Clinical, biochemical, and molecular characterization of mucopolysaccharidosis type III in 34 Egyptian patients.

Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are four MPS III subtypes (A, B, C, and D) that are clinically indistinguishable with variable rates of progression. A retrospective analysis was carried out on 34 patients with MPS III types at Cairo University Children's Hospital. We described the clinical, biochemical, and molecular spectrum of MPS III patients. Of 34 patients, 22 patients had MPS IIIB, 7/34 had MPS IIIC, 4/34 had MPS IIIA, and only 1 had MPS IIID. All patients presented with developmental delay/intellectual disability, and speech delay. Ataxia was reported in a patient with MPS IIIC, and cerebellar atrophy in a patient with MPS IIIA. We reported 25 variants in the 4 MPS III genes, 11 of which were not previously reported. This is the first study to analyze the clinical and genetic spectrum of MPS III patients in Egypt. This study explores the genetic map of MPS III in the Egyptian population. It will pave the way for a national registry for rare diseases in Egypt, a country with a high rate of consanguineous marriage and consequently a high rate of autosomal recessive disorders.

Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders.

Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.

Remodeling Immune Response in A Celiac Disease Patient Using Herbal Supplementation: A Clinical Case-Study.

Background: Celiac disease (CD) is an autoimmune disorder characterized by abnormal serological response (autoimmune anti-tissue-Transglutaminase antibodies) triggered by gluten ingestion in genetically predisposed individuals. The only available effective management for those patients is a strict gluten-free diet. Aim: To investigate the improvement of CD after completing a traditional herbal supplementation and alternative medicine treatment. Case description, treatment, and results: A 23-year-old female presented with a confirmed CD diagnosis (positive anti-tissue Transglutaminase IgA with infiltration of mixed inflammatory cell detected in small bowel biopsy). After 9 months of alternative treatment with traditional herbal supplementation (Taraxaf®, Ferrolina®, and Indomirol®), the clinical, laboratory, and endoscopy profile tests have shown an overall improvement with negative results for anti-tissue Transglutaminase IgA, and normal small bowel mucosal appearance. She was returned to an ordinary diet containing gluten. Conclusion: A traditional herbal supplementation with specific doses followed by a physician's instruction led to obvious improvement in this CD patient.

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

ASAH1-related disorders: Description of 15 novel pediatric patients and expansion of the clinical phenotype.

Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clinical, biomarker and genetic spectrum of 15 Egyptian children from 14 unrelated families with biallelic pathogenic variants in ASAH1 (12 Farber and 3 SMA-PME). Recruited children were nine females/six males ranging in age at diagnosis from 13 to 118 months. We detected ASAH1 pathogenic variants in all 30 alleles including three novel variants (c.1126A>G (p.Thr376Ala), c.1205G>A (p.Arg402Gln), exon-5-deletion). Both total C26-Ceramide and its trans- isomer showed 100% sensitivity for the detection of ASAH1-related disorders in tested patients. A 10-year-old girl with the novel variant c.1205G>A (p.Arg402Gln) presented with a new peculiar phenotype of PME without muscle atrophy. We expanded the phenotypic spectrum of ASAH1-related disorders and validated the biomarker C26-Ceramide for supporting diagnosis in symptomatic patients.

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

PURPOSE: The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy. METHODS: Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients. RESULTS: Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months). CONCLUSIONS: These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.

Knowledge, Awareness, and Practices toward Colorectal Cancer and Its Dietary and Lifestyle-Related Risk Factors among Jordanian University Students: A Cross-Sectional Study.

Background: Globally, colorectal cancer (CRC) incidence is rising, and it is a leading cause of mortality, with greater death rates pronounced in developing countries, including Jordan. Understanding knowledge and awareness of etiologic factors, unhealthy lifestyles, and dietary patterns is crucial for combating ailments. Hence, this study is aimed at investigating the level of knowledge and awareness of CRC-related risk factors, practices, and possible associations of studied variables among young Jordanians. Methodology. A cross-sectional, observational study was conducted using an online self-reported assessment of anthropometrics, knowledge, awareness, and dietary and lifestyle practices toward CRC and its related risk factors. Results: A study of 795 Jordanian university students found that 93.8% were Jordanians, 73.0% were female, aged 18-24, and single. Most participants were from medical and science schools (69.4%). The vast majority (about 84%) were found to have good knowledge and awareness of CRC and its risk factors, but this was not reflected in their dietary practices. There are significant differences in physical activity, smoking, vegetable consumption, and serving sizes of red meat and processed meats between the sexes. Academic study specialties significantly impact knowledge and awareness. Conclusion: The study reveals that while young Jordanian university students have good knowledge and awareness about CRC and its risk factors, these levels are not reflected in their dietary behaviors and food choices for CRC prevention, highlighting the need for national programs to improve these practices, particularly in the younger population.

