Publications by authors named "Camilo Toro"

91 Publications

Chediak-Higashi syndrome: a review of the past, present, and future.

Drug Discov Today Dis Models 2020 9;31:31-36. Epub 2019 Dec 9.

Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Since the initial description of Chediak-Higashi syndrome (CHS), over 75 years ago, several studies have been conducted to underscore the role of the lysosomal trafficking regulator gene in the pathogenesis of disease. CHS is a rare autosomal recessive disorder, which is caused by biallelic mutations in the highly conserved gene. The disease is characterized by partial oculocutaneous albinism, prolonged bleeding, immune and neurologic dysfunction, and risk for the development of hemophagocytic lympohistiocytosis (HLH). The presence of giant secretory granules in leukocytes is the classical diagnostic feature, which distinguishes CHS from closely related Griscelli and Hermansky-Pudlak syndromes. While the exact mechanism of the formation of the giant granules in CHS patients is not understood, dysregulation of LYST function in regulating lysosomal biogenesis has been proposed to play a role. In this review, we discuss the clinical characteristics of the disease and highlight the functional consequences of enlarged lysosomes and lysosome-related organelles (LROs) in CHS.
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http://dx.doi.org/10.1016/j.ddmod.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793027PMC
December 2019

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

Muscle Nerve 2021 Jan 2. Epub 2021 Jan 2.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW.

Methods: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography.

Results: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement.

Discussion: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
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http://dx.doi.org/10.1002/mus.27159DOI Listing
January 2021

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.

Genet Med 2020 Nov 26. Epub 2020 Nov 26.

Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.

Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).

Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.

Results: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.

Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
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http://dx.doi.org/10.1038/s41436-020-01027-3DOI Listing
November 2020

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Authors:
Laura Cif Diane Demailly Jean-Pierre Lin Katy E Barwick Mario Sa Lucia Abela Sony Malhotra Wui K Chong Dora Steel Alba Sanchis-Juan Adeline Ngoh Natalie Trump Esther Meyer Xavier Vasques Julia Rankin Meredith W Allain Carolyn D Applegate Sanaz Attaripour Isfahani Julien Baleine Bettina Balint Jennifer A Bassetti Emma L Baple Kailash P Bhatia Catherine Blanchet Lydie Burglen Gilles Cambonie Emilie Chan Seng Sandra Chantot Bastaraud Fabienne Cyprien Christine Coubes Vincent d'Hardemare Asif Doja Nathalie Dorison Diane Doummar Marisela E Dy-Hollins Ellyn Farrelly David R Fitzpatrick Conor Fearon Elizabeth L Fieg Brent L Fogel Eva B Forman Rachel G Fox William A Gahl Serena Galosi Victoria Gonzalez Tracey D Graves Allison Gregory Mark Hallett Harutomo Hasegawa Susan J Hayflick Ada Hamosh Marie Hully Sandra Jansen Suh Young Jeong Joel B Krier Sidney Krystal Kishore R Kumar Chloé Laurencin Hane Lee Gaetan Lesca Laurence Lion François Timothy Lynch Neil Mahant Julian A Martinez-Agosto Christophe Milesi Kelly A Mills Michel Mondain Hugo Morales-Briceno John R Ostergaard Swasti Pal Juan C Pallais Frédérique Pavillard Pierre-Francois Perrigault Andrea K Petersen Gustavo Polo Gaetan Poulen Tuula Rinne Thomas Roujeau Caleb Rogers Agathe Roubertie Michelle Sahagian Elise Schaefer Laila Selim Richard Selway Nutan Sharma Rebecca Signer Ariane G Soldatos David A Stevenson Fiona Stewart Michel Tchan Ishwar C Verma Bert B A de Vries Jenny L Wilson Derek A Wong Raghda Zaitoun Dolly Zhen Anna Znaczko Russell C Dale Claudio M de Gusmão Jennifer Friedman Victor S C Fung Mary D King Shekeeb S Mohammad Luis Rohena Jeff L Waugh Camilo Toro F Lucy Raymond Maya Topf Philippe Coubes Kathleen M Gorman Manju A Kurian

Brain 2020 12;143(11):3242-3261

Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
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http://dx.doi.org/10.1093/brain/awaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719027PMC
December 2020

Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome.

Mol Genet Metab 2020 Sep - Oct;131(1-2):98-106. Epub 2020 Oct 14.

