SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

Biallelic NUDT2 variants defective in mRNA decapping cause a neurodevelopmental disease.

Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.

Long-term effectiveness of carglumic acid in patients with propionic acidemia (PA) and methylmalonic acidemia (MMA): a randomized clinical trial.

BACKGROUND: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare, autosomal recessive inborn errors of metabolism that require life-long medical treatment. The trial aimed to evaluate the effectiveness of the administration of carglumic acid with the standard treatment compared to the standard treatment alone in the management of these organic acidemias. METHODS: The study was a prospective, multicenter, randomized, parallel-group, open-label, controlled clinical trial. Patients aged ≤ 15 years with confirmed PA and MMA were included in the study. Patients were followed up for two years. The primary outcome was the number of emergency room (ER) admissions because of hyperammonemia. Secondary outcomes included plasma ammonia levels over time, time to the first episode of hyperammonemia, biomarkers, and differences in the duration of hospital stay. RESULTS: Thirty-eight patients were included in the study. On the primary efficacy endpoint, a mean of 6.31 ER admissions was observed for the carglumic acid arm, compared with 12.76 for standard treatment, with a significant difference between the groups (p = 0.0095). Of the secondary outcomes, the only significant differences were in glycine and free carnitine levels. CONCLUSION: Using carglumic acid in addition to standard treatment over the long term significantly reduces the number of ER admissions because of hyperammonemia in patients with PA and MMA.

Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish.

Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.

A homozygous nonsense mutation in DCBLD2 is a candidate cause of developmental delay, dysmorphic features and restrictive cardiomyopathy.

DCBLD2 encodes discodin, CUB and LCCL domain-containing protein 2, a type-I transmembrane receptor that is involved in intracellular receptor signalling pathways and the regulation of cell growth. In this report, we describe a 5-year-old female who presented severe clinical features, including restrictive cardiomyopathy, developmental delay, spasticity and dysmorphic features. Trio-whole-exome sequencing and segregation analysis were performed to identify the genetic cause of the disease within the family. A novel homozygous nonsense variant in the DCBLD2 gene (c.80G > A, p.W27*) was identified as the most likely cause of the patient's phenotype. This nonsense variant falls in the extracellular N-terminus of DCBLD2 and thus might affect proper protein function of the transmembrane receptor. A number of in vitro investigations were performed on the proband's skin fibroblasts compared to normal fibroblasts, which allowed a comprehensive assessment resulting in the functional characterization of the identified DCBLD2 nonsense variant in different cellular processes. Our data propose a significant association between the identified variant and the observed reduction in cell proliferation, cell cycle progression, intracellular ROS, and Ca2 + levels, which would likely explain the phenotypic presentation of the patient as associated with lethal restrictive cardiomyopathy.

Inherited Metabolic Causes of Stroke in Children: Mechanisms, Types, and Management.

A stroke should be considered in cases of neurologic decompensation associated with inherited metabolic disorders. A resultant stroke could be a classical ischemic stroke (vascular stroke) or more commonly a "metabolic stroke." A metabolic stroke begins with metabolic dysfunctions, usually caused by a stressor, and leads to the rapid onset of prolonged central neurological deficits in the absence of vessel occlusion or rupture. The cardinal features of a metabolic stroke are stroke-like episodes without the confirmation of ischemia in the typical vascular territories, such as that seen in classic thrombotic or embolic strokes. Identifying the underlying cause of a metabolic stroke is essential for prompt and appropriate treatment. This study reviews the major inherited metabolic disorders that predispose patients to pediatric stroke, with an emphasis on the underlying mechanisms, types, and management.

Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy.

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.

Diversity of Phenotype and Genetic Etiology of 23 Cystinuria Saudi Patients: A Retrospective Study.

