Publications by authors named "Ronen Spiegel"

86 Publications

Hypocalcemia as the Initial Presentation of Type 2 Bartter Syndrome - A Family Report.

J Clin Endocrinol Metab 2021 Nov 9. Epub 2021 Nov 9.

Pediatric Endocrine Institute, Ha'Emek Medical Center, Afula, Israel.

Context: Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Type 2 BS results from a defect in the renal outer medullary potassium channel encoded by the KCNJ1 gene. Type 2 BS presents with polyhydramnios, intrauterine growth retardation, prematurity, failure to thrive, polyuria, hypercalciuria, and life-threatening episodes of dehydration. Hypocalcemia is a very rare presenting symptom of BS, with only a few published cases reporting it as the initial manifestation of type 2 BS.

Case Description: We describe a child who presented with hypocalcemic seizure at the age of 2.3 years that was first related to vitamin D deficiency and high-phosphate soft drink consumption. However, later whole exome sequencing (WES) identified a previously described homozygous missense mutation c.212C>T, p.T71M in the KCNJ1 gene associated with type 2 BS. Six additional family members with the same mutation and diagnosed clinically with BS are also reported, two presenting with hypocalcemia associated with vitamin D deficiency.

Conclusions: This report expands the clinical spectrum associated with KCNJ1 mutations and emphasizes the role of WES in unsolved cases of hypocalcemia when genetic disease is suspected. It also highlights the hazardous effects of phosphate-containing soft drinks on calcium metabolism.
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http://dx.doi.org/10.1210/clinem/dgab821DOI Listing
November 2021

Generation and characterization of iPSC lines from two nuclear envelopathy patients with a homozygous nonsense mutation in the TOR1AIP1 gene.

Stem Cell Res 2021 10 20;56:102539. Epub 2021 Sep 20.

The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. Electronic address:

LAP1 is an inner nuclear membrane protein encoded by TOR1AIP1. A homozygous c.961C > T loss of function mutation in TOR1AIP1 that affects both isoforms of LAP1 was recently described. This mutation leads to the development of a severe multisystemic nuclear envelopathy syndrome. Here we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines derived from skin fibroblasts of two patients carrying the homozygous c.961C > T mutation. These novel lines can be used as a powerful tool to investigate the molecular mechanism by which LAP1 deficiency leads to the development of this severe hereditary disorder.
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http://dx.doi.org/10.1016/j.scr.2021.102539DOI Listing
October 2021

The effects of the COVID-19 pandemic on patients with lysosomal storage disorders in Israel.

Orphanet J Rare Dis 2021 09 8;16(1):379. Epub 2021 Sep 8.

Metabolic Clinic, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the causative agent of the current COVID-19 pandemic. Lysosomal storage disorders (LSD) comprise of 70 inherited inborn errors of metabolism. Affected individuals suffer from multi-systemic involvement with variable severity and rate of disease progression between different diseases. Some of the LSDs have established treatments, whether parenteral or oral therapies. The full impact of the COVID-19 pandemic together with the lockdown on the wellbeing and medical management of patients with rare diseases, such as LSDs, is widely unknown. Herein, we describe the effects of the COVID-19 pandemic and its associated mandatory home lockdown on patients with LSDs in Israel.

Results: We present a prospective multi-center questionnaire study including 48 LSD patients from four medical centers in Israel. The study objective was to assess the impact of the COVID-19 pandemic restrictions on individuals with LSDs in Israel, as reported by their caregivers. Secondary objectives were to assess the morbidity from SARS CoV-2 in LSD patients and the impact of changes in mood and behavior on compliance to treatment and to assess the relationship between changes in mood to changes in cognition and behavior. Thirty one of 38 patients (82%) who received any kind of regular treatment did not miss treatments. Among patients receiving enzyme replacement therapy (ERT) in the in-hospital setting, 5 patients (20%) experienced treatment disruptions. Four patients had tested positive for SARS-Cov-2 virus infection by PCR. Seven out of the 48 patients (14%) described mood changes with cognitive and motor deterioration during the home quarantine.