NIH Undiagnosed Diseases Program, National Institutes of Health, Bethesda, MD, USA; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I. Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.
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http://dx.doi.org/10.1016/j.ymgme.2020.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749052PMC
October 2020

Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science.

Genet Med 2021 Feb 23;23(2):259-271. Epub 2020 Oct 23.

Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, USA.

Purpose: The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.

Methods: We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.

Results: Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.

Conclusion: Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
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http://dx.doi.org/10.1038/s41436-020-00984-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867619PMC
February 2021

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

Science 2020 11 1;370(6519). Epub 2020 Oct 1.

Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, USA.

Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.
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http://dx.doi.org/10.1126/science.aay8826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818661PMC
November 2020

Diagnosis of Chediak Higashi disease in a 67-year old woman.

Am J Med Genet A 2020 12 29;182(12):3007-3013. Epub 2020 Sep 29.

Section of the Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, Maryland, USA.

Chediak-Higashi disease is a rare disease caused by bi-allelic mutations in the lysosomal trafficking regulator gene, LYST. Individuals typically present in early childhood with partial oculocutaneous albinism, a bleeding diathesis, recurrent infections secondary to immune dysfunction, and risk of developing hemophagocytic lymphohistiocytosis (HLH). Without intervention, mortality is high in the first decade of life. However, some individuals with milder phenotypes have attenuated hematologic and immunologic presentations, and lower risk of HLH. Both classic and milder phenotypes develop progressive neurodegeneration in early adulthood. Here we present a remarkable patient diagnosed with Chediak-Higashi disease at age 67, many decades after the diagnosis is usually established. Diagnosis was suspected by observing the pathognomonic granules within leukocytes, and confirmed by identification of bi-allelic mutations in LYST, reduced LYST mRNA expression, enlarged lysosomes within fibroblasts, and decreased NK cell lytic activity. This case further expands the phenotype of Chediak-Higashi disease and highlights the need for increased awareness. Individuals with milder phenotypes may escape early diagnosis, but identification is important for close monitoring of potential complications, and to further our understanding of the function of LYST.
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http://dx.doi.org/10.1002/ajmg.a.61886DOI Listing
December 2020

A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot.

Br J Ophthalmol 2020 Aug 4. Epub 2020 Aug 4.

National Eye Institute, Bethesda, Maryland, USA

Aim: To describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated 'macular cherry-red spot'.

Methods: Seven patients with sialidosis type I (mutations in ) and one with galactosialidosis (mutations in ) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years.

Results: The mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50)+0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to age-matched controls (p<0.0001).

Conclusion: Most of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear.

Trial Registration Number: NCT00029965.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316826DOI Listing
August 2020

A feasibility study of mHealth and wearable technology in late onset GM2 gangliosidosis (Tay-Sachs and Sandhoff Disease).

Orphanet J Rare Dis 2020 08 3;15(1):199. Epub 2020 Aug 3.

Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Background: As part of a late onset GM2 gangliosidosis natural history study, digital health technology was utilized to monitor a group of patients remotely between hospital visits. This approach was explored as a means of capturing continuous data and moving away from focusing only on episodic data captured in traditional study designs. A strong emphasis was placed on real-time capture of symptoms and mobile Patient Reported Outcomes (mPROs) to identify the disease impact important to the patients themselves; an impact that may not always correlate with the measured clinical outcomes assessed during patient visits. This was supported by passive, continuous data capture from a wearable device.

Results: Adherence rate for wearing the device and completing the mPROs was 84 and 91%, respectively, resulting in a rich multidimensional dataset. As expected for a six-month proof-of-concept study in a disease that progresses slowly, statistically significant changes were not expected or observed in the clinical, mPROs, or wearable device data.

Conclusions: The study demonstrated that patients were very enthusiastic and motivated to engage with the technology as demonstrated by excellent compliance. The combination of mPROs and wearables generates feature-rich datasets that could be a useful and feasible way to capture remote, real-time insight into disease burden.
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http://dx.doi.org/10.1186/s13023-020-01473-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397597PMC
August 2020

yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development.

PLoS Genet 2020 06 16;16(6):e1008841. Epub 2020 Jun 16.

Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of America.

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.
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http://dx.doi.org/10.1371/journal.pgen.1008841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319359PMC
June 2020

Neurological manifestations of Erdheim-Chester Disease.