Phytochemical analysis, antioxidant, and antimicrobial activities of Jordanian Pomegranate peels.

Pomegranate (Punica granatum) peels have shown numerous health benefits such as antioxidant, anti-inflammatory, and antimicrobial activities. These health activities are owed to the unique phytochemical components present in pomegranate peels. Variations in the pomegranate cultivar, geographical region, and extraction methods significantly affect the phytochemical composition and concentrations of pomegranate fruits and their peels, hence their health outcomes. Therefore, this study aimed to examine the phytochemical contents of pomegranate peels of Jordanian origin and their antioxidant and antimicrobial activities. Among the 6 extracts of pomegranate peels tested, the ethanol extract exhibited the highest total phenolic content (TPC = 297.70 ± 1.73 mg GAE/g DW), highest total flavonoids content (TFC = 116.08 ± 3.46 mg RE/g DW), highest hydrolyzable tannins (HT) contents (688.50 ± 3.54 mg TE/g DW). Whereas the highest condensed tannins (CT) content was found in both the ethanol (13.87 ± 0.58 mg CE/g DW) and methanol (13.84 ± 0.55 mg CE/g DW) extracts. For the antioxidant activities, the water extract of pomegranate peels displayed the highest inhibitory effect on DPPH radicals (9.43 ± 0.06 µmole TE/g DW), while for the ABTS+ assay the methanol and ethanol extracts exhibited the highest activities of 11.09 ± 0.02 and 11.09 ± 0.06 µmole TE/g DW, respectively. For the FRAP assay, the aqueous methanol extract exhibited the highest reducing activity (1.60 ± 0.09 mmole Fe (II)/g DW). As for the antimicrobial activities of various extracts of pomegranate peels, the highest antimicrobial activity against Micrococcus luteus was achieved by the ethanol extract (MIC = 6.25 mg/mL), whereas the lowest antimicrobial activity was observed against Candida krusei using the methanol extract (MIC = 100 mg/mL). These results indicate that pomegranate peels of Jordanian origin are rich in phytochemical content and exhibited strong antioxidant and antimicrobial activities making these agroindustrial by-products potential candidates for various medical applications and possible safe sources for important bioactive components.

Homogentisate 1,2-dioxygenase (HGD) gene variants in young Egyptian patients with alkaptonuria.

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys. The genetic basis of AKU in Egypt is completely unknown. We evaluated the clinical and genetic spectrum of six pediatric and adolescents AKU patients from four unrelated Egyptian families. All probands had a high level of HGA in urine by qualitative GC/MS before genetic confirmation by Sanger sequencing. Recruited AKU patients were four females and two males (median age 13 years). We identified four different pathogenic missense variants within HGD gene. Detected variants included a novel variant c.1079G > T;p.(Gly360Val) and three recurrent variants; c.1078G > C;p.(Gly360Arg), c.808G > A;p.(Gly270Arg) and c.473C > T;p.(Pro158Leu). All identified variants were properly segregating in the four families consistent with autosomal recessive inheritance. In this study, we reported the phenotypic and genotypic spectrum of alkaptonuria for the first time in Egypt. We further enriched the HGD-variant database with another novel pathogenic variant. The recent availability of nitisinone may promote the need for genetic confirmation at younger ages to start therapy earlier and prevent serious complications.

Association of salary and intention to stay with the job satisfaction of the dietitians in Jordan: A cross-sectional study.

This cross-sectional study aimed to determine job satisfaction among the Jordanian dietitians, the factors associated with job satisfaction, and the relationship between job satisfaction and intent to stay. A convenience sample of 600 dieticians performed a self-reported online survey. Most of the participants were females (83.2%), <30 years of age (68.3%) with a BSc degree in nutrition (77.3%). Results revealed that 20% of the dietitians were dissatisfied at work, 69.8% were neither dissatisfied nor satisfied, and 10.2% were satisfied. The satisfaction for the total score in all examined domains was neither dissatisfaction nor satisfaction, except for the salary. Participants with higher monthly salaries were 1.53 more likely to have higher job satisfaction than those with lower monthly salaries (CI 95%, (0.503-2.55)). Intention to stay was positively correlated with the total job satisfaction and all domains except the knowledge and skills domain (p-value = 0.22). The main aspect that needs to be addressed and re-evaluated is to improve dietitians job satisfaction is the salary. The findings of this study point to improving dietitians' work status to attain the best possible health care achievements.

An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients.

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.

The Emergence of Rift Valley Fever in Gedaref State Urges the Need for a Cross-Border One Health Strategy and Enforcement of the International Health Regulations.