Background: Cystinuria is an inborn error of metabolism that manifests with renal stones due to defective renal epithelial cell transport of cystine which resulted from pathogenic variants in the SLC3A1 and/or SLC7A9 genes. Among nephrolithiasis diseases, cystinuria is potentially treatable, and further stone formation may be preventable. We report 23 patients who were identified biochemically and genetically to have cystinuria showing the diversity of the phenotype of cystinuria and expanding the genotype by identifying a broad spectrum of mutations. Patients and Methods: This is a multicenter retrospective chart review, where clinical and biochemical data, genetic analysis and the progress of the disease were documented over five years at two centers from 2014 to 2019. Results: Of 23 patients who were identified biochemically and/or genetically to have cystinuria, 14 (62%) were male. Thirteen patients were homozygous, and two were heterozygous for the SLC3A1 gene. Seven were homozygous and one was compound heterozygous for the SLC7A9 gene. We have detected 12 genetic variants including five novel variants. SLC3A1 gene variant c.1400 T > A (p.Met467Lys) is found in 38% of our cohort. Although 21 patients required surgical intervention, none developed ESRD. The number of stone episodes per year varied widely (median frequency of 0.45 stones/ per year, range between 0.06 and 78.2), with no significant difference in stone events per year between sexes (P = 0.73). Conclusion: Despite the high rate of consanguinity in Saudi Arabia, there was a broad spectrum of genetic variants. Most of our patients are homozygous recessive for SLC genes with multiple generations affected which indicates early screening and prevention of disease in these families. Phenotypic heterogeneity is well documented in our cohort even with the same genotype and the first stone episode age was variable but most commonly seen in the first decade of life.

A Trial of Favipiravir and Hydroxychloroquine combination in Adults Hospitalized with moderate and severe Covid-19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety. Thus, we want to prove the clinical effectiveness of the combination as therapy. TRIAL DESIGN: This is an Open label, multicenter, randomized controlled clinical trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. PARTICIPANTS: All study procedures will be conducted in eight centres in Saudia Arabia: King Abdulaziz Medical City National Guard Health Affairs in Riyadh. King Abdulaziz Hospital - Al Ahsa, Saudi Arabia AlMadina General Hospital, Madnia, Saudi Arabia Al-Qatif Central Hospital, Saudi Arabia Imam Abdulrahman Al Faisal Hospital, Dammam, Saudi Arabia King Abdulaziz Medical City, Jeddah, Saudi Arabia King Abdulaziz Hospital, Makkah, Saudi Arabia Imam Abdulrahman Alfaisal Hospital, Riyadh, Saudi Arabia Inclusion Criteria • Should be at least 18 years of age, • Male or nonpregnant female, • Diagnosed with COVID-19 by PCR confirmed SARS-coV-2 viral infection. • Able to sign the consent form and agree to clinical samples collection (or their legal surrogates if subjects are or become unable to make informed decisions).. • Moderate or Severe COVID-19, defined as oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or significant clinical symptoms that require hospital admission. • patients had to be enrolled within 10 days of disease onset. Exclusion Criteria • Patients who are pregnant or breastfeeding. • Will be transferred to a non-study site hospital or discharged from hospital within 72 hours. • Known sensitivity/allergy to hydroxychloroquine or Favipiravir • Current use of hydroxychloroquine for another indication • Prior diagnosis of retinopathy • Prior diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency • Major comorbidities increasing the risk of study drug including: i. Hematologic malignancy, ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy, iii. Known history of ventricular arrhythmias, iv. Current use of drugs that prolong the QT interval, Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), HIV. • The investigator believes that participating in the trial is not in the best interests of the patient, or the investigator considers unsuitable for enrollment (such as unpredictable risks or subject compliance issues). • Clinical prognostic non-survival, palliative care, or in deep coma and no have response to supportive treatment within three hours of admission • Patient with irregular rhythm • Patient with a history of heart attack (myocardial infarction) • Patient with a family history of sudden death from heart attack before the age of 50 • Take other drugs that can cause prolonged QT interval • Patient who is receiving immunosuppressive therapy (cyclosporin) which cannot be switched to another agent or adjusted while using the investigational drug • Gout/history of Gout or hyperuricemia (above the ULN), hereditary xanthinuria or xanthine calculi of the urinary tract. INTERVENTION AND COMPARATOR: The treatment intervention would be for a maximum of 10 days from randomization and it would be as follows: Favipiravir for 10 days: Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days) Hydroxychloroquine for 5 days: (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily. Reference Comparator Therapy: Standard of care is defined as: Treatment that is accepted by medical experts as a proper treatment for Covid-19 disease. Standard care comprised of, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, extracorporeal membrane oxygenation (ECMO), and antiviral therapy except Favipiravir. Also, it may include intravenous fluids and medications for symptoms relief . MAIN OUTCOMES: The primary endpoint is the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first (14 days from Randomization). RANDOMISATION: Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. The patients will be randomized utilizing Web based data entry System with a stratification based on the centre and the ICU admission. BLINDING (MASKING): This is an Open label study and only the analyst will be blinded during the study conduct. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Under the classical two arm parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). TRIAL STATUS: Protocol version 3.1 (dated 11 Aug 2020), and currently recruitment is ongoing. The date recruitment started was May 21, 2020 and the investigators anticipate the trial will finish recruiting by the end of December 2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04392973 , 19 May 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Clinical presentation of seven patients with Methylenetetrahydrofolate reductase deficiency.

