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Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations.
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Péptidos , Humanos , Péptidos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Masculino , FemeninoRESUMEN
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
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Errores Innatos del Metabolismo de los Aminoácidos , Descarboxilasas de Aminoácido-L-Aromático , Humanos , Prevalencia , Dopamina/metabolismo , Genotipo , Errores Innatos del Metabolismo de los Aminoácidos/epidemiología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Aminoácidos/genéticaRESUMEN
Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
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Enfermedades Mitocondriales , Enfermedades Musculares , Humanos , Mitocondrias/genética , ADN Mitocondrial/genética , Enfermedades Mitocondriales/genética , Síndrome , Inestabilidad GenómicaRESUMEN
Introduction: Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may develop refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. Newborn screening has the potential to identify and enable treatment of affected individuals before they become significantly ill. Methods: Measuring orotic acid as part of expanded newborn screening using flow injection analysis tandem mass spectrometry. Results: Since the addition of orotic acid measurement to the Israeli routine newborn screening program, 1,492,439 neonates have been screened. The screen has identified ten Muslim Arab newborns that remain asymptomatic so far, with DBS orotic acid elevated up to 10 times the upper reference limit. Urine organic acid testing confirmed the presence of orotic aciduria along with homozygous variations in the UMPS gene. Conclusion: Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotic aciduria.
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Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives.
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Galactosemias , Humanos , Recién Nacido , Galactosemias/diagnóstico , Tamizaje Neonatal/métodos , Proyectos Piloto , UTP-Hexosa-1-Fosfato Uridililtransferasa , Racemasas y EpimerasasRESUMEN
Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-onset chronic diarrhea. Genomic deletions in chromosome 16, encompassing a sequence termed the 'intestine-critical region (ICR)', were recently identified as the cause of an autosomal recessive congenital enteropathy. The regulatory sequence within the ICR is flanked by an unannotated open reading frame termed PERCC1, which plays a role in enteroendocrine cell (EEC) function. We investigated two unrelated children with idiopathic congenital diarrhea requiring home parenteral nutrition attending the Irish Intestinal Failure Program. Currently 12 and 19-years old, these Irish male patients presented with watery diarrhea and hypernatremic dehydration in infancy. Probands were phenotyped by comprehensive clinical investigations, including endoscopic biopsies and serum gastrin level measurements. Following negative exome sequencing, PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each proband and their parents. In both patients, serum gastrin levels were low and failed to increase following a meal challenge. While no deletions involving the ICR were detected, targeted sequencing of the PERCC1 gene revealed a shared homozygous c.390C > G stop gain variant. We report clinical and molecular findings in two unrelated patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation.
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Codón sin Sentido , Gastrinas , Adolescente , Adulto , Niño , Humanos , Masculino , Adulto Joven , Diarrea/genética , Gastrinas/genética , Mutación , FenotipoRESUMEN
Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34+ hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.
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Síndrome de Kearns-Sayre , Humanos , Niño , Preescolar , Eliminación de Secuencia , Síndrome de Kearns-Sayre/genética , Mitocondrias/genética , ADN Mitocondrial/genética , Células Madre HematopoyéticasRESUMEN
Hermansky-Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism (OCA) and bleeding diathesis. To date, 11 HPS types have been reported (HPS-1 to HPS-11), each defined by disease-causing variants in specific genes. Variants in the HPS1 gene were found in approximately 15% of HPS patients, most of whom harbor the Puerto Rican founder mutation. In this study, we report six affected individuals from three nonconsanguineous families of Ashkenazi Jewish descent, who presented with OCA and multiple ecchymoses and had normal platelet number and size. Linkage analysis indicated complete segregation to HPS3. Sequencing of the whole coding region and the intron boundaries of HPS3 revealed a heterozygous c.1163+1G>A variant in all six patients. Long-range PCR amplification revealed that all affected individuals also carry a 14,761bp deletion that includes the 5'UTR and exon 1 of HPS3, encompassing regions with long interspersed nuclear elements. The frequency of the c.1163+1G>A splice site variant was found to be 1:200 in the Ashkenazi Jewish population, whereas the large deletion was not detected in 300 Ashkenazi Jewish controls. These results present a novel HPS3 deletion mutation and suggest that the prevalence of HPS-3 in Ashkenazi Jews is more common than previously thought.
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PURPOSE: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. METHODS: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. RESULTS: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. CONCLUSION: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.
