A 12‐YEAR‐OLD GIRL WITH SEIZURES AND DEMENTIA

CLINICAL HISTORY

The patient was the product of a normal pregnancy and birth and followed normal developmental milestones apart from some difficulty with fine motor skills. She walked and talked at 1 year of age. At the age of 7 years, she had an episode of generalized convulsive status epilepticus, and was told that she had suffered from a viral encephalitis. She developed recurrent seizures at the age of 8 years. A decline in school performance was noted around this time. At 10 years of age, the seizures became more frequent, and she developed a global developmental regression, with loss of language and cognition. She also developed a movement disorder with chorea and myoclonus.

The neurological examination showed cognitive impairment. She could not speak, but she was able to follow basic commands and follow visual cues. There were no dysmorphic features and no neurocutaneous signs. Her head size, weight and height were normal for age. She had impairment of vertical gaze and she had abnormal pursuit movements. Indirect fundoscopy was normal. She had difficulty protruding her tongue, and there was constant drooling. There was no focal motor weakness, but all purposeful movement contained chorea and myoclonus. Startle myoclonus was inducible in the facial muscles. There were no abnormalities noted in the general physical examination.

Three separate evaluations for the underlying etiology had failed to demonstrate a diagnosis before presentation to our center. Normal or unremarkable laboratory testing included amino acid and organic acid profiles, complete blood count, renal and liver function, ammonia and lactate/pyruvate ratio. Mitochondrial analysis, including electron transport chain testing on muscle and mitochondrial DNA screening, was normal. Direct microscopy of skeletal muscle on review of an outside report was normal, although slides were not available. Her electroencephalogram (EEG) showed intermittent rhythmic slowing in the frontal regions, and a slow background consistent with an encephalopathy. EEG seizure demonstrating the abrupt onset of generalized epileptiform activity, maximal in the posterior head regions (Figure 1). A generalized clonic seizure was recorded with a generalized ictal EEG pattern, out of sleep. Flash visual evoked responses were normal.

Figure 1.

RADIOLOGY

A brain magnetic resonance scan (MRI) showed diffuse volume loss. Sagittal T1‐weighted and axial T2‐weighted MRI of the brain demonstrated generalized atrophy, compensatory ventriculomegaly and thinning of the corpus callosum (Figure 2).

Figure 2.

PATHOLOGY

A punch skin biopsy was obtained from the lower back area. Electron microscopy demonstrated numerous globoid filamentous inclusions within sweat gland duct epithelial cells. The filaments were tightly packed, measured approximately 10 nm, and had a randomly intersecting felt‐like pattern (Figure 3). The filaments did not appear to be membrane bound.

Figure 3.

DIAGNOSIS

Lafora body disease.

DISCUSSION

The clinical and histopathological features were first described by Gonzalo Lafora, a Spanish neurologist, in 1911, while working with Alzheimer in Munich 12, 13. The characteristic clinical presentation is the onset of myoclonus and multiple seizure types in a previously normal child. The mean age of onset is 14 years and ranges from 10 to 17 years (17). Cognitive decline is prominent, while ataxia, dyskinesias and spasticity develop later.

The EEG is characterized by background slowing and generalized polyspikes, which may be more prominent in the posterior head regions. 11, 16.

The differential diagnosis of this presentation includes the progressive myoclonic epilepsies such as Unverricht‐Lundborg disease (EPM1), early onset Dentato‐Pallido‐Luysian Atrophy, Sialidosis, Spielmeyer‐Vogt disease (Neuronal Ceroid Lipofuscinosis type 3), and MERRF (myoclonic epilepsy with ragged red fibers). Other causes of seizures and progressive neurological deterioration in this age group include Homocystinuria, X‐linked Adrenoleukodystrophy, Gaucher disease type 3 and Hallervorden‐Spatz disease (14). Lafora body disease is differentiated clinically from EPM1 by the rapid decline in cognition.

Pathological appearance. 

On macroscopic examination, the brain will appear normal or atrophic. Microscopic examination will demonstrate Lafora bodies in the cytoplasm of neurons and astrocytes in the cortex, thalamus, cerebellum and subcortical nuclei. Lafora bodies are also present in other body tissues, including the myoepithelial cells of apocrine glands and eccrine gland duct cells.

Lafora bodies consist of polyglucosans (polymers of sulphated polysaccharides) and have a deep staining core (PAS‐positive) with a spiculated outline surrounded by a zone of intermediate stain intensity (4). The ultrastructural appearance of the Lafora body from our case is shown in Figure 3.

Normal apocrine gland or duct cells in the axilla may contain PAS‐positive bodies that can lead to a misdiagnosis of Lafora body disease. In skin taken from outside the axilla or genital regions, however, apocrine cells are absent, and Lafora bodies are present in eccrine duct cells, decreasing the risk of a false positive diagnosis (1).

Research in the genetics and proteomics of Lafora body disease had advanced rapidly since the gene was found in 1998. Mutations in the EPM2A gene cause up to 80% of Lafora body disease and are inherited in an autosomal recessive manner. The gene has been localized to the long arm of chromosome 6 (6q24), and encodes for a dual phosphatase 331 amino acid protein, laforin, normally located at the plasma membrane and rough endoplasmic reticulum (15). Various mutations (mostly deletions) result in loss of function of the laforin protein 9, 10. The overexpressed non‐functional protein aggregates with glycogen‐microsomal complexes 5, 18, and may cause cell death by non‐apoptotic neuronal degeneration (7). A second gene causing Lafora body disease, NHLRC1, was identified in 2003 on chromosome 6p22.3 (3), and encodes for malin, an E3 ubiquitin ligase involved in proteolysis cascades.

The classic presentation of Lafora body disease described above has recently been demonstrated to be associated with a mutation in exon 4 of the EPM2A gene. A clinical variant consisting of early childhood onset dyslexia and learning disorder followed later by epilepsy and neurological deterioration, is associated with a mutation in exon 1 of the EPM2A gene 2, 6, and in one case of an EPM2B gene mutation. Patients usually die within 2–10 years after onset of the disease. The EPM2B mutation is associated with a slower progression of disease with or without a late onset of disease (8).

Genetic testing is available; however, the number of mutations is large, and gene sequencing is necessary. The current standard of diagnosis remains a skin biopsy.