Diagnosing The Specific Type Of

Once the clinician is convinced that a patient has the PME syndrome, the critical question is to determine which specific disorder is present. This is essential for proper clinical and genetic counseling of the family (see "Treatment'' section).

It is now possible to provide a specific diagnosis in life for the majority of patients with PME using clinical methods and minimally invasive investigations. An approach to this problem has been described previously. The clinician should first consider the five major disorders causing PME. Once these conditions are excluded, the rarer disorders should be considered (1-3).

Clinical Features

Although patients with the PME syndrome superficially may appear to have similar clinical features, knowledge of the specific clinical patterns of the common causes of PME often allows the differential diagnosis to be narrowed. Age at onset of symptoms provides some guidance in making the diagnosis, although MERRF may begin at any age. Certain seizure patterns are helpful; very prominent myoclonus suggests Unverricht-Lundborg disease, MERRF, or sialidosis. Partial seizures, particularly of occipital origin, can occur in a variety of the disorders but are often noted in Lafora disease. Characteristic fun-dal changes are almost invariable in sialidosis and are frequent in the NCLs. Dementia is a constant feature of Lafora disease and NCLs, whereas it is characteristically absent or mild in Unverricht-Lundborg disease and sialidosis type I. The presence of deafness, lipomas, optic atrophy, myopathy, or neuropathy are clinical pointers to MERRF. Neuropathy may also occur in sialidosis. Dys-morphic features are usual in sialidosis type II and may occur in MERRF.

Family History

A detailed family history, including examination of relatives, is essential. Recessive inheritance is usual, and the finding of parental consanguinity or early clinical signs in asymptomatic siblings would support this pattern. Maternal transmission is characteristic of MERRF. In MERRF and the autosomal dominant disorders, older relatives may be found to have mild, incomplete forms of the condition.


Findings that may be useful in specific diagnosis include vertex spikes as the main epileptiform abnormality in sialidosis, activation of epileptiform abnormalities in non-REM sleep in the sialidoses and the late-infantile and juvenile forms of NCL, photosensitivity to single flashes in late infantile and adult NCL, and absent ERG in late infantile and juvenile NCL (11).

Laboratory Findings

Hematologic examination may reveal lymphocyte vacu-olation in sialidosis and in certain cases of NCL. Routine biochemical tests are not helpful, with the exception of elevated lactate levels in blood and cerebrospinal fluid in some cases of MERRF.

Pathologic Studies

A tissue diagnosis is essential for a number of these disorders. Skin biopsy with or without skeletal-muscle biopsy is the initial procedure. Lafora disease can be reliably diagnosed by examining eccrine sweat gland duct cells with stains for polysaccharides (36). The diagnosis of NCL may be suggested by an acid phosphatase stain, but electron microscopy of the skin biopsy specimen is essential for the definitive identification of inclusions. These inclusions are detectable in many cell types in the late infantile form of the disease, but diagnostic inclusions may be limited to eccrine secretory cells in the juvenile and adult varieties (58). False negative skin biopsies in Lafora disease and in late infantile and juvenile NCL are due to failure to examine the appropriate cell type properly. In suspected Lafora disease, sweat gland ducts must be included in the biopsy and properly examined. Where doubt remains, skin biopsy should be repeated because of the serious prognostic implications of the diagnosis of Lafora disease. The reliability of diagnosis of Kufs' disease from skin biopsy is not yet clear.

Study of muscle biopsy specimens with modified Gomori's trichrome and oxidative enzyme reactions may demonstrate ragged red fibers in MERRF. Abnormal mitochondria may be identified in muscle or skin using electron microscopy. Normal light and electron microscopic studies of muscle do not rule out the diagnosis of MERRF, and a second biopsy may be indicated in clinically suspicious cases.

Molecular Biological Studies

Molecular biological studies are playing an increasing role in the diagnosis of the PMEs. Simple DNA tests for the dodecamer repeat in Unverricht-Lundborg disease and mitochondrial DNA mutations in MERRF are readily available. Testing for mutations associated with Lafora disease, neuronal ceroid lipofuscinososes, and sialidoses is available from more specialized or research-oriented laboratories (see http://www.genetests.org).

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