Developmental regression describes a child who begins to lose his previously acquired milestones skills after he has reached a certain developmental stage and though affects his childhood development. It is associated with neurodegenerative diseases including leukodystrophy and neuronal ceroid lipofuscinosis diseases (NCLs), one of the most frequent childhood-onset neurodegenerative disorders. The current study focused on screening causative genes of developmental regression diseases comprising neurodegenerative disorders in Egyptian patients using next-generation sequencing (NGS)-based analyses as well as developing checklist to support clinicians who are not familiar with these diseases. A total of 763 Egyptian children (1 to 11 years), mainly diagnosed with developmental regression, seizures, or visual impairment, were studied using whole exome sequencing (WES). Among 763 Egyptian children, 726 cases were early clinically and molecularly diagnosed, including 482 cases that had pediatric stroke, congenital infection, and hepatic encephalopathy; meanwhile, 192 had clearly dysmorphic features, 31 showed central nervous system (CNS) malformation, 17 were diagnosed by leukodystrophy, 2 had ataxia telangiectasia, and 2 were diagnosed with tuberous sclerosis. The remained 37 out of 763 candidates were suspected with NCLs symptoms; however, 28 were confirmed to be NCLs patients, 1 was Kaya-Barakat-Masson syndrome, 1 was diagnosed as infantile neuroaxonal dystrophy, and 7 cases required further molecular diagnosis. This study provided an NGS-based approach of the genetic causes of developmental regression and neurodegenerative diseases as it comprised different variants and de novo mutations with complex phenotypes of these diseases which in turn help in early diagnoses and counseling for affected families.

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Background: Ataxia Telangiectasia (A-T) is a rare neurodegenerative disorder that affects a number of different systems of the body. Aim of the work:To identify the spectrum of clinical presentations of children with A-T. Methods: Retrospective cohort study of data of 35 children with confirmed diagnosis of A-T. Results: A-T clinical spectrum was diverse with two distinct presentations according to age of onset of symptoms; classic early onset among 29 (82%) (mean age± SD= 2.9 ± 0.63 years) and variant late in 6 (17%) (mean age± SD=9.83 ± 1.34 years). In early onset A-T the leading presentations were classic; ataxia in 100%, telangiectasis (100%), dysarthria (62%), cerebellar atrophy (58%), repeated sinopulmonary infections (48%), autoimmune vitiligo in one child, but not peripheral neuropathy or postural scoliosis. While among those with late onset A-T, the leading presentations were extrapyramidal manifestations and dystonia in (66.6%), late development of ataxia (100%), telangiectasis (50%), dysarthria (66.6%), repeated sinopulmonary infections (16.6%), cerebellar atrophy (16.6%) and peripheral neuropathy (50%). All 35 (100%) had elevated alfa fetoprotein, 74% had reduced IgE levels and 68% had reduced IgA levels. Acute lymphoblastic leukemia (ALL) complicated the course of 17.2% and 16.6% of early and variant late onset A-T respectively, and preceded the onset of ataxia among 50% of affected cases. Conclusion: Ataxia telangiectasia is a rare neurologic disease with various clinical presentations. A-T clinical spectrum is diverse with two distinct presentations according to age of presentation: classic early onset and variant late onset. Immune dysregulation is more pronounced among the early onset group. ALL might be the initial presentation of A-T that precedes the onset of ataxia and of telangiectasis.