The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

Clinical and Genetic Spectrum of Patients With Mitochondrial Disease in a Pediatric Egyptian Cohort: Novel Variants and Phenotypic Expansion.

Mitochondrial disorders exhibit clinical and genetic diversity. Nearly 400 distinct genes, located in both the mitochondrial and nuclear genomes, harbor pathogenic variants that can produce a broad spectrum of mitochondrial diseases. This work aims to explore the genetic etiology of a cohort of Egyptian pediatric patients who were clinically suspected of having a mitochondrial disorder. A total of 49 patients from 44 unrelated families were studied. Selection criteria included age below 18 years and meeting Morava criteria (a score ≥ 3). The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying mitochondrial disorder Exome sequencing, including mitochondrial genome sequencing, was carried out for each participant. Causative variants likely responsible for the phenotypes were identified in 68% of the study population. The mitochondrial subgroup constituted 41% of the studied population with a median age of 4 years. No primary pathogenic variants in mitochondrial DNA were detected. Pathogenic or likely pathogenic variants in eight mitochondrial genes were identified in 78% of the mitochondrial cohort. Additionally, seven novel variants were identified. Nonmitochondrial diagnoses accounted for 27% of the study population. In 32% of cases, disease-causing variants were not identified. The current study underscores the diverse phenotypic and genetic landscape of mitochondrial disorders among Egyptian patients.

A homozygous loss-of-function variant in BICD2 is associated with lissencephaly and cerebellar hypoplasia.

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients.

Further Insights into Developmental Brain Malformations and Leukoencephalopathy Associated with 6p25.3 Deletion.

We report a new patient who presented with dysmorphic features and congenital heart disease. In addition, her brain magnetic resonance imaging revealed leukoencephalopathy, cavum septum pellucidum, perisylvian polymicrogyria, and focal occipital pachygyria. Her regular karyotype showed 46,XX add 6 (p25) due to malsegregation of a maternal balanced translocation 46,XX,t(6;7)(p25;q33) while the array-comparative genomic hybridization identified a 3.307 Mb heterozygous deletion at 6p25.3-p25.2 and 23.95 Mb duplication at 7q33-q36.3. A previous patient with the same developmental brain malformations and leukoencephalopathy with 6p25 deletion including TUBB2A and TUBB2B genes had been reported. Thus, confirming that these specific developmental brain malformations are due to TUBB2A and TUBB2B haploinsufficiency. Our report is the first to present the developmental brain malformations associated with whole gene deletions of the two tubulin genes and provide further insights into the etiology of developmental brain malformations and white matter abnormalities associated with 6p25 deletions.

Phenotypic and mutational spectrum of thirty-five patients with Sjögren-Larsson syndrome: identification of eleven novel ALDH3A2 mutations and founder effects.

Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disorder characterized by congenital ichthyosis, spastic diplegia and intellectual disability. It is an inborn error of lipid metabolism caused by biallelic mutations in the ALDH3A2 gene encoding the fatty aldehyde dehydrogenase that plays a pivotal role in metabolism of long-chain aliphatic aldehydes and alcohols. In this report, we describe the clinical, neuro-radiological and molecular findings of 35 patients with SLS. All patients shared the typical clinical manifestations of SLS including spasticity, ichthyosis and intellectual disability. Brain MRI demonstrated deep while matter affection in all patients that varied in severity. Mutational analysis of the ALDH3A2 gene revealed 16 distinct mutations including 11 previously unreported ones. Three mutations (p.S365L, p.R9* and p.G400R) were recurrent in our patients with frequencies ranging from 12 to 24%. Interestingly, patients carrying the two new mutations p.R9* and p.G400R shared similar haplotypes suggesting possible founder effects in our population. In conclusion, we present a large cohort of patients from the same ethnicity with the characteristic clinical and brain imaging findings of SLS but with variable inter and intra familial severity and expressivity. We also identified many novel and founder ALDH3A2 mutations thus expanding the mutational spectrum of the disorder.

GAPO syndrome in seven new patients: Identification of five novel ANTXR1 mutations including the first large intragenic deletion.

