Examining the effects of prenatal alcohol exposure on performance of the sustained attention to response task in children with an FASD.

Prenatal alcohol exposure (PAE), the leading known cause of childhood developmental disability, has long-lasting effects extending throughout the lifespan. It is well documented that children prenatally exposed to alcohol have difficulties inhibiting behavior and sustaining attention. Thus, the Sustained Attention to Response Task (SART), a Go/No-go paradigm, is especially well suited to assess the behavioral and neural functioning characteristics of children with PAE. In this study, we utilized neuropsychological assessment, parent/guardian questionnaires, and magnetoencephalography during SART random and fixed orders to assess characteristics of children 8-12 years old prenatally exposed to alcohol compared to typically developing children. Compared to neurotypical control children, children with a Fetal Alcohol Spectrum Disorder (FASD) diagnosis had significantly decreased performance on neuropsychological measures, had deficiencies in task-based performance, were rated as having increased Attention-Deficit/Hyperactivity Disorder (ADHD) behaviors and as having lower cognitive functioning by their caretakers, and had decreased peak amplitudes in Broadmann's Area 44 (BA44) during SART. Further, MEG peak amplitude in BA44 was found to be significantly associated with neuropsychological test results, parent/guardian questionnaires, and task-based performance such that decreased amplitude was associated with poorer performance. In exploratory analyses, we also found significant correlations between total cortical volume and MEG peak amplitude indicating that the reduced amplitude is likely related in part to reduced overall brain volume often reported in children with PAE. These findings show that children 8-12 years old with an FASD diagnosis have decreased amplitudes in BA44 during SART random order, and that these deficits are associated with multiple behavioral measures.

The Fetus with Ganglionic Eminence Abnormality: Head Size and Extracranial Sonographic Findings Predict Genetic Diagnoses and Postnatal Outcomes.

BACKGROUND AND PURPOSE: Ganglionic eminence abnormalities on fetal MR imaging are associated with cerebral malformations. Their presumed genetic basis and associated postnatal outcomes remain largely unknown. We aimed to elucidate these through a multicenter study. MATERIALS AND METHODS: Between January 2010 and June 2020, seven hospitals in 2 countries performing fetal MR imaging examinations identified fetal MR imaging studies demonstrating ganglionic eminence enlargement, cavitation, or both. Cases with no genetic diagnosis, no whole exome sequencing, or no outcome of a liveborn child were excluded. Head size was classified as large (fronto-occipital diameter > 95th centile), small (fronto-occipital diameter <5th centile), or normal. RESULTS: Twenty-two fetuses with ganglionic eminence abnormalities were identified. Of 8 with large heads, 2 were diagnosed with MTOR mutations; 1 with PIK3CA mutation-producing megalencephaly, polymicrogyria, polydactyly, hydrocephalus (MPPH) syndrome; 3 with TSC mutations; 1 with megalencephaly capillary malformation syndrome; and 1 with hemimegalencephaly. Cardiac rhabdomyoma was present prenatally in all cases of TSC; mutation postaxial polydactyly accompanied megalencephaly capillary malformation and MPPH. Of 12 fetuses with small heads, 7 had TUBA1A mutations, 1 had a TUBB3 mutation, 2 had cobblestone lissencephaly postnatally with no genetic diagnosis, 1 had a PDHA1 mutation, and 1 had a fetal akinesia dyskinesia sequence with no pathogenic mutation on trio whole exome sequencing. One of the fetuses with a normal head size had an OPHN1 mutation with postnatal febrile seizures, and the other had peri-Sylvian polymicrogyria, seizures, and severe developmental delay but no explanatory mutation on whole exome sequencing. CONCLUSIONS: Fetal head size and extracranial prenatal sonographic findings can refine the phenotype and facilitate genetic diagnosis when ganglionic eminence abnormality is diagnosed with MR imaging.

Caudal regression syndrome in a fetus of a glucokinase-maturity-onset diabetes of the young pregnancy.