Ann Clin Transl Neurol 2020 04 29;7(4):497-506. Epub 2020 Mar 29.

NINDS, NIH, Bethesda, Maryland.

Objective: To characterize the spectrum of neurologic involvement in Erdheim-Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes.

Methods: Sixty-two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data.

Results: Ninety-four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD. The most common neurologic findings were cognitive impairment, peripheral neuropathy, pyramidal tract signs, cranial nerve involvement, and cerebellar ataxia. Imaging revealed atrophy and demyelination along with focal lesions that were located throughout the nervous system, dura, and extra-axial structures. The BRAF V600E variant correlated with cerebral atrophy. Brain pathology revealed lipid-laden, phagocytic macrophages (histiocytes) accompanied by demyelination and axonal degeneration.

Interpretation: In patients with ECD, neurologic morbidity is common and contributes significantly to disability. Since neurologic symptoms can be the presenting feature of ECD and, given the mean delay in ECD diagnosis is 4.2 years, it is critical that neurologists consider of ECD and other histiocytosis in patients with inflammatory, infectious, or neoplastic-appearing white matter. Furthermore, given the broad spectrum of neurologic involvement, neurologists have an important role in a team of specialists treating ECD patients.
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http://dx.doi.org/10.1002/acn3.51014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187721PMC
April 2020

A novel frameshift mutation in SOX10 causes Waardenburg syndrome with peripheral demyelinating neuropathy, visual impairment and the absence of Hirschsprung disease.

Am J Med Genet A 2020 05 9;182(5):1278-1283. Epub 2020 Mar 9.

NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages. Here we report a 12-year-old boy with a novel de novo SOX10 frameshift mutation and unique combination of clinical features including primary peripheral demyelinating neuropathy, hearing loss and visual impairment but absence of Hirschsprung disease and the typical pigmentary changes of hair or skin. This expands the spectrum of currently recognized phenotypes associated with WS and illustrates the phenotypic heterogeneity of SOX10-associated WS.
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http://dx.doi.org/10.1002/ajmg.a.61542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167353PMC
May 2020

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I.

J Clin Med 2020 03 4;9(3). Epub 2020 Mar 4.

Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into the category of the so-called orphan diseases, for which no therapy is currently available. In this study we aimed to identify potential therapeutic modalities, targeting primarily patients affected by type I sialidosis, the attenuated form of the disease. We tested the beneficial effects of a recombinant protective protein/cathepsin A (PPCA), the natural chaperone of NEU1, as well as pharmacological and dietary compounds on the residual activity of mutant NEU1 in a cohort of patients' primary fibroblasts. We observed a small, but consistent increase in NEU1 activity, following administration of all therapeutic agents in most of the fibroblasts tested. Interestingly, dietary supplementation of betaine, a natural amino acid derivative, in mouse models with residual NEU1 activity mimicking type I sialidosis, increased the levels of mutant NEU1 and resolved the oligosacchariduria. Overall these findings suggest that carefully balanced, unconventional dietary compounds in combination with conventional therapeutic approaches may prove to be beneficial for the treatment of sialidosis type I.
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http://dx.doi.org/10.3390/jcm9030695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141319PMC
March 2020

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.

J Clin Invest 2020 01;130(1):507-522

Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland, USA.

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.
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http://dx.doi.org/10.1172/JCI131116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934229PMC
January 2020

Circle of Willis anomalies in Turner syndrome: Absent A1 segment of the anterior cerebral artery.

Birth Defects Res 2019 11 18;111(19):1584-1588. Epub 2019 Oct 18.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: Turner syndrome (TS) is the most common sex chromosome disorder in women and is associated with a higher than expected death rate secondary to cerebrovascular disease, including stroke. This study evaluates the cerebral vascular anatomy of individuals with TS.

Methods: Twenty-one women with TS had brain magnetic resonance angiography (MRA). These MRAs were evaluated in a blinded manner with a control group of 25 men and 25 women who had MRA imaging for multiple indications including migraine headaches, psychiatric disorders, and seizures.

Results: Twenty-nine percent of women with TS were missing an A1 segment of the anterior cerebral artery (ACA) compared to 0% in the control group (p < .001). There were no other significant differences in the circle of Willis (COW) in women with TS compared with the control group. A complete COW was found in 3 of 21 (14%) of women with TS and 12 of 47 (26%) controls (p = .36).

