A novel variant of RBCK1 gene causes mild polyglucosan myopathy.

Homozygous or compound heterozygous pathogenic variants of the RBCK1 gene can result in a systemic disorder characterized by the accumulation of complex carbohydrate molecules, namely polyglucosan bodies in the muscular tissues. The role of this gene in the pathophysiology of the disorder at the molecular level remains unclear. Being a very rare disorder, the medical knowledge is based on just a few reported cases. Here we report a 7-year-old girl who presented with exercise intolerance and hepatosplenomegaly. Her liver profile was constantly raised. The genetic investigation has revealed a variant of the RBCK1 gene of unknown significance, which has later been confirmed as pathogenic via a variety of clinical, genetic, and histopathological approaches. More importantly, it is evident that the availability of sophisticated genetic testing, such as whole-exome sequencing, has significantly improved the knowledge of and diagnosis of many rare metabolic disorders.

Oxandrolone for growth hormone-treated girls aged up to 18 years with Turner syndrome.

BACKGROUND: The final adult height of untreated girls aged up to 18 years with Turner syndrome (TS) is approximately 20 cm shorter compared with healthy females. Treatment with growth hormone (GH) increases the adult height of people with TS. The effects of adding the androgen, oxandrolone, in addition to GH are unclear. Therefore, we conducted this systematic review to investigate the benefits and harms of oxandrolone as an adjuvant therapy for people with TS treated with GH. OBJECTIVES: To assess the effects of oxandrolone on growth hormone-treated girls aged up to 18 years with Turner syndrome. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was October 2018. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) that enrolled girls aged up to 18 years with TS who were treated with GH and oxandrolone compared with GH only treatment. DATA COLLECTION AND ANALYSIS: Three review authors independently screened titles and abstracts for relevance, selected trials, extracted data and assessed risk of bias. We resolved disagreements by consensus, or by consultation with a fourth review author. We assessed trials for overall certainty of the evidence using the GRADE instrument. MAIN RESULTS: We included six trials with 498 participants with TS, 267 participants were randomised to oxandrolone plus GH treatment and 231 participants were randomised to GH only treatment. The individual trial sample size ranged between 22 and 133 participants. The included trials were conducted in 65 different paediatric endocrinology healthcare facilities including clinics, centres, hospitals and academia in the USA and Europe. The duration of interventions ranged between 3 and 7.6 years. The mean age of participants at start of therapy ranged from 9 to 12 years. Overall, we judged only one trial at low risk of bias in all domains and another trial at high risk of bias in most domains. We downgraded the level of evidence mainly because of imprecision (low number of trials, low number of participants or both). Comparing oxandrolone plus GH with GH only for final adult height showed a mean difference (MD) of 2.7 cm in favour of oxandrolone plus GH treatment (95% confidence interval (CI) 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; moderate-quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm. For adverse events, we based our main analysis on reliable date from two trials with overall low risk of bias. There was no evidence of a difference between oxandrolone plus GH and GH for adverse events (RR 1.81, 95% CI 0.83 to 3.96; P = 0.14; 2 trials, 170 participants; low-quality evidence). Six out of 86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events, mainly signs of virilisation (e.g. deepening of the voice). One trial each investigated the effects of treatments on speech (voice frequency; 88 participants), cognition (51 participants) and psychological status (106 participants). The overall results for these comparisons were inconclusive (very low-quality evidence). No trial reported on health-related quality of life or all-cause mortality. AUTHORS' CONCLUSIONS: Addition of oxandrolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS. Adverse effects identified included virilising effects such as deepening of the voice, but reporting was inadequate in some trials.

Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

A novel variant in ATM gene causes ataxia telangiectasia revealed by whole-exome sequencing.

Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder caused by variants in ATM gene and characterized by progressive neurologic impairment, cerebellar ataxia, and oculo-cutaneous telangiectasia. Immunodeficiency with a recurrent sinopulmonary infections are observed in patients with A-T. Here, we report a novel stop codon variant, c.5944 C>T (p.Gln1982*), revealed by whole-exome sequencing in a 9-year old boy. He presented with recurrent upper respiratory tract infections, failure to thrive, developmental delay, ataxic gait, and bulbar telangiectasia.

Prevalence of Thinness, Stunting and Anemia Among Rural School-aged Sudanese Children: A Cross-sectional Study.