BACKGROUND: Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is a form of diabetes caused by heterozygous inactivating mutations in the GCK gene. Affected individuals maintain their fasting glucose levels at a higher set point (5.4-8.3 mmol/l) than the general population. Hyperglycaemia in women with Type 1 or Type 2 diabetes is known to confer increased risk of fetal congenital abnormalities. The association between GCK-MODY and congenital abnormalities, however, remains uncertain. CASE REPORT: A 35-year-old woman in her third pregnancy was diagnosed with gestational diabetes at 13 weeks' gestation (fasting blood glucose 6.0 mmol/L, 1-h blood glucose 9.2 mmol/l, 2-h blood glucose 7.3 mmol/l). The morphology scan at 19+2 weeks' gestation showed a Type III sacral agenesis. The woman elected to terminate the pregnancy. Her postpartum oral glucose tolerance test was suggestive of GCK-MODY (fasting blood glucose 7.4 mmol/l, 1-h blood glucose 9.3 mmol/l, 2-h blood glucose 7.3 mmol/l). Mutation analysis of the GCK gene identified a novel heterozygous GCK missense mutation, p.V199M, classified as likely pathogenic, providing molecular confirmation of the suspected GCK-MODY diagnosis. DISCUSSION: Sacral agenesis is a rare form of sacral abnormality affecting 0.005% to 0.1% of pregnancies. It is a subtype of the caudal regression sequence, a cardinal feature of diabetic embryopathy. This case raises the question as to whether hyperglycaemia in GCK-MODY may increase the risk of fetal caudal regression syndrome as reported in women with pre-existing diabetes mellitus. Improved diagnostic rates of GCK-MODY, and MODY registers that include pregnancy outcomes, are important to further elucidate risk of congenital abnormalities in GCK-MODY.

Broadening the phenotype of LRP2 mutations: a new mutation in LRP2 causes a predominantly ocular phenotype suggestive of Stickler syndrome.

Two siblings, from a consanguineous Iraqi family, were investigated to identify the underlying genetic cause of their high myopia, esotropia, vitreous changes and cataract. Subsequent investigation identified low molecular weight proteinuria as part of their syndrome. Exome sequencing of one of the probands revealed a new non-synonymous variant in the LRP2 gene. Sanger sequencing confirmed the mutation and segregation in the family. No mutation was identified in COL9A1/2, COL11A1/2, or COL2A1 genes. The variant (c.11483A>G; p.Asp3828Gly) is predicted to be damaging and is conserved among vertebrate species. Mutations in LRP2 have been shown to cause the Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome, a syndrome associated with facial dysmorphism, ocular anomalies, sensorineural hearing loss, low molecular weight proteinuria, and diaphragmatic hernia and absent corpus callosum, although there is variability in the expression of some features. This family shows a milder phenotype with a predominant eye phenotype similar to the Stickler syndrome and only a few features of the DBS, including microglobulinuria. The presence of microglobulinuria was only detected after molecular results were known. In conclusion, with the identification of a new mutation in LRP2 associated with a predominant eye phenotype similar to the Stickler syndrome, we have broadened the phenotypic spectrum of LRP2 mutations.

Familial cerebral cavernous haemangioma diagnosed in an infant with a rapidly growing cerebral lesion.

Cavernous haemangiomas of the central nervous system are vascular malformations best imaged by MRI. They may present at any age, but to our knowledge only 39 cases in the first year of life have previously been reported. A familial form has been described and some of the underlying genetic mutations have recently been discovered. We present the clinical features and serial MRI findings of an 8-week-old boy who presented with subacute intracranial haemorrhage followed by rapid growth of a surgically proven cavernous haemangioma, mimicking a tumour. He also developed new lesions. A strong family history of neurological disease was elucidated. A familial form of cavernous haemangioma was confirmed by identification of a KRIT 1 gene mutation and cavernous haemangiomas in the patient and other family members. We stress the importance of considering cavernous haemangiomas in the context of intracerebral haemorrhage and in the differential diagnosis of rapidly growing lesions in this age group. The family history is also important in screening for familial disease.