Conclusion: Women with TS have a significantly different intracranial vascular anatomy, specifically the absence of the A1 segment of the ACA when compared to male and female controls. More research in brain imaging in women with TS and stroke and other cerebrovascular diseases is needed to determine the clinical significance of this anomaly.
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http://dx.doi.org/10.1002/bdr2.1609DOI Listing
November 2019

Chronic Dengue Virus Panencephalitis in a Patient with Progressive Dementia with Extrapyramidal Features.

Ann Neurol 2019 11 11;86(5):695-703. Epub 2019 Sep 11.

Section of Infections of the Nervous System, Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Objective: To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program.

Methods: Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing, and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established postmortem.

Results: Using VirScan, enrichment of dengue viral antibodies was detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but postmortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months antemortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency, and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system.

Interpretation: Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting, and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system causing a panencephalitis and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Furthermore, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiology. ANN NEUROL 2019;86:695-703.
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http://dx.doi.org/10.1002/ana.25588DOI Listing
November 2019

Botulinum toxin and occupational therapy for Writer's cramp.

Toxicon 2019 Nov 24;169:12-17. Epub 2019 Jul 24.

Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Writer's cramp (WC) is a form of focal hand dystonia, for which focal botulinum neurotoxin (BoNT) injections are the current best therapy. Past studies have shown that some types of rehabilitative therapy can be useful. We hypothesized that BoNT together with a specific type of occupational therapy would be better than BoNT alone for treating WC patients comparing the effects with a patient-rated subjective scale.

Methods: Twelve WC patients were randomized to two groups. Six received only BoNT therapy and 6 received BoNT & occupational therapy. The occupational therapy involved specific exercises of finger movements in the direction opposite to the dystonic movements during writing. BoNT was injected by movement disorders neurologists in the affected muscles under electromyography-guidance. The primary outcome was the patient-rated subjective scale at 20 weeks. Secondary exploratory outcomes included the writer's cramp rating scale (WCRS), writer's cramp impairment scale (WCIS), the writer's cramp disability scale (WCDS), handgrip strength and kinetic parameters.

Results: The patient-rated subjective scale scores at 20 weeks were not significantly different between the two groups. Significant objective improvement was noted in the BoNT & occupational therapy group, as noted by the decrease (28%) in WCIS scores.

Conclusions: Improvement of the primary outcome measure, the patient-rated subjective scale, was not achieved. However, significant improvement was found in the BoNT & occupational therapy group in a secondary measure of impairment. Our hypothesis-driven study results are likely limited by small sample size, and further large-scale studies of occupational therapy methods to improve the efficacy of BoNT seems worthwhile.
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http://dx.doi.org/10.1016/j.toxicon.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754272PMC
November 2019

Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.

Am J Hum Genet 2019 06 30;104(6):1127-1138. Epub 2019 May 30.

Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Human Biochemical Genetics Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl/H exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.
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http://dx.doi.org/10.1016/j.ajhg.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562152PMC
June 2019

The neuropsychological phenotype of Chediak-Higashi disease.

Orphanet J Rare Dis 2019 05 6;14(1):101. Epub 2019 May 6.

National Human Genome Research Institute, Bethesda, MD, USA.

Background/objectives: Chediak-Higashi Disease (CHD) is a rare autosomal disorder, purported to have cognitive and neurological impairments. Prior descriptions of cognitive impairment, however, are solely based on subjective, unstructured observations rather than on formal neuropsychological measures.

Methods: Four pediatric and 14 adult patients with diagnostically confirmed CHD were administered a neuropsychological battery assessing memory, attention, processing speed, psychomotor speed, language fluency, executive function, and general intelligence. Nine of the adult patients received follow-up evaluations to elucidate the longitudinal progression or stability of cognition over time.

Results: Pediatric CHD patients performed within the average range. Adult patients, however, performed below average on nearly all measures administered, and endorsed subjective reports of learning difficulties and poor academic performance in childhood. In particular, patients struggled with memory and psychomotor speed tasks, with 75% or more of patients scoring in the bottom 2.3 percentile in these two domains. No significant declines in cognition were observed among the patients who completed follow-up evaluations (M = 39.90, SD = 8.03 months between visits). Exploratory analyses suggested that adult patients who had classic CHD and previously received bone marrow transplants (BMTs; n = 3) exhibited moderately greater cognitive impairment than adult patients who had atypical CHD and had not received BMTs (n = 10).