GAPO syndrome is a very rare disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy. It is caused by biallelic mutations in the ANTXR1 gene. Herein, we describe the clinical and molecular findings of seven new patients with GAPO syndrome. Our patients presented with the characteristic clinical features of the syndrome except for one patient who did not display total alopecia till the age of two years. Strikingly, optic atrophy and glaucoma were observed in all patients and one patient showed keratopathy in addition. Moreover, craniosynstosis was an unusual associated finding in one patient. Mutational analysis of ANTXR1 gene identified five novel homozygous mutations including two frameshift, two splice site and a large intragenic deletion of exon 3. Our results reinforce the clinical characteristics of the syndrome, expand the mutational spectrum and provide more insights into the role of the ANTXR1 protein in the regulation of extracellular matrix.

Polymorphisms of Immunoglobulin G Fc Receptors in Pediatric Guillain-Barré Syndrome.

Introduction Guillain-Barré syndrome (GBS) is an autoimmune peripheral neuropathy characterized by demyelination and axonal damage. Biallelic functional polymorphisms in the immunoglobulin G Fc receptors (FcγR)-FcγRIIA: H131/R131, FcγRIIIA: V158/F158, and FcγRIIIB: NA1/NA2 affect the affinity of the IgG-FcγR interaction, therefore, diseases such as GBS in which this interaction plays a critical role might be influenced by the polymorphisms. Methods We evaluated the role of FcγR polymorphisms in susceptibility to GBS in Egyptian pediatric patients and the association of the variant alleles with neurophysiological types, severity, and outcome of the disease. A total of 50 patients with GBS and 50 controls were examined for FcγR polymorphisms by allele-specific polymerase chain reaction. Results FcγRIIA H131 allele (p = < 0.0001; odds ratio [OR] = 4.78; 95% confidence interval [CI], 2.62-8.70) and FcγRIIA H/H131 genotype (p = < 0.0001 ; OR = 10.56; 95% CI, 3.59-31.06) were significantly increased in GBS patients while FcγRIIIA and FcγRIIIB allelic distributions were similar among patients and controls. The FcγR genotypes showed no association with neurophysiological types of GBS, severity or outcome of the disease. Conclusions These findings reflect that FcγRIIA H131 allele may represent a risk marker for susceptibility to GBS.

Skeletal and cardiac muscle involvement in children with glycogen storage disease type III.

UNLABELLED: Glycogen storage disease type III (GSD III) may present with hepatic disease or may involve both skeletal and cardiac muscles as well. To assess the prevalence of neuromuscular and cardiac involvement in a group of children with GSD III, 28 children with GSD III, diagnosed by enzymatic assay, were enrolled in the study after an informed consent was obtained from their parents/guardians and after the study protocol was approved by our institutional ethical committee. Their mean age was 6.6 + 3.1 years. All cases were assessed neurologically by clinical examination, electromyography (EMG), and nerve conduction velocity. The heart was examined clinically by electrocardiogram and echocardiography. Seventeen patients (61 %) had myopathic changes by EMG, three of them had associated neuropathic changes. Creatine phosphokinase (CPK) was elevated in all myopathic cases except one. Children with myopathic changes were significantly older (p = 0.02), and CPK was significantly higher (p < 0.0001). Nine cases had left ventricular (LV) hypertrophy, seven of them had myopathic changes by EMG. CONCLUSION: Myopathic changes are not uncommon in children with GSD III. Myopathic changes tend to occur in older age and are associated with higher CPK level. Cardiac muscle involvement is less common in this age group and may, on occasion, occur alone without skeletal muscle involvement. Despite mild degrees of affection in this age group, it is recommended to perform prospective annual screening using EMG and echocardiography in order to augment dietary therapy regimen to prevent progression to life threatening complications.

PRRT2 mutations: exploring the phenotypical boundaries.

