Cerebrospinal fluid (CSF) fistulas are characterized by the egress of CSF from the intracranial cavity through an osteodural disruption between the subarachnoid space and a pneumatized structure within the skull base. Depending on the cause, CSF fistulas are classified as acquired or congenital, and acquired fistulas are further classified as traumatic, nontraumatic, or spontaneous. Spontaneous CSF fistulas are considered to result from a multifactorial process and have been postulated to represent a variant of idiopathic intracranial hypertension. However, an anatomic predisposition involving thinning of the cranial base, such as pneumatization of the sinus walls, must also be present. This process creates areas of structural weakness that act as potential pathways for CSF leaks, which most commonly occur in the ethmoid roof, sphenoid sinus, and temporal bone. Because CSF leaks may be overlooked, a result of their asymptomatic or subtle, intermittent course, a high level of suspicion is crucial in making an early diagnosis. However, CSF fistulas may be well seen at computed tomography (CT), which depicts bone defects, and magnetic resonance cisternography, which reveals the contents of herniated tissue. Knowledge of the location and size of the bone defect and herniated contents is crucial for the selection of surgical approach and grafting material.

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Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

We describe a 4-year-old male child born to non-consanguineous Spanish parents with progressive encephalopathy (PE), microcephaly, and hypertonia. Whole exome sequencing revealed compound heterozygous BRAT1 mutations [c.1564G > A (p.Glu522Lys) and c.638dup (p.Val214Glyfs*189)]. Homozygous and compound heterozygous BRAT1 mutations have been described in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). The seven previously described patients suffered from uncontrolled seizures, and all of those patients died in their first months of life. BRAT1 acts as a regulator of cellular proliferation and migration and is required for mitochondrial function. The loss of these functions may explain the cerebral atrophy observed in this case of PE. This case highlights the extraordinary potential of next generation technologies for the diagnosis of rare genetic diseases, including PE. Making a prompt diagnosis of PE is important for genetic counseling and disease management.

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