BACKGROUND: Nutritional status of school-aged children has an important impact on their physical and mental development. Data on anemia, thinness and wasting among school-aged Sudanese children were limited. AIM: To determine the prevalence of anemia, thinness and wasting among school-aged Sudanese children. SUBJECTS AND METHODS: This cross-sectional study enrolled 835 primary school children aged 6-14 years, who live in Dolgo area in the northern region of Sudan. Weight and height of each child were measured and body mass index (BMI) was calculated. All measurements were plotted on the World Health Organization (WHO) height for age and BMI charts. Hemoglobin was also measured for all participants, and anemia was defined according to the WHO standards. RESULTS: Anthropometric measurements showed that 59 children (7.1%) were stunted and 193 were thin (23.1%). The prevalence of anemia was 29.7%. Stunting, thinness and anemia were significantly common in children <10 years of age (p < 0.0001). CONCLUSIONS: We found a high prevalence of stunting, thinness and anemia among school-aged children in a rural area in Sudan. Our findings warrant the need to implement interventions to improve nutritional status of children in Sudan.

Prenatal Diagnosis of c.437-1G>A Mutation in the MAN2B1 Gene in a Family With Alpha-Mannosidosis: Unraveling Clinical Presentation and Treatment Outcomes in a Novel Prenatal Case.

Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement therapy (ERT) should be initiated early to achieve optimal outcomes. This report describes how alpha-mannosidosis diagnosis in a seven-year-old girl led to a successful prenatal diagnosis in the subsequent pregnancy and pre-symptomatic treatment at the early disease stage. The index patient was a seven-year-old girl who was referred with a confirmed diagnosis of alpha-mannosidosis based on the presence of homozygous c.437-1G>A mutation in the MAN2B1 gene. A prenatal diagnosis was made in the subsequent pregnancy through molecular analysis, which revealed the same homozygous variant. The patient was treated at the fifth week of age and showed mild skeletal involvement and normal development at ERT initiation. At 11 months of age, the ERT level increased to 15.8 µmol/l/h. The motor assessment showed that the patient was developmentally normal and was able to maintain her sitting and walking for a few steps only. Prenatal molecular screening in affected families can allow for the early identification and implementation of appropriate management strategies for alpha-mannosidosis.

Cystic Lung Changes, Bronchiectasis, and a Heterozygous-Primary Ciliary Dyskinesia-Associated Variant in the DNAH5 Gene: A Diagnostic Challenge.

BACKGROUND Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease that can present at different ages with different phenotypes. Missed and delayed diagnoses are fairly common. Many variants in the DNAH5 gene have been described that confirm the diagnosis of PCD. Advances in medicine, especially in molecular genetics, have led to increasingly early discoveries of such cases, especially in those with nonclassical presentations. CASE REPORT This report describes a patient with bronchiectasis, lung cysts, finger clubbing, and failure to thrive who was misdiagnosed for several years as having asthma. Many differentials were suspected and worked up, including a suspicion of PCD. Genetic tests with whole-exome sequencing (WES) and whole-genome sequencing (WGS) detected a heterozygous, likely pathogenic, variant in the DNAH5 gene associated with PCD. CONCLUSIONS Despite a thorough workup done for this case, including a genetic workup, a PCD diagnosis was not established. We plan to reanalyze the WGS in the future, and with advent of technology and better coverage of genes, a genetic answer for this challenging case may resolve this diagnostic quandary in the future.

Association of angiotensin converting enzyme gene insertion/deletion polymorphism and familial hypercholesterolemia in the Saudi population.

BACKGROUND: The study of the association between genotype and phenotype is of great importance for the prediction of multiple diseases and pathophysiological conditions. The relationship between angiotensin converting enzyme (ACE) Insertion/Deletion (I/D) polymorphism and Familial Hypercholesterolemia (FH) has been not fully investigated in all the ethnicities. In this study we sought to determine the frequency of I/D polymorphism genotypes of ACE gene in Saudi patients with FH. RESULTS: This is a case-control study carried out purely in Saudi population. Genomic DNA was isolated from 128 subjects who have participated in this study. ACE gene I/D polymorphism was analyzed by polymerase chain reaction in 64 FH cases and 64 healthy controls. There was no statistically significant difference between the groups with respect to genotype distribution. Furthermore, we did not find any significant difference in the frequency of ACE I/D polymorphism in FH subjects when stratified by gender (p = 0.43). CONCLUSION: Our data suggest that ACE gene I/D polymorphism examined in this study has no role in predicting the occurrence and diagnosis of FH.

