Publications by authors named "Pedro Mancias"

27 Publications

  • Page 1 of 1

A De Novo case of autosomal dominant mitochondrial membrane protein-associated neurodegeneration.

Mol Genet Genomic Med 2021 May 27:e1706. Epub 2021 May 27.

Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Background: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a genetic neurodegenerative condition previously thought to be inherited only in an autosomal recessive pattern through biallelic pathogenic variants in C19orf12. Recent evidence has proposed that MPAN can also follow autosomal dominant forms of inheritance. We present a case of a de novo pathogenic variant in C19orf12 identified in a female with clinical features consistent with a diagnosis of MPAN, adding further evidence that the disease can be inherited in an autosomal dominant fashion.

Methods: A 17-year-old Hispanic female was born to non-consanguineous healthy parents. She developed progressive muscle weakness and dystonia beginning when she was 12 years old. Trio, whole-exome sequencing with mitochondrial genome sequencing, and deletion/duplication analysis of both nuclear and mitochondrial genomes was performed in December 2019.

Results: Whole-exome sequencing analysis revealed a single de novo variant in C19orf12. The specific variant is c.256C>T (p.Q86X) located in exon 3.

Conclusion: Our clinical report provides further clinical evidence that MPAN can be inherited in an autosomal dominant or recessive fashion. The patient's age of onset and clinical symptoms are very similar to the previous patient published with this specific variant as well as others with heterozygous pathogenic variants in C19orf12 in Gregory et al. 2019. Our case report highlights the importance of considering both autosomal dominant and autosomal recessive version of MPAN with all patients demonstrating clinical features suggestive of MPAN.
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http://dx.doi.org/10.1002/mgg3.1706DOI Listing
May 2021

Biallelic Pathogenic Variants in Associated With Congenital Myopathy.

Neurol Genet 2021 Jun 26;7(3):e589. Epub 2021 Apr 26.

Division of Neurology and Developmental Neuroscience (D.G.C., I.H., D.P., T.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital (D.G.C., I.H., D.P., J.R.L.), Houston, TX; Department of Molecular and Human Genetics (D.G.C., J.F., I.H., Z.C.A., H.D., R.A.G., D.M., D.P., J.E.P., J.R.L.), Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center (S.N.J., R.A.G., J.R.L.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (D.M.), Faculty of Medicine, Kuwait University, Safat, Kuwait; Division of Child and Adolescent Neurology (P.M.), Department of Pediatrics, University of Texas Health Science Center, Houston, TX; Pathology and Laboratory Medicine (M.B.B.), University of Texas Health Science Center at Houston-McGovern Medical School, Houston, TX; and Department of Pediatrics (J.R.L.), Baylor College of Medicine, Houston, TX.

Objective: Pathogenic variants in , the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic variants.

Methods: Clinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with -related congenital myopathy.

Results: A homozygous variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with -related congenital myopathy, were not observed in the patient reported here.

Conclusions: This report provides further evidence for the association of biallelic variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.
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http://dx.doi.org/10.1212/NXG.0000000000000589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105884PMC
June 2021

Office of Medical Education: Opportunities for Trainees to Engage and Lead in Curricular Innovation and Reform.

MedEdPORTAL 2021 03 4;17:11112. Epub 2021 Mar 4.

Executive Associate Vice Chancellor, Diversity, Equity, and inclusion, Health Sciences Center, University of New Mexico; President, Building the Next Generation of Academic Physicians Inc.; Executive Director, Latino Medical Student Association Inc.

Introduction: The AAMC prioritizes promoting a diverse and culturally competent workforce which is thought to have a positive impact on the health of people living in the US. There is a lack of diversity in the current landscape of academic medicine and strategies are needed to effect change. This module introduced undergraduate and graduate medical trainees to leadership skills and opportunities in curriculum innovation and reform by learning about and interacting with the office of medical education (OME) at their institutions.

Methods: We implemented a workshop using small-group case discussions and didactics to help medical students and residents learn how to: (1) describe the structure and functions of an OME, (2) describe leadership competencies associated with various roles within the OME, and (3) identify opportunities for trainees to engage with the OME on curricular innovation and reform, especially advancing diversity and inclusion.

Results: Across three sites, 45 learners completed partial or full workshop evaluations. Of learners, 22 (49%) were and 13 (29%) were in identifying leadership opportunities for trainees to become engaged through the OME. There was a statistically significant increase in confidence after the workshop in "discussing an interdisciplinary approach to the creation of a medical education innovation," and, "assessing the need for curricula change." Over 90% of attendees agreed learning objectives were met.

