Introduction to phacomatoses (neurocutaneous disorders) in childhood

PRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.

Section: Paroxysmal Dyskinesiasmentioning

confidence: 99%

PRRT2 Related Epilepsies: A Gene Review

Massimino

Portale

Sapuppo

et al. 2021

“…[20][21][22] Electroencephalogram (EEG) can show variable generalized 2.5-to 4Hz spike-wave pattern and slowing during ictal and interictal periods up to EEG status epilepticus during fasting period with a great response after meal or intravenous glucose administration. 6 MRI can show signs of leukoencephalopathy, 23 but findings are generally normal, while FDG-PET reveals a large reduction in glucose uptake in the cerebral cortex or, in patients with PED, in basal ganglia. 24,25 They have also been described varying degrees of mental retardation in association with speech disorders.…”

Section: Diagnosismentioning

confidence: 99%

“…Early diagnosis of GLUT1DS is critical as it responds well to ketogenic diets (KDs). 5,6 Genetics GLUT1 belongs to the GLUT family of glucose transporters, which includes 13 proteins (gene identifier SLC2A, protein identifier GLUT). GLUT1/SLC2A1 (OMIM 138140) was the first gene of this group to be discovered in 1985.…”

Section: Introductionmentioning

confidence: 99%

SLC2A1 and Its Related Epileptic Phenotypes

Patanè

Pasquetti

Sullo

et al. 2021

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is caused by heterozygous, mostly de novo, mutations in SLC2A1 gene encoding the glucose transporter GLUT1, the most relevant energy transporter in the blood–brain barrier. GLUT1DS includes a broad spectrum of neurologic disturbances, from severe encephalopathy with developmental delay, to epilepsy, movement disorders, acquired microcephaly and atypical mild forms. For diagnosis, lumbar puncture and genetic analysis are necessary and complementary; an immediate response to ketogenic diet supports the diagnosis in case of high suspicion of disease and negative exams. The ketogenic diet is the first-line treatment and should be established at the initial stages of disease.

“…9 Unfortunately, it does not happen with the neuropsychiatric disorders, as there is generally a worsening with age, becoming the most matter of concern in some patients in adulthood. 19,20 Genetics and Biological Mechanisms PCDH19 gene is located at Xq22.1, consisting of six exons. His protein (protocadherin-19) is a delta2 protocadherin subfamily of calcium-dependent cell-adhesion molecules.…”

Section: Introductionmentioning

confidence: 99%

PCDH19-Related Epilepsies

Mazzurco¹,

Pulvirenti

Caccamo

et al. 2021

Self Cite

Protocadherin-19 (PCDH19) is considered one of the most relevant genes related to epilepsy. To date, more than 150 mutations have been identified as causative for PCDH19-female epilepsy (also known as early infantile epileptic encephalopathy-9, EIEE9), which is characterized by early onset epilepsy, intellectual disabilities, and behavioral disturbances. More recently, mosaic-males (i.e., exhibiting the variants in less than 25% of their cells) have been described as affected by infant-onset epilepsy associated with intellectual disability, as well as compulsive or aggressive behavior and autistic features. Although little is known about the physiological role of PCDH19 protein and the pathogenic mechanisms that lead to EIEE9, many reports and clinical observation seem to suggest a relevant role of this protein in the development of cellular hyperexcitability. However, a genotype–phenotype correlation is difficult to establish. The main feature of EIEE9 consists in early onset of seizures, which generally occur in clusters lasting 1 to 5 minutes and repeating up to 10 times a day for several days. Seizures tend to present during febrile episodes, similarly to the first phases of Dravet syndrome and PCDH19 variants have been found in ∼25% of females who present with features of Dravet syndrome and testing negative for SCN1A variants. There is no “standardized” treatment for PCDH19-related epilepsy and most of the patients receiving a combination of several drugs. In this review, we focus on the latest researches on these aspects, with regard to protein expression, its known functions, and the mechanisms by which the protein acts. The clinical phenotypes related to PCDH19 mutations are also discussed.