The progressive myoclonic epilepsies (PME) represent a genetically heterogeneous group of epilepsies that associate, as a hallmark, cortical myoclonus, other types of epileptic seizures, and a progressive neurologic deterioration, particularly cerebellar dysfunction and cognitive decline. Onset may be at any age ranging from the neonatal period to adulthood, but most of the PME start in childhood or adolescence. Myoclonus in PME is typically multifocal and is precipitated by posture, action, or external stimuli such as light, sound, or touch. It is particularly apparent in facial and distal limb musculature. Bilateral massive myoclonic jerks, which tend to involve proximal limb muscles, may also occur. Except for cortical myoclonus, patients have other seizure types such as absence seizures and generalized tonic–clonic seizures. As the disease progresses, ataxia and cognitive decline become obvious (1–4).

For most of the PME, the specific diagnosis is challenging at the onset of the disease, either due to limited experience of the clinicians with these rare disorders, to the confounder of the more benign myoclonic epilepsies that have to be ruled out, or to the overlap of the clinical phenotypes at the beginning of the clinical course. In its florid form with unremitting myoclonic seizures and progressive neurologic deterioration, the diagnosis of the PME syndrome can hardly be missed.

A large number of specific etiologies account for this clinical phenotype, most of them due to specific genetic disorders, usually autosomal recessive. The most common etiologies are summarized in Table 28.1.

NEURONAL CEROID LIPOFUSCINOSES

The neuronal ceroid lipofuscinoses (NCL) represent the largest group of PME. Despite having different underlying genetic and biochemical etiologies, they are grouped together based on the common pathologic findings of autofluorescent pigment accumulations. Their incidence is higher in the Scandinavian countries, but they are not restricted to a particular geographic territory or ethnic population. Incidence ranges from 2.2 in 100,000 in Sweden to 7 in 100,000 in Iceland (5,6). In the United States the incidence estimated at 1.6 to 2.4 per 100,000 (6).

Traditionally, NCL were classified based on the age of onset, the most prominent clinical features (cognitive and motor decline, ataxia, retinopathy evolving into blindness and myoclonic epilepsy), and the pathology findings on electron microscopy into infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) forms. They were also known by their eponyms Haltia–Santavuori disease, Janský–Bielschowsky disease, Batten–Spielmeyer–Vogt disease, and Kufs disease. Less common forms of NCL were initially named based on the countries of origin of the first reported patients (Table 28.1). The childhood forms are sometimes collectively referred to as Batten’s disease.

Currently, NCL are classified based on the affected genes, at least 14 genes being anticipated, from CLN1 to CLN14. Thirteen of these have already been identified (CLN1-8 and CLN10-14). CLN9 refers to the predicted locus in a family who do not appear to have mutations in any of the known genetic forms (7).

Up-to-date information on various NCL mutations can be found in the online database maintained by Dr. Sara Mole from University College London (www.ucl.ac.uk/ncl/).

Clinical Features

CLN1 (INCL, Santavuori–Haltia disease, OMIM#256730) disease was probably reported for the first time by Hagberg in 1968 (8), but was characterized in terms of clinical and neuropathologic features in 1973 by Pirkko Santavuori and Matti Haltia (9,10). CLN1 usually presents in the second half of the first year of life with central hypotonia, irritability, and deceleration of head growth. These are quickly followed by the onset of myoclonic jerks and other seizure types. Patients have blindness secondary to progressive optic atrophy and the electroretinogram (ERG) components disappear by 4 years of age. Hand-wringing may be present during the disease course, raising the differential diagnosis of Rett syndrome. However, unlike Rett syndrome, with CLN1 deterioration continues until death in early childhood. Most children die around 10 years of age (11). Brain MR imaging demonstrates progressive cerebral atrophy associated with abnormal signal in the thalami and basal ganglia, and thin, hyperintense, periventricular rims of white matter (4,12). Neurophysiologic findings, while etiologically nonspecific, are distinctive and include abnormalities of the awake and sleep background, loss of sleep spindles by the age of 2, and an evolution toward an isoelectric EEG after the age of 3. These neurophysiologic findings are a reflection of the neuronal degeneration and brain atrophy. Of all the NCLs, CLN1 disease has the widest range of ages of onset, determined by the combination of particular mutations present. Although the majority of patients have infantile onset, some have late-infantile, juvenile, and even adult onset as late as 40 years of age (13,14).

