van den Ameele J, Jedlickova I, Pristoupilova A, Sieben A, Van Mossevelde S, Ceuterick-de Groote C, Hůlková H, Matej R, Meurs A, Van Broeckhoven C, Berkovic SF, Santens P, Kmoch S, Dermaut B. Teenage-onset progressive myoclonic epilepsy due to a familial C9orf72 repeat expansion. Neurology. 2018 Feb 20;90(8):e658-e663.
The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously.
To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME.
We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions.
C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.
From the article
C9orf72 hexanucleotide repeat expansions are the main cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Average age at onset is in the 6th decade, with a range between 27 and 83 years. Since their first description in 2011, the clinical phenotype associated with these mutations has expanded beyond the FTD/ALS spectrum. Parkinsonism and psychiatric features are well established now, and hyperkinetic or cerebellar movement disorders have been described. Seizures are rarely described and PME has not been reported…
A 33-year-old woman was referred to the neurology department of a tertiary care hospital in Belgium because of progressive cognitive decline and speech difficulties. She had had epilepsy with generalized tonic-clonic seizures and myoclonic jerks since the age of 15 but was seizure-free for several years under treatment with valproic acid, levetiracetam, and clobazam. She was reportedly well before the age of 15, with average school performance…
Neuropsychological testing 3 months after initial evaluation showed mostly deficits in attention and executive functions and to a lesser extent in verbal memory . EEG repeatedly showed a moderate increase in slow activity in the theta and delta range, as well as occasional low-amplitude, generalized spike-wave discharges with central maximum, without clear photosensitivity.
The family history revealed several patients with adult-onset psychiatric or neurodegenerative disorders…
MRI of the brain revealed generalized cerebral and cerebellar atrophy, mostly in the bilateral parietal lobes with concordant relative hypometabolism on FDG-PET imaging. Skin and muscle biopsy were normal as were mitochondrial enzyme activities in muscle. Genetic testing for autosomal dominant spinocerebellar ataxias (SCA1-2-3-6-7-17), dentatorubral-pallidoluysian atrophy, Huntington disease, and familial Alzheimer disease (PSEN1-2, APP) was normal. Microarray-based comparative genomic hybridization did not reveal pathologic copy number variations. Whole exome sequencing (WES) of the patient and her maternal aunt was performed in the context of the ANCL Gene Discovery Consortium.12 The WES dataset was filtered for variants in PME causative genes, namely KCNC1, CERS1, PRICKLE1, EPM2A, GOSR2, KCTD7, LMNB2, NHLRC1, PRDM8, CSTB, SCARB2, and DNAJC5,13 having a minor allele frequency <5% in the ExAC database. Using this approach, we did not detect any candidate variants in the proband. Additional searching for genetic alterations in a wider spectrum of epilepsy genes 14 did not reveal any potential candidate mutations.
Electron microscopy (EM) examination of a brain biopsy from the patient's right parietal lobe at age 34 showed some nonspecific increase in lipopigment, but no evidence of Lafora bodies or material diagnostic for NCL. EM analysis of the muscle biopsy of the maternal aunt was more ambiguous and suggested presence of pathologic storage material in the form of lipopigment with occasional fingerprints, although insufficient to establish a definite diagnosis of adult neuronal ceroid lipofuscinosis (ANCL) or Kufs disease. Subsequent expert review of the biopsy findings within the same Consortium excluded the diagnosis of ANCL.
Next we tested for C9orf72 repeat expansion, which was positive in both our patient and the affected aunt, as well as in 2 distant family members. Short-repeat PCR 3 excluded a repeat size of less than 80 bp in the proband and her aunt. Further analysis of the brain biopsy with light microscopy examination showed clear neuronal cytoplasmic inclusions that stained positive for p62, but were negative for ubiquitin, TDP-43, and its hyperphosphorylated form . Autofluorescence was slightly increased and ANCL-related staining for SCMAS, CathD, and LAMP2 were negative. Additional staining for amyloid, tau, FUS, and [alpha]-synuclein did not reveal pathologic changes….
This report supports the novel and emerging concept of disease anticipation in families segregating a C9orf72 repeat expansion.17 Symptoms associated with C9orf72 repeat expansions typically manifest after the 4th decade,5 as illustrated by the proband's mother (II-2, onset around 47 years) and maternal aunt (II-4, onset around 55 years). Our patient had her first epileptic seizure more than 30 years earlier at age 15 and quickly thereafter developed progressive cognitive decline. Short-repeat PCR did not reveal the presence of short expansions in the proband or maternal aunt, and it is not yet possible to determine the exact length of longer repeat expansions. Although many factors may contribute to the clinical variation, one can speculate that meiotic repeat instability in the mother has resulted in a further expansion of the hexanucleotide repeat in the proband, resulting in the very early onset and atypical PME presentation.