Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene.

AMPA-type glutamate receptors (AMPARs) are postsynaptic ionotropic receptors which mediate fast excitatory currents. AMPARs have a heterotetrameric structure, variably composed by the four subunits GluA1-4 which are encoded by genes GRIA1-4. Increasing evidence support the role of pathogenic variants in GRIA1-4 genes as causative for syndromic intellectual disability (ID). We report an Italian pedigree where some male individuals share ID, seizures and facial dysmorphisms. The index subject was referred for severe ID, myoclonic seizures, cerebellar signs and short stature. Whole exome sequencing identified a novel variant in GRIA3, c.2360A > G, p.(Glu787Gly). The GRIA3 gene maps to chromosome Xq25 and the c.2360A > G variant was transmitted by his healthy mother. Subsequent analysis in the family showed a segregation pattern compatible with the causative role of this variant, further supported by preliminary functional insights. We provide a detailed description of the clinical evolution of the index subjects and stress the relevance of myoclonic seizures and cerebellar syndrome as cardinal features of his presentation.

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

The noncoding RNA AK127244 in 2p16.3 locus: A new susceptibility region for neuropsychiatric disorders.

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.

Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome.

Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype. Functional analysis in transiently transfected COS-1 and JEG-3 cells showed a near-complete inactivation of TH transport for p.G564R, whereas considerable cell-type-dependent residual transport activity was observed for p.G564E. Both mutants showed a strong decrease in protein expression levels, but differentially affected Vmax and Km values of T3 transport. Our findings illustrate that different mutations affecting the same residue may have a differential impact on SLC16A2 transporter function, which translates into differences in severity of the clinical phenotype.

Repetitive Sleep Starts in Allan-Herndon-Dudley Syndrome.

Allan-Herndon-Dudley syndrome (AHDS) is caused by mutations in the SLC16A2 gene, encoding for the monocarboxylate transporter 8 (MCT8). Central hypothyroidism and chronic peripheral thyrotoxicosis result in a severe phenotype, mainly characterized by poor growth, intellectual disability, spastic tetraparesis, and movement disorders, including paroxysmal ones (startle reaction and paroxysmal dyskinesias). Seizures are rarely reported. We conducted a retrospective analysis on video electroencephalography (EEG) recordings in four subjects with AHDS, focused on paroxysmal events. Among other manifestations recorded on EEG, we diagnosed repetitive sleep starts (RSS) in all subjects. RSS are a paroxysmal nonepileptic phenomenon occurring during sleep, similar to epileptic spasms in their clinical and electromyography characteristics, but not related to any EEG change. This is the first report on RSS in AHDS. We present video-EEG polygraphic documentation, suggesting that RSS could be underestimated or misdiagnosed. The importance of a correct diagnosis is crucial in a therapeutic perspective.

Role of UBE3A and ATP10A genes in autism susceptibility region 15q11-q13 in an Italian population: a positive replication for UBE3A.

The aetiology of autism is still largely unknown despite analyses from family and twin studies demonstrating substantial genetic role in the aetiology of the disorder. Data from linkage studies and analyses of chromosomal abnormalities identified 15q11-q13 as a region of particular aetiopathogenesis interest. We screened a set of markers spanning two known imprinted, maternally expressed genes, UBE3A and ATP10A, harboured in this candidate region. We replicated evidence of linkage disequilibrium (LD) at marker D15S122, located at the 5' end of UBE3A and originally reported by Nurmi et al. (2001). The potential role of UBE3A in our family-based association study is further supported by the association of two haplotypes that include one of the alleles of D15S122 and by the transmission disequilibrium test (TDT) evidence of the same allele in a parent of origin effect analysis. In a secondary analysis, we provided the first evidence of a significant association between first word delay and psychomotor regression with the 15q11-q13 region. Our data support a potential role of UBE3A in the complex pathogenic mechanisms of autism.

Scurvy hidden behind neuropsychiatric symptoms.

Approaching an uncommon disease may result in diagnostic delay even in patients with typical clinical features. In this respect, diseases related to nutritional deficiencies may represent a diagnostic challenge. We describe a 2.5-year-old child with typical features of scurvy, who was referred for autistic-like behavior and severe muscle weakness and pain in lower limbs. Extensive investigations for non-nutrition-related disorders were first performed, including a muscle biopsy showing a selective type II fibers hypotrophy. Scurvy was eventually considered, after recalling the child's peculiar dietary habits.

Treatment for Chiari 1 malformation (CIM): analysis of a pediatric surgical series.

Children may present a peculiar picture of CIM, as syncopes and acute paraparesis. In a series of 99 children operated for CIM at FINCB there were no major surgical morbidity nor mortality. The preoperative symptoms improved more in this pediatric series than in the adult cases treated at the same institution in the same period; a reason could be the shorter duration of symptoms and another the children plasticity. An untreated nonsyndromic craniosynostosis was present in 10 cases. In our hands, the results of the limited extradural decompression were poor. In some CIM associated with psychiatric symptoms an unexpected improvement was observed after tonsilar resection. The associated Syringomyelia reduced in more than 80% of children and disappeared in a significant number. The rare associated tethered cord (5%) needed a double treatment, detethering by itself being insufficient to treat also tonsillar descent. The clinical symptoms are often more serious in children than in the adults, but the results of surgery, especially on the syrinx, are better.

