Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2.

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant.

RTN4IP1 pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the RTN4IP1 gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.

Characterization of the Phenotype Associated with Microduplication Reciprocal to NF1 Microdeletion Syndrome.

17q11.2 microduplication syndrome is a recently described relatively rare condition associated with a nonspecific phenotype. Intellectual disability, developmental delay, and dysmorphisms are the only clinical features common to a majority of cases. Seventeen patients have been reported so far. Here, we present another patient with 17q11.2 duplication and no signs of neurofibromatosis type 1, identified by array-CGH. We compared clinical features and genetic data with those of previously reported patients with 17q11.2 microduplications. We also analyzed the gene content of the duplicated region in order to investigate the possible role of specific genes in the clinical phenotype of our patient.

Clinical and Molecular Cytogenetic Characterization of a de novo Interstitial 1p31.1p31.3 Deletion in a Boy with Moderate Intellectual Disability and Severe Language Impairment.

Interstitial 1p deletions are rare events. Very few cases of 1p31.1p31.3 deletions characterized by variable phenotypes have been reported. No clear genotype-phenotype correlation has been determined yet. We present a child with a de novo interstitial 1p31.1p31.3 deletion, identified by array CGH, associated with intellectual disability and severe language impairment. The deleted region contains 20 OMIM genes, but we focused on GADD45A (MIM 126335; growth arrest- and DNA damage-inducible gene), LRRC7 (MIM 614453; leucine-rich repeat-containing protein 7), and NEGR1 (MIM 613173; neuronal growth regulator 1). We discuss whether these genes play a role in determining the phenotype of our patient in order to investigate the possibility of a genotype-phenotype correlation.

PANDAS and PANS: Clinical, Neuropsychological, and Biological Characterization of a Monocentric Series of Patients and Proposal for a Diagnostic Protocol.

Objectives: Whether PANS (pediatric acute-onset neuropsychiatric syndrome) and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) represent true clinical entities is debated and data for a characteristic phenotype are still controversial. In this study, we aim to characterize clinical, neuropsychological, and biochemical aspects in a sample of PANS and PANDAS patients. Methods: Patients fulfilling a clinical diagnosis of PANS or PANDAS from 2014 to 2017 were enrolled. Neurological and psychiatric examination and biochemical and instrumental assessment results were collected. A neuropsychological battery was administered. For comparison purposes, a control group of patients with Sydenham's chorea (SC) was evaluated. Descriptive and comparative statistical analyses were performed. Results: Seven subjects received a diagnosis of PANS, 12 of PANDAS, and 11 of SC. Clinical presentation of PANS children showed statistically significant differences compared with both PANDAS and SC, in particular, with the presence of obsessive symptoms, behavioral regression, and somatic symptoms in the first group. Moreover, all PANS patients showed some neuropsychological deficits in visual-motor abilities, short- and long-term memory, and processing speed. Conclusions: Our experience confirms that patients with PANS had a complex clinical presentation and a compromised neuropsychological profile with respect to patients with PANDAS or SC. However, the absence of biological markers or instrumental alterations made the diagnosis of the two entities, PANS and PANDAS, a matter of exclusion. For these reasons, we propose a pilot diagnostic protocol that (when applied in a prospective manner) will allow comparison with similar childhood-onset neuropsychiatric disorders, such as obsessive-compulsive or tic disorders, and efficacy evaluation of different therapeutic approaches.

Congenital nystagmus in two infants born from mothers exposed to methadone during pregnancy.

BACKGROUND: Methadone is commonly prescribed as a substitute for illicit opioids. Use of methadone during pregnancy is associated with neonatal abstinence syndrome (NAS), reduced head circumference as well as a slight increase in neonatal mortality and morbidity. Less is known about the effects of methadone on the visual system. CASES: We report two Italian cases of nystagmus in infants born from mothers exposed to methadone during pregnancy. Ophthalmic or central disorders were excluded as a cause of nystagmus in both infants. The first case was followed at 3, 6 and 12 months while the second one was evaluated at 5 and 8 months. Both infants had normal neurological and cognitive development. Their first evaluation revealed different characteristics but both showed progressive improvement in ocular disorder, persistence of pendular horizontal nystagmus and nearly normal visual acuity. CONCLUSION: This report, the first description of Italian cases of nystagmus related to use of methadone during pregnancy, underlies the importance of a careful investigation of drug use in pregnancy in cases of unexplained congenital nystagmus.