scholarly journals P.075 Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

2019 ◽  
Vol 46 (s1) ◽  
pp. S34
Author(s):  
L Gauquelin ◽  
FK Cayami ◽  
L Sztriha ◽  
G Yoon ◽  
LT Tran ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Craniofacial Development ◽  
Clinical Spectrum ◽  
Treacher Collins Syndrome ◽  
Cross Sectional ◽  
Related Disorder ◽  
Molecular Features ◽  
Pathogenic Variants ◽  
Motor Difficulties ◽  
Hypomyelinating Leukodystrophy

Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

scholarly journals Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

2019 ◽  
Vol 5 (6) ◽  
pp. e369 ◽  
Author(s):  
Laurence Gauquelin ◽  
Ferdy K. Cayami ◽  
László Sztriha ◽  
Grace Yoon ◽  
Luan T. Tran ◽  
...  
Keyword(s):  
Brain Mri ◽  
Rna Polymerase Iii ◽  
Craniofacial Development ◽  
Treacher Collins Syndrome ◽  
Molecular Characteristics ◽  
Cross Sectional ◽  
Related Disorder ◽  
Pathogenic Variants ◽  
T2 Hyperintensity ◽  
Hypomyelinating Leukodystrophy

ObjectiveTo determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants.MethodsA cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed.ResultsFourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified.ConclusionsThis study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

scholarly journals Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ana Vitoria Barban Margutti ◽  
Wilson Araújo Silva ◽  
Daniel Fantozzi Garcia ◽  
Greice Andreotti de Molfetta ◽  
Adriana Aparecida Marques ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
In Silico Analysis ◽  
Cross Sectional Study ◽  
Clinical Severity ◽  
Cross Sectional ◽  
Maple Syrup ◽  
Molecular Features ◽  
Pathogenic Variants ◽  
Study Results ◽  
Urine Disease

Abstract Background Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. Results Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. Conclusion Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

scholarly journals Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

2019 ◽  
Author(s):  
Ana Vitoria Barban Margutti ◽  
Wilson Araújo Silva ◽  
Daniel Fantozzi Garcia ◽  
Greice Andreotti de Molfetta ◽  
Adriana Aparecida Marques ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
In Silico Analysis ◽  
Cross Sectional Study ◽  
Clinical Severity ◽  
Cross Sectional ◽  
Maple Syrup ◽  
Molecular Features ◽  
Pathogenic Variants ◽  
Study Results ◽  
Urine Disease

Abstract Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving PCR and sequencing. Results: Nine new variants predicted as pathogenic were found between 30 variants identified in the 21 patients analyzed: two in the BCKDHA gene (p.Gly56Arg, and p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs*13, p.Phe149Cysfs*9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and four variants showed no pathogenicity according to in silico analysis. Conclusion: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

scholarly journals Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

2020 ◽  
Author(s):  
Ana Vitoria Barban Margutti ◽  
Wilson Araújo Silva ◽  
Daniel Fantozzi Garcia ◽  
Greice Andreotti de Molfetta ◽  
Adriana Aparecida Marques ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Cross Sectional Study ◽  
Clinical Severity ◽  
Cross Sectional ◽  
Maple Syrup ◽  
Molecular Features ◽  
Pathogenic Variants ◽  
Study Results ◽  
Genes Encoding ◽  
Urine Disease

Abstract Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. Results: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs*13, p.Phe149Cysfs*9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. Conclusion: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

scholarly journals Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

2020 ◽  
Author(s):  
Félixe Pelletier ◽  
Stefanie Perrier ◽  
Ferdy K Cayami ◽  
Amytice Mirchi ◽  
Stephan Saikali ◽  
...  
Keyword(s):  
Short Stature ◽  
Hypogonadotropic Hypogonadism ◽  
Autosomal Recessive Disorder ◽  
Cross Sectional Study ◽  
Delayed Puberty ◽  
Cross Sectional ◽  
Pathogenic Variants ◽  
Neurological Features ◽  
A Prospective Study ◽  
Growth Abnormalities

Abstract Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

scholarly journals Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

2020 ◽  
Author(s):  
Ana Vitoria Barban Margutti ◽  
Wilson Araújo Silva ◽  
Daniel Fantozzi Garcia ◽  
Greice Andreotti de Molfetta ◽  
Adriana Aparecida Marques ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Cross Sectional Study ◽  
Clinical Severity ◽  
Cross Sectional ◽  
Maple Syrup ◽  
Molecular Features ◽  
Pathogenic Variants ◽  
Study Results ◽  
Genes Encoding ◽  
Urine Disease

Abstract Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. Results: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs*13, p.Phe149Cysfs*9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. Conclusion: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

scholarly journals Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 2824
Author(s):  
Jan H. Döring ◽  
Julian Schröter ◽  
Jerome Jüngling ◽  
Saskia Biskup ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Transmembrane Domain ◽  
Potassium Conductance ◽  
Epileptic Encephalopathy ◽  
Clinical Spectrum ◽  
The Novel ◽  
Developmental Abnormalities ◽  
Pathogenic Variants ◽  
Infantile Seizures ◽  
Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

scholarly journals ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

2021 ◽  
Vol 12 ◽  
Author(s):  
Philippe A. Salles ◽  
Ignacio F. Mata ◽  
Tobias Brünger ◽  
Dennis Lal ◽  
Hubert H. Fernandez
Keyword(s):  
Original Description ◽  
Rapid Onset ◽  
Acute Onset ◽  
Clinical Spectrum ◽  
Pes Cavus ◽  
Sodium Potassium ◽  
Pathogenic Variants ◽  
Alternating Hemiplegia Of Childhood ◽  
The Central Nervous System ◽  
Neurological Features

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.

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