TABLE 28.1

CLN2 (LINCL, Janský–Bielschowsky disease, OMIM#204500) was reported initially by Jan Janský and Max Bielschowsky in two separate reports from 1908 and 1913 (15,16). The disease presents between 2.5 and 4 years. Seizures usually are the first manifestation, with myoclonic seizures, tonic–clonic seizures, atonic seizures, and atypical absences paralleling an arrest of cognitive development. Myoclonus and ataxia are prominent early in the course of the disease. Retinopathy is often not present early and may be missed after progression to more severe neurologic deficits. Axial hypotonia with appendicular hypertonia and spasticity, frequent seizures, near-continuous myoclonus, and an extended vegetative state are characteristic until death in early adolescence. Rare cases presenting late (8 years) have been reported in the literature, showing slow regression with death as late as 40 years of age (17). Brain MR imaging in CLN2 demonstrates progressive cerebral atrophy affecting predominantly the infratentorial region. The EEG shows background slowing and disorganization with generalized epileptiform discharges. A remarkable feature is marked photosensitivity, where low-frequency flashes may provoke giant posterior evoked responses. Visual evoked potentials (VEPs) are abnormally broad and of high amplitude, and sensory evoked potentials (SEPs) are enlarged. The electroretinogram (ERG) becomes progressively attenuated (18).

CLN3 (JNCL, Batten–Spielmeyer–Vogt disease, OMIM#204200) was the first recognized NCL. It may have been reported as early as 1826 by Otto Christian Stengel, who described a “strangely sickness among four siblings” in an isolated mining community in Røros, Norway, which fits the clinical phenotype of JNCL (19). Nevertheless, the cardinal features of cerebral and macular degenerations were first demonstrated by Frederick Batten in 1903 (20), and similar case reports came later from Walther Spielmeyer and Heinrich Vogt (21,22). The major clinical characteristics include an age of onset between 4 and 10 years, progressive visual failure, and gradual development of dementia. Ocular pathology is initially a pigmentary retinopathy often misdiagnosed as retinitis pigmentosa or cone dystrophy. During adolescence, extrapyramidal signs (rigidity, hypokinesia, shuffling gait, impaired balance) and epilepsy are more prominent; seizures are a relatively minor manifestation. Neuropsychiatric symptoms such as anxiety and aggression often occur (23). The clinical course is variable, but inexorably progressive toward death in the second or third decade. Some CLN3 disease presents in adulthood with visual failure sometimes later accompanied with heart failure (4,24). Brain MRI shows cerebral and cerebellar atrophy in the late teenage years and is normal before the age of 10 years. The EEG shows background slowing and generalized epileptiform discharges that often are of the slow-spike-and-wave type. Sleep activates the epileptic abnormality, but photic stimulation does not. VEPs are of low amplitude and sometimes cannot be elicited. The ERG is flat (18).

CLN4 (ANCL, Kufs disease, OMIM#162350) is a typical adult-onset NCL originally reported by Hugo Kufs (25). It presents as a PME syndrome around the age of 30, although other patients present with a picture of dementia and extrapyramidal or cerebellar disturbance. Visual auras may occur before some seizures. Blindness is notably absent, and the optic fundi are normal. The clinical course from onset to death is approximately 12 years (26). The EEG shows generalized fast spike-and-wave discharges with marked photosensitivity. Single flashes may evoke paroxysmal discharges. The background activity may be normal in the early stages, and ERGs are normal (26).

CLN5 (OMIM#256731) was first reported in Finnish patients, and thus it was referred to as the Finnish variant of LINCL. Nevertheless, CLN5 has more recently been observed in many other European countries, in North and South America, and in the Middle East; therefore, it should be considered in the differential diagnosis for any patient with suspected NCL with onset in late infancy up to adulthood (27). CLN5 typically begins slightly later than CLN 2, between 4 and 7 years of age, but adult cases are also reported. The usual course starts with deteriorations of the motor skills and is followed by progressive visual failure, dementia, myoclonus, and seizures. The speed of progression is variable, but ultimately death occurs between the ages of 14 and 36 years (28). Brain imaging shows prominent cerebellar atrophy and in addition, on T2-weighted images the thalamic signal intensity is low compared to that of the caudate, while increased signal intensity is seen in the periventricular white matter and the posterior limb of the internal capsule (29). Neurophysiologic examination shows giant visual evoked potentials, exaggerated somatosensory evoked potentials, and occipital interictal epileptiform discharges in response to photic stimulation, similar to CLN2.

CLN6 (OMIM#601780) overlaps in terms of age of onset with the CLN1, CLN2, and CLN3 diseases. It can start from 18 months to 8 years, but in the majority of children onset is between 3 and 5 years. Early visual failure occurs in about half of the patients. The most prominent symptoms are motor impairment, dysarthria, and ataxia. Seizures are very common, and usually start before 5 years of age. Deterioration is rapid after diagnosis and most children die between the ages of 5 and 12 years. MR imaging shows progressive cerebral and cerebellar atrophy. As in CLN2 disease, EEG shows progressive background slowing and high amplitude discharges in the posterior head regions in response to photic stimulation.

CLN7 (OMIM#610951) was reported initially in the Turkish population; hence the name of Turkish variant (30). It usually starts usually between 2 and 7 years. Psychomotor regression or seizures are the initial presenting signs. Progressive cognitive and motor deterioration, myoclonus, personality changes, and blindness occur later. The disease has a rapidly progressing course. A Rett syndrome-like onset was also reported (31).

CLN8 (OMIM#600143) disease can present based on the mutation as either as childhood-onset intractable epilepsy starting between 5 and 10 years of age followed by progressive cognitive decline and vision loss (30), or as a mild developmental delay in late infancy followed by a florid PME with progressive myoclonus and seizures starting between 3 and 6 years (32).

CLN9 (OMIM#609055) is clinically indistinguishable from juvenile CLN3 disease and was reported in two sisters and two brothers who presented with progressive ataxia, seizures, and vision loss by age of 4 years (7).

CLN10 (OMIM#610127) disease can occur in a congenital form with primary microcephaly, neonatal epilepsy, respiratory insufficiency, and rigidity (33); or in late-onset forms that may be seen in older children and adults (34). In one patient, missense mutations caused a childhood onset neurodegenerative disease with ataxia, retinopathy, severe cognitive decline, and apparently no seizures at 17 years of age (34).

CLN11 (OMIM#614706) disease was reported in an Italian family and is characterized by rapidly progressive visual loss due to retinopathy, epilepsy, and progressive ataxia secondary to cerebellar atrophy. Neurophysiologic evaluation reveals attenuation of the ERG and the presence of generalized, but posteriorly dominant, EEG discharges. MRI was indicative of pronounced cerebellar atrophy (35).

CLN12 (OMIM#606693) disease was reported in a Belgian family. The index case had unsteady gait, myoclonus, and mood disturbance from age 11 to 13, progressing to clear extrapyramidal involvement with akinesia and rigidity and dysarthric speech. There was no retinal involvement (36).

CLN13 (OMIM#615362) disease is an adult-onset NCL. The clinical phenotype is characterized by behavioral abnormalities and dementia, which may be associated with motor dysfunction, ataxia, extrapyramidal signs, and bulbar signs (37).

CLN14 has been reported in a Mexican family with a history of vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material on pathology (38).

Genetics

The various NCL are genetically distinct and occur worldwide, but with peculiar patterns of geographical clustering. Inheritance is autosomal recessive with the exception of CLN4, which is autosomal dominant. Recent progress in the molecular genetics of this complex group of disorders led to the identification of 13 out of 14 anticipated genes (Table 28.2) [recently reviewed in (39)]. In CLN1 disease, there is a lack of activity of the lysosomal palmitoyl protein thioesterase (PPT1). CLN2 is due to absent activity of tripeptidyl peptidase (TPP1). The CLN3 gene encodes a protein with unknown function that is localized predominantly in the endolysosomal system. CLN4 is due to mutations in the DNAJC5 gene. CLN5 encodes a soluble protein that is directed to the lysosomes; CLN6 and CLN8 encode proteins localizing to the endoplasmic reticulum. The exact function of these three proteins is not known. CLN7 gene encodes a protein that belongs to the large major facilitator superfamily. CLN10 gene encodes a lysosomal enzyme—cathepsin D. The protein product in CLN11 belongs to the protein family of granulins. CLN12 is due to mutations in the ATP13A2 gene. CLN13 is due to cathepsin F deficiency. CLN14 results from mutations that occur in the KCTD7 gene. Despite these diverse genetic etiologies and biochemical abnormalities, all NCLs are characterized by neuronal and extraneural accumulations of lipofuscin-like ceroid lipopigments. The accumulated material occurs either as granular osmiophilic deposits (GROD), curvilinear profiles (CLP), fingerprint profiles (FPP), or rectilinear complexes (RLC), and is not disease-specific; furthermore, findings may depend on the tissue examined (Figure 28.1).

Diagnosis

Diagnosis is suspected based on the clinical presentation and often is prompted by the presence of visual changes and cognitive deterioration in a patient with epilepsy. The age of onset remains the most useful element for the identification of a particular type of NCL. In newborns with primary microcephaly and seizures, an enzymatic assay for CTSD should be performed initially, and if normal, possible PPT1 or TPP1 deficiencies should be investigated. For infants older than 6 months, the workup is usually initiated by testing the PPT1 and TPP1 activities. If normal, the ultrastructural findings on electron microscopy may be helpful for pinpointing a specific diagnosis. Further molecular genetic testing should be performed if storage material is present. In school-aged children, the approach is similar, starting with noninvasive enzyme assays and assessment for possible lymphocyte vacuoles, followed by electron microscopic examination of skin or lymphocytes and targeted molecular diagnosis based on the types of storage material. In young adults, demonstrating an autosomal dominant pattern of inheritance will point toward CLN4; otherwise the diagnostic approach is similar.

FIGURE 28.1 The main electron microscopic findings in neuronal ceroid lipofuscinosis. (A) Granular osmiophilic deposits (GROD) in a pericyte from a patient with CLN1. (B) A curvilinear body in an unmyelinated nerve cell from a patient with CLN2. (C) A fingerprint profile in an endothelial cell from a patient with CLN3.

TABLE 28.2

UNVERRICHT–LUNDBORG DISEASE

Unverricht–Lundborg disease (EPM1A, OMIM#254800) is the prototypical PME, given the presence of incessant myoclonus, epilepsy, and neurodegeneration affecting the cerebellum, thalamus, and spinal cord in the absence of any storage material on neuropathology (40). It is also referred to as Baltic myoclonic epilepsy or Baltic myoclonus, since initial reports came from Sweden and Estonia (41,42). Clusters of the disease also occur in southern Europe and North Africa (43), but the disease is found sporadically worldwide (44).

Clinical Features

Unverricht-Lundborg disease is characterized by a clinical onset with myoclonus or tonic–clonic seizures between the ages of 8 and 13 years, on average 10 years. The myoclonus is usually quite severe and may be precipitated by movement, stress, or sensory stimuli. Repetitive morning myoclonus frequently buildsup into tonic–clonic seizures (45,46). In contrast to other forms of PME, it appears to be progressive only in adolescence, with dramatic worsening of myoclonus and ataxia early in the course of the disease and relative stabilization of the symptoms in early adulthood (47). Seizures may be difficult to control, but progression in terms of cognitive decline is minimal or absent. The clinical course is variable, and there may be considerable intrafamily variation in the severity of the seizures. Some patients are relatively mildly affected and survive to old age, whereas others have a fulminant course, although this very unfavorable outcome seems to be rare now and may have been related in the past to the unrecognized deleterious effects of phenytoin, which was associated with accelerated motor and intellectual deterioration, marked ataxia, and death (48).

The electroencephalogram (EEG) background may show some diffuse theta that increases over years as well as some frontal beta activity. Epileptiform activity consists of 3 to 5 Hz spike–wave or multiple spike–wave activity with an anterior predominance. Sporadic focal spikes, particularly in the occipital region, may be seen but are usually not prominent. Photosensitivity typically is marked. The spike–wave activity is diminished during non-rapid eye movement (NREM) sleep (46,49).

Genetics

Unverricht–Lundborg was linked to the long arm of chromosome 21 in Finnish cases in 1991 (50), and the gene for cystatin B was identified as the responsible gene in 1996 (51). The clinical prediction that similar cases seen outside the Baltic region have the same condition was confirmed by showing the identification of mutations in the cystatin B gene (EPM1) in families from around the world. The commonest mutation, responsible for about 90% of abnormal alleles, is an unstable expansion of a dodecamer repeat in the 5’ untranslated promoter region (52).

Diagnosis

Unverricht–Lundborg disease is recognized by its characteristic age of onset and clinical presentation. Diagnosis is confirmed by molecular genetic study of the cystatin B gene.

PRICKLE1 GENE RELATED PME

Clinical phenotypes similar to Unverricht–Lundborg disease were reported in relation to mutations involving the PRICKLE1 gene and are labeled PME type 1B (EPM1B, OMIM#612437) (53–55). In all cases the disorder is progressive and has an earlier age of onset and a slightly more severe course. Common clinical features included myoclonic and tonic–clonic seizures, progressive ataxia, tremor, and extensor plantar responses. Some patients also developed upward gaze palsy.

LAFORA DISEASE

Lafora disease (EPM2A, EPM2B, OMIM#254780) is an autosomal recessive progressive neurodegenerative disorder characterized by the presence of Lafora bodies, which are intraneuronal polyglucosan inclusions found in the brain but also in a variety of other tissues, including the heart, skeletal muscle, liver, and sweat gland duct cells (56,57).

Clinical Features

Onset of Lafora disease is between the ages of 8 and 18 years, with a mean age of onset of 14 years. Initial features can include headache, difficulties in school, myoclonic jerks, generalized seizures, and visual hallucination. Focal seizures, particularly arising from the occipital regions, occur in approximately half the patients. Visual hallucinations are frightening and have been shown to be both epileptic and psychotic. Antiepileptic medications do help, but the seizures, especially the atypical absences and myoclonus, always remain intractable and all the while worsen. EEG background activity is initially well organized and the interictal epileptiform discharges are enhanced by photic stimulation, but rapidly becomes disorganized; the sleep features are obscured by the multifocal epileptiform abnormalities, and later disappear.

The prognosis of Lafora disease is dismal. The clinical picture, including the relatively narrow age range of onset and relentlessly progressive course to death within 2 to 10 years of onset, is constant in all reports with the exception of a few cases. These cases, sometimes erroneously labeled “Lundborg-type,” had symptoms beginning in late adolescence or early adult life with a milder protracted course. They may represent a genetic subtype of Lafora disease separate from the classic form (58). Recognition of Lafora disease in its fully developed form is not difficult; however, at onset, the disorder may resemble a typical benign adolescent generalized epilepsy with no evidence of cognitive decline.

Genetics

Lafora disease is an autosomal recessive condition. The largest series have been reported from southern Europe, but it is found worldwide, without a marked racial or ethnic predilection (59). It can be classified as a glycogen storage disease given that pathogenicity is secondary to the accumulation of insoluble precipitates of polyglucosans that form the Lafora bodies. Mutation in either the EPM2A gene, which encodes a protein-tyrosine phosphatase known as laforin, or in the EPM2B, which codes for an E3 ubiquitin ligase known as malin, lead to the accumulation of polyglucosans (59–61).

Diagnosis

The initial suspicion for this debilitating diagnosis is based on the clinical picture, including the age of onset, the progressive neurocognitive impairment, and the frequent focal occipital lobe seizures (62). Diagnosis is confirmed by identifying Lafora bodies in the eccrine sweat gland ducts via skin biopsies (56) (Figure 28.2). Molecular diagnosis is also available.

PME 3

PME type 3 (EPM3, OMIM#611726) occurs with mutations in the KCTD7 gene (38,63,64). The clinical phenotype demonstrated a rapid progressive neurodegeneration characterized by early onset of intractable myoclonic seizures (before 24 months of age). A later report also identified intracellular accumulation of autofluorescent lipopigment storage material, consistent with NCL (designated CLN14), suggesting that the ultrastructural findings on skin biopsies may vary (38).

ACTION-MYOCLONUS RENAL-FAILURE SYNDROME

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