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Trastornos de la Motilidad Ciliar , Ciliopatías , Proteínas del Citoesqueleto , Animales , Humanos , Ratones , Axonema/genética , Cilios/metabolismo , Trastornos de la Motilidad Ciliar/genética , Trastornos de la Motilidad Ciliar/metabolismo , Trastornos de la Motilidad Ciliar/patología , Ciliopatías/genética , Ciliopatías/metabolismo , Ciliopatías/patología , Proteínas del Citoesqueleto/genética , Mutación , Proteínas/genética , Pez Cebra/genéticaRESUMEN
Avoidance of fasting and regular ingestion of uncooked-cornstarch have long been the mainstay dietary treatment of Glycogen Storage Disease type Ia (GSD-Ia). However, GSD-Ia patients who despite optimal dietary treatment show poor glycemic control and are intolerant to cornstarch, present a complex clinical challenge. We pursued Whole Exome Sequencing (WES) in three such unrelated patients, to both confirm a molecular diagnosis of GSD-Ia, and seek additional variants in other genes (e.g. genes associated with amylase production) which may explain their persistent symptoms. WES confirmed the GSD-Ia diagnosis, with all three probands harboring the homozygous p.R83C variant in G6PC. While no other significant variants were identified for patients A and B, a homozygous p.G276V variant in the SI gene was detected in patient C, establishing the dual-diagnosis of GSD-Ia and Sucrase-Isomaltase Deficiency. To conclude, we suggest that WES should be considered in GSD-Ia patients who show persistent symptoms despite optimal dietary management.
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Glucosa-6-Fosfatasa , Enfermedad del Almacenamiento de Glucógeno Tipo I , Glucosa-6-Fosfatasa/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , AlmidónRESUMEN
BACKGROUND: HPS-1 is a genetic type of Hermansky-Pudlak syndrome (HPS) with highly penetrant pulmonary fibrosis (HPSPF), a restrictive lung disease that is similar to idiopathic pulmonary fibrosis (IPF). Hps1ep/ep (pale ear) is a naturally occurring HPS-1 mouse model that exhibits high sensitivity to bleomycin-induced pulmonary fibrosis (PF). Traditional methods of administering bleomycin as an intratracheal (IT) route to induce PF in this model often lead to severe acute lung injury and high mortality rates, complicating studies focusing on pathobiological mechanisms or exploration of therapeutic options for HPSPF. METHODS: To develop a murine model of HPSPF that closely mimics the progression of human pulmonary fibrosis, we investigated the pulmonary effects of systemic delivery of bleomycin in Hps1ep/ep mice using a subcutaneous minipump and compared results to oropharyngeal delivery of bleomycin. RESULTS: Our study revealed that systemic delivery of bleomycin induced limited, acute inflammation that resolved. The distinct inflammatory phase preceded a slow, gradually progressive fibrogenesis that was shown to be both time-dependent and dose-dependent. The fibrosis phase exhibited characteristics that better resembles human disease with focal regions of fibrosis that were predominantly found in peribronchovascular areas and in subpleural regions; central lung areas contained relatively less fibrosis. CONCLUSION: This model provides a preclinical tool that will allow researchers to study the mechanism of pulmonary fibrosis in HPS and provide a platform for the development of therapeutics to treat HPSPF. This method can be applied on studies of IPF or other monogenic disorders that lead to pulmonary fibrosis.
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Síndrome de Hermanski-Pudlak , Fibrosis Pulmonar Idiopática , Albinismo , Animales , Bleomicina/toxicidad , Modelos Animales de Enfermedad , Fibrosis , Trastornos Hemorrágicos , Síndrome de Hermanski-Pudlak/inducido químicamente , Síndrome de Hermanski-Pudlak/genética , Fibrosis Pulmonar Idiopática/patología , Pulmón , RatonesRESUMEN
Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the de novo coenzyme A (CoA) synthesis starting from pantothenate. Mutations in PPCS cause autosomal-recessive dilated cardiomyopathy, often fatal, without apparent neurodegeneration, whereas pathogenic variants in PANK2 and COASY, two other genes involved in the CoA synthesis, cause Neurodegeneration with Brain Iron Accumulation (NBIA). PPCS-deficiency is a relatively new disease with unclear pathogenesis and no targeted therapy. Here, we report the generation of induced pluripotent stem cells from fibroblasts of two PPCS-deficient patients. These cellular models could represent a platform for pathophysiological studies and testing of therapeutic compounds for PPCS-deficiency.
