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CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks. [ABSTRACT FROM AUTHOR]

Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion‐channel genes being implicated, including those encoding the GABAA receptor. Here, we evaluated the frequency of additional mutations in the GABAA receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25‐bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABAA receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals. [ABSTRACT FROM AUTHOR]

Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the α1 subunit of the γ-aminobutyric acid receptor subtype A (GABA[sub A]), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA[sub A] receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans. [ABSTRACT FROM AUTHOR]

Abstract: Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity. [Copyright &y& Elsevier]

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs∗48] and c.3709C>T [p.Arg1237∗]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328∗] and c.6232G>T [p.Glu2078∗]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes. [Copyright &y& Elsevier]