Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors

Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy (vol 47, pg 73, 2015)

"Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy" published in Nature Genetics (2015), volume 47, pp.73-77

SCN3A ‐related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation

Objective Pathogenic variants in SCN3A , encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood‐onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A ‐related neurodevelopmental disorder. Methods Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type vs. variant Nav1.3 subunits co‐expressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293 T cells). Results Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4–6 of domains II‐IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. Interpretation Our study defines SCN3A‐ related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis

Caractéristiques Cliniques Et Impact Du Syndrome De Smith-Magenis : Étude d’une série de 47 patients

Le syndrome de Smith-Magenis est un syndrome délétionnel récurrent caractérisé par l’association de traits dysmorphiques, de troubles du comportement et de troubles du sommeil. Une déficience intellectuelle de sévérité variable est fréquente mais non systématique. Il implique une prise en charge médicale multidisciplinaire du fait des possibles malformations associées, essentiellement cardiaques et rénales, et des éventuelles complications (scoliose, problèmes ORL, anomalies ophtalmologiques, problèmes dentaires, métaboliques et endocriniens). Dans cette étude rétrospective, nous reprenons et discutons les caractéristiques cliniques et diagnostiques d’une cohorte de 47 patients ainsi que les répercussions du syndrome en termes d’impact familial, de prise en charge et de scolarité

Hereditary urogenital adysplasia: families with recurrence of uterine and renal malformations.

In 1980, Schimke and King introduced the term hereditary urogenital adysplasia to describe recurrence of kidney and uterine malformations which had been observed in several families. They suggested an autosomal dominant inheritance with variable expressivity and penetrance. Now, 35 years later, research is focused towards understanding the underlying genetic causes of this condition. We review the embryonic development of Müllerian and Wolffian ducts and the genes that have been involved in uterine malformations, congenital anomalies of kidney and urinary tract and hereditary urogenital adysplasia in humans.Hereditary urogenital adysplasi

Mania following acute decompensation in ornithine transcarbamylase deficiency.

Background Ornithine transcarbamylase deficiency is the most common urea cycle disorder and presents an X-linked pattern of inheritance. Both males and females may be affected with variation in severity and age of onset. Psychiatric symptoms, including episodic psychosis, atypical depression, confusion, erratic behavior or delirium, are possible presentations of late-onset disease. Manic behaviors have previously been reported with hyperammonemia induced by valproic acid. Usually, psychiatric behaviors cease with normalization of ammonia levels. Case report We report a family with two males with confirmed late-onset OTC deficiency (and other adult males with unexplained lethal encephalopathy) due to a missense mutation in OTC (c.119G>A; p.R40H). One 29-year-old male individual, with no psychiatric history, presented hypomanic symptoms with a significant shift from his personality in the days following his first major episode of acute decompensation. Ammonia levels were measured as 245, 30, 11, 106, 20, 38 and 17 micromol/L on days 2, 5, 8, 9, 9, 9, and 10, respectively, following the acute crisis onset. Symptoms of vomiting, confusion, tremors and loss of consciousness stopped at day 5. Hypomanic symptoms were noted from day 5 and were finally controlled with long-acting quetiapine ten days after normalization of serum ammonia levels (daily levels were normal from day 10 to day 21). CT scan of the brain was normal. Conclusion Illustrated by this case report, occurrence of mania secondary to a hyperammonic crisis may be the consequence of dysregulated neurotransmission balance in brain, which can persist after normalization of serum ammonia levels

Complex congenital heart disease : about a case of Noonan syndrome.