Conclusions: We observed high rates of treatment adherence and low morbidity through the COVID-19 pandemic in patients with LSDs in Israel. LSDs patients can be a model for patients with complex chronic diseases requiring routine treatments and surveillance during a pandemic or other disruption of daily routine.
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http://dx.doi.org/10.1186/s13023-021-02007-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424165PMC
September 2021

High Prevalence of Hearing Impairment in Primary Congenital Hypothyroidism.

Eur Thyroid J 2021 Jun 3;10(3):215-221. Epub 2020 Sep 3.

Pediatric Endocrine Institute, Ha'Emek Medical Center, Afula, Israel.

Background: An association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation.

Methods: Audiometry was undertaken prospectively in 66 patients aged 3-21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies.

Results: HI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 μg/dL, = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies.

Conclusions: Our findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.
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http://dx.doi.org/10.1159/000509775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216036PMC
June 2021

Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

J Med Genet 2021 Mar 5. Epub 2021 Mar 5.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.

Methods: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.

Results: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was , which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in and pathogenic variants in accounted for 18% and 9% of cases, respectively. , and were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with and lower motor neuron signs with . When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for .

Conclusion: represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between and -associated disorders.
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http://dx.doi.org/10.1136/jmedgenet-2020-107497DOI Listing
March 2021

Favorable outcomes following early onset oral miglustat in early infantile Niemann Pick Type C.

Mol Genet Metab Rep 2021 Jun 6;27:100739. Epub 2021 Mar 6.

Department of Pediatrics B, Emek Medical Center, Afula, Israel.

Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive neurodegenerative course, which entails significant morbidity and usually results in death within 5 years. Miglustat, an iminosugar that selectively inhibits the glycosylceramide synthase enzyme, is known to stabilize or delay neurological progression in individuals with NPC, but its impact on affected infants is yet to be elucidated. We present two siblings with early infantile NPC due to the previously reported devastating homozygous mutation c.2279_2281delTCT in . Their considerably discrepant neurological disease courses were dependent on the timing of initiation of miglustat treatment. The outcomes support the significant role of early treatment with miglustat in the disease course of early infantile NPC and suggest that therapy should be considered even before the occurrence of neurological involvement. Moreover, this report emphasizes the importance of early diagnosis, in light of the availability of a potential disease-modifying medication.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941164PMC
June 2021

A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment.

Metab Brain Dis 2021 04 20;36(4):581-588. Epub 2021 Jan 20.

Pediatric Department B' Emek Medical Center, 1834111, Afula, Israel.

Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient's derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.
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http://dx.doi.org/10.1007/s11011-021-00671-1DOI Listing
April 2021

The role of orotic acid measurement in routine newborn screening for urea cycle disorders.

J Inherit Metab Dis 2021 05 30;44(3):606-617. Epub 2020 Nov 30.

Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.
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http://dx.doi.org/10.1002/jimd.12331DOI Listing
May 2021

Author Correction: Inhaled nitric oxide therapy in acute bronchiolitis: A multicenter randomized clinical trial.

Sci Rep 2020 Oct 14;10(1):17640. Epub 2020 Oct 14.

Saban Pediatric Medical Center, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560737PMC
October 2020

Myoclonic tremor status as a presenting symptom of adenylosuccinate lyase deficiency.

Eur J Med Genet 2020 Dec 3;63(12):104061. Epub 2020 Sep 3.

Metabolic-Neurogenetic Clinic, Israel; Pediatric Neurology Unit, Israel; Pediatric Movement Disorders Service, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address:

Adenylosuccinate lyase deficiency is a rare autosomal recessive disorder of purine metabolism. The disorder manifests with developmental delay, postnatal microcephaly, hypotonia, involuntary movements, epileptic seizures, ataxia and autistic features. Paroxysmal non-epileptic motor events are not a typical presentation of the disease. We describe an 8-year-old boy who presented with an infantile onset of prolonged episodes of multifocal sustained myoclonic tremor lasting from minutes to days on a background of global developmental delay and gait ataxia. Ictal EEG during these episodes was normal. Ictal surface EMG of the involved upper limb showed a muscular activation pattern consistent with cortical myoclonus. Brain MRI showed mild cerebral atrophy. Whole exome sequencing revealed a novel homozygous variant in the ADSL gene: c.1027G > A; p. Glu343Lys, inherited from each heterozygous parent. There was a marked elevation of urine succinyladenosine, confirming the diagnosis of adenylosuccinate lyase deficiency. In conclusion, myoclonic tremor status expands the spectrum of movement disorders seen in adenylosuccinate lyase deficiency.
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http://dx.doi.org/10.1016/j.ejmg.2020.104061DOI Listing
December 2020

