Davide Mei

Idiopathic Epilepsies with Seizures Precipitated by Fever and SCN1A Abnormalities

Summary:  Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype–genotype correlations with SCN1A alterations.

SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis

Objective:  We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).

Germline and mosaic mutations of FLN1 in men with periventricular heterotopia

Objective: To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1 mutations in four men. Background: X-linked PNH caused by FLN1 mutations (MIM #300049) implies prenatal or early postnatal lethality in boys and 50% recurrence risk in daughters of affected women. Methods: Clinical examination, cognitive testing, MRI, and mutation analysis (denaturing high-performance liquid chromatography and direct sequencing) on blood lymphocytes and single hair roots were performed for nine affected individuals, including three men. Neuropathologic study of the brain was performed for an affected boy. Results: In two families, missense mutations were transmitted from mother to son (Met102Val) and from father to daughter (Ser149Phe), causing mild phenotypes in both genders, including unilateral PNH. In a third family, a man was mosaic for an A>G substitution (intron 11 acceptor splice site) on leukocyte DNA and hair roots (mutant = 42% and 69%). Single hair root analysis confirmed that the mutation was not present in all ectodermal derivative cells. A healthy daughter had inherited the X chromosome from her father’s wild-type germinal cell population. In the fourth family, an eight-base deletion (AGGAGGTG, intron 25 donor splice site) led to early deaths of boys. Postmortem study in a newborn boy revealed PNH and cardiovascular, genitourinary, and gut malformations. Conclusions: Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. Mutation analysis of FLN1 should support genetic counseling in men with periventricular nodular heterotopia.

Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.

Background: Subcortical band heterotopia (SBH) is a neuronal migration disorder. DCX mutations are responsible for almost all familial cases, 80% of sporadic female cases, and 25% of sporadic male cases of SBH, and are associated with more severe gyral and migration abnormality over the anterior brain regions. Somatic mosaicism has previously been hypothesized in a patient with posteriorly predominant SBH and a mutation of the LIS1 gene, which is usually mutated in patients with severe lissencephaly. The authors identified mosaic mutations of LIS1 in two patients (Patients 1 and 2) with predominantly posterior SBH. Methods: After ruling out DCX mutations, the authors performed sequencing of the LIS1 gene in lymphocyte DNA. Because sequence peaks in both patients were suggestive of mosaic mutations, they followed up with denaturing high-pressure liquid chromatography analysis on blood and hair root DNA and compared the areas of heteroduplex and homoduplex peaks. A third patient showing the same mutation as Patient 2 but with no evidence of mosaicism was used for comparing the phenotype of mosaic vs full mutation. Results: The two patients with posterior SBH harbored a missense (Arg241Pro) and a nonsense (R8X) mosaic mutation of LIS1. The rate of mosaicism in Patient 1 was 18% in the blood and 21% in the hair roots, whereas in Patient 2 it was 24% and 31% in the same tissues. The patient with a full R8X mutation of LIS1 had severe lissencephaly. Conclusions: Subcortical band heterotopia can occur with mosaic mutations of the LIS1 gene. Mutation analysis of LIS1, using highly sensitive techniques such as denaturing high-pressure liquid chromatography, should be considered for patients with posteriorly predominant subcortical band heterotopia and pachygyria.

Protocadherin 19 mutations in girls with infantile-onset epilepsy.

Objective: To explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy. Methods: We studied a cohort of 117 female patients with febrile seizures (FS) and a wide spectrum of epilepsy phenotypes including focal and generalized forms with either sporadic or familial distribution. Results: PCDH19 screening showed point mutations in 13 probands (11%). Mean age at seizure onset was 8.5 months; 8 patients (62%) presented with FS, 4 (33%) with cluster of focal seizures, and 1 with de novo status epilepticus (SE). Subsequent seizure types included afebrile tonic-clonic, febrile, and afebrile SE, absences, myoclonic, and focal seizures. Seven patients (54%) had a clinical diagnosis consistent with Dravet syndrome (DS); 6 (46%) had focal epilepsy. In most patients, seizures were particularly frequent at onset, manifesting in clusters and becoming less frequent with age. Mental retardation was present in 11 patients, ranging from mild (7; 64%) to moderate (1; 9%) to severe (3; 27%). Five patients (38%) had autistic features in association to mental retardation. Mutations were missense (6), truncating (2), frameshift (3), and splicing (2). Eleven were new mutations. Mutations were inherited in 3 probands (25%): 2 from apparently unaffected fathers and 1 from a mother who had had generalized epilepsy. Conclusions: PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented.

Glucose Transporter 1 Deficiency as a Treatable Cause of Myoclonic Astatic Epilepsy

OBJECTIVE To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. DESIGN Genetic analysis. SETTING Ambulatory and hospitalized care. PATIENTS Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. MAIN OUTCOME MEASURE Any SLC2A1 mutations. RESULTS Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. CONCLUSIONS Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.

Mosaic SCN1A Mutation in Familial Severe Myoclonic Epilepsy of Infancy

Summary:  Purpose: Mutations of the α1 subunit sodium channel gene (SCN1A) cause severe myoclonic epilepsy of infancy (SMEI). Mutations of SCN1A have been found in 40 to 100% of SMEI patients and are de novo in the majority of individuals.

PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine

ABSTRACT Objective: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms. Methods: We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families. Results: We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family. Conclusion: Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.

Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations.

Summary:  Introduction: To determine the occurrence of neuroradiological abnormalities and to perform genotype–phenotype correlations in severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome).

Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria‐SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative β‐sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X‐inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X‐inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non‐syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal. Ann Neurol 2003