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Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4–5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

Mitochondrial DNA depletion syndromes (MDSs) are autosomal recessive diseases characterized by a severe decrease in mitochondrial DNA content leading to dysfunction of the affected organ. Autosomal recessive mutations in MPV17 have been identified in the hepatocerebral form of MDS. We describe the clinical features, biochemical and molecular results of a Saudi infant with a new mutation of MPV17 and compared the features to those of previously reported cases. We stress the importance of such rare cases particularly in countries with high consanguineous marriage rate.

Abstract The phenotypic spectrum of glucose transporter type 1 (GLUT1) deficiency syndrome is now known to be a continuum that includes the classic phenotype as well as atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal nonepileptic findings such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. We report the case of a mentally normal child with history of infantile seizures, which remitted but later developed nonepileptic movement disorder, responsive to carbohydrate intake, with a novel frameshift mutation (c.1344_1347delCTAC p.Y449fs) in the last exon of the GLUT1 gene. This case further broadens the phenotypic spectrum of GLUT1 deficiency syndrome. We provide evidence from this case and previous reports that mutations affecting the length and composition of the intracellular C-terminal domain of the GLUT1 protein have a variable and somewhat unpredictable range of pathological effects. These range from null phenotypes associated with C-terminal domain absence, to milder presentations associated with C-terminal domains comprising partially and (in this case study) completely abnormal amino acid sequences.

Abstract To evaluate ictal serum levels of heart type fatty acid binding protein (H-FABP) in children with intractable epilepsy as a marker of cardiac ischemia in comparison to their levels in the interictal period and that of controls. The study included 23 seizure episodes recorded in 14 patients with intractable seizures. Serum levels of H-FABP in the ictal and interictal periods were done as well as simultaneous electrocardiogram, Holter and video electroencephalography recordings with evaluation of changes in the heart rate (HR), and HR variability parameters. Levels of H-FABP were higher in the patients' group whether in the ictal or interictal periods compared to the control group. However, levels were not significantly different in the ictal period compared to the interictal one. Ictal tachycardia was recorded in 95% and bradycardia in 5% of the studied seizures episodes. Premature atrial and ventricular contractions were recorded in the 1 st postictal hour of 8.7% and 30.4% of the recorded seizures, respectively. Interictal values showed significant increase minutes before the onset of the seizures and remained high 2 hours postictally. All time domain HR variability parameters were lower in the patients' group. Our results showed significant increase in the serum levels of H-FABP in our patients' group, which might suggest a degree of myocardial ischemia even in asymptomatic patients. Though bradycardia, prolonged QTc and arrhythmic changes were reported in few cases, the importance of the results warrants studying those changes at least in patients with refractory seizures.

Abstract Several mechanisms have been proposed to explain the weight gain associated with Valproic acid (VPA) use but it is still not clear. We aimed to investigate the effect of VPA on the level of two of the peptides involved in the regulation of the energy balance (ghrelin and resistin) in children with epilepsy and their relation to growth parameters, VPA level and characteristics of their epileptic disorder. A cross-sectional study was conducted on 34 children with epilepsy on VPA monotherapy. Growth parameters (weight, height and body mass index) were evaluated and trough serum VPA, serum ghrelin and resistin levels were measured and results were compared to the matched controls. Ghrelin levels were significantly higher in the patients than the control group (mean 110.2 ± 41.23 pg/mL and 55.73 ± 24.9 pg/mL, respectively), while resistin levels were not different in both groups (mean 1.68 ± 1.82 ng/mL and 1.0 ± 0.22 ng/mL). Levels of resistin were high in patients with idiopathic epilepsy compared to the control group. Ghrelin and resistin levels did not show a significant correlation to growth parameters. The degree of seizure control and the VPA levels did not seem to affect the results of either hormone. In conclusion, ghrelin levels are increased in children with epilepsy in comparison to healthy controls, which may be a part of hormonal dysfunction secondary to seizures. Our results did not demonstrate a role of VPA use in the observed changes.

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.

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.

Glutaric acidemia type 1 (GA1) is an inherited metabolic autosomal recessive disorder that is caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Untreated patients suffer primarily from severe striatal damage. More than 250 variants in the GCDH gene have been reported with a variable frequency among different ethnic groups. In this study, we aimed to characterize 89 Egyptian patients with GA1 and identify the variants in the 41 patients who were available for genotyping. All of our patients demonstrated clinical, neuroradiological, and biochemical characteristics that are consistent with a diagnosis of GA1. All patients presented with variable degrees of developmental delay ranging from mild to severe. Most of the 89 patients presented with acute onset type (71.9%), followed by insidious (19%) and asymptomatic (9%). A delay in diagnosis was inversely associated with macrocephaly. The prevalence rate ratio (PR) for macrocephaly that was associated with each 6-month delay was 0.95 (95%CI 0.91–0.99). However, high body weight was associated with a higher likelihood of having macrocephaly (PR 1.16, 95%CI 1.06–1.26 per 1 SD increment of Z score weight). However, body weight was inversely associated with the morbidity score. Consanguinity level was 64% among our patient’s cohort and was positively associated with the C5DC level (β (95%CI) 1.06 (0.12–1.99)). Forty-one patients were available for genotyping and were sequenced for the GCDH gene. We identified a total of 25 variants, of which the following six novel variants were identified: three missense variants, c.320G > T (p.Gly107Val), c.481C > T (p.Arg161Trp) and c.572 T > G (p.Met191Arg); two deletions, c.78delG (p.Ala27Argfs34) and c.1035delG (p.Gly346Alafs*11); and one indel, c.272_331del (p.Val91_Lys111delinsGlu). All of the novel variants were absent in the 300 normal chromosomes. The most common variant, c.*165A > G, was detected in 42 alleles, and the most commonly detected missense variant, c.1204C > T (p.Arg402Trp), was identified in 29 mutated alleles in 15/41 (34.2%) of patients. Our findings suggest that GA1 is not uncommon organic acidemia disease in Egypt; therefore, there is a need for supporting neonatal screening programs in Egypt.

Abstract Acute pancreatitis associated with valproic acid (VPA) treatment is reported in literature. Amylases however are not specifically originated in the pancreas. Other organs, such as salivary glands, may be involved in causing higher serum activity. Thus, we aimed to investigate whether serum total amylase and particularly its pancreatic isoenzyme and lipase levels are altered in the course of treatment with VPA in children with epilepsy. The study was conducted on 45 children with epilepsy on VPA monotherapy. Trough serum VPA, serum total amylase, lipase, and pancreatic amylase levels were evaluated in the patients and results were compared to a matched control group. Though all patients were asymptomatic for acute pancreatitis, serum total amylase levels were elevated in 40%. Patients with increased levels of total amylase did not differ from the rest of patients regarding the characteristics of epilepsy syndrome or the degree of seizure control. Nevertheless, there was significant positive correlation between total amylase and VPA trough serum levels. Five patients had simultaneous elevation of total amylase, pancreatic isoenzyme and lipase levels, though in none of them reaching three folds the upper limit. They had no symptoms suggestive of acute or intermittent pancreatitis and their ultrasonic examination was normal. Follow up showed normalization of their serum levels. In conclusion, our results demonstrate the limited specificity of total amylase level as a marker for pancreatic injury. Whenever there is suspicion, a workup including pancreatic isoenzymes is advisable. The implication of asymptomatic elevation of pancreatic isoenzymes needs to be further investigated.