Discussion: This workshop succeeded in promoting awareness of the structure and function of OMEs and confidence in seeking opportunities to become engaged in medical education, especially in advancing diversity and inclusion.
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http://dx.doi.org/10.15766/mep_2374-8265.11112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970638PMC
March 2021

Hispanic Identity and Its Inclusion in the Race Discrimination Discourse in the United States.

Acad Med 2021 06;96(6):788-791

J.P. Sánchez is professor, Department of Emergency Medicine, vice chair for Diversity, Equity, and Inclusion, and fellowship director for Emergency Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.

As protests against racism occur all over the United States and medical institutions face calls to incorporate antiracism and health equity curricula into professional training and patient care, the antiracism discourse has largely occurred through a Black/African American and White lens. Hispanics, an umbrella category created by the U.S. government to include all people of Spanish-speaking descent, are the largest minority group in the country. Hispanics are considered an ethnic rather than a racial group, although some Hispanics self-identify their race in terms of their ethnicity and/or country of origin while other Hispanics self-identify with any of the 5 racial categories used by the U.S. government (White, Black/African American, American Indian or Alaska Native, Asian, or Native Hawaiian or Other Pacific Islander). Expanding the antiracism discourse in medicine to include Hispanic perspectives and the diversity of histories and health outcomes among Hispanic groups is crucial to addressing inequities and disparities in health and medical training. A lack of inclusion of Hispanics has contributed to a growing shortage of Hispanic physicians and medical school faculty in the United States as well as discrimination against Hispanic physicians, trainees, and patients. To reverse this negative trend and advance a health care equity and antiracist agenda, the authors offer steps that medical schools, academic medical centers, and medical accreditation and licensing bodies must take to increase the representation of Hispanics and foster their engagement in this evolving antiracism discourse.
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http://dx.doi.org/10.1097/ACM.0000000000003904DOI Listing
June 2021

Uniparental Disomy Leading to a Rare Juvenile Form of ALS.

J Pediatr Perinatol Child Health 2020 10;4(4):107-110. Epub 2020 Oct 10.

Department of Neurology, McGovern Medical School, University of Texas Houston Health Science Center, Houston, Texas, USA.

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http://dx.doi.org/10.26502/jppch.74050049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592712PMC
October 2020

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.

J Clin Invest 2019 12;129(12):5568-5583

The Jackson Laboratory, Bar Harbor, Maine, USA.

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.
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http://dx.doi.org/10.1172/JCI130600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877339PMC
December 2019

Genetic Testing Practices of Genetic Counselors, Geneticists, and Pediatric Neurologists With Regard to Childhood-Onset Neurogenetic Conditions.

J Child Neurol 2019 03 4;34(4):177-183. Epub 2019 Jan 4.

Genetic Counseling Program, University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.

Identifying genetic diagnoses for neurologic conditions with a considerable hereditary component, such as autism spectrum disorder, intellectual disability, and epilepsy, is critical to providing proper medical management for patients and their families. However, many patients with these conditions are not tested appropriately or receive no genetic testing at all. The current study was designed to characterize the genetic testing practices of the providers most likely to evaluate or order genetic testing for these patients: pediatric neurologists, geneticists, and genetic counselors. Significant variance was present between testing strategies selected by pediatric neurologists and those by geneticists and genetic counselors, supporting the need for updated genetic testing guidelines that are consistent across specialties. Pediatric neurologists also report lower confidence in ordering genetic testing and desire further education regarding genetic testing. Together, these results propose that continued integration of genetics providers, such as genetic counselors, into pediatric neurology clinics may improve utilization of genetic testing while reducing the burden on pediatric neurologists.
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http://dx.doi.org/10.1177/0883073818821036DOI Listing
March 2019

Transverse Myelitis and Guillain-Barré Syndrome Associated with Cat-Scratch Disease, Texas, USA, 2011.

Emerg Infect Dis 2018 09;24(9):1754-1755

We describe a case of coexisting transverse myelitis and Guillain-Barré syndrome related to infection with Bartonella henselae proteobacterium and review similar serology-proven cases. B. henselae infection might be emerging as a cause of myelitis and Guillain-Barré syndrome and should be considered as an etiologic factor in patients with such clinical presentations.
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http://dx.doi.org/10.3201/eid2409.180008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106413PMC
September 2018

Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency.

Mol Genet Metab 2017 11 25;122(3):117-121. Epub 2017 Aug 25.