16p13 microduplication without CREBBP involvement: Moving toward a phenotype delineation.

The short arm of chromosome 16 is one of the less stable regions of our genome, as over 10% of the euchromatic region of 16p is composed of highly complex low copy repeats that are known to be predisposed to rearrangements mediated by non-allelic homologous recombination. The 16p13.3p13.13 molecular region has been defined as the 16p duplication hotspot, and duplications of chromosome 16p13 have recently been confirmed to cause a recognizable syndrome, with CREBBP being the main phenotype-causing gene. To date, only one case report is present in the literature with a 16p13 duplication without CREBBP involvement; we describe here a second analogous case with a not previously reported 16p13.2p13.13 microduplication. This paper allows us to better delineate the clinical features of 16p13 microduplications that do not encompass CREBBP and, concurrently, to narrow the molecular region responsible for congenital heart defects in 16p duplications as well as to propose GRIN2A as a candidate gene for epilepsy.

Enigmatic osteomyelitis and bilateral upper limb palsy in a neonate.

This report describes a male infant who developed right upper limb palsy 5 days after birth and contralateral paralysis at 14 days. Abnormal in utero posture of the right arm had resulted in a difficult cephalic delivery. Right shoulder osteomyelitis was diagnosed at age 16 days from clinical, hematologic, and radiologic findings. Antibiotics were administered, followed by complete resolution of the symptoms in 2 weeks. Electromyographic and nerve conduction studies demonstrated direct involvement of the right brachial plexus, secondary to the osteomyelitis, explaining the unilateral onset and the persistent neurogenic pattern involving the muscles innervated by the right posterior branch to the brachial plexus. However, somatosensory evoked potentials indicated damage to the cervical spinal cord likely related to the birth trauma, which in all likelihood was the cause of the left limb palsy and contributed to the right limb picture.

PDCD10 gene mutations in multiple cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

MEF2C deletions and mutations versus duplications: a clinical comparison.

5q14.3 deletions including the MEF2C gene have been identified to date using genomic arrays in patients with severe developmental delay or intellectual disability, stereotypic behavior, epilepsy, cerebral malformations and a facial gestalt not really distinctive though characterized by broad and/or high, bulging forehead, upslanting palpebral fissures, flat nasal root and bridge, small, upturned nose, hypotonic small mouth resulting in cupid bow/tented upper lip. MEF2C mutations have been also identified in patients with overlapping phenotype so that it is considered the gene responsible for the 5q14.3 deletion syndrome. To date, one single duplication including MEF2C has been reported in a patient with intellectual disability but its clinical significance remains uncertain also because of the large size of the imbalance. Here we present two further patients with 5q14.3 duplications including MEF2C. Their phenotype indeed suggest the pathogenic effect of the MEF2C duplication although other duplicated genes also brain expressed might contribute to the clinical features. In none of them a clear-cut syndrome can be identified. A comparison between MEF2C deleted/mutated and duplicated patients is also presented.

Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2.

Episodic ataxia type 2 is a rare autosomal dominant disease characterized by recurrent attacks of vertigo and cerebellar ataxia. The disease was caused by mutations in the CACNA1A gene, on chromosome 19p. We perform a mutational screening in a group of 43 unrelated patients. Forty-two patients presented episodes of disequilibrium and ataxia, and one child was studied because of the occurrence of episodic torticollis. The genetic analysis showed 15 mutated patients (35%). In 13 cases we found novel CACNA1A gene mutations, including missense, protein truncating, and aberrant splicing mutations. Two truncating mutations lead to the uppermost premature stop so far reported, challenging recent hypotheses on dominant negative effect. In patients without CACNA1A mutations, molecular testing for CACNB4 gene mutations excluded this genetic subtype. Clinical features of mutated subjects mostly confirmed previous sign and symptoms associated with EA2, including paroxysmal torticollis and mental retardation. CACNA1A mutated patients have an earlier age at onset, interictal nystagmus, and abnormalities of ocular movements. A review of all CACNA1A mutations so far reported showed that they are mainly located downstream exon 18. Our data substantially increase the number of the described CACNA1A mutations, and propose clinical and molecular criteria for a more focused genetic screening.

X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.

Among creatine deficiency syndromes, an X-linked condition related to a defective creatine transport into the central nervous system has been described recently. Hallmarks of the disease are the absence of a creatine signal at brain spectroscopy, increased creatine levels in blood and urine, ineffectiveness of oral supplementation, and a mutation in the SLC6A8 (Online Mendelian Inheritance in Man [OMIM] 300036) creatine transporter gene. We report on a patient in whom a novel mutation (1221-1223delTTC) was identified.