Methylenetetrahydrofolate reductase deficiency; MTHFR (MIM 236250) is widely studied with more than 200 reported cases up to our knowledge from pediatrics to adult patients. Clinical presentation of MTHFR deficiency has a wide spectrum and its severity correlates with the degree of the enzyme activity. We report here seven pediatric cases with variable presentations including apnea at early infancy, in addition to hydrocephalus that needed drainage.

Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay.

BACKGROUND: RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1), also known as SmgGDS, is a guanine nucleotide exchange factor (GEF) that regulates small GTPases, including, RHOA, RAC1, and KRAS. RAP1GDS1 was shown to be highly expressed in different tissue types including the brain. However, mutations in the RAP1GDS1 gene associated with human diseases have not previously been reported. METHODS: We report on four affected individuals, presenting intellectual disability, global developmental delay (GDD), and hypotonia. The probands' DNA was subjected to whole-genome sequencing, revealing a homozygous splice acceptor site mutation in the RAP1GDS1 gene (1444-1G > A). Sanger sequencing was performed to confirm the segregation of the variant in two Saudi families. The possible aberrant splicing in the patients' RNA was investigated using RT-PCR and changes in mRNA expression of the patients were confirmed using qRT-PCR. RESULTS: The identified splice variant was found to segregate within the two families. RT-PCR showed that the mutation affected RAP1GDS1 gene splicing, resulting in the production of aberrant transcripts in the affected individuals. Quantitative gene expression analysis demonstrated that the RAP1GDS1 mRNA expression in all the probands was significantly decreased compared to that of the control, and Sanger sequencing of the probands' cDNA revealed skipping of exon 13, further strengthening the pathogenicity of this variant. CONCLUSION: We are the first to report the mutation of the RAP1GDS1 gene as a potential cause of GDD and hypotonia. However, further investigations into the molecular mechanisms involved are required to confirm the role of RAP1GDS1 gene in causing GDD and hypotonia.

A Missense Mutation in the UGDH Gene Is Associated With Developmental Delay and Axial Hypotonia.

UDP-glucose dehydrogenase (UGDH) encodes an oxidoreductase that converts two successive oxidations of UDP-glucose to produce UDP-glucuronic acid, a key component in the synthesis of several polysaccharides such as glycosaminoglycan and the disaccharide hyaluronic acid. UGDH is critical to the production of extracellular matrix components which are essential to the migration and connectivity of neurons early in human brain development. In this report, we describe one child of a consanguineous family who presented with distinct clinical features including global developmental delay, axial hypotonia, bilateral undescended testis, and subtle dysmorphic features. Whole genome sequencing and a segregation was performed to identify the genetic cause of the disease within the family. Though mutations in the UGDH protein have been described as causing developmental delay in various model organisms, to our knowledge, this is the first identification of the novel homozygous missense variant in exon8 of UGDH NM_003359.3: c.950 G>A (p.Arg317Gln) and most likely the cause of the patient's phenotype. This variant falls in an active region and replaces the highly conserved Arginine 317 residues across mammals.

Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder mostly presented in children. The disorder is described as having subacute encephalopathy with confusion, dystonia, and dysarthria triggered by febrile illness that leads to neuroregression and death if untreated. Using biotin and thiamine at an early stage of the disease can lead to significant improvement. METHODS: BTBGD is a treatable disease if diagnosed at an early age and has been frequently reported in Saudi population. Keeping this in mind, the current study screened 3000 Saudi newborns for the SLC19A3 gene mutations using target sequencing, aiming to determine the carrier frequency in Saudi Population and whether BTBGD is a good candidate to be included in the newborn-screened disorders. RESULTS: Using targeted gene sequencing, DNA from 3000 newborns Saudi was screened for the SLC19A3 gene mutations using standard methods. Screening of the SLC19A3 gene revealed a previously reported heterozygous missense mutation (c.1264A>G (p.Thr422Ala) in six unrelated newborns. No probands having homozygous pathogenic mutations were found in the studied cohort. The variant has been frequently reported previously in homozygous state in Saudi population, making it a hot spot mutation. The current study showed that the carrier frequency of SLC19A3 gene mutation is 1 of 500 in Saudi newborns. CONCLUSION: For the first time in the literature, we determined the carrier frequency of SLC19A3 gene mutation in Saudi population. The estimated prevalence is too rare in Saudi population (at least one in million); therefore, the data are not in favor of including such very rare disorders in newborn screening program at population level. However, a larger cohort is needed for a more accurate estimate.