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Cardiomiopatía Dilatada , Células Madre Pluripotentes Inducidas , Coenzima A , Fibroblastos , Humanos , Mutación/genéticaRESUMEN
Sanfilippo Syndrome, or mucopolysaccharidosis type III (MPS III), is a group of autosomal-recessive lysosomal storage disorders leading to tissue accumulation of heparan sulfate. MPS III is caused by deficiency in one of 4 enzymes involved in lysosomal degradation of heparan sulfate. Based on the relevant enzyme deficiency, 4 types have been recognized. MPS III constitutes a progressive neurodegenerative and systemic disorder. Parents of children diagnosed with MPS III were interviewed using a retrospective questionnaire based on the known clinical manifestations of MPS III. Eight patients from 4 unrelated families of varied ethnic origin were included. All children were diagnosed with MPS type III-A. Average age at diagnosis was 6.1 years. The most common early clinical manifestations leading to parental suspicion of illness were speech delay and coarse facial features. All children were reported to have global developmental delay, sleep disorders, recurrent infections, hyperactivity, and decreased hearing. The time from first medical inquiry until diagnosis was over 2 years on average, consistent with the delay in diagnosis described in the literature. MPS III children frequently undergo early and repeated ear, nose and throat surgeries, thus we suggest that a high index of suspicion is warranted in relevant clinical circumstances.
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BACKGROUND: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown. METHODS: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology. RESULTS: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability. CONCLUSIONS: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.
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Sordera , Pez Cebra , Adolescente , Adulto , Animales , Niño , Preescolar , Sordera/genética , Endocitosis , Humanos , Túbulos Renales Proximales/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Ratones , Mutación , Proteinuria/metabolismo , Proteínas de Transporte Vesicular/genética , Adulto Joven , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Pruebas Genéticas , Enfermedades Renales , Niño , Humanos , Enfermedades Renales/genética , Fenotipo , Derivación y Consulta , Secuenciación del Exoma/métodosRESUMEN
Background: Genetic conditions contribute a significant portion of disease etiologies in children admitted to general pediatric wards worldwide. While exome sequencing (ES) has improved clinical diagnosis and management over a variety of pediatric subspecialties, it is not yet routinely used by general pediatric hospitalists. We aim to investigate the impact of exome sequencing in sequencing-naive children suspected of having monogenic disorders while receiving inpatient care. Methods: We prospectively employed exome sequencing in children admitted to the general pediatric inpatient service at a large tertiary medical center in Israel. Genetic analysis was triggered by general and/or subspecialist pediatricians who were part of the primary inpatient team. We determined the diagnostic yield among children who were referred for exome sequencing and observed the effects of genetic diagnosis on medical care. Results: A total of fifty probands were evaluated and exome sequenced during the study period. The most common phenotypes included were neurodevelopmental (56%), gastrointestinal (34%), and congenital cardiac anomalies (24%). A molecular diagnosis was reached in 38% of patients. Among seven patients (37%), the molecular genetic diagnosis influenced subsequent clinical management already during admission or shortly following discharge. Conclusion: We identified a significant fraction of genetic etiologies among undiagnosed children admitted to the general pediatric ward. Our results support that early application of exome sequencing may be maximized by pediatric hospitalists' high index of suspicion for an underlying genetic etiology, prompting an in-house genetic evaluation. This framework should include a multidisciplinary co-management approach of the primary care team working alongside with subspecialties, geneticists and bioinformaticians.
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BACKGROUND: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome. METHODS: Nine patients underwent meticulous visual function history and medical documents' review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible. RESULTS: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer-inner plexiform layer (IPL) measurement was possible, also showed diffused thinning. CONCLUSIONS: This study compiled data regarding neuro-ophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies.
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Corea , Errores Innatos del Metabolismo , Atrofia Óptica , Paraplejía Espástica Hereditaria , Corea/diagnóstico , Corea/fisiopatología , Humanos , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/fisiopatología , Atrofia Óptica/diagnóstico , Atrofia Óptica/fisiopatología , Fenotipo , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/fisiopatología , Tomografía de Coherencia Óptica/métodos , Agudeza VisualRESUMEN
BACKGROUND: The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far. OBJECTIVE: We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques. METHODS: Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families. RESULTS: Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46. CONCLUSIONS: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.