Clinical manifestations

Presentation and course

The progressive myoclonus epilepsies are a group of heterogeneous and rare disorders clinically characterized by the presence of myoclonic and tonic-clonic seizures, myoclonus, and progressive neurologic deterioration that may include progressive dementia, cerebellar ataxia, neuropathy, and myopathy. Myoclonus in progressive myoclonus epilepsy is typically fragmentary and multifocal, often precipitated by posture, action, or external stimuli such as light, sound, or touch. Bilateral massive myoclonic jerks that tend to involve muscles of proximal limbs may also occur. The age of onset, presenting symptoms, predominance of symptoms as seizures or myoclonus over cerebellar signs, and dementia vary substantially across the different disorders (08).

The 5 major progressive myoclonus epilepsy entities are Unverricht-Lundborg disease, myoclonic epilepsy with ragged red fibers (MERRF), Lafora disease, the neuronal ceroid lipofuscinoses, and sialidoses.

Unverricht-Lundborg disease is considered the commonest form of progressive myoclonus epilepsy. The age of onset is 6 to 15 years of age. Action and stimulus-sensitive myoclonic jerks are the first symptom in at least half of patients. The myoclonus is typically resistant to medication and progresses in severity, and although fluctuations from day to day are common, it usually becomes severe enough to interfere with daily living activities in later stages. Generalized tonic-clonic seizures are common although they are usually well controlled with antiepileptic drugs, and the frequency tends to decrease with age. Other seizure types such as absences can be observed. With progression of the disease, patients develop ataxia, intention tremor, and dysarthria. Dementia is not a hallmark of the disease and, when present, is usually mild (30).

Lafora disease is a severe form of progressive myoclonus epilepsy that typically presents during late childhood or adolescence. Seizure types include myoclonus, occipital seizures, atypical absences, and complex partial and generalized tonic-clonic seizures. Myoclonus is typically fragmentary, asymmetric, arrhythmic, and progressively disabling. Cognitive decline, dysarthria, and ataxia appear early and invariably evolve, leading to high-degree incapacity. Outcome is fatal, usually within 10 years of onset, from status epilepticus or respiratory problems (58; 08).

Myoclonus epilepsy with ragged red fibers (MERRF) is one of the commonest causes of progressive myoclonus epilepsy and typically begins in childhood or adolescence. MERRF is characterized by myoclonus, generalized epilepsy, ataxia, and a constellation of symptoms that include myopathy, neuropathy, and dementia. Patients may develop deafness and optic atrophy. As a mitochondrial disease, the clinical symptoms are variable and the syndrome exhibits intrafamilial variation in age of onset and clinical severity. Less common features include cardiomyopathy, pigmentary retinopathy, pyramidal signs, ophthalmoparesis, multiple lipomas, and diabetes (15; 17). There is an overlap with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, but MERRF usually has a longer course and is associated with milder behavioral and cognitive deficits.

The neuronal ceroid lipofuscinoses comprise a large group of inherited, progressive neurodegenerative disorders characterized by the accumulation of an abnormal lipopigment in lysosomes. Historically, the neuronal ceroid lipofuscinoses were clinically categorized by age of onset into congenital, infantile (Santavuori-Haltia), late-infantile (Jansky-Bielschowsky), juvenile (Batten disease, Spielmeyer-Vogt), adult (Kufs and Parry disease), and Northern epilepsy. Increasing recognition of genetic and phenotypic heterogeneity has prompted a new classification scheme that takes into account recent genetic and biochemical advances (63). Collectively, symptoms include a progressive myoclonic epilepsy syndrome, progressively severe visual impairment, a characteristic movement disorder, loss of cognitive/developmental skills, and, in older children, a neuropsychiatric disorder. The adult form (Kufs disease), which usually manifests at around 30 years of age, may present with progressive myoclonus epilepsy (type A) or motor disability and dementia (type B), but there is no visual involvement. Northern epilepsy syndrome is characterized by epilepsy and cognitive decline, but does not present as a progressive myoclonus epilepsy (39; 38).

Sialidoses type 1 begins at 8 to 25 years of age and is characterized by progressive visual loss and disabling progressive myoclonus epilepsy with preserved cognitive status. Sialidoses type 2 is a severe infantile-onset disease associated with dysmorphic features, bone deformities, hepatomegaly, and neurosensorial hypoacusia. The neurologic symptoms include progressive cognitive decline, ataxia, and convulsive seizures; myoclonus usually presents later, more frequently in the second decade of life. In both types, the presence of a cherry-red spot on funduscopy is characteristic (45; 33; 21).

The syndrome of action myoclonus with or without renal failure syndrome is a fatal form of progressive myoclonus epilepsy characterized by onset at 15 to 25 years of age, prominent and debilitating action myoclonus, ataxia, and renal failure, but no cognitive deterioration (02; 04).

Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME) is a rare recessive disorder characterized by the combination of progressive myoclonic epilepsy and low motor neuron disease. A subtype with ASAH1 mutations presents with onset in early childhood with proximal muscular weakness followed by generalized epilepsy with myoclonic and absence seizures in late childhood or early adolescence and cognitive impairment of variable degree. The course is progressive with muscle wasting and uncontrolled epileptic seizures (24; 65; 23; 48).

Other rare diseases that can occasionally manifest as progressive myoclonus epilepsies are summarized in Table 1.

Table 1. Other Rare Diseases That May Present as a Progressive Myoclonus Epilepsy

• Celiac disease • Dentatorubral-pallidoluysian atrophy • Familial encephalopathy with neuroserpin inclusion bodies • Galactosialidosis • Gaucher disease type 3 (non-neuronopathic form) • GM1 and GM2 gangliosidosis • Huntington disease (juvenile form)

Prognosis and complications

The prognosis of a progressive myoclonus epilepsy is disease-specific and, thus, highly variable. On the mildest side of the spectrum is Unverricht-Lundborg disease, with approximately half of the patients leading a normal life. The prognosis of MERRF and the neuronal ceroid lipofuscinoses is highly variable, even in individuals from the same family harboring the same mutation. The prognosis in sialidoses is poor, mainly resulting from the development of severe myoclonus in a few years. Lafora disease, progressive myoclonus epilepsy related to SCARB2 mutations (with or without renal failure), and SMAPME associated to mutations in ASAH1 lead to unavoidable incapacity and death, usually within a decade of disease onset.

Biological basis

Etiology and pathogenesis

Most progressive myoclonus epilepsies are caused by a pathogenic mutation in a gene inherited as an autosomal recessive trait. Less common progressive myoclonus epilepsies are inherited as an autosomal dominant trait (ie, some forms of adult neuronal ceroid lipofuscinosis) or through mitochondrial inheritance (ie, MERRF). The genes responsible for the most common types of progressive myoclonus epilepsy and their products are summarized in Table 2.

In addition, new phenotypes have been identified in some families and/or individuals harboring novel mutations in other genes (Table 3).

Table 2. Most Common Types of Progressive Myoclonus Epilepsy

Progressive myoclonus epilepsy type	Gene	Gene product	Common mutations
Unverricht-Lundborg disease	CSTB	Cystatin B	GC-rich dodecamer expansion
Lafora disease
	EPM2A	Laforin	Point mutations, deletions
	EPM2B	Malin	Point mutations, deletions
Neuronal ceroid lipofuscinoses
Congenital	CLN10/CTSD	Cathepsin D	Point mutations
Infantile
Classical (Haltia-Santavuori)	CLN1/PPT1	PPT1	Point mutations, deletions
Late infantile
Classical (Jansky- Bielschowsky)	CLN2	TPP1	Point mutations, deletions
Variants late-infantile	CLN5, CLN6, CLN8	CLN5, CLN6, CLN8	Point mutations, deletions
	CLN7/MFSD8	MFSD8	Point mutations
Juvenile
Spielmeyer-Sjögren-Vogt	CLN3	Battenin	1 Kb deletion, point mutations
Adult
Parry disease (AD)	DNAJC5	DNAJC5	Point mutations, deletions
Kufs type A (AR)	CLN6	CLN6	Point mutations
Sialidosis type 1	NEU1	Sialidase 1	Point mutations
MERFF	MT-TK	tRNA lysine	Point mutations

AD: autosomal dominant; AR: autosomal recessive; DNAJC5: DnaJ homolog subfamily C member 5; MFSD8: major facilitator superfamily domain-containing protein 8; MT-TK: mitochondrially encoded tRNA lysine; PPT1: palmitoyl-protein thioesterase 1; TPP1: tripeptidyl-peptidase 1

Table 3. New Forms of Progressive Myoclonus Epilepsy

PME subtype (EPM designation in OMIM)	Gene	Protein function	Inheritance	References
PME type 1B (EPM1B)	PRICKLE1	Nuclear receptor	AR	(05)
AMRF (EPM4)	SCARB2	Lysosomal membrane protein	AR	(07; 16)
PME type 3 (EPM3)	KCTD7	Modulation of potassium ion channel function	AR	(57; 54)
North Sea PME (EPM6)	GOSR2	Cathepsin D	AR	(12)
MEAK (EPM7)	KCNC1	Neuronal voltage-gated potassium ion channel	AD/de novo	(41)
PME type 8 (EPM8)	CERS1	Ceramide synthase-1	AR	(59)
PME type 9 (EPM9)	LMNB2	Nuclear lamin protein	AR	(14)
PME type 10 (EPM10)	PRMD8	Unknown function	AR	(55)

AD: autosomal dominant; AMRF: action myoclonus with or without renal failure; AR: autosomal recessive; MEAK: myoclonic epilepsy with ataxia due to potassium channel mutation

Most of the known genes causing progressive myoclonus epilepsy encode lysosomal proteins. Despite increasing knowledge of the genes and proteins involved in progressive myoclonus epilepsy disorders, little is presently known about the pathogenic mechanisms leading to neurodegeneration and epilepsy (44).

Lafora disease is caused by mutations in either EPM2A or EPM2B, which encode the interacting proteins laforin, a dual-specificity phosphatase, and malin, an ubiquitin E3 ligase (37; 52; 11). Laforin and malin regulate glycogen synthesis, and their malfunction results in the formation of an abnormal glucose polymer that accumulates in the brain and other tissues (Lafora bodies) (31). This accumulation, other malfunctioning pathways where laforin and malin are involved, or both, result in progressive neurodegeneration and epileptic seizures. Experimental work has shown that neurons have the enzymatic machinery for synthesizing glycogen, but that it is suppressed by the laforin-malin complex. Disturbance of this mechanism, as a consequence of mutations in laforin or malin, would explain the accumulation of a poorly branched glycogen. This abnormal glycogen might result in the activation of the apoptotic program (60). Although Lafora bodies accumulate in many different tissues, such as muscle, heart, or liver, other systemic symptoms are rare.

Classical Unverricht-Lundborg disease is caused by mutations in the CSTB gene encoding cystatin B. The most prevalent genetic defect is the expansion of an unstable polymorphic dodecamer repeat in the promoter region of CSTB, which accounts for more than 90% of mutated alleles (43; 28). Because of the role of cystatin B as an inhibitor of lysosomal cysteine proteases, the defective protein is presumed to lead to increased abnormal apoptosis and/or altered redox homeostasis, leading to neuronal degeneration and death. However, the pathogenesis of this “common” form of progressive myoclonus epilepsy remains mostly unknown (32; 44). Pathology in Unverricht-Lundborg disease is unremarkable (30).

Mutations in the 9 genes known to cause neuronal ceroid lipofuscinosis lead to defects of lysosomal enzymes (CTSD/CLN10, PPT1/CLN1, TPPI/CLN2, CLN5) or transmembrane proteins whose functions are not yet defined (CLN3, CLN4, CLN6, CLN7, CLN8). Despite genetic and clinical heterogeneity, the different forms are grouped together on the basis of pathologic grounds due to the common presence of neuronal and extraneural autofluorescent pigment deposits. Under the electron microscope, the accumulated material takes 3 different forms: granular osmiophilic deposits, curvilinear profiles, and fingerprint bodies. The form that predominates in a particular patient correlates with the particular genetic type of neuronal ceroid lipofuscinosis (40). The relationship between genetic defects associated with the major neuronal ceroid lipofuscinosis forms, the accumulation of storage material, and tissue dysfunction and/or damage is still unknown. Degeneration and cell loss involve mostly neuronal cells, suggesting that neuronal ceroid lipofuscinosis proteins may be most critical for neuronal metabolism of neurons (39).

In sialidoses, the enzymatic deficiency of sialidase 1 results in lysosomal storage of sialylated glycopeptides and oligosaccharides (09). Sialidase 1 is a negative regulator of lysosomal exocytosis, thus, the impaired function of neuraminidase is related to exacerbation of lysosomal exocytosis (64). Light and electron microscopy reveals cytoplasmic vacuolation involving neurons and perineuronal and interfascicular oligodendroglia, endothelial, and perithelial cells. Vacuolations are associated with diffuse neuronal intracytoplasmic storage of lipofuscin-like pigment. These changes can be observed in the neocortex, basal ganglia, thalamus, brainstem, spinal cord, and extra-nervous organs (01).

MERRF is caused by mutations in genes contained in mitochondrial DNA (mtDNA) and, thus, inherited by maternal inheritance. The A8344G mutation in the MT-TK gene encoding tRNA lysine is found in more than 80% of patients with MERRF. Less common mutations in the MT-TL1, MT-TH, and MT-TS1 genes have been described (53; 17). Mutations in mtDNA genes cause mitochondrial protein synthesis defects, resulting in respiratory chain enzyme deficiencies that lead to impaired aerobic ATP production (oxidative phosphorylation). This forces greater reliance on ATP synthesis via anaerobic glycolysis with concomitant increases in lactic acid. Neuropathological studies have revealed prominent loss of neurons in the cerebellum, brainstem, and spinal cord.

Action myoclonus-renal failure syndrome is caused by mutations in SCARB2, a gene encoding lysosome membrane protein 2, a chaperone that escorts glucocerebrosidase to the lysosome (07). Mutations in SCARB2 are also found in adult patients with progressive myoclonus epilepsy without renal failure (16). Some patients also present peripheral neuropathy or dilated cardiomyopathy.

MEAK (EPM7), myoclonus epilepsy and ataxia due to a potassium channel dysfunction, is a form of progressive myoclonus epilepsy clinically similar to Unverricht-Lundborg disease, which is caused by a recurrent de novo heterozygous mutation (c.959G> A, p.Arg320His) in the KCNC1 gene coding for the Kv3.1 protein (a subunit of the Kv3 subfamily of voltage-gated potassium channels). Loss of function of this protein causes disruption of the firing properties of fast-spiking neurons, affects neurotransmitter release, and induces cell death. The most affected neurons include inhibitory GABAergic interneurons and cerebellar neurons that may contribute to the main clinical symptoms of seizures or myoclonus and ataxia or tremor respectively (41).

Epidemiology

The specific entities causing progressive myoclonus epilepsy are rare diseases, and epidemiological data are not readily available for the majority. Unverricht-Lundborg disease, considered the most common progressive myoclonus epilepsy, has its highest prevalence in Finland, with 1 case for each 20,000 births (42). For MERRF, studies in northern European countries have estimated the prevalence of the m.8344A>G mutation to be 0 to 1.5 per 100,000 (15; 46; 49). Neuronal ceroid lipofuscinoses have a prevalence of approximately 1.5 to 9 per million population, and the incidence ranges in different countries from 1.3 to 7 per 100,000 live births (39).

Prevention

Prompt diagnosis, establishment of the mode of inheritance, and genetic testing of relatives may allow genetic counseling and prevention of transmission of the genetic defect.

Differential diagnosis

Differential diagnosis between the different forms of progressive myoclonus epilepsy is not always easy, and they are best distinguished on the basis of age at onset and concomitant signs and symptoms associated with myoclonic epilepsy.

Progressive myoclonus epilepsies starting during adolescence (mainly Unverricht-Lundborg disease and Lafora disease) may occasionally be misdiagnosed as idiopathic generalized epilepsy, specifically juvenile myoclonic epilepsy. Clinical refractoriness or atypical EEG findings, such as a slow background, may lead to a suspicion of progressive myoclonus epilepsy. In some patients, diagnosis is reached only after follow-up, due to the development of cerebellar signs and/or cognitive decline.

Diagnostic workup

The first stage of the diagnostic approach should be based on a detailed clinical evaluation considering age at onset; geographic and ethnic origin; family history; associated neurologic symptoms, including dementia and sensory loss, and neurophysiologic features. At a second stage, further specific laboratory analysis, molecular genetic testing, and/or histological studies should lead to the diagnosis of the specific disease in the majority of the patients (06).

Neurophysiology. The EEG background may be relatively well-preserved in the early phases, but as the condition progresses generalized slow activity appears, especially in progressive myoclonus epilepsies associated with cognitive impairment. Generalized epileptiform abnormalities, such as fast spike-and-wave, multiple spike-and-wave, or multiple-spike discharges, are commonly recorded spontaneously and/or elicited by intermittent photic stimulation. Spontaneous myoclonic jerks may be associated with EEG paroxysms in routine recordings, although jerk-locked back averaging may be necessary to detect a time-locked EEG correlate. Focal epileptiform abnormalities with predominant posterior location are common in Lafora disease, but may also occur in Unverricht-Lundborg disease, MERRF, and juvenile neuronal ceroid lipofuscinosis (08). Electroencephalographic sleep patterns may become disorganized or even be absent. With a few exceptions, epileptiform activity is often less apparent than in the waking state.

Features that may be useful for specific diagnosis include the finding of vertex spikes and fast rhythms in sialidoses, activation of epileptiform abnormalities in non-REM sleep in sialidoses and in the late-infantile and juvenile forms of neuronal ceroid lipofuscinosis, photosensitivity to single flashes in late-infantile and adult neuronal ceroid lipofuscinosis, and absent electroretinogram in late-infantile and juvenile neuronal ceroid lipofuscinosis (08).

Somatosensory evoked potentials frequently show giant responses whereas visual and brainstem evoked responses are usually normal. Magnetic stimulation of the cortex and peripheral stimulation show an exaggerated effect of afferent input on motor cortical excitability (47).

Laboratory findings. Routine biochemical tests are not helpful, with the exception of elevated lactate levels in blood and CSF in some cases of MERRF and proteinuria with impaired renal function in the action myoclonus-renal failure syndrome.

Some useful, specific tests are urinary thin-layer chromatographic oligosaccharide screen for the sialidosis and urinary sediment dolichol estimation for the neuronal ceroid lipofuscinoses. Specific enzyme assays using fibroblast cultures and specific substrates may be useful to confirm the diagnosis in sialidosis (sialidase 1 and beta-galactosidase) and in some types of neuronal ceroid lipofuscinosis (palmitoyl protein thioesterase 1, tripeptidyl-peptidase 1, and cathepsin D).

