochrome C oxidase, and in that sense have some similarity to mitochondrial disorders.

WILSON'S DISEASE

Wilson’s disease, a.k.a. hepatolenticular degeneration, is an autosomal recessive disease characterized by accumulation of copper in the liver, brain, and other tissues. It is caused by mutations of ATP7B which encodes an ATPase that is important for removing excess copper from the body. Copper accumulating in hepatocytes causes liver disease leading to cirrhosis. Failure of elimination of copper through the bile causes leakage of copper into plasma and its deposition in the brain, especially basal ganglia, and other tissues. A visible marker of Wilson’s disease is the Kayser-Fleischer ring, a brownish band caused by copper deposition at the outer edge of the cornea. The neurological manifestations of Wilson’s disease consist of movement disorders, dystonia, and psychiatric symptoms. These are due to damage of the basal ganglia and other structures from copper deposition. Repeated bouts of hepatic encephalopathy can also cause similar symptoms.

Updated: January, 2016


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