Inhaled nitric oxide therapy in acute bronchiolitis: A multicenter randomized clinical trial.

Sci Rep 2020 06 15;10(1):9605. Epub 2020 Jun 15.

Saban Pediatric Medical Center, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.

Currently, there are no approved treatments for infants with acute bronchiolitis, the leading cause for hospitalization of infants worldwide, and thus the recommended approach is supportive. Inhaled Nitric oxide (iNO), possesses anti-viral properties, improves oxygenation, and was shown to be safe in infants with respiratory conditions. Hospitalized infants with acute bronchiolitis were therefore recruited to a prospective double-blinded, multi-center, randomized controlled pilot study. They received intermittent high dose iNO (160 ppm) plus oxygen/air for 30 min or oxygen/air alone (control), five times/day, up to 5 days. Sixty-nine infants were enrolled. No difference was observed in frequencies of subjects with at least one Adverse Event (AE) in iNO (44.1%) vs. control (55.9%); neither was Methemoglobin >7% safety threshold. No drug-related serious AEs (SAEs) were reported. Analysis of Per-Protocol population revealed that length of stay (LOS), time to SpO ≥92%, and time to mTal clinical score ≤5 improved by 26.7 ± 12.7 (Welch's t-test p = 0.04), 20.8 ± 8.9 (p = 0.023), and 14.6 ± 9.1 (p = 0.118) hours, respectively, in the iNO group compared to the control. Overall, high dose iNO (160ppm) was safe, well-tolerated, reduced LOS and showed rapid improvement of oxygen saturation, compared to the standard therapy. Further investigation in larger cohorts is warranted to validate these encouraging efficacy outcomes. (Trial registration: NCT03053388).
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http://dx.doi.org/10.1038/s41598-020-66433-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295966PMC
June 2020

Campylobacter gastroenteritis in children in north-eastern Israel comparison with other common pathogens.

Sci Rep 2020 04 2;10(1):5823. Epub 2020 Apr 2.

The Ruth and Baruch Rappaport School of Medicine, Technion, Haifa, Israel.

Gastroenteritis is common among children. Campylobacter jejuni is one of the main causative bacterial pathogens, together with Shigella, Salmonella and invasive Escherichia coli. Campylobacteriosis is a zoonotic, usually self-limited disease that does not always require antibiotic treatment. In cases of protracted diarrhoea in healthy children or immunocompromised patients, antibiotic treatment is recommended, and the drug of choice is still macrolides, with very low resistance rates in Campylobacter species. However, it is crucial to isolate the causative organism, because some cases, such as Shigella encephalitis, call for initiation of empiric antibiotic treatment. In this study, we compared the incidence, epidemiology, clinical findings and laboratory results of gastroenteritis with dysentery caused by these organisms in children in our area. C. jejuni was found to be the leading pathogen in children hospitalized with bacterial gastroenteritis, followed by Shigella and Salmonella. Macrolides were the drug of choice for Campylobacter, and ceftriaxone and ciprofloxacin were the best empiric treatments for Shigella and Salmonella, respectively.
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http://dx.doi.org/10.1038/s41598-020-62744-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118081PMC
April 2020

The utility of next generation sequencing in the correct diagnosis of congenital hypochloremic hypokalemic metabolic alkalosis.

Eur J Med Genet 2019 Oct 17;62(10):103728. Epub 2019 Jul 17.