editorial reviewedWe present the case of a young girl in whom pre-natal echocardiography showed double outlet right ventricle associated with severe infundibular- and pulmonary valve stenosis. The genetic testing has shown a mutation on the LZTR1 gene, which confirms the diagnosis of a Noonan Syndrome, also present in the mother and an elder sister. The infant was born premature at 34 weeks and 5 days of gestational age. During the neonatal period, feeding difficulties are noted linked to oral aversion and exacerbated by difficulties in the mother-child bond. At 1 month of age, the child presented hypoxic spells caused by the infundibular stenosis which required emergency aorto-pulmonary anastomosis placement ensuring sufficient pulmonary blood flow. This anastomosis needed to be replaced by a larger one at 9th month of age. The child is now 4 years old and has undergone a complete surgical correction. The multidisciplinary management englobes not only follow up in cardiology, genetics, neurology, ophthalmology and hematology but also feeding support and psychomotor development support. The socio-economic precariousness of the family leads to a constant assistance to allow the best possible development of the child

Femoral Facial Syndrome: Long term follow-up and associated Müllerian aplasia.

Daentl femoral-facial syndrome (FFS) includes bilateral femoral hypoplasia and particular facial features: long philtrum with thin upper lip, micrognathia with or without cleft palate, upward-slanted palpebral fissures, and hypoplastic alae nasi with a broad tip. The syndrome is clinically heterogeneous, and other malformations have been associated. Psychomotor and cognitive developments are usually normal. Etiology of this syndrome remains currently unknown. Most of the cases are sporadic. Non-genetic factors as maternal diabetes mellitus have been associated. Reports of familial cases have otherwise suggested autosomal dominant inheritance. Our patient was the first child of unrelated parents. Very short femora were detected at fourth month of pregnancy. Birth height was 40 cm at term. FFS was diagnosed at birth, based on severe bilateral femoral hypoplasia and characteristic facial features with Pierre Robin sequence. Early psychomotor development was normal and walking alone was acquired at age two despite the absence of hip joints. At age seventeen, she was investigated for primary amenorrhea and was shown to have uterine aplasia, and thus Mayer-Rokitansky-Kuster-Hauser syndrome. Endocrine workup noted hyperandrogenism due to both ovarian and adrenal androgen overproduction. Recently, array CGH investigation identified a 1485 kb duplication at 9q31.1, including the gene SMC2, and a 853 kb deletion at 12q24.33 including the genes P2RX2, PEGAM5, GOLGA3, POLE1, CHFR, ZNF26, ZNF140, ZNF10 and ZNF268. Unfortunately, samples of parents were not available. Long term follow up of our patient underlined orthopedic problems as the major handicap in the FFS syndrome, cognitive development being normal. Unexpected discover was the association with mullerian agenesis. Both may reflect different defects in the primary axial mesodermal development, being the consequences of same environmental or/and genetic factors during blastogenesis. Among these genetic factors, we suggest the possible involvement of the two copy number variants reported here. Reports of other patients would be required to confirm this

Intellectual disability and cancer susceptibility in a family with inherited 14q32.13q32.2 deletion.

Located in 14q32.13, DICER1 codes for an RNase III endoribonuclease essential in the processing of microRNAs. These microRNAs are functional non-coding RNAs that regulate gene expression at a post-transcriptional level by interfering with translation and degradation of target messenger RNAs. Their deregulations have been implicated in several human diseases and cancers. Germline mutations in DICER1 are associated with a low susceptibility risk to tumor development. Inactivating mutations have been identified in patients and families with various benign and malignant tumors, especially pleuropulmonary blastoma, cystic nephroma and ovarian Sertoli-Leydig tumors. Germline DICER1 deletion has not been reported so far. We report a 7-year-old girl with an inherited DICER1 deletion. She was referred for mild intellectual deficiency, a medical history of cystic nephroma and dysmorphic features. Her father, two paternal uncles and the paternal grandmother had mild to moderate intellectual disabilities. The deceased grandmother had presented uterin and ovarian tumors. Array-CGH analysis identified a 5041kb deletion in 14q32.13-q32.2 in the patient, the father, the two uncles and the paternal grandmother. The deletion contained 50 coding genes and led to DICER 1 haploinsufficiency which was responsible for cancer susceptibility. Moreover, transmission of the deletion was related to intellectual disability in this family. The 14q32.13q32.2 locus has been previously associated with autosomal recessive mental retardation, suggesting the presence in the region of genes implicated in cerebral development and cognitive functions