Conclusions: Adult patients with CHD uniformly exhibit deficits in multiple domains, but in psychomotor speed and memory, in particular. Based on their neuropsychological profile, their ability to hold jobs and succeed in school may require support and special accommodations. The source of cognitive deficits is probably multifactorial including central nervous system involvement in CHD, and, for those transplanted, BMT-related side effects and complications. Absence of cognitive decline at three-year follow-up is encouraging but does not exclude progression at a slower time-scale. Future work should elucidate the possible effects and timing of BMT on cognition, as well as the mechanisms driving neuropsychological impairment in CHD.
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http://dx.doi.org/10.1186/s13023-019-1049-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503440PMC
May 2019

Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.

J Med Genet 2019 08 25;56(8):499-511. Epub 2019 Mar 25.

Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.

Background: Spinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in The AFG3L2 protein is a subunit of mitochondrial -AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.

Methods: We derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual -AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, HEK293 T cells by CRISPR/Cas9-genome editing and murine fibroblasts.

Results: We found that SCA28 cells carrying missense changes have normal levels of assembled -AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells.

Conclusion: Our data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.
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http://dx.doi.org/10.1136/jmedgenet-2018-105766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678042PMC
August 2019

Emerging molecular mechanisms of vascular dementia.

Curr Opin Hematol 2019 05;26(3):199-206

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California.

Purpose Of Review: Microvascular ischemic disease of the brain is a common cause of cognitive impairment and dementia, particularly in the context of preexisting cardiovascular risk factors and aging. This review summarizes our current understanding of the emerging molecular themes that underlie progressive and irreparable vascular disease leading to neuronal tissue injury and dementia.

Recent Findings: Cardiometabolic risk factors including diabetes and hypertension are known to contribute to vascular disease. Currently, the impact of these risk factors on the integrity and function of the brain vasculature has been target of intense investigation. Molecularly, the consequences associated with these risk factors indicate that reactive oxygen species are strong contributors to cerebrovascular dysfunction and injury. In addition, genetic linkage analyses have identified penetrant monogenic causes of vascular dementia. Finally, recent reports begun to uncover a large number of polymorphisms associated with a higher risk for cerebrovascular disease.

Summary: A comprehensive picture of key risk factors and genetic predispositions that contribute to brain microvascular disease and result in vascular dementia is starting to emerge. Understanding their relationships and cross-interactions will significantly aid in the development of preventive and intervention strategies for this devastating condition.
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http://dx.doi.org/10.1097/MOH.0000000000000502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986812PMC
May 2019

Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.

Neurol Genet 2019 Feb 24;5(1):e305. Epub 2019 Jan 24.

Department of Human Genetics (B.N., Q.S.P.), Graduate School of Public Health, University of Pittsburgh; Department of Medical Sciences (E.G., A.B.), University of Torino, Italy; Department of Radiology (R.R.), Uppsala University, Sweden; Department of Medical Genetics (A.L.), British Columbia Children's Hospital, Vancouver, Canada; Department of Genome Sciences (M. Spielmann), University of Washington, Seattle; Department of Pediatrics (M.K.K., R.A., M.K.), McGovern Medical School, University of Texas, Houston; Departments of Clinical Genomics and Neurology (R.G.), Mayo Clinic, Rochester, MN; Department of Pathology (M.A.), King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Imaging (M. Sharma), Western University, London, Canada; Departments of Pathology and Clinical Neurological Sciences (R.H.), Western University and London Health Sciences Centre, Canada; Office of the Clinical Director (W.A.G., C.T.), NHGRI; and NIH Undiagnosed Diseases Program (W.A.G., C.T.), Office of the Director, NIH, Bethesda, MD.

Objective: Clinical, radiologic, and molecular analysis of patients with genomic deletions upstream of the gene.

Methods: Detailed neurologic, MRI examinations, custom array comparative genomic hybridization (aCGH) analysis, and expression analysis were performed in patients at different clinical centers. All procedures were approved by institutional review boards of the respective institutions.