Delta Like-1 Gene Mutation: A Novel Cause of Congenital Vertebral Malformation.

Skeletal development throughout the embryonic and postnatal phases is a dynamic process, based on bone remodeling and the balance between the activities of osteoclasts and osteoblasts modulating skeletal homeostasis. The Notch signaling pathway is a regulator of several developmental processes, and plays a crucial role in the development of the human skeleton by regulating the proliferation and differentiation of skeletal cells. The Delta Like-1 (DLL1) gene plays an important role in Notch signaling. We propose that an identified alteration in DLL1 protein may affect the downstream signaling. In this article, we present for the first time two siblings with a mutation in the DLL1 gene, presenting with congenital vertebral malformation. Using variable in silico prediction tools, it was predicted that the variant was responsible for the development of disease. Quantitative reverse-transcription polymerase chain reaction (PCR) for the Notch signaling pathway, using samples obtained from patients, showed a significant alteration in the expression of various related genes. Specifically, the expression of neurogenic locus notch homolog protein 1, SNW domain-containing protein 1, disintegrin, and metalloproteinase domain-containing proteins 10 and 17, was upregulated. In contrast, the expression of HEY1, HEY2, adenosine deaminase (ADA), and mastermind-like-1 (MAML-1) was downregulated. Furthermore, in a phosphokinase array, four kinases were significantly changed in patients, namely, p27, JANK1/2/3, mitogen- and stress-activated protein kinases 1 and 2, and focal adhesion kinase. Our results suggest an implication of a DLL1 defect related to the Notch signaling pathway, at least in part, in the morphologic abnormality observed in these patients. A limitation of our study was the low number of patients and samples. Further studies in this area are warranted to decipher the link between a DLL1 defect and skeletal abnormality.

Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

INTRODUCTION: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA. METHODS: This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (≤15 years of age) will be randomized 1:1 to receive twice daily carglumic acid (50 mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1 month follow-up period after the study. DISCUSSION: Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA. TRIAL REGISTRATION: King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015.

Report of a Case that Expands the Phenotype of Infantile Krabbe Disease.

BACKGROUND Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disease caused by the deficiency of lysosomal galactocerebrosidase. The most common form is infantile Krabbe disease, which is usually diagnosed within the first year of life and has high morbidity and mortality. Patients usually present with irritability, progressive neurodegeneration, spasticity, and peripheral neuropathy. This report is of a 6-year-old girl who had Krabbe disease since she was 5 weeks of age. CASE REPORT A 6-year-old female Saudi patient had initially presented at 5 weeks of age with hypoventilation, recurrent attacks of fever, and failure to thrive. The patient also skin hypopigmentation involving the face, neck, upper extremities, and lower extremities. Peripheral blood galactocerebrosidase enzyme activity was normal but was reduced in tissue fibroblasts. Whole exome sequencing (WES) and whole genome sequencing (WGS) showed a homozygous mutation in the GALC gene c.334A>G (p.Thr112Ala), which was previously reported in a compound heterozygous state with another mutation. CONCLUSIONS This case report describes a patient with homozygous mutation status Krabbe disease. Although this patient had the phenotype of early infantile-onset Krabbe disease, which usually has high morbidity and mortality, her condition is now relatively stable at 6 years of age, which could be due to relatively higher enzyme activity. This case also expanded the presentation or typical phenotype of infantile Krabbe disease as the patient also presented with hypoventilation and skin hypopigmentation.

The landscape of early infantile epileptic encephalopathy in a consanguineous population.

PURPOSE: Epileptic encephalopathies (EE), are a group of age-related disorders characterized by intractable seizures and electroencephalogram (EEG) abnormalities that may result in cognitive and motor delay. Early infantile epileptic encephalopathies (EIEE) manifest in the first year of life. EIEE are highly heterogeneous genetically but a genetic etiology is only identified in half of the cases, typically in the form of de novo dominant mutations. METHOD: This is a descriptive retrospective study of a consecutive series of patients diagnosed with EIEE from the participating hospitals. A chart review was performed for all patients. The diagnosis of epileptic encephalopathy was confirmed by molecular investigations in commercial labs. In silico study was done for all novel mutations. A systematic search was done for all the types of EIEE and their correlated genes in the literature using the Online Mendelian Inheritance In Man and PubMed databases. RESULTS: In this case series, we report 72 molecularly characterized EIEE from a highly consanguineous population, and review their clinical course. We identified 50 variants, 26 of which are novel, causing 26 different types of EIEE. Unlike outbred populations, autosomal recessive EIEE accounted for half the cases. The phenotypes ranged from self-limiting and drug-responsive to severe refractory seizures or even death. CONCLUSIONS: We reported the largest EIEE case series in the region with confirmed molecular testing and detailed clinical phenotyping. The number autosomal recessive predominance could be explained by the society's high consanguinity. We reviewed all the EIEE registered causative genes in the literature and proposed a functional classification.