Neuroimaging. Structural brain MR is usually normal or shows diffuse atrophy in later stages. A MR imaging and MR spectroscopy study in patients with Unverricht-Lundborg disease showed loss of bulk of the basis pontis, medulla, and cerebellar hemispheres as well as spectroscopy abnormalities in the pons, suggesting that brainstem involvement could play a role in the pathophysiology of the disease (36). In Lafora disease, abnormalities in spectroscopy, mainly in the frontal cortex, cerebellum, and basal ganglia, have been described (61).

Pathological studies. Lafora disease can be reliably diagnosed by examining eccrine sweat gland duct cells with periodic acid-Schiff (10). In cases of neuronal ceroid lipofuscinosis not confirmed by enzyme analysis, identification of typical inclusions with electron microscopy examination of peripheral white blood cells or skin will confirm the diagnosis. These inclusions are detectable in many cell types in the late-infantile form of the disease, but in the juvenile and adult varieties diagnostic inclusions may be limited to eccrine secretory cells (40). False-negative skin biopsies in Lafora disease and in late-infantile and juvenile neuronal ceroid lipofuscinosis are mostly attributed to failure to examine the appropriate cell type properly (06).

Study of muscle biopsy specimens with modified Gomori trichome and oxidative enzyme reactions may demonstrate ragged red fibers in MERRF (25). Abnormal mitochondria may be identified in muscle or skin using electron microscopy studies. Normal light and electron microscopic studies of muscle do not rule out the diagnosis of MERRF.

Genetic testing confirms the diagnosis in most cases of progressive myoclonus epilepsy. However, it must be accepted that some cases will not be classified even after careful clinical and genetic studies (20).

Management

Treatment of these disorders may be distressingly difficult. Overall, treatment of progressive myoclonus epilepsies remains limited to symptomatic management of seizures, myoclonus, and intercurrent complications. There is no specific treatment for most genetic disorders underlying a progressive myoclonus epilepsy syndrome. Once the diagnosis is confirmed, informed genetic counseling should be provided, together with psychological support, to parents, patients, and siblings, especially in those diseases with the worst prognosis.

Available data on the efficacy of drugs are primarily anecdotal or observational and come from small groups of patients. Traditional antiepileptic drugs useful in the treatment of progressive myoclonus epilepsies are valproate and clonazepam (26). However, valproate inhibits carnitine uptake and should not be used in mitochondrial disorders. Newer drugs shown to be effective include piracetam, levetiracetam, and topiramate (19; 35; 03). Two, small open-label studies support a beneficial role of zonisamide in the symptomatic treatment of progressive myoclonus epilepsies (62; 27). There is anecdotal evidence of the potential benefit of perampanel in the treatment of seizures and other neurologic symptoms such as ataxia or cognitive impairment in Lafora disease (50; 18). Perampanel also has been found to be useful for the treatment of myoclonus in patients with Unverricht-Lundborg disease although psychological and behavioral side effects may limit its use (13). Two clinical trials have failed to show the efficacy of brivaracetam in action myoclonus in patients with Unverricht-Lunborg disease (29).

Drugs that may worsen myoclonus, such as phenytoin, vigabatrin, carbamazepine, and gabapentin, should be systematically avoided. Lamotrigine has an unpredictable effect on myoclonus and must be used with caution (22).

Combinations of antioxidant vitamins and cofactors, like coenzyme Q10 and L-carnitine supplementation, can be used in patients with mitochondrial disorders.

Specific treatment with enzyme replacement and gene therapy are attractive therapeutic options. A multicenter, open-label study evaluated the effect of enzyme-replacement therapy with intraventricular infusion of recombinant human tripeptidyl peptidase 1 (cerliponase alfa) in 24 patients with ceroid lipofuscinosis type 2 (51). The treatment resulted in less decline in motor and language function than in historical controls. Among others, emerging adverse events included pyrexia, vomiting, and hypersensitivity reactions; also, infections developed in the intraventricular device that was used to administer the infusion.