Several genetic diseases disrupt metabolic processes in neurons and glia, resulting in progressive disorders that present early in life. These diseases can be grouped by the cells or compartment affected (neurons vs. white matter), the subcellular organelle affected (e.g., lysosome, peroxisome, or mitochondrion), or the metabolic pathway affected (e.g., sphingolipidoses, very long–chain fatty acid metabolism). The mutations underlying these diseases typically affect synthetic or degradation pathways that are specific to the nervous system.
Neuronal storage diseases are characterized by the accumulation of storage material within neurons, typically leading to neuronal death. Cortical neuronal involvement leads to loss of cognitive function and may also cause seizures. Most commonly, they are autosomal recessive disorders caused by the deficiency of a specific enzyme involved in the catabolism of sphingolipids (including the gangliosides), mucopolysaccharides, or mucolipids; others appear to be caused by defects in protein or lipid trafficking within neurons. Several examples of these diseases, such as Tay-Sachs and Niemann-Pick diseases and mucopolysaccharidoses, are discussed in Chapter 7.
Mitochondrial encephalomyopathies are disorders of oxidative phosphorylation, often affecting multiple tissues including skeletal muscle (Chapter 22). When they involve the brain, gray matter is more severely affected than white matter, as would be expected because of the greater metabolic requirements of neurons. These disorders may be caused by mutations in the mitochondrial or the nuclear genomes.
Toxic and acquired metabolic diseases are relatively common causes of neurologic illnesses. Because of its high metabolic demands, the brain is particularly vulnerable to nutritional diseases and alterations in metabolic state.
Some of these disorders have uneven pathologic lesions and distinct clinical presentations because of unique features or requirements of different anatomic regions of the brain. A few of the more common types of injury are discussed here.
In addition to the systemic effects of thiamine deficiency (beriberi), it also may be associated with the abrupt onset of confusion, abnormalities in eye movement and ataxia, syndrome termed Wernicke encephalopathy. Treatment with thiamine reverses these deficits, but if treatment is delayed the result is a largely irreversible profound memory disturbance called Korsakoff syndrome. Because the two syndromes are closely linked, the term Wernicke-Korsakoff syndrome is often used. The syndrome is particularly common in the setting of chronic alcoholism but also may be encountered in patients with thiamine deficiency resulting from gastric disorders, gastric bypass surgery, or persistent vomiting.
MORPHOLOGYWernickeencephalopathyischaracterizedbyfociofhemorrhageandnecrosis,particularlyinthemammillarybodiesbutalsoadjacenttotheventricles,especiallythethirdandfourthventricles.Earlylesionsshowdilatedcapillarieswithprominentendothelialcellsandprogresstohemorrhage.Asthelesionsresolve,acysticspaceappearsalongwithhemosiderin-ladenmacrophages.LesionsinthemedialdorsalnucleusofthethalamusseemtobestcorrelatewiththememorydisturbanceinKorsakoffsyndrome.
In addition to causing anemia, deficiency of vitamin B12 may lead to neurologic deficits associated with changes in the spinal cord, resulting in a syndrome called subacute combined degeneration of the spinal cord. As the name implies, both ascending and descending tracts of the spinal cord are affected. Symptoms develop over weeks. Early clinical signs often include mild ataxia and lower-extremity numbness and tingling, which can progress to spastic weakness of the lower extremities; sometimes, complete paraplegia ensues. Prompt vitamin replacement therapy produces clinical improvement; however, if paraplegia has developed, recovery is poor.