Yield of karyotyping in children with developmental delay and/or dysmorphic features in Sohag University Hospital, Upper Egypt

Background: Global developmental delay (GDD) represents a measurable lag in a young child's achievement of developmental milestones compared to age matched children. Affection of two or more developmental domains is fundamental for assumption of GDD. Many chromosomal abnormalities are responsible for developmental delay or mental retardation and can be detected using G-banded karyotyping. Aim of the work: This work aimed to determine the yield of karyotyping in children with GDD and/or dysmorphic features in Sohag University Hospital, Upper Egypt. Subjects and methods: All children presenting with GDD and/or dysmorphic features, with abnormal karyotyping or other genetic testing were included. Full history, thorough clinical and detailed neurological examinations were done. The results of other investigations done for the patients, including neuroimaging and electroencephalography (EEG), were utilized (if available). Results: The total number of patients included was 395 patients, out of 646 patients who did karyotype; the mean age of presentation was 24.7 ± 32.1 (SD) months, there were 243 (61.5%) males and 152 (38.5%) females. The positive yield of karyotyping in children with developmental delay and/or dysmorphic features, including classic Down features, was 61.1%; however, with exclusion of Down syndrome and other suspected trisomies, it became 7.4%. The most prevalent chromosomal abnormality was trisomy 21-Down syndrome (364 patients/92.2%), followed by structural chromosomal abnormalities and marker chromosome in 19 patients (4.8%) and, lastly, sex chromosome abnormalities (8 patients/2.0 %). The main complaint was GDD in half of the patients (205/51.9%), while the majority of patients had microcephaly. Conclusion: G-banded karyotyping is a useful tool with reasonable yield in evaluation of children with developmental delay and/or dysmorphic features, especially in countries with limited resources. Keywords: Global developmental delay (GDD), Dysmorphic features, Karyotyping, Down syndrome, Structural chromosomal abnormalitie

Multidisciplinary approach for evaluation of neurocutaneous disorders in children in Sohag University Hospital, Upper Egypt

Background: Neurocutaneous syndromes (NCS) are a broad term for a group of neurologic disorders that involve the nervous system and the skin. The most common examples are neurofibromatosis type 1 (NF-1) and type 2 (NF-2), tuberous sclerosis (TS), Sturge–Weber syndrome (SWS), ataxia telangiectasia (AT), and Von Hippel Lindau disease (VHL). These disorders are characterized clinically by neurological manifestations such as convulsions, mental retardation and learning disabilities in addition to cutaneous manifestations, and lastly tubers (benign growths found in different organs of the body). Aim of the study: This study aimed to identify clinical, imaging, and neurophysiological profiles of neurocutaneous disorders. Children presented to the Pediatric neurology and Dermatology clinics, Sohag University Hospital who fulfilled the criteria for diagnosis of specific neurocutaneous syndromes were eligible for this study. Patients and methods: All studied patients were subjected to thorough clinical history, full clinical examination, developmental assessment, and dermatological examination. Computed tomography of the brain (CT) and electroencephalography (EEG), ophthalmic, and phoniatric evaluation were also done for all children. Echocardiography was done for only twenty children. Results: During the period of the study we diagnosed 27 cases with neurocutaneous disorders, tuberous sclerosis represented the majority of cases as it was detected in 12 cases (44.45%). The main complaint was convulsions in 19 cases (70.37%), whereas skin pigmentation was detected in 18 cases (66.66%). Developmental assessment showed that global developmental delay was found in 20 cases (74%). CT of the brain showed that 15 cases (55.55%) had intracranial calcifications and abnormal EEG findings were detected in 23 cases (85.2%). 85% of the studied children had various degrees of mental retardation. Echocardiography showed that three cases (15%) had ventricular wall tumor mostly rhabdomyoma. Conclusion: Neurocutaneous disorders had multiple clinical presentations and required a team work approach including various specialties in their evaluation and management

Propionic and Methylmalonic Acidemias: Initial Clinical and Biochemical Presentation

PA and MAA have numerous nonspecific presentations, potentially leading to delayed diagnosis or misdiagnosis. In this paper, we present the clinical and biochemical characteristics of MMA and PA patients at initial presentation. Results. This is a retrospective review of 20 patients with PA (n=10) and MMA (n=10). The most observed symptoms were vomiting (85%) and refusing feeding (70%). Ammonia was 108.75±9.3 μmol/l, showing a negative correlation with pH and bicarbonate and positive correlation with lactate and anion gap. Peak ammonia did not correlate with age of onset (r=0.11 and p=0.64) or age at diagnosis (r=0.39 and p=0.089), nor did pH (r=0.01, p=0.96; r=−0.25, p=0.28) or bicarbonate (r=0.07, p=0.76; r=−0.22, p=0.34). There was no correlation between ammonia and C3 : C2 (r=0.1 and p=0.96) or C3 (r=0.23 and p=0.32). The glycine was 386±167.1 μmol/l, and it was higher in PA (p=0.003). There was a positive correlation between glycine and both pH (r=0.56 and p=0.01) and HCO3 (r=0.49 and p=0.026). There was no correlation between glycine and ammonia (r=−0.435 and p=0.055) or lactate (r=0.32 and p=0.160). Conclusion. Clinical presentation of PA and MMA is nonspecific, though vomiting and refusing feeding are potential markers of decompensation. Blood gas, lactate, and ammonia levels are also good predictors of decompensation, though increasing levels of glycine may not indicate metabolic instability

Clinical and molecular spectrum of a large Egyptian cohort with ALS2‐related disorders of infantile‐onset of clinical continuum IAHSP/JPLS

This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation

Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction

Biallelic Mutations in Snx14 Cause A Syndromic Form of Cerebellar Atrophy and Lysosome-Autophagosome Dysfunction

Pediatric-onset ataxias often present clinically with developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a novel clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in sorting nexin 14 (SNX14), encoding a ubiquitously expressed modular PX-domain-containing sorting factor. We found SNX14 localized to lysosomes, and associated with phosphatidyl-inositol (3,5)P2, a key component of late endosomes/lysosomes. Patient cells showed engorged lysosomes and slower autophagosome clearance rate upon starvation induction. Zebrafish morphants showed dramatic loss of cerebellar parenchyma, accumulated autophagosomes, and activation of apoptosis. Our results suggest a unique ataxia syndrome due to biallelic SNX14 mutations, leading to lysosome-autophagosome dysfunction.PubMedWo