Vikki Stefans - Academia.edu (original) (raw)

Papers by Vikki Stefans

Research paper thumbnail of <i>GMPPB</i>-Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation

Human Mutation, Sep 23, 2015

Mutations in GDP-mannose pyrophosphorylase B (GMPPB), a catalyst for the formation of the sugar d... more Mutations in GDP-mannose pyrophosphorylase B (GMPPB), a catalyst for the formation of the sugar donor GDP-mannose, were recently identified as a cause of muscular dystrophy resulting from abnormal glycosylation of α-dystroglycan. In this series, we report nine unrelated individuals with GMPPB-associated dystroglycanopathy. The most mildly affected subject has normal strength at 25 years, whereas three severely affected children presented in infancy with intellectual disability and epilepsy. Muscle biopsies of all subjects are dystrophic with abnormal immunostaining for glycosylated α-dystroglycan. This cohort, together with previously published cases, allows preliminary genotype-phenotype correlations to be made for the emerging GMPPB common variants c.79G>C (p.D27H) and c.860G>A (p.R287Q). We observe that c.79G>C (p.D27H) is associated with a mild limb-girdle muscular dystrophy phenotype, whereas c.860G>A (p.R287Q) is associated with a relatively severe congenital muscular dystrophy typically involving brain development. Sixty-six percent of GMPPB families to date have one of these common variants.

Research paper thumbnail of Follow up on pediatric swallowing videofluoroscopy

Developmental Medicine & Child Neurology, Nov 23, 1987

Research paper thumbnail of Access to novel therapies for Duchenne muscular dystrophy—Insights from expert treating physicians

Annals of the Child Neurology Society, Jun 11, 2024

Research paper thumbnail of Access to novel therapies for Duchenne muscular dystrophy—Insights from expert treating physicians

Annals of the Child Neurology Society, Jun 11, 2024

Research paper thumbnail of Thrombotic Microangiopathy (TMA): A potential adverse reaction post Zolgensma (onasemnogene abeparvovec-xioi) therapy for Spinal Muscular Atrophy (SMA) (5483)

Research paper thumbnail of Limb-Girdle Muscular Dystrophy R9 due to a Novel Complex Insertion/Duplication Variant in FKRP Gene

Child Neurology Open

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by p... more Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogene...

Research paper thumbnail of Limb-Girdle Muscular Dystrophy R9 due to a Novel Complex Insertion/Duplication Variant in FKRP Gene

Child Neurology Open

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by p... more Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogene...

Research paper thumbnail of Anti-dopaminergic medication related myopathy causing respiratory muscle weakness without neuroleptic malignant syndrome (P3.461)

Objective: We report a case of toxic myopathy with severe respiratory muscle weakness due to anti... more Objective: We report a case of toxic myopathy with severe respiratory muscle weakness due to anti-dopaminergic medications. Background: Several studies report muscle toxicity related to anti-dopaminergic medications, with up to 10% of patients developing serum creatine kinase (CK) elevation. While CK elevation can be extreme in neuroleptic malignant syndrome, severe motor weakness has rarely been reported. Design/Methods: Case report Results: A 29-year-old man with history of obsessive compulsive disorder and Tourette’s syndrome presented to the hospital for worsening dyspnea. A year prior, after an increased risperidone dose from 0.5mg to 1mg daily, the patient developed severe proximal muscle weakness, including respiratory weakness, with an elevated CK of 5932 units/L. Electromyography revealed a myopathic process. Muscle biopsy showed many degenerating, vacuolated fibers with a histiocytic infiltrate and a few T-cells. After discontinuation of risperidone, the patient improved c...

Research paper thumbnail of Combination molecular therapies for type 1 spinal muscular atrophy

Research paper thumbnail of Clinical Reasoning: A 6 year old boy with muscle twitching

Research paper thumbnail of Pseudometabolic Presentation of Dystrophinopathy in a Family Due to a Rare Nonsense Mutation

Journal of Clinical Neuromuscular Disease

Research paper thumbnail of BAG3 Myopathy Presenting With Prominent Neuropathic Phenotype and No Cardiac or Respiratory Involvement

Journal of Clinical Neuromuscular Disease

Research paper thumbnail of A novel noncoding FKRP mutation in early onset limb-girdle muscular dystrophy

Neurology Genetics

Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the ar... more Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Research paper thumbnail of Dystrophinopathy in a Family Due to a Rare Nonsense Mutation Causing Predominant Behavioral Phenotype

Journal of Pediatric Neurology

Dystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DM... more Dystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are neede...

Research paper thumbnail of Constitutive activation of the PI3K‐AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome

American Journal of Medical Genetics Part A

Research paper thumbnail of Toxic Myopathy due to Antidopaminergic Medication Without Neuroleptic Malignant Syndrome

Journal of Clinical Neuromuscular Disease

Research paper thumbnail of Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect

Molecular genetics and metabolism, 2018

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phe... more Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.

Research paper thumbnail of De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

Cold Spring Harbor molecular case studies, 2017

Using whole-exome sequencing, we identified seven unrelated individuals with global developmental... more Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

Research paper thumbnail of Omics and EBM: Towards the Art of Individualization or the Standardization of Science - Which Way is this Train Headed?