This study investigated the causative agent of a haemorrhagic fever epidemic in Gedaref state, south-east Sudan. Six cases of febrile illness with haemorrhagic manifestations presented at outpatient health-clinics. Blood samples were collected from the patients and shipped to Khartoum where they were tested for dengue virus (DENV), chikungunya virus (CHIKV), and Rift Valley fever virus (RVFV) using real-time qPCR. Fifty percent (3/6) of them tested positive for RVFV and neither DENV or CHIKV was detected. All patients were males between 20 and 48 years old who had no history of recent travel. This finding describes the first emergence of RVFV in Gedaref state. Considering that the state hosts a major market of livestock, and it has one of the largest-seasonal open pastures in the country that is usually flooded with herds from the neighbouring states and countries during the rainy season, this emergence could represent a major threat to public health in the region and countries importing animals and/or animal products from east Africa. Therefore, we urge the policymakers of the health and animal resources sectors to implement a one health strategy with a well-established early warning surveillance and response system to prevent the establishment of the disease in the area.

The first laboratory-confirmed imported infections of SARS-CoV-2 in Sudan.

BACKGROUND: The rapidly growing pandemic of coronavirus disease 2019 (COVID-19) has challenged health systems globally. Here we report the first identified infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; aetiology of COVID-19) among recent international arrivals to Sudan and their contacts. METHODS: Suspected cases were identified clinically and/or epidemiologically. Samples from suspected cases and their contacts were tested in the National Influenza Centre following World Health Organization protocols. Two real-time reverse transcription quantitative polymerase chain reaction assays were used to detect and confirm SARS-CoV-2 infection. RESULTS: Seven cases of COVID-19, including two deaths, were confirmed in Sudan between 27 February and 30 March 2020. Suspected cases were identified and tested. As of 30 March, no local transmission was yet reported in the country. Fifty-nine percent of the suspected cases were international travellers coming from areas with current COVID-19 epidemics. Cough and fever were the major symptoms, presented by 65% and 60% of the suspected cases, respectively. By early April, an additional seven cases were confirmed through limited contact tracing that identified the first locally acquired infections in recent contact with imported cases. CONCLUSIONS: The high mortality rate of COVID-19 cases in Sudan might be due to limitations in test and trace and case management services. Unfortunately, infections have spread further into other states and the country has no capacity for mass community screening to better estimate disease prevalence. Therefore external support is urgently needed to improve the healthcare and surveillance systems.

"Kankasha" in Kassala: A prospective observational cohort study of the clinical characteristics, epidemiology, genetic origin, and chronic impact of the 2018 epidemic of Chikungunya virus infection in Kassala, Sudan.

BACKGROUND: The public health impact of Chikungunya virus (CHIKV) is often underestimated. Usually considered a mild condition of short duration, recent outbreaks have reported greater incidence of severe illness, fatality, and longer-term disability. In 2018/19, Eastern Sudan experienced the largest epidemic of CHIKV in Africa to date, affecting an estimated 487,600 people. Known locally as Kankasha, this study examines clinical characteristics, risk factors, and phylogenetics of the epidemic in Kassala City. METHODOLOGY/PRINCIPAL FINDINGS: A prospective cohort of 102 adults and 40 children presenting with chikungunya-like illness were enrolled at Kassala Teaching Hospital in October 2018. Clinical information, socio-demographic data, and sera samples were analysed to confirm diagnosis, characterise illness, and identify viral strain. CHIKV infection was confirmed by real-time reverse transcription-PCR in 84.5% (120/142) of participants. Nine (7.5%) CHIKV-positive participants had concurrent Dengue virus (DENV) infection; 34/118 participants (28.8%) had a positive Rapid Diagnostic Test for Plasmodium falciparum; six (5.0%) had haemorrhagic symptoms including two children with life-threatening bleeding. One CHIKV-positive participant died with acute renal injury. Age was not associated with severity of illness although CHIKV-infected participants were younger (p = 0.003). Two to four months post-illness, 63% of adults available for follow-up (30) were still experiencing arthralgia in one or more joints, and 11% remained moderately disabled on Rapid3 assessment. Phylogenetic analysis showed all CHIKV sequences from this study belonged to a single clade within the Indian Ocean Lineage (IOL) of the East/Central/South African (ECSA) genotype. History of contact with an infected person was the only factor associated with infection (p = 0.01), and likely related to being in the same vector environment. CONCLUSIONS/SIGNIFICANCE: Vulnerability to CHIKV remains in Kassala and elsewhere in Sudan due to widespread Aedes aegypti presence and mosquito-fostering household water storage methods. This study highlights the importance of increasing awareness of the severity and impact of CHIKV outbreaks, and the need for urgent actions to reduce transmission risk in households.

Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome.

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits. It manifests as multiple skin nodules, patchy hyperpigmentation, joint contractures and severe pain with movement. HFS shows some clinical overlap to Farber disease (FD), a recessive lysosomal storage disorder. RESULTS: We here present the largest cohort of independent, genetically confirmed HFS cases reported to date: in 19 unrelated index patients, we identified ten distinct homozygous ANTXR2 mutations, three of which are novel frame-shift variants. The associated clinical data are consistent with the previous hypothesis of non-truncating variants in the terminal exons 13-17 to confer rather mild phenotypes. The novel observation of gender-dependent disease manifestation in our cohort received support from a meta-analysis of all previously published cases. Untargeted blood-based metabolomics revealed patient samples to be biochemically distinct from control samples. Numerous potential HFS biomarker metabolites could thus be identified. We also found metabolomics profiles of HFS patients to highly overlap with those from FD patients. CONCLUSIONS: Our study extends the mutational spectrum for HFS, suggests gender-dependency of manifestation, and provides pilot metabolomics data for biomarker identification and a better pathomechanistic understanding of the disorder.

Detection of Crimean-Congo Haemorrhagic Fever cases in a severe undifferentiated febrile illness outbreak in the Federal Republic of Sudan: A retrospective epidemiological and diagnostic cohort study.

BACKGROUND: Undifferentiated febrile illness (UFI) is one of the most common reasons for people seeking healthcare in low-income countries. While illness and death due to specific infections such as malaria are often well-quantified, others are frequently uncounted and their impact underappreciated. A number of high consequence infectious diseases, including Ebola virus, are endemic or epidemic in the Federal Republic of Sudan which has experienced at least 12 UFI outbreaks, frequently associated with haemorrhage and high case fatality rates (CFR), since 2012. One of these occurred in Darfur in 2015/2016 with 594 cases and 108 deaths (CFR 18.2%). The aetiology of these outbreaks remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We report a retrospective cohort study of the 2015/2016 Darfur outbreak, using a subset of 65 of 263 outbreak samples received by the National Public Health Laboratory which met selection criteria of sufficient sample volume and epidemiological data. Clinical features included fever (95.8%), bleeding (95.7%), headache (51.6%) and arthralgia (42.2%). No epidemiological patterns indicative of person-to-person transmission or health-worker cases were reported. Samples were tested at the Public Health England Rare and Imported Pathogens Laboratory using a bespoke panel of likely pathogens including haemorrhagic fever viruses, arboviruses and Rickettsia, Leptospira and Borrelia spp. Seven (11%) were positive for Crimean-Congo haemorrhagic fever virus (CCHFV) by real-time reverse transcription PCR. The remaining samples tested negative on all assays. CONCLUSIONS/SIGNIFICANCE: CCHFV is an important cause of fever and haemorrhage in Darfur, but not the sole major source of UFI outbreaks in Sudan. Prospective studies are needed to explore other aetiologies, including novel pathogens. The presence of CCHFV has critical infection, prevention and control as well as clinical implications for future response. Our study reinforces the need to boost surveillance, lab and investigative capacity to underpin effective response, and for local and international health security.

Biallelic variants in KIF14 cause intellectual disability with microcephaly.

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients.

AIM: Molybdenum cofactor deficiency (MoCD) and Sulfite oxidase deficiency (SOD) are rare autosomal recessive conditions of sulfur-containing amino acid metabolism with overlapping clinical features and emerging therapies. The clinical phenotype is indistinguishable and they can only be differentiated biochemically. MOCS1, MOCS2, MOCS3, and GPRN genes contribute to the synthesis of molybdenum cofactor, and SUOX gene encodes sulfite oxidase. The aim of this study was to elucidate the clinical, radiological, biochemical and molecular findings in patients with SOD and MoCD. METHODS: Detailed clinical and radiological assessment of 9 cases referred for neonatal encephalopathy with hypotonia, microcephaly, and epilepsy led to a consideration of disorders of sulfur-containing amino acid metabolism. The diagnosis of six with MoCD and three with SOD was confirmed by biochemical tests, targeted sequencing, and whole exome sequencing where suspicion of disease was lower. RESULTS: Novel SUOX mutations were detected in 3 SOD cases and a novel MOCS2 mutation in 1 MoCD case. Most patients presented in the first 3 months of life with intractable tonic-clonic seizures, axial hypotonia, limb hypertonia, exaggerated startle response, feeding difficulties, and progressive cystic encephalomalacia on brain imaging. A single patient with MoCD had hypertrophic cardiomyopathy, hitherto unreported with these diseases. INTERPRETATION: Our results emphasize that intractable neonatal seizures, spasticity, and feeding difficulties can be important early signs for these disorders. Progressive microcephaly, intellectual disability and specific brain imaging findings in the first year were additional diagnostic aids. These clinical cues can be used to minimize delays in diagnosis, especially since promising treatments are emerging for MoCD type A.

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.