A number sign (#) is used with this entry because progressive myoclonic epilepsy-3 with or without intracellular inclusions (EPM3) is caused by homozygous or compound heterozygous mutation in the KCTD7 gene (611725) on chromosome 7q11.

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).

Van Bogaert et al. (2007) reported a consanguineous Moroccan family in which 3 members had early-onset progressive myoclonic epilepsy. Multifocal myoclonic seizures began between 16 and 24 months of age after normal initial development. Two patients had secondary generalization. Neurodegeneration and regression occurred with seizure onset. Other features included mental retardation, dysarthria, truncal ataxia, and loss of fine finger movements. One patient had several episodes of myoclonic status epilepticus and developed permanent myoclonus affecting the face, tongue, and limbs. Two patients showed transient neurologic improvement when the epilepsy was controlled. EEG showed slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges, and photosensitivity. Ultrastructural analysis of a skin biopsy was normal.

Staropoli et al. (2012) reported 2 Mexican sibs with onset of severe intractable myoclonic seizures at ages 9 and 8 months, respectively, after normal development. Myoclonic movements involved mainly the face and extremities, and were often precipitated or worsened by fevers. Normal development occurred until about 18 months of age, at which point motor and speech regression were noted. At ages 12 and 10 years, both sibs had microcephaly, were nonverbal, and were without spontaneous motor function. Neither showed a response to visual threat and both had diminished pupillary light reflexes; 1 also had bilateral optic atrophy without retinopathy. Brain imaging showed global cortical and cerebellar atrophy and thinning of the corpus callosum. Skin biopsy of 1 patient showed CLN-type storage material in fibroblasts, neurons, and eccrine secretory epithelial cells. Electron microscopy of lymphocytes showed lysosomal storage material containing fingerprint-like profiles and granular osmiophilic deposits. The axon of a myelinated nerve contained vacuole-bound rectilinear profiles. Immunoblot analysis of lymphocytes showed increased levels of mitochondrial ATP synthase subunit C in fingerprint, rectilinear, and curvilinear storage profiles, similar to that observed in CLN3 (204200). Both sibs died from complications of progressive disease in their mid-teens.

Kousi et al. (2012) reported 9 patients from 6 unrelated Turkish families and 1 Pakistani family with EPM3. Three of the families were consanguineous. All patients were alive at the time of the study and were between 3.2 and 14 years of age. The mean age at presentation was 19 months, and most presented with myoclonic and/or tonic-clonic seizures. One patient presented with ataxia. Six of the 9 patients had a favorable response to antiepileptic drug treatment with multiple agents. Psychomotor decline, including ataxia, became evident soon after onset of seizures and resulted in severe motor and mental retardation. Some patients developed scoliosis. All patients had abnormal EEG findings in various brain regions. None had retinal findings, and none of the patients tested had evidence of neuronal ceroid lipofuscinosis on skin biopsy.

Mastrangelo et al. (2019) reported 2 patients, a 17-year-old Italian girl (patient 1) and a 7-year-old Pakistani girl (patient 2), with EPM3. Patient 1 presented at 10 months of age with action myoclonus and developed epilepsy resembling epilepsia partialis continua at 2 years of age. She had progressive motor and verbal deterioration as well as drug-resistant epilepsy and recurrent status epilepticus. Brain MRI at ages 4, 7, and 10 years were normal, but mild frontoinsular atrophy was seen on brain MRI at age 11 years. There were no ultrastructural features of neuronal ceroid lipofuscinosis on a skin biopsy. Patient 2 presented with failure to thrive, neurologic regression, and slowing of head growth at 8 months of age. At 13 months of age, she had epileptic and nonepileptic myoclonic jerks and severe generalized hypotonia. Brain MRI at age 15 months showed anterior white matter atrophy. At age 7 years, she had absent speech, axial hypotonia, and tetraparesis with limb spasticity. Ultrastructural examination of a skin biopsy showed lysosomal storage material consistent with neuronal ceroid lipofuscinosis.

By linkage mapping, Van Bogaert et al. (2007) identified a locus for EPM3 on chromosome 7q11.2 (maximum multipoint lod score of 4.0 at D7S663).

In affected members of a consanguineous Moroccan family with progressive myoclonic epilepsy, Van Bogaert et al. (2007) identified a homozygous mutation in the KCTD7 gene (R99X; 611725.0001).

In 2 Mexican sibs with progressive myoclonic epilepsy and pathologic findings of neuronal ceroid lipofuscinosis in multiple cell types, Staropoli et al. (2012) identified a homozygous mutation in the KCTD7 gene (R184C; 611725.0002). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. KCTD7 mutations were not found in 32 additional CLN samples.

In affected members of 7 unrelated families with progressive myoclonic epilepsy-3, Kousi et al. (2012) identified 6 different mutations in the KCTD7 gene (see, e.g., 611725.0003-611725.0007). All mutations were in the homozygous or compound heterozygous state. The initial mutations were found in 2 probands by homozygosity mapping followed by candidate gene sequencing, and the other mutations were found by screening of the gene in 108 Turkish patients and 1 Pakistani patient with the phenotype. Four mutations were missense, 1 was an in-frame deletion, and 1 was truncating. None of 22 additional patients with neuronal ceroid lipofuscinosis carried mutations in the KCTD7 gene.

In a 17-year-old Italian patient and a 7-year-old Pakistani patient with EPM3, Mastrangelo et al. (2019) identified homozygous missense mutations in the KCTD7 gene (A178V, 611725.0008 and G58R, 617725.0009, respectively). The mutations were identified by next-generation sequencing of a panel of 95 genes associated with early-onset epilepsies. The mutation segregated with the phenotype in both families.