Results: Five patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations. Patients had unique nonrecurrent deletions upstream of the , varying in size from 250 kb to 670 kb. Deletion junctions were embedded in repetitive elements. Expression analysis revealed increased expression in patient cells.

Conclusions: Our findings confirmed the association between upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition. Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of duplications, patients with deletions upstream of had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI. aCGH analysis defined a smaller minimal critical region required for disease causation and revealed that deletions occur at repetitive DNA genomic elements. Search for structural variants (duplications and upstream deletions) should be an integral part of the investigation of patients with autosomal dominant adult-onset leukodystrophy.
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http://dx.doi.org/10.1212/NXG.0000000000000305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384018PMC
February 2019

PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells.

JCI Insight 2019 02 21;4(4). Epub 2019 Feb 21.

Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI).

Poly(ADP-ribosyl)ation refers to the covalent attachment of ADP-ribose to protein, generating branched, long chains of ADP-ribose moieties, known as poly(ADP-ribose) (PAR). Poly(ADP-ribose) polymerase 1 (PARP1) is the main polymerase and acceptor of PAR in response to DNA damage. Excessive intracellular PAR accumulation due to PARP1 activation leads cell death in a pathway known as parthanatos. PAR degradation is mainly controlled by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose-acceptor hydrolase 3 (ARH3). Our previous results demonstrated that ARH3 confers protection against hydrogen peroxide (H2O2) exposure, by lowering cytosolic and nuclear PAR levels and preventing apoptosis-inducing factor (AIF) nuclear translocation. We identified a family with an ARH3 gene mutation that resulted in a truncated, inactive protein. The 8-year-old proband exhibited a progressive neurodegeneration phenotype. In addition, parthanatos was observed in neurons of the patient's deceased sibling, and an older sibling exhibited a mild behavioral phenotype. Consistent with the previous findings, the patient's fibroblasts and ARH3-deficient mice were more sensitive, respectively, to H2O2 stress and cerebral ischemia/reperfusion-induced PAR accumulation and cell death. Further, PARP1 inhibition alleviated cell death and injury resulting from oxidative stress and ischemia/reperfusion. PARP1 inhibitors may attenuate the progression of neurodegeneration in affected patients with ARH3 deficiency.
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http://dx.doi.org/10.1172/jci.insight.124519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478412PMC
February 2019

A suite of automated sequence analyses reduces the number of candidate deleterious variants and reveals a difference between probands and unaffected siblings.

Genet Med 2019 08 31;21(8):1772-1780. Epub 2019 Jan 31.

Office of the Clinical Director, National Human Genome Research Institute, and Undiagnosed Diseases Program and Network, Office of the Director, National Institutes of Health, Bethesda, MD, USA.

Purpose: Develop an automated exome analysis workflow that can produce a very small number of candidate variants yet still detect different numbers of deleterious variants between probands and unaffected siblings.

Methods: Ninety-seven outbred nuclear families from the Undiagnosed Diseases Program/Network included single probands and the corresponding unaffected sibling(s). Single-nucleotide polymorphism (SNP) chip and exome analyses were performed on all, with proband and unaffected sibling considered independently as the target. The total burden of candidate genetic variants was summed for probands and siblings over all considered disease models.

Results: Exome analysis workflow include automated programs for ethnicity-matched genotype calling, salvage pathway for Mendelian inconsistency, compound heterozygous recessive detection, BAM file regional curation, population frequency filtering, pedigree-aware BAM file noise evaluation, and exon deletion filtration. This workflow relied heavily on BAM file analysis. A greater average pathogenic variant number was found compared with unaffected siblings. This was significant (p < 0.05) when using published recommended thresholds, and implies that causal variants are retained in many probands' lists.

Conclusion: Using Mendelian and non-Mendelian models, this agnostic exome analysis shows a difference between a small group of probands and their unaffected siblings. This workflow produces candidate lists small enough to pursue with laboratory validation.
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http://dx.doi.org/10.1038/s41436-019-0434-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669106PMC
August 2019

Novel pathogenic variants causing dysarthria, ataxia, and sensory neuropathy.

Ann Clin Transl Neurol 2019 01 9;6(1):154-160. Epub 2018 Nov 9.

Board of Governors Regenerative Medicine Institute Cedars-Sinai Medical Center Los Angeles California.

encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency.
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http://dx.doi.org/10.1002/acn3.661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331954PMC
January 2019