BACKGROUND: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However it remains unknown whether PRRT2 mutations are causal in other epilepsy syndromes. After we discovered a PRRT2 mutation in a large family with ICCA containing one individual with febrile seizures (FS) and one individual with West syndrome, we analysed PRRT2 in a heterogeneous cohort of patients with different types of infantile epilepsy. METHODS: We screened a cohort of 460 patients with B(F)IC or ICCA, fever related seizures or infantile epileptic encephalopathies. All patients were tested for point mutations using direct sequencing. RESULTS: We identified heterozygous mutations in 16 individuals: 10 familial and 6 sporadic cases. All patients were diagnosed with B(F)IC, ICCA or PD. We were not able to detect mutations in any of the other epilepsy syndromes. Several mutation carriers had learning disabilities and/or impaired fine motor skills later in life. CONCLUSIONS: PRRT2 mutations do not seem to be involved in the aetiology of FS or infantile epileptic encephalopathies. Therefore B(F)IC, ICCA and PD remain the core phenotypes associated with PRRT2 mutations. The presence of learning disabilities or neuropsychiatric problems in several mutation carriers calls for additional clinical studies addressing this developmental aspect in more detail.

Cerebral Folate Transport Deficiency in 2 Cases with Intractable Myoclonic Epilepsy.

Cerebral folate transport deficiency due to folate receptor 1 gene (FOLR1) gene mutation results from impaired folate transport across the blood: choroidplexus: cerebrospinal fluid (CSF) barrier. This leads to low CSF 5-methyltetrahydrofolate, the active folate metabolite. We are reporting two children with this treatable cerebral folate transport deficiency. Eight years and 9-month-old female presented with delayed milestones followed by regression, seizures, and intention tremors. On examination child had microcephaly, generalized hypotonia, hyperreflexia, unsteady gait, and incoordination. Magnetic resonance imaging (MRI) of brain revealed dilated ventricular system and cerebellar atrophy. Computed tomography (CT) of brain showed brain calcifications. Whole exome sequencing was finally performed, revealing homozygous nonsense pathogenic variant in FOLR1 gene in exon 3 c.C382T p.R128W, confirming the diagnosis of cerebral folate deficiency. Twelve-year-old female child presented with global developmental delay since birth, myoclonic jerks and cognitive regression. Child had generalized hypotonia and hyperreflexia. Her coordination was markedly affected with intention tremors andunbalanced gait. CT brain showed bilateral basal ganglia and periventricular calcifications with brain atrophic changes. MRI brain showed a prominent cerebellar folia with mild brain atrophic changes. Genetic testing showed a homozygous pathogenic variant was identified in FOLR1 C.327_328 delinsAC, p.Cys109Ter. Both patients were started on intramuscular folinic acid injections with a decrease in seizure frequency. However, their seizures did not stop completely due to late initiation of therapy. In conclusion, cerebral folate transport deficiency should be suspected in every child with global developmental delay, intractable myoclonic epilepsy, ataxia with neuroimaging suggesting cerebellar atrophy and brain calcifications. Response to folinic acid supplementation is partial if diagnosed late and treatment initiation is delayed.

Lumbar Sympathetic Block to Treat CRPS in an 18-Month-Old Girl: A Breaking Barriers Case Report and Review of Literature.

BACKGROUND: Children under the age of 3 years have been diagnosed with complex regional pain syndrome (CRPS). They were found to be functionally disadvantaged and psychologically distressed in relation to children with other painful conditions. CASE PRESENTATION: An 18-month-old baby girl was referred to the pain clinic with a history of severe right lower limb pain that had begun 2 months earlier. The parents were unable to recall any trauma before the painful situation. Pain and allodynia were severe and extended from the toes to the gluteus area. She was low weight for her age (6700 g). The patient was on the maximum doses of gabapentin and amitriptyline accepted for her body weight and did not have the possibility to start rehabilitation due to severe pain and allodynia. After discussing the risks and potential benefits of a planned lumbar sympathetic block (LSB), the parents approved the interventional procedure. This is the first case report describing the LSB technique at such a young age. METHOD: A lumbar sympathetic block was carried on at the third lumbar vertebral level, fluoroscopy-guided, and under general anesthesia (GA) initiated with ketamine iv. A 4-cm needle was introduced using a tunneled vision approach in an oblique view at the L3 level until adequate depth was confirmed in the lateral position. Safety considerations were taken in relation to the radiation dose and all drugs injected with dose adjustment to her body weight. The block was successful (the skin temperature increased by 2.8 °C) and was uneventful. Pain and allodynia were completely alleviated in the recovery room. At the follow-up after 3 and 8 weeks, the parents reported an 80% improvement in pain and allodynia, a 70% improvement in sleep, a weight gain of 900 g, and that she had started rehabilitation. CONCLUSIONS: Lumbar sympathetic blocks can be considered at a very young age to treat CRPS if other non-invasive measures fail.

