Four out of the 11 patients are of German origin. Variants in
EPM2A or
EPM2B were detected by NGS in all 11 index patients with suspected LD or unclassified progressive myoclonus epilepsy. Variants of various types were detected in
EPM2A in six patients (three of them of German origin) and in
EPM2B in five patients (one of them of German origin; see Table
1). Five
EPM2A variants (c.259A > G, c.290 T > G, c.759delinsCATGCA, c.836G > T, c.917A > T) and three
EPM2B variants (c.385C > T, c.583del, and c.730delG) have not been reported in the LD literature or in the Lafora gene mutation database (
http://projects.tcag.ca/lafora/) before [
5]. The mean age of disease onset is 13,7 ± 0,6 years (mean ± SEM) in the patients bearing
EPM2A variants and 14,6 ± 2,3 years in those carrying
EPM2B variants. The cumulative mean age of onset of this cohort is 14,1 ± 1,0 years (range: 8–21 years).
Table 1
Genotypes of LD patients living in Germany
|
EPM2A
|
NC_000006.11: | NM_005670.3: | | | |
1a | g.146056376 T > C | c.259A > G | p.(Lys87Glu) | Homo. | |
2a | g.[146056360_146056366del]; [145,948,631 T > A] | c.[269_275del];[917A > T] | p.[(Lys90Serfs*35);(Asp306Val)] | Comp. het. | |
3a | g.146056345A > C | c.290 T > G | p.(Leu97Arg) | Homo. | |
4 | g.146007412G > A | c.322C > T | p.(Arg108Cys) | Homo. | |
5a | g.145948789delinsTGCATG | c.759delinsCATGCA | p.(Ala254Metfs*33) | Homo. | |
6a | g.145948712C > A | c.836G > T | p.(Gly279Val) | Homo. | |
|
EPM2B
|
NC_000006.11: | NM_198586.2: | | | |
7a | g.18122453G > A | c.385C > T | p.(Pro129Ser) | Homo. | |
8, 9 | g.18122402C > T | c.436G > A | p.Asp146Asn | Homo. | |
10a | g.[18122402C > T]; [18122108delC] | c.[436G > A];[730delG] | p.[(Asp146Asn);(Val244Serfs*51)] | Comp. het. | |
11a | g.18122255del | c.583del | p.(Asp195Ilefs*37) | Homo. | |
In the following paragraphs, we shortly outline the disease courses of the patients bearing novel variants (also see Table
2). The anticonvulsants valproate (11/12), perampanel (8/12), levetiracetam/brivaracetam (7/12), and clobazam (6/12) were the most used ones in our cohort indicating a good of effectiveness of these drugs in LD (see Additional file
1: Table S1).
Table 2
Disease courses of LD patients living in Germany
|
EMP2A
|
1a | Tur | F | yes | c.259A > G (homo.) | 14 | 15 | 15 | 15 | 18 | 4 | Gelastic seizures |
2a | Ger | F | no | c.[269_275del];[917A > T] | 17 | 15 | 17 | 16 | 18 | 3–4 | Congenital hypothyroidism, polyneuropathy |
3a | Ger | F | no | c.290 T > G (homo.) | 14 | 15 | 17 | 17 | 25 | 3 | Psychogenic seizures |
4a | Leb | F | yes | c.322C > T (homo.) | 12 | n/a | n/a | n/a | 18 | 4 | Vision loss |
4b | Leb | M | yes | c.322C > T (homo.) | 11 | n/a | n/a | < 16 | 16 | 1–2 | |
5a | Rus | M | yes | c.759delinsCATGCA | 14 | 14 | 17 | 15 | 21 | 3 | Aggressiveness |
6a | Ger | M | no | c.836G > T (homo.) | 18 | 16 | 19 | 20 | 24 | 3 | |
|
EMP2B
|
7a | Syr | F | yes | c.385C > T (homo.) | 11 | 15 | 15 | 15 | 19 | 4 | Optic hallucinations, hypothyroidism, hepatomegaly |
8 | Tur | M | yes | c.436G > A (homo.) | 17 | 17 | 23 | 26 | 30 | 3–4 | Diabetes mellitus with coma and cataract, hypothyroidism, arterial hypertension |
9 | Tur | F | yes | c.436G > A (homo.) | 23 | 21 | – | 23 | 25 | 2 | |
10a | Ger | F | no | c.[436G > A];[730delG] | 16 | 17 | – | – | 23 | 1 | |
11a | Ira | M | yes | c.583del (homo.) | 8 | 13 | – | 8 | 13 | 1–2 | Psychogenic seizures |
Case vignettes of index patients with novel variants (Table 2)
Patient nr. 1 is a homozygous carrier of the EPM2A variant c.259A > G. Her parents are of Turkish origin and are consanguineous. Retrospectively, the first symptom were recurrent episodes of explosive headache at the age of 12 years. Next, myoclonic and atonic seizures with consecutive falls developed. Aged 15 years, she developed tonic-clonic, visual, gelastic and absence seizures and (negative) myoclonus aggravated. Shortly later, she also developed severe ataxia and progressive cognitive decline. At the age of 19 years, the patient is wheelchair-bound and exhibits severe dysarthria as well as dysphagia requiring percutaneous endoscopic gastrostomy (PEG).