Pediatrics & Therapeutics, 2012

Research paper thumbnail of Early identification and habilitation services

The Journal of the Arkansas Medical Society, 1988

Research paper thumbnail of <i>GMPPB</i>-Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation

Human Mutation, Sep 23, 2015

Mutations in GDP-mannose pyrophosphorylase B (GMPPB), a catalyst for the formation of the sugar d... more Mutations in GDP-mannose pyrophosphorylase B (GMPPB), a catalyst for the formation of the sugar donor GDP-mannose, were recently identified as a cause of muscular dystrophy resulting from abnormal glycosylation of α-dystroglycan. In this series, we report nine unrelated individuals with GMPPB-associated dystroglycanopathy. The most mildly affected subject has normal strength at 25 years, whereas three severely affected children presented in infancy with intellectual disability and epilepsy. Muscle biopsies of all subjects are dystrophic with abnormal immunostaining for glycosylated α-dystroglycan. This cohort, together with previously published cases, allows preliminary genotype-phenotype correlations to be made for the emerging GMPPB common variants c.79G>C (p.D27H) and c.860G>A (p.R287Q). We observe that c.79G>C (p.D27H) is associated with a mild limb-girdle muscular dystrophy phenotype, whereas c.860G>A (p.R287Q) is associated with a relatively severe congenital muscular dystrophy typically involving brain development. Sixty-six percent of GMPPB families to date have one of these common variants.

Research paper thumbnail of Follow up on pediatric swallowing videofluoroscopy

Developmental Medicine & Child Neurology, Nov 23, 1987

Research paper thumbnail of Access to novel therapies for Duchenne muscular dystrophy—Insights from expert treating physicians

Annals of the Child Neurology Society, Jun 11, 2024

Research paper thumbnail of Access to novel therapies for Duchenne muscular dystrophy—Insights from expert treating physicians

Annals of the Child Neurology Society, Jun 11, 2024

Research paper thumbnail of Thrombotic Microangiopathy (TMA): A potential adverse reaction post Zolgensma (onasemnogene abeparvovec-xioi) therapy for Spinal Muscular Atrophy (SMA) (5483)

Research paper thumbnail of Limb-Girdle Muscular Dystrophy R9 due to a Novel Complex Insertion/Duplication Variant in FKRP Gene

Child Neurology Open

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by p... more Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogene...

Research paper thumbnail of Limb-Girdle Muscular Dystrophy R9 due to a Novel Complex Insertion/Duplication Variant in FKRP Gene

Child Neurology Open

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by p... more Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogene...

Research paper thumbnail of Anti-dopaminergic medication related myopathy causing respiratory muscle weakness without neuroleptic malignant syndrome (P3.461)

Objective: We report a case of toxic myopathy with severe respiratory muscle weakness due to anti... more Objective: We report a case of toxic myopathy with severe respiratory muscle weakness due to anti-dopaminergic medications. Background: Several studies report muscle toxicity related to anti-dopaminergic medications, with up to 10% of patients developing serum creatine kinase (CK) elevation. While CK elevation can be extreme in neuroleptic malignant syndrome, severe motor weakness has rarely been reported. Design/Methods: Case report Results: A 29-year-old man with history of obsessive compulsive disorder and Tourette’s syndrome presented to the hospital for worsening dyspnea. A year prior, after an increased risperidone dose from 0.5mg to 1mg daily, the patient developed severe proximal muscle weakness, including respiratory weakness, with an elevated CK of 5932 units/L. Electromyography revealed a myopathic process. Muscle biopsy showed many degenerating, vacuolated fibers with a histiocytic infiltrate and a few T-cells. After discontinuation of risperidone, the patient improved c...

Research paper thumbnail of Combination molecular therapies for type 1 spinal muscular atrophy

Research paper thumbnail of Clinical Reasoning: A 6 year old boy with muscle twitching

Research paper thumbnail of Pseudometabolic Presentation of Dystrophinopathy in a Family Due to a Rare Nonsense Mutation

Journal of Clinical Neuromuscular Disease

Research paper thumbnail of BAG3 Myopathy Presenting With Prominent Neuropathic Phenotype and No Cardiac or Respiratory Involvement

Journal of Clinical Neuromuscular Disease

Research paper thumbnail of A novel noncoding FKRP mutation in early onset limb-girdle muscular dystrophy

Neurology Genetics

Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the ar... more Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Research paper thumbnail of Dystrophinopathy in a Family Due to a Rare Nonsense Mutation Causing Predominant Behavioral Phenotype

Journal of Pediatric Neurology

Dystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DM... more Dystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are neede...

Research paper thumbnail of Constitutive activation of the PI3K‐AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome

American Journal of Medical Genetics Part A

Research paper thumbnail of Toxic Myopathy due to Antidopaminergic Medication Without Neuroleptic Malignant Syndrome

Journal of Clinical Neuromuscular Disease

Research paper thumbnail of Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect

Molecular genetics and metabolism, 2018

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phe... more Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.

Research paper thumbnail of De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

Cold Spring Harbor molecular case studies, 2017

Using whole-exome sequencing, we identified seven unrelated individuals with global developmental... more Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

Research paper thumbnail of Omics and EBM: Towards the Art of Individualization or the Standardization of Science - Which Way is this Train Headed?

Pediatrics & Therapeutics, 2012

Research paper thumbnail of Early identification and habilitation services

The Journal of the Arkansas Medical Society, 1988