Effect of Helicobacter pylori Eradication on Serum Level of Valproic Acid in Children with Idiopathic Generalized Epilepsy.

BACKGROUND/OBJECTIVES: The purpose of this study was to determine the influence of H. pylori eradication on the serum level of the orally administered valproic acid (VPA) in children with idiopathic generalized epilepsy; Methods: This prospective cohort observational study included 100 children with idiopathic generalized epilepsy, recruited from a neurology clinic from May 2021 to December 2021. The patients were divided into two groups, each containing 50 children. The first group had a positive H. pylori stool antigen and H. pylori-related symptoms, while the second group had a negative antigen. H. pylori Eradication therapy was given to the positive H. pylori group. The serum level of VPA was obtained at baseline and 4 weeks after eradication therapy. RESULTS: Despite there being no significant difference between the H. pylori-positive and H. pylori-negative groups regarding the baseline VPA serum level (79.9 ± 13.9 and 77.9 ± 13.1 mcg/mL), respectively, the serum VPA level had significantly increased after H. pylori eradication therapy (99.4 ± 11 mcg/mL) (p value = 0.000), as opposed to the H. pylori-negative group (85.3 ± 10.9 mcg/mL) (p value = 0.142). Furthermore, there was a statistically significant association with a negative correlation between the VPA serum level after eradication and the number of epileptic attacks per month (p value = 0.033, R value = -0.301) and the dose of VPA (p value = 0.046, R value = -0.284). CONCLUSIONS: The eradication of H. pylori resulted in a highly significant improvement in the serum level of the orally given VPA in children with idiopathic generalized epilepsy, as well as an indirect decrease in the frequency of epileptic events per month, allowing for dose reduction. Eradication therapy may have anticonvulsant properties and might indirectly aid in the management of epileptic activity. H. pylori screening for children with idiopathic generalized epilepsy can optimize serum VPA levels, potentially leading to better seizure control. To our knowledge, this is the first study in the literature to describe the effect of H. pylori eradication on the serum level of the orally administered VPA in children with idiopathic generalized epilepsy.

Cold Agglutinin Disease and Autoimmune Hemolytic Anemia with Pulmonary Embolism as a Presentation of COVID-19 Infection.

BACKGROUND: Lymphopenia, thrombocytopenia, and elevated D-dimer and ferritin levels are frequently reported in patients with severe coronavirus disease 2019 (COVID-19). Here we report a case of cold agglutinin disease (CAD), autoimmune hemolytic anemia (AIHA), and pulmonary embolism as a presentation of COVID-19 infection. CASE REPORT: A 51-year-old African-American woman presented to the emergency room with fever and shortness of breath. She was tachycardic, febrile, and had an oxygen saturation of 88% on room air. Laboratory studies showed hemoglobin (Hb) 5.1 g/dL, D-dimer 4.55 µg/mL, and C-reactive protein 12.3 mg/dL. Computed tomography scan of the chest showed acute pulmonary embolism involving the bilateral lower lobe segmental branches. Her influenza test was negative, but her SARS-CoV-2 test returned positive. Due to severe anemia, she was not started on any anticoagulation. Haptoglobin was low. Direct antiglobulin test returned positive for anticomplement and negative for anti-immunoglobulin G. Cold agglutinin titer was 80. Mycoplasma, Epstein-Barr virus, parvovirus, human immunodeficiency viruses, and acute hepatitis screen were negative. Abdominal and pelvic computed tomography showed a normal liver and spleen without lymphadenopathy. Peripheral blood smear showed red blood cell agglutination. On Day 2, she became hypoxic requiring 6 L oxygen. Since her Hb remained stable, she was started on low-intensity unfractionated heparin. Inflammatory markers subsequently improved and she was weaned off oxygen. Her Hb remained stable at 9 g/dL and she was discharged home. After 2 weeks, her Hb increased to 11 g/dL. CONCLUSION: As exemplified in this case report, COVID-19 infection can lead to thromboembolism, CAD, and AIHA and it should be recognized as a potential etiology to such rare diseases.

Initial levetiracetam versus valproate monotherapy in antiseizure medicine (ASM)-naïve pediatric patients with idiopathic generalized epilepsy with tonic-clonic seizures.

INTRODUCTION: Levetiracetam (LEV) is a second-generation antiseizure medicine (ASM) with broad-spectrum efficacy and tolerability. Few studies have compared the efficacy of valproate (VPA) and LEV as monotherapy in the pediatric population. Herein, we compare the efficacy, tolerability and safety of LEV monotherapy with those of VPA monotherapy in ASM-naïve pediatric patients with idiopathic generalized epilepsy with tonic-clonic (GTC) seizures. METHODS: We retrospectively analyzed the clinical and electroencephalographic (EEG) data of these ASM-naïve pediatric patients who were treated with either oral VPA or oral LEV as monotherapy for over 2 years at our center. RESULTS: This study included 60 patients with a seizure onset age between 2 months and 12 years. The patients on VPA (29 patients) and LEV monotherapy (31 patients) showed similar favorable 6-month treatment outcomes (complete seizure control in 79.31% vs 80.64%, p = 0.468052). Age at epilepsy onset, epilepsy syndrome, EEG features and ASM dose were not significant predictors of the 6-month treatment outcomes in either group. Lower seizure frequency at presentation was a predictor of favorable 6-month treatment outcomes in the LEV group but not in the VPA group. VPA and LEV treatment showed similar favorable 6-month treatment outcomes in the febrile seizures plus and patients with unidentified epilepsy syndrome subgroups. None of the patients discontinued VPA or LEV due to treatment-associated adverse effects. DISCUSSION: Our study showed that compared to VPA monotherapy, LEV monotherapy in ASM-naïve infants and children with idiopathic generalized epilepsy with GTC seizures has a similarly favorable efficacy and tolerability, independent of age, EEG features and epilepsy syndrome.

Implementation of ketogenic diet in children with drug-resistant epilepsy in a medium resources setting: Egyptian experience.

BACKGROUND: Even with the extensive use of ketogenic dietary therapies (KD), there still exist many areas of the world that do not provide these treatments. Implementing the ketogenic diet in different countries forms a real challenge in order to match the cultural and economic differences. AIM: To assess the feasibility of implementing a ketogenic diet plan in a limited resource setting with identification of the compliance, tolerability and side effects in the target population and to assess the efficacy of the ketogenic diet in children with intractable epilepsy. METHOD OF THE STUDY: The medical records of 28 patients with intractable epilepsy, treated at The Children's Hospital - Cairo University from December 2012 to March 2014 with ketogenic dietary therapy were reviewed. The non-fasting protocol was followed without hospital admission. All children were started on a standardized classic ketogenic diet with a ratio ranging from 2.5-4:1 (grams of fat to combined carbohydrate and protein). Patients were followed at 1, 3 and 6 months after diet initiation. RESULTS: The median age was 60 months (range, 30-110). After 1 month from diet initiation, 16 patients (57%) remained on the diet. One of them (6.3%) had more than 90% reduction in seizure frequency, an additional 6 patients (37.5%) had a 50-90% reduction in seizure frequency. In total, seven out of the 16 patients continuing the diet for 1 month (43.8%) had more than 50% improvement in seizure control from the base line. Despite having 50-90% seizure control, three children discontinued the diet after one month.Three months after diet initiation, 6 patients (22%) remained on diet, 4 of them (66.7%) had more than 50% reduction in seizure frequency.At 6 months, only 3 patients remained on diet, 2 of them (66.6%) had 50-90% reduction in seizure frequency, while one patient (33.3%) showed better than 90% decrease in seizure. CONCLUSION: The current study shows that the ketogenic diet could be implemented in medium resources countries and should be included in the management of children with intractable epilepsy.

Pediatric-onset multiple sclerosis in Egypt: a multi-center registry of 186 patients.

INTRODUCTION: Although the frequency of pediatric-onset multiple sclerosis (POMS) has increased in recent decades, it is still highly uncommon, which creates a need for the involvement of more registries from various clinical centers. OBJECTIVE: To characterize the demographic, clinical, and paraclinical features of Egyptian patients with POMS. PATIENTS AND METHODS: A retrospective chart review study was undertaken on 237 Egyptian patients with demyelinating events which started before the age of 18 years who attended one of five tertiary referral centers in Cairo, Egypt. RESULTS: Multiple sclerosis was diagnosed in 186 patients, 47 (25.27%) patients had disease onset before the age of 12 years; "early-onset pediatric multiple sclerosis (EOPMS)". The mean age of disease onset was (14.13±2.49 years), with a female:male ratio of 1.62:1, none of the enrolled patients had a primary progressive course (PPMS), whereas 10 patients (5.38%) had a secondary progressive form. Approximately two-thirds of the patients had monofocal disease onset, and less than 10% presented with encephalopathy; most of them had EOPMS. Motor weakness was the presenting symptom in half of the patients, whereas cerebellar presentation was detected in 34.95%, mainly in EOPMS. Seizures (not related to encephalopathy) were more frequent in those with EOPMS. Initial brain magnetic resonance images were positive in all patients, with detected atypical lesions in 29.03%, enhanced lesions in 35.48%, black holes in 13.98%, and infratentorial in 34.41%. Cervical cord involvement was found in 68.28%. More than two-thirds of the patients received either immunomodulatory or immunosuppressant (IS) treatment throughout their disease course, and about half of them received their treatment within the first year from symptoms onset, with a more favorable outcome, and patients with highly active disease received natalizumab, fingolimod, or other IS. CONCLUSION: The results from this registry - the largest for MS in the Arab region to date - are comparable to other registries. Immunomodulatory therapies in POMS are well tolerated and efficacious and they can improve the long-term outcome in children.

Lysosomal Storage Disorders in Egyptian Children.

OBJECTIVE: To describe the spectrum, relative prevalence and molecular background of lysosomal storage disorders in Egypt. METHODS: The authors evaluated the selective screening program for the diagnosis of lysosomal storage disorders in Egyptian children presenting to the inherited metabolic disease unit at Cairo University Children's Hospital, the largest tertiary care pediatric hospital in Egypt, over a six-year period (April 2008 through April 2014). During this period, 1,065 suspected children were assessed clinically, biochemically and some genetically. RESULTS: Two hundred and eleven children (aged 44 ± 32 mo; 56 % boys, 82 % with consanguineous parents) were confirmed with 21 different lysosomal disorders. The diagnostic gap ranged between 2 mo and 14 y (average 25 mo). Mucopolysaccharidoses were the most common group of diseases diagnosed (44.5 %), while Maroteaux-Lamy, Gaucher and nephropathic cystinosis were the most commonly detected syndromes (17.1, 14.7 and 13.7 %, respectively). Eighty mutant alleles and 17 pathogenic mutations were detected in 48 genetically assessed confirmed patients (30 Gaucher, 16 cystinosis and two Niemann-Pick type C patients). CONCLUSIONS: This report is the first to describe relative frequency and spectrum of clinical and molecular data in a large cohort of Egyptian lysosomal patients. The crude estimate denotes that over 80 % of Egyptian lysosomal patients do not have access to optimal diagnosis. Upgrading diagnostic and genetic services for lysosomal storage disorders in Egypt is absolutely necessary.