Methionine adenosyltransferase I/III deficiency: beyond the central nervous system manifestations.

Methionine adenosyltransferase (MAT) I/III deficiency (OMIM # 250850) is caused by a mutation in MAT1A, which encodes the two hepatic MAT isozymes I and III. With the implementation of newborn screening program to discover hypermethioninemia due to cystathionine beta-synthase deficiency, more cases are being discovered. While the majority of patients are asymptomatic, some might have central nervous system (CNS) and extra-CNS manifestations. Although neurologic manifestations and demyelination have been correlated to MAT deficiency in many reported cases, none of the previous reports focused on extra-CNS manifestations associated with the disease. This is a retrospective chart review for a 40-month-old patient with confirmed diagnosis of MAT deficiency. He was found to have a novel homozygous disease-causing variant in MAT1A (NM_000429.2) c.1081G>T (p.Val361Phe). Interestingly, our patient had an unexplained zinc and iron deficiency in addition to mild speech delay. We reviewed the literature and summarized all the reported extra-CNS manifestations. In conclusion, MAT deficiency patients should be thoroughly investigated to check for CNS and extra-CNS manifestations associated with the disease. Keeping in consideration the challenge of assuming correlation, a scrutinized look at extra-CNS manifestations and their course with time might pave the way to understanding the pathophysiology of the disease and MAT1A function.

PRUNE Syndrome Is a New Neurodevelopmental Disorder: Report and Review.

PRUNE syndrome, or neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (OMIM#617481), is a new rare autosomal recessive neurodevelopmental disease that is caused by homozygous or compound heterozygous mutation in PRUNE1 on chromosome 1q21. Here, We report on 12-month-old and 30-month-old girls from 2 unrelated Saudi families with typical presentations of PRUNE syndrome. Both patients had severe developmental delay, progressive microcephaly, and dysmorphic features. Brain magnetic resonance imaging showed slight thinning in the corpus callosum, mild frontal brain atrophy, and delayed myelination in one of the patients. Both patients had the same missense mutation in PRUNE1 (c.383G>A, p.Arg128Gln), which was not reported before in a homozygous state. We compared our patients to previously reported cases. In conclusion, We suggest that clinicians consider PRUNE syndrome in any child presenting with dysmorphic features, developmental delay, progressive microcephaly, central hypotonia, peripheral spasticity, delayed myelination, brain atrophy, and a thin corpus callosum.

Clinical, Biochemical, and Molecular Features in 37 Saudi Patients with Very Long Chain Acyl CoA Dehydrogenase Deficiency.

BACKGROUND: Very long chain acyl CoA dehydrogenase (VLCAD) deficiency (OMIM#201475) is an autosomal recessive disorder of fatty acid beta oxidation caused by defect in the ACADVL. The aim of this study was to analyze the clinical, biochemical, and molecular features of VLCAD deficiency in Saudi Arabia, including the treatment and outcome. METHODS: We carried out a retrospective chart review analysis of 37 VLCAD deficiency patients from two tertiary centers in Saudi Arabia, over a 14-year period (2002-2016). Twenty-three patients were managed at King Abdul-Aziz Medical City and fourteen patients at King Fahad Medical City. RESULTS: Severe early onset VLCAD deficiency is the most frequent phenotype in our patients, caused by four different mutations in ACADVL; 31 patients (83.7%) had a homozygous nonsense mutation in exon 2 of ACADVL c.65C>A;p. Ser22X. Twenty-three patients died before the age of 2 years, despite early detection by newborn screening and implementation of treatment, including supplementation with medium chain triglycerides. CONCLUSION: This study reports the clinical, biochemical, molecular findings, treatment, and outcome of patients with VLCAD deficiency over the last 14 years. We identified the most common variant and one new variant in ACADVL. Despite early diagnosis and treatment, the outcome of VLCAD deficiency in this Saudi Arabian population remains poor. Preventive measures, such as prenatal diagnosis, could be implemented.