A Niemann-Pick Disease Type C2 with Severe Pulmonary Involvement and Limited Therapeutic Options: A Case Report.

Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder. There are two types, NPC1, which is the predominant form (95%), and the rare NPC2, which represents less than 5% of the reported cases. Niemann-Pick disease type C2 usually presents with respiratory symptoms, cholestasis, neurological impairment, and hepatosplenomegaly. Case report: Here, we report a 3-year-old boy who presented to our hospital with exacerbation of chronic lung disease requiring invasive ventilatory support. He was previously diagnosed with interstitial lung disease. His parents used to instill olive oil in his nose (a few drops in each nostril daily for several months) to treat frequent nasal bleeding. A detailed history revealed prolonged neonatal jaundice for four months, with hepatosplenomegaly. In his second year, generalized hypotonia and delayed psychomotor development were observed. Upon presentation to our institute, chest CT showed evidence of intraparenchymal fat; therefore, lipoid pneumonia and lipid storage disease were suspected. The bronchoalveolar lavage results suggested pulmonary alveolar proteinosis (PAP). Whole-exome sequencing (WES) revealed a class one homozygous pathogenic variant in the NPC2 gene. Our patient faced a range of difficulties, including prolonged mechanical ventilation and diagnostic and therapeutic challenges. Conclusion: Niemann-Pick disease type C2 is a progressive and lethal condition that requires a high index of suspicion to pinpoint the diagnosis. Gene study remains the method of choice to confirm the diagnosis. There are limited choices of therapeutic interventions; therefore, genetic counseling and the prevention of recurrence should be the ultimate goal for affected families.

A Biallelic Variant in FRA10AC1 Is Associated With Neurodevelopmental Disorder and Growth Retardation.

Objectives: Our objective was to identify the genetic cause in a family with a remarkable history of neurodevelopmental disease and growth retardation. Methods: A neurologic evaluation was performed, and DNA samples were obtained from the affected siblings and parents to perform whole-exome sequencing (WES). Results: Both siblings presented with dysmorphic features, failure to thrive, global developmental delay, generalized hypotonia, feeding problems, and congenital heart disease. WES revealed a homozygous nonsense variant in the FRA10AC1 gene in both siblings. Discussion: A recent study has reported the first association of biallelic variants in the spliceosomal C complex gene, FRA10AC1, with syndromic neurodevelopmental disease and growth retardation in 5 patients from 3 consanguineous families complex. In this study, we provide the first confirmation of the reported FRA10AC1-related neurologic syndrome in an additional family.

Further clinical and genetic evidence of ASC-1 complex dysfunction in congenital neuromuscular disease.

Transcriptional coregulators modulate the efficiency of transcription factors. Bi-allelic variants in TRIP4 and ASCC1, two genes that encode members of the tetrameric coregulator ASC-1, have recently been associated with congenital bone fractures, hypotonia, and muscular dystrophy in a total of 22 unrelated families. Upon exome sequencing and data repository mining, we identified six new patients with pathogenic homozygous variants in either TRIP4 (n = 4, two novel variants) or ASCC1 (n = 2, one novel variant). The associated clinical findings confirm and extend previous descriptions. Considering all patients reported to date, we provide supporting evidence suggesting that ASCC1-related disease has a more severe phenotype compared to TRIP4-related disorder regarding higher incidence of perinatal bone fractures and shorter survival.

The first Saudi baby with classic homocystinuria diagnosed by universal newborn screening.

Classic homocystinuria (CH) is an inborn error of metabolism caused by cystathionine beta-synthase enzyme deficiency. Affected patients present with intellectual disability and other comorbidities. If diagnosed early in infancy and started treatment, inevitable complications can be prevented. Newborn screening (NBS) uses tandem mass-spectroscopy (MSMS) to measure the amino acid levels. In CH, the first-tier screening test is the measurement of methionine by MSMS. If methionine remained elevated in the recall sample, plasma level for homocysteine is performed. A newborn infant underwent routine NBS in our institute that showed elevated methionine in the first and the recall sample. Thereafter, total serum homocysteine was found to be elevated, consistent with the diagnosis of CH. An early medical and dietary management was commenced for this first Saudi baby diagnosed with homocystinuria by universal NBS. This report demonstrates that NBS for CH is feasible and effective in preventing the disease burden.

