Epilepsy, Progressive Myoclonic 3

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Description from OMIM

Mutations in the KCTD7 gene cause a severe neurodegenerative phenotype characterized by onset of intractable myoclonic seizures before age 2 years and accompanied by developmental regression. The initial description was consistent with a form of progressive myoclonic epilepsy (designated here as EPM3), whereas a later report identified intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis (designated CLN14). Ultrastructural findings on skin biopsies thus appear to be variable. However, clinical features are generally consistent between reports (summary by Staropoli et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800). For a general phenotypic description and a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730).

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Seizures nervous 100 % 22748208 2014-04-02
Developmental delay nervous 100 % 22748208 2014-04-02
Visual acuity decrease nervous 67 % 22748208 2014-04-02
Cerebral atrophy nervous 67 % 22748208 2014-04-02
Optic atrophy nervous 33 % 22748208 2014-04-02
Ataxia nervous 17 % 22748208 2014-04-02
Microcephaly nervous 17 % 22748208 2014-04-02

List of references:

A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system.
John F Staropoli, Amel Karaa, Elaine T Lim, Andrew Kirby, Naser Elbalalesy, Stephen G Romansky, Karen B Leydiker, Scott H Coppel, Rosemary Barone, Winnie Xin, Marcy E MacDonald, Jose E Abdenur, Mark J Daly, Katherine B Sims, Susan L Cotman,

Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14.

American journal of human genetics - Jul 2012