Patient nr. 2 is compound heterozygous for the known variant c.269_275del and the novel variant c.917A > T in EPM2A. Her parents are German and nonconsanguineous. She developed myoclonic seizures as first disease symptom at the age of 15 years. However, an EEG at the age of 6 years, performed due to headaches showed posterior slow waves, which were interpreted as a variant of the basic rhythm at that time. Since the beginning of the epilepsy, the young woman lost major cognitive and motor functions and suffers from ataxia. She developed polyneuropathy of the lower extremities. About 3 years later, she can walk only few steps with lots of support and needs help with all activities of daily living.
Patient nr. 3 is a homozygous carrier of the EPM2A variant c.290 T > G. She is of German origin and her parents are considered nonconsanguineous based on family history. She had onset of tonic-clonic seizures at the age of 14 years. Shortly later, she developed myoclonic and absence seizures, ataxia and cognitive decline. She exhibits a slow progression and is still able to walk and speak 12 years after onset of symptoms.
Patient nr. 5 is homozygous for the EPM2A variant c.759delinsCATGCA. His parents are Russian and are consanguineous. He developed tonic-clonic seizures at the age of 15 years. The patient showed striking social difficulties and increased aggressiveness. After the age of 17 years, psychomotor skills reduced, and the patient developed tremor, ataxia and progressive cognitive decline. At the age of 20, he has lost many everyday skills and suffers from frequent seizures, while refusing medication. Due to severe dysphagia a PEG was implanted. At the age of 23 years he is wheelchair-bound and shows severe dysarthria.
Patient nr. 6 carries the homozygous c.836G > T variantin EPM2A. He is of German origin and his parents are considered nonconsanguineous based on family history. Myoclonic seizures started at the age of 16. About the same time, visual auras occurred followed by tonic-clonic and absence seizures about 1 year later. Thereafter, he developed mild ataxia and a cognitive decline. At the age of 24, daily drop attacks and myoclonic seizures were the main problem of the patient. His sister carried the same homozygous mutation in EPM2A, but her course of the disease was more severe and she died at the age of 24.
Patient nr. 7 carries the homozygous c.385C > T variant in EPM2B. She is of Syrian origin and her parents are consanguineous. She suffered the first and second tonic-clonic seizure at the age of 11 and 13 years. Thereafter, the frequency of seizures increased and since the age of 15, she has been suffering from intermittent myoclonic seizures and progressive dysarthria, ataxia, optic hallucinations and dementia. At the current age of 19 years, the patient is wheelchair-bound and suffers from severe dysphagia requiring PEG.
Patient nr. 10 is compound heterozygous for the known variant c.436G > A and the novel variant c.730delG in EPM2B. She is German and her parents are nonconsanguineous. She first developed tonic-clonic and absence seizures at the age of 16. About 1 year later, myoclonic seizures started. A juvenile myoclonic epilepsy was suspected. After initiating a therapy with Valproate, tonic-clonic seizures were well under control for about 4 years. Meanwhile, myoclonic seizures accelerated under different medications and the EEG worsened. At the age of 23, the patient’s cognitive skills are still preserved, and he does not suffer from ataxia.
Patient nr. 11 is homozygous for the c.583del variant in EPM2B. He is Iraqi and his parents are consanguineous. His epilepsy started at the age of 9 years with generalized tonic-clonic seizures. Later, he developed myoclonic seizures (especially negative myoclonus), psychogenic seizures and cognitive decline. His motor abilities are relatively well preserved (now aged 14).