Department of Pediatrics B, Emek Medical Center, Afula, Israel; Genetic Institute, Emek Medical Center, Afula, Israel; Rappaport School of Medicine, Technion, Haifa, Israel. Electronic address:

Persistent hypokalemic hypochloremic metabolic alkalosis represents a heterogeneous group of genetic disorders of which the most common is Bartter syndrome (BS). BS is an inherited renal tubulopathy caused by defective salt reabsorption in the thick ascending loop of Henle, which results in persistent hypokalemic hypochloremic metabolic alkalosis. Here we report a 10-year-old girl of a consanguineous family. She presented prenatally with severe polyhydramnios and distended bowel loops. Thereafter, she displayed failure to thrive and had recurrent admissions due to dehydration episodes associated with diarrhea, and characterized by hypokalemia, hypochloremia and metabolic alkalosis. BS was considered her working diagnosis for several years despite negative genetic analysis of the known genes associated with BS. Whole exome sequencing identified a novel homozygous c.1652delT deleterious frameshift mutation in the SLC26A3 gene, which confirmed the diagnosis of congenital chloride diarrhea (CCD), a rare autosomal recessive disease that mimics biochemically BS. A review of twelve additional reported cases of CCD that were initially misdiagnosed as BS, emphasizes CCD in the differential diagnosis of BS, and highlights the clinical discrepancies between these two entities. Taken together, our report further emphasizes the typical clinical features of CCD, and the importance of next generation sequencing in the diagnosis of syndromes with genetic heterogeneity. We suggest including SLC26A3 in the extended BS targeted gene panels.
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http://dx.doi.org/10.1016/j.ejmg.2019.103728DOI Listing
October 2019

Gaucher disease type 3c: New patients with unique presentations and review of the literature.

Mol Genet Metab 2019 06 21;127(2):138-146. Epub 2019 May 21.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address:

Gaucher disease (GD) is the most prevalent lysosomal disorder caused by GBA mutations and abnormal glucocerebrosidase function, leading to glucocerebrosideaccumulation mainly in the liver, spleen, bone marrow, lungs, and occasionally in the central nervous system. Gaucher disease type 3c (GD3c) is a rare subtype of the subacute/chronic neuronopathic GD3, caused by homozygosity for the GBA p.Asp448His (D409H) mutation. GD3c is characterized mainly by cardiovascular and neuro-ophthalmological findings. In this paper, we describe four new GD3c patients exhibiting rare cardiovascular, pulmonary and psychiatric findings, as well as atypical disease courses. Review of the GD3c-related literature revealed clinical descriptions of 36 patients, presenting predominantly with cardiovascular calcifications; 15%, including Patient 1b in this study, had non-calcified lesions - fibrosis and atherosclerosis. Only 7.5% of patients have been described without heart disease, including Patient 3; however, Patient 2 had a fulminant coronary disease. Neurological findings in GD3c consist mainly of oculomotor apraxia (80%), which is absent in Patient 3, while other neurological findings are common (65%) but diverse. Patient 1b developed a psychiatric behavioral disorder, which has not been previously described in GD3c. Patient 1b also had interstitial lung disease, which was only described in one GD3c patient as pulmonary fibrosis. In view of these unique features, we recommend a revised surveillance protocol; however, further studies are required to establish the management of these patients and the role of GBA in the described pathologies.
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http://dx.doi.org/10.1016/j.ymgme.2019.05.011DOI Listing
June 2019

Biotinidase Deficiency: A Treatable Neurological Inborn Error of Metabolism.

Isr Med Assoc J 2019 Mar;21(3):219-221

Department of Pediatrics B, Emek Medical Center, Afula, Israel.

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March 2019

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.

Nat Commun 2019 02 12;10(1):708. Epub 2019 Feb 12.

Pediatric Department B' Emek Medical Center, Afula, 1834111, Israel.

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.
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http://dx.doi.org/10.1038/s41467-018-07953-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372652PMC
February 2019

Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy.

Nat Commun 2019 02 5;10(1):605. Epub 2019 Feb 5.

Department of Pediatrics B', Emek Medical Center, Afula, Israel.

Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum depending on the availability of both isoforms in the nuclear envelope throughout life.
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http://dx.doi.org/10.1038/s41467-019-08493-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363790PMC
February 2019

Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome.

