Progressive Myoclonic Encephalopathies

Question 1

Unverricht disease (Unverricht–Lundborg disease, progressive myoclonic epilepsy 1 (EPM1), Baltic myoclonus, Mediterranean myoclonus)

Semiology

Answer 1

Characterized by:

• cortical myoclonus
• generalised tonic–clonic seizures (GTCSs)
• mild progressive ataxia.

Patients are initially neurologically normal. Mild cognitive deterioration also occurs with time.

A characteristic feature of UL is the relative remission over days.

Question 2

Unverricht disease (Unverricht–Lundborg disease, progressive myoclonic epilepsy 1 (EPM1), Baltic myoclonus, Mediterranean myoclonus)

Etiology

Answer 2

Autosomal recessive disorder caused by mutations of the CTSB gene (21q22.3), which encodes Cystatin B an inhibitor of lysosomal cysteine proteases.

Question 3

Lafora disease (Lafora body disease, PME with polyglucosan bodies)

Semiology

Answer 3

Mainly myoclonia and occipital seizures (spontaneous or photic induced), and sometimes GTCS.

Behavioral and cognitive decline may be the initial manifestations

Question 4

Lafora disease (Lafora body disease, PME with polyglucosan bodies)

Etiology

Answer 4

Autosomal recessive.

Genes: EPM2A (6q24) - protein Laforin

EPM2B (6p22) - protein Malin (milder course)

Lafora bodies are PAS positive diastase resistant polyglucosan inclusions.

Question 5

Ceroid Lipofuscinoses

Semiology

Answer 5

Rapid and progressive neurocognitive deterioration.

Visual loss due to retinal atrophy is a prominent feature of all but the adult form.

Myoclonia and multiple seizure types occur.

Ataxia, dementia and behavioral problems.

Progressive deterioration of background (“vanishing EEG activity” in infantile NCL).

Question 6

Ceroid Lipofuscinoses

Etiology

Answer 6

Mainly autosomal recessive. Seven NCL gene loci have been identified:

CLN1 - PPT1 (1p32) - Palmythoil protein thioesterase.

CLN2 - TPP1 (11p15) - Trypeptidyl peptidase I

CLN3 - CLN3 (16p12) - protein CLN3

CLN4- Unknown

CLN5 - CLN5 (13q21) - protein CLN5

CLN6 - CLN6 (15q21) - protein CLN6

CLN8 - CLN8 (8p22) - protein CLN8

CLN10 - CTSD (11p15) - Cathepsin D.

In general, the disease is characterized by the intracellular accumulation of lipopigments.

Question 7

Sialidosis (type I and II)

Semiology

Answer 7

Visual impairment, myoclonus and other seizure types, ataxia. Cherry red spots in the retina.

Types I and II have the same clinical manifestations, but type II is more severe

Question 8

Sialidosis (type I and II)

Etiology

Answer 8

Result from the inherited deficiency of the lysosomal enzyme alpha-N-acetylneuraminidase due to mutations in the gene NEU1 (6p21), which codes for the protein Neuraminidase.

Question 9

Myoclonic epilepsy associated with ragged red fibers (MERRF)

Semiology

Answer 9

MERRF is characterized by:
1- Cortical Myoclonus

2- Ataxia
3- Mild atrophy
4- Cognitive Impairment

Both genders equally affected.

Progressive ataxia is the main cause of disability. Myopathy is mild, but exercise intolerance is prominent.

Lactic acidosis, peripheral neuropathy and short stature are common. Strokes may occur (as in MELAS).

The phenotype depends on the mutation load.

Question 10

Myoclonic epilepsy associated with ragged red fibers (MERRF)

Etiology

Answer 10

The gene is MT-TK, which codes for mitochondrial tRNA lysine.

Question 11

Dentatorubral-pallidoluysian atrophy (DRPLA, Naito-Oyanagi syndrome)

Semiology

Answer 11

Cerebellar ataxia and dementia are the main features.


If onset before early adulthood, cortical myoclonus and other seizure types are observed. In older onsets, seizures may be milder or absent.

Question 12

Dentatorubral-pallidoluysian atrophy (DRPLA, Naito-Oyanagi syndrome)

Etiology

Answer 12

DRPLA gene ATN1 codes for the protein Atrophin1.



The molecular defect is a trinucleotide expansion. Anticipation is also observed.

Question 13

Angelman syndrome

Semiology

Answer 13

Defined by:

Severe developmental delay.

Severe speech impairment, gait ataxia



Myoclonic jerks



Other epileptic seizures

.

Happy demeanor with excessive chortling



Question 14

Angelman syndrome

Etiology

Answer 14

Failure of expression of the maternal copy of the gene UBE3A (15q11-q13), which encodes Ubiquitin Ligase 3A.



Usually maternal de novo deletion (approximately 70% of cases).