Department of Neurology & Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Neuromuscular Center, Institute for Exercise and Environmental Medicine of Texas Health Presbyterian Hospital, Dallas, USA; North Texas VA Health Care System, Dallas, TX, USA. Electronic address:

Objective: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis.

Methods: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response.

Results: Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal.

Conclusions: The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder.
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http://dx.doi.org/10.1016/j.ymgme.2017.08.007DOI Listing
November 2017

Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS.

EMBO Mol Med 2016 12 1;8(12):1421-1437. Epub 2016 Dec 1.

Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan

A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria-associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS-linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IPR3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)-mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IPR3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R- and SOD1-linked ALS Furthermore, our discovery of the selective enrichment of IPR3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.
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http://dx.doi.org/10.15252/emmm.201606403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167132PMC
December 2016

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

Genet Med 2017 01 19;19(1):45-52. Epub 2016 May 19.

Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.

Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.

Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.

Results: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.

Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.
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http://dx.doi.org/10.1038/gim.2016.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116288PMC
January 2017

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.

Cell Rep 2015 Aug 6;12(7):1169-83. Epub 2015 Aug 6.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.
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http://dx.doi.org/10.1016/j.celrep.2015.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545408PMC
August 2015

Sural sparing pattern discriminates Guillain-Barré syndrome from its mimics.

Muscle Nerve 2014 Nov 24;50(5):780-4. Epub 2014 Sep 24.

Department of Neurology, University Düsseldorf, Medical Faculty, Düsseldorf, Germany.

Introduction: Electrodiagnostic features of demyelination are essential for establishing the diagnosis in demyelinating subtypes of Guillain-Barré syndrome (GBS), but they may also occur in disorders that mimic GBS clinically. Information about their frequency in GBS mimics is sparse.

Methods: Evaluation of electrodiagnostic features from 38 patients with suspected GBS in whom the diagnosis was later refuted (GBS mimics). Their diagnostic accuracy was analyzed by comparison with nerve conduction studies (NCS) from 73 confirmed GBS patients.

Results: Disorders that mimicked GBS clinically at the time of hospital admission included other inflammatory, metabolic, toxic, or infectious neuropathies and spinal cord disorders. The sural sparing pattern was the most specific electrodiagnostic feature for demyelinating GBS.

Conclusions: Common electrodiagnostic abnormalities in early demyelinating GBS do not usually exclude other rare differential diagnoses. An exception to this is the sural sparing pattern described here, which strongly supports the diagnosis of demyelinating GBS.
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http://dx.doi.org/10.1002/mus.24226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431612PMC
November 2014

Cerebral sinovenous thrombosis associated with iron deficiency anemia secondary to severe menorrhagia: a case report.

J Child Neurol 2014 Sep 20;29(9):NP62-4. Epub 2013 Sep 20.

Department of Pediatrics, The University of Texas Health Science Center, Houston, TX, USA

Cerebral sinovenous thrombosis is a rare condition presenting with a wide spectrum of nonspecific symptoms that can make early diagnosis difficult. Cerebral sinovenous thrombosis has been associated with various etiologies. Iron deficiency anemia associated with cerebral sinovenous thrombosis in teenagers is rare. We present a teenage patient with complete thrombosis of the vein of Galen, straight sinus, and left internal cerebral vein associated with iron deficiency anemia due to severe menorrhagia. Mechanisms that can explain the association between iron deficiency anemia and thrombosis are discussed.
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http://dx.doi.org/10.1177/0883073813500715DOI Listing
September 2014

Dysferlinopathy presenting as rhabdomyolysis and acute renal failure.

J Child Neurol 2013 Apr 1;28(4):502-5. Epub 2012 May 1.

Department of Pediatrics, Division of Child and Adolescent Neurology, University of Texas Medical School at Houston, Houston, TX 77030, USA.

Dysferlinopathies are a heterogeneous group of autosomal recessive muscle disorders resulting from defects or deficiencies in dysferlin. Reported phenotypes range from isolated hyperCKemia to muscular dystrophy. We present a 15-year-old male adolescent who was diagnosed with a dysferlinopathy after presenting with acute renal failure secondary to rhabdomyolysis.
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http://dx.doi.org/10.1177/0883073812444607DOI Listing
April 2013

Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations.

Neurogenetics 2007 Nov 24;8(4):257-62. Epub 2007 Aug 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm 604B, Houston, TX 77030, USA.

Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies. We ascertained ten consecutive patients with various EGR2 mutations, report a novel de novo mutation, and provide longitudinal clinical data to characterize the natural history of the peripheral neuropathy. We confirmed that respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations and can be useful in guiding molecular diagnosis. We also contrast morphological studies in the context of the I268N homozygous recessive mutation affecting the NAB repressor binding site and the R359W dominant-negative mutation in the zinc-finger domain.
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http://dx.doi.org/10.1007/s10048-007-0094-0DOI Listing
November 2007

Living-donor nerve transplantation for global obstetric brachial plexus palsy.

J Reconstr Microsurg 2006 May;22(4):245-54

Division of Immunology and Organ Transplantation, Department of Surgery, Houston, TX, USA.

The first reported case of live-donor nerve transplantation is presented, performed in an 8-month-old infant with global obstetric brachial plexus palsy (OBPP) and four root avulsions who had undergone prior sural nerve autografting at 3 months. Cross-chest C7 nerve transfer and temporary tacrolimus/prednisone immunosuppression were utilized. Acute rejection was prevented, with no observable complications from the immunosuppressive medications, ipsilateral deficits resulting from the use of the contralateral C7 root as a donor nerve, or untoward effects on growth and development occurring over a 2-year follow-up period. Although some return of sensory and motor responses on nerve conduction studies was documented, the failure to observe a clinically significant functional improvement in the affected limb directly attributable to the transplant may have been due to performing the procedure too late and/or inadequate follow-up. Results of additional cases performed earlier than in this patient with longer follow-up will need to be evaluated to determine whether the procedure proves to be a viable therapeutic option for treatment of global OBPP with four or five root avulsions.
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http://dx.doi.org/10.1055/s-2006-939929DOI Listing
May 2006

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Brain 2006 Aug 19;129(Pt 8):2093-102. Epub 2006 May 19.

Peripheral Neuropathy Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.
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http://dx.doi.org/10.1093/brain/awl126DOI Listing
August 2006

SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation.

Hum Mutat 2005 Apr;25(4):372-83

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF. Here we show that the LITAF transcript appears to result from a DNA sequencing error. We screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families we identified nine different nucleotide variations in SIMPLE that were not detected in control chromosomes. SIMPLE mutations can occur de novo, associated with sporadic CMT1 and may convey both demyelinating and axonal forms. Bioinformatics analyses and other observations of SIMPLE suggest that 1) it could be a member of the RING finger motif-containing subfamily of E3 ubiquitin ligases that are associated with the ubiquitin-mediated proteasome processing pathway, 2) it could interact through its PPXY motifs with a WW domain containing protein, for instance with NEDD4, an E3 ubiquitin ligase, and 3) it could interact through the PSAP motif with TSG10, a protein associated with endosomal multivesicular protein sorting. Since both SIMPLE and Hrs are endosomal proteins and have both PPXY and P(S/T)AP motifs, we hypothesize that SIMPLE, like Hrs, is potentially a clathrin adaptor aiding in the retention of ubiquitinated proteins on to the endosomes. Thus the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease.
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http://dx.doi.org/10.1002/humu.20153DOI Listing
April 2005

Poliomyelitis-like syndrome in a child with West Nile virus infection.

Pediatr Infect Dis J 2004 Aug;23(8):788-9

Division of Infectious Diseases, UT-Medical School at Houston, Houston, TX, USA.

West Nile virus (WNV) infections of the central nervous system are very uncommon in U.S. children. We report a child with a poliomyelitis-like presentation in which WNV was the only detected pathogen. WNV has not previously been associated with a poliomyelitis-like presentation in children.
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http://dx.doi.org/10.1097/01.inf.0000134309.46460.82DOI Listing
August 2004

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.

Nat Genet 2004 Apr 7;36(4):361-9. Epub 2004 Mar 7.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, Texas 77030, USA.

The molecular mechanisms by which different mutations in the same gene can result in distinct disease phenotypes remain largely unknown. Truncating mutations of SOX10 cause either a complex neurocristopathy designated PCWH or a more restricted phenotype known as Waardenburg-Shah syndrome (WS4; OMIM 277580). Here we report that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway. We observe similar results for truncating mutations of MPZ that convey distinct myelinopathies. Our experiments show that triggering NMD and escaping NMD may cause distinct neurological phenotypes.
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http://dx.doi.org/10.1038/ng1322DOI Listing
April 2004

Trigeminal myokymia in a young girl.

J Child Neurol 2003 Aug;18(8):572-4

Department of Neurology, The University of Texas Medical School at Houston, 77030, USA.

Myokymia results from complex bursts of repetