Five major categories of familial polymyoclonus of late childhood and adolescence have been delineated: (1) Laforaor amyloid-body type, (2) juvenile cerebroretinal degeneration, (3) cherry-red spot myoclonus (sialidosis or a-neuraminidase deficiency), (4) mitochondrial encephalopathy, and (5) a more benign degenerative disease (dyssynergia cerebellaris myoclonica of Hunt). Familial myoclonus may also be a prominent feature of two other diseases—GM2 gangliosidosis and Gaucher disease—which occasionally have their onset in this age period.
This disease, which is inherited as an autosomal recessive trait, was first identified by Lafora in 1911 on the basis of the large basophilic cytoplasmic bodies that were found in the dentate, brainstem, and thalamic neurons. These inclusions have been shown by Yokoi and colleagues to be composed of a glucose polymer (polyglucosan; abnormally shaped glycogen molecules). Possibly some of the cases of familial myoclonus epilepsy reported by Unverricht and by Lundborg were of this type, but because these authors provided no pathologic data, one cannot be sure. The disease is the result of mutations in EPM2A or the NHLRC1, which code for laforin and malin, which regulate glycogen production.
Beginning in late childhood and adolescence (11 to 18 years) in a previously normal individual, the disease announces itself by a seizure, a burst of myoclonic jerks, or both. In about half the cases there are focal (often occipital) seizures. The illness may at first be mistaken for ordinary epilepsy, but within a few months it becomes evident that something far more serious is occurring. The myoclonus becomes widespread and can be evoked as a startle by noise, an unexpected tactile stimulus (even the tap of a reflex hammer), and also by excitement, or certain sustained motor activities. An evoked train of myoclonic jerks may progress to a generalized seizure with loss of consciousness. As the disease advances, the myoclonus interferes increasingly with the patient’s motor activities until voluntary function is seriously impaired. Speech may be marred, much as it is in chorea. Close examination may also reveal an alteration in muscle tone and a slight degree of cerebellar ataxia. At this time, or even before the onset of myoclonus and seizures, the patient may experience visual hallucinations or exhibit irritability, odd traits of character, uninhibited or impulsive behavior, and, ultimately, progressive failure in all cognitive functions. Deafness has been an early sign in a few cases. Rigidity or hypotonia, impaired tendon reflexes, acrocyanosis, and rarely corticospinal tract signs are late findings. Finally, the patient becomes cachectic and bedfast and succumbs to intercurrent infection. Most do not survive beyond their twenty-fifth birthday. Nonetheless there are isolated reports of Lafora-body disease in which symptoms began as late as age 40 years, with death as late as age 50 years. These late cases may constitute a separate genetic type.