A t(5;16)(p15.32;q23.3) generating 16q23.3 --> qter duplication and 5p15.32 --> pter deletion in two siblings with mental retardation, dysmorphic features, and speech delay.

We report on two siblings (half brothers on the paternal side) with a syndrome consisting of delayed development, cardiac anomalies, chest deformity, hip rotation, metatarsus adductus, genital hypoplasia, dysmorphic face, depressed nasal bridge, mental retardation, and speech delay. All metaphases examined showed a normal karyotype in the patients, their father, and both mothers. High-resolution array CGH examination revealed a 16q (6 Mb) duplication dup(16)(16q23.3 --> 16qter) and a 5p (0.97 Mb) terminal deletion del(5)(p15.32 --> pter) in both affected boys but not their healthy siblings or parents. Interphase fluorescence in situ hybridization (FISH) confirmed both the 16q duplicated region and the 5p terminal deletion. Clinical abnormalities in the patients included thin upper lip, clinodactyly, and foot deformity, which were reported previously with duplications in 16q23.3. Pectus excavatum, hip rotation, metatarsus adductus, umbilical hernia, brachycephaly, and esotropia were not reported previously in chromosome 16q duplications but may be features that occur intermittently. The 5p deleted region has been associated previously only with speech delay, which was present in both patients. These patients display certain phenotypic characteristics not reported previously in 16q duplication and confirm 5p terminal deletion as an important chromosome anomaly for speech delay.

A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder.

Peroxisomal biogenesis disorders (PBD) are groups of inherited neurometabolic disorders caused by defects in PEX genes. We report on a female infant, born to a consanguineous parents (first degree cousins), who presented with inactivity, poor sucking, and hypotonia early in the neonatal period. She had subtle dysmorphic features. Liver function tests were impaired with raised liver enzymes, conjugated and unconjugated hyperbilirubinemia. CT of the brain showed diffuse bilateral changes. She developed seizures with an abnormal EEG. Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD. Studies in fibroblasts including plasmalogen biosynthesis, peroxisomal fatty acid alfa and beta oxidation confirmed the diagnosis of PBD. Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts. The patient was assigned to the PEX19 complementation group. Subsequent mutation analysis of the PEX19 gene revealed homozygosity for a c.320delA frameshift mutation. The patient had a stormy course with multiple admissions to the pediatric intensive care unit with pneumonia, liver impairment, sepsis, and epilepsy. At 1 year of age she developed metabolic acidosis with normal anion gap, proteinuria, aminoaciduria, and glucosuria consistent with a renal tubular defect. Abdominal ultrasound showed multiple gallstones. Other causes of gallstones like haemoglobinopathy were excluded. So far, only two siblings had been reported with mutations in the PEX19 gene. Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD.

Comment on: Prediction of retinopathy of prematurity using the screening algorithm WINROP in a Saudi cohort of preterm infants.

[No Abstract Available].

Comment on: Sensitivity and specificity of cerebrospinal fluid glucose measurement by an amperometric glucometer.

[No Abstract Available].

Molecular and clinical characteristics of very-long-chain acyl-CoA dehydrogenase deficiency: A single-center experience in Saudi Arabia.

OBJECTIVES: To describe the clinical and molecular characteristics of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.   Methods: A retrospective observational cross-sectional analysis was conducted on all patients with VLCAD deficiency at  (Genetic/Metabolic Section), Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia from 2000 to 2019. Demographic, clinical, and laboratory data were abstracted from the electronic hospital records using a case report form. Results: A total of 14 children were analyzed. Six presented with hypoglycemia, 4 with cardiomyopathy, and 10 had rhabdomyolysis. Five patients had early onset severe phenotype, while 9 had mild form. The molecular study revealed homozygous mutations in ACADVL in all 14 patients. Three variants were not reported before. All patients were treated with medium-chain triglyceride and carnitine. Ten patients are alive and have normal development, while 4 died. Conclusion: Most of the patients in this cohort presented in the neonatal period either by newborn screening or clinically with hypoglycemia, cardiomyopathy, and rhabdomyolysis. The new molecular variants detected in this study broaden the genetic spectrum of VLCAD deficiency in Saudi Arabia.