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Purpose We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Methods We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. Results In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. Conclusion We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

Objective: To determine the efficacy of steroid therapy in Sydenham’s chorea in children. Study Design: Comparative prospective study. Place and Duration of Study: Inpatient and Outpatient Department of Pediatric Neurology, Children Hospital and Institute of Child Health, Lahore Pakistan, from Dec 2019 to May 2020. Methodology: Sixty-eight children of Sydenham’s chorea were divided in Group A and B. Each Group was treated with Diazepam (0.3mg-1mg/kg/day) and an injection of Benzathine Penicillin. Group-B was given additional oral prednisolone (2mg/kg/day) for four weeks, with tapering in the next two weeks. Epidemiological data, clinical features and laboratory parameters were collected. The Universiade Federal de Minas Gerais Sydenham’s chorea Rating Scale (USCRS) was applied to both groups at the presentation after two weeks and four weeks. Results: Out of 68 patients, the mean Universidade Federal de Minas Gerais (UFMG) Sydenham's Chorea Rating Scale (USCRS) got progressively better in Group-B (mean score improvement was 25.73±5.56 at two weeks and 41.06±6.89 at four weeks) than in Group-A (mean score improvement was 9.12±3.75 at two weeks and 17.97±3.89 at four weeks) with p-value of <0.05. Conclusion: Steroid therapy significantly improved patients with Sydenham’s chorea compared to those who did not receive any steroid therapy.Keywords: Efficacy, Steroid therapy, Sydenham chorea.