J Inherit Metab Dis 2019 03 28;42(2):264-275. Epub 2019 Jan 28.

Rappaport Faculty of Medicine, Technion- Israel Institute of Technology, Haifa, Israel.

Mitochondrial aconitase is the second enzyme in the tricarboxylic acid (TCA) cycle catalyzing the interconversion of citrate into isocitrate and encoded by the nuclear gene ACO2. A homozygous pathogenic variant in the ACO2 gene was initially described in 2012 resulting in a novel disorder termed "infantile cerebellar retinal degeneration" (ICRD, OMIM#614559). Subsequently, additional studies reported patients with pathogenic ACO2 variants, further expanding the genetic and clinical spectrum of this disorder to include milder and later onset manifestations. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene. Most patients present in early infancy with severe truncal hypotonia, truncal ataxia, variable seizures, evolving microcephaly, and ophthalmological abnormalities of which the most dominant are esotropia and optic atrophy with later development of retinal dystrophy. Most patients remain nonambulatory and do no acquire any language, but a subgroup of patients share a more favorable course. Brain magnetic resonance imaging (MRI) is typically normal within the first months but global atrophy gradually develops affecting predominantly the cerebellum. Ten of our patients were homozygous to the previously reported c.336C>G founder mutation while the other six patients were all compound heterozygotes displaying 10 novel mutations of whom 2 were nonsense predicting a deleterious effect on enzyme function. Structural protein modeling predicted significant impairment in aconitase substrate binding in the additional missense mutations. This study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of ACO2 deficiency.
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http://dx.doi.org/10.1002/jimd.12022DOI Listing
March 2019

Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review.

Metab Brain Dis 2019 04 12;34(2):557-563. Epub 2019 Jan 12.

Department of Pediatrics B, Emek Medical Center, Afula, Israel.

D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.
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http://dx.doi.org/10.1007/s11011-019-0384-xDOI Listing
April 2019

A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels.

Metab Brain Dis 2017 12 13;32(6):2131-2137. Epub 2017 Sep 13.

Pediatric Department B, Emek Medical Center, 1834111, Afula, Israel.

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.
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http://dx.doi.org/10.1007/s11011-017-0109-yDOI Listing
December 2017

Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors.

Ann Neurol 2017 Sep 30;82(3):317-330. Epub 2017 Aug 30.

Division of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain.

Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330.
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http://dx.doi.org/10.1002/ana.24998DOI Listing
September 2017

Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency.

PLoS One 2017 2;12(5):e0176363. Epub 2017 May 2.

Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.

Mitochondrial respiratory chain dysfunction has been identified in a number of neurodegenerative disorders. Infantile cerebellar-retinal degeneration associated with mutations in the mitochondrial aconitase 2 gene (ACO2) has been recently described as a neurodegenerative disease of autosomal recessive inheritance. To date there is no biomarker for ACO2 deficiency and diagnosis relies on genetic analysis. Here we report global metabolic profiling in eight patients with ACO2 deficiency. Using an LC-MS-based metabolomics platform we have identified several metabolites with affected plasma concentrations including the tricarboxylic acid cycle metabolites cis-aconitate, isocitrate and alpha-ketoglutarate, as well as phosphoenolpyruvate and hydroxybutyrate. Taken together we report a diagnostic metabolic fingerprint for mitochondrial aconitase 2 deficiency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176363PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413020PMC
September 2017

De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy.

Eur J Med Genet 2017 Jun 5;60(6):317-320. Epub 2017 Apr 5.

Pediatric Department B, Emek Medical Center, Afula, Israel; Rappaport School of Medicine, Technion, Haifa, Israel. Electronic address:

De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations.
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http://dx.doi.org/10.1016/j.ejmg.2017.04.001DOI Listing
June 2017

Homozygous mutation in PTRH2 gene causes progressive sensorineural deafness and peripheral neuropathy.

Am J Med Genet A 2017 Apr;173(4):1051-1055

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

PTRH2 is an evolutionarily highly conserved mitochondrial protein that belongs to a family of peptidyl-tRNA hydrolases. Recently, patients from two consanguineous families with mutations in the PTRH2 gene were reported. Global developmental delay associated with microcephaly, growth retardation, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, and sensorineural hearing loss were present in all patients, while facial dysmorphism with widely spaced eyes, exotropia, thin upper lip, proximally placed thumbs, and deformities of the fingers and toes were present in some individuals. Here, we report a new family with three siblings affected by sensorineural hearing loss and peripheral neuropathy. Autozygosity mapping followed by exome sequencing identified a previously reported homozygous missense mutation in PTRH2 (c.254A>C; p.(Gln85Pro)). Sanger sequencing confirmed that the variant segregated with the phenotype. In contrast to the previously reported patient, the affected siblings had normal intelligence, milder microcephaly, delayed puberty, myopia, and moderate insensitivity to pain. Our findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants.
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http://dx.doi.org/10.1002/ajmg.a.38140DOI Listing
April 2017

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization.

Neuromuscul Disord 2017 Feb 24;27(2):136-140. Epub 2016 Nov 24.

Institute of Child Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.
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http://dx.doi.org/10.1016/j.nmd.2016.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5280189PMC
February 2017

Novel Homozygous Missense Mutation in SPG20 Gene Results in Troyer Syndrome Associated with Mitochondrial Cytochrome c Oxidase Deficiency.

JIMD Rep 2017 19;33:55-60. Epub 2016 Aug 19.

Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia (HSP) caused by deleterious mutations in the SPG20 gene. Although the disease is associated with a loss of function mechanism of spartin, the protein encoded by SPG20, the precise pathogenesis is yet to be elucidated. Recent data indicated an important role for spartin in both mitochondrial maintenance and function. Here we report a child presenting with progressive spastic paraparesis, generalized muscle weakness, dysarthria, impaired growth, and severe isolated decrease in muscle cytochrome c oxidase (COX) activity. Whole exome sequencing identified the homozygous c.988A>G variant in SPG20 gene (p.Met330Val) resulting in almost complete loss of spartin in skeletal muscle. Further analyses demonstrated significant tissue specific reduction of COX 4, a nuclear encoded subunit of COX, in muscle suggesting a role for spartin in proper mitochondrial respiratory chain function mediated by COX activity. Our findings need to be verified in other Troyer syndrome patients in order to classify it as a form of HSP caused by mitochondrial dysfunction.
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http://dx.doi.org/10.1007/8904_2016_580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413448PMC
August 2016

Diagnosis of familial Mediterranean fever following the initial presentation of monoarthritis.

Int J Rheum Dis 2018 Mar 16;21(3):755-760. Epub 2016 Jun 16.

Rappaport School of Medicine, Technion, Haifa, Israel.

Aims: To determine if familial Mediterranean fever (FMF) genetic testing should be advised in children with initial presentation of monoarthritis and to identify clinical parameters associated with FMF-induced arthritis that warrant genetic investigation.

Methods: A prospective study of 71 otherwise healthy children admitted to our pediatric department between 2010-2013 with a first episode of idiopathic monoarthritis. Demographic, clinical and laboratory data were documented and genetic assay of the five common mutations in our population of the MEFV gene that cause FMF syndrome were analyzed in the entire study population. Statistical analysis compared two groups according to FMF status (FMF arthritis and idiopathic arthritis).

Results: Among the cohort seven (10%) children harbored two pathogenic mutations in the MEFV gene, thus confirming diagnosis of FMF. This FMF-induced arthritis group had a statistically significant female predominance compared with the idiopathic arthritis group (six [86%] vs. 19 [30%], respectively) (P = 0.006, odds ration [OR] = 14.2). In addition, associated abdominal pain during the attack (two [28%] vs. two [3%], respectively) (P = 0.04, OR = 12.4) and a family history of FMF (two [29%] vs. five [8%], respectively) (P = 0.1, OR 4.7,) were more common in the FMF-induced arthritis group.

Conclusions: In Mediterranean populations where FMF is relatively common we recommend for every child with a first episode of arthritis, without an identifying cause to strongly consider MEFV genetic testing of the common mutations in the relevant population.
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http://dx.doi.org/10.1111/1756-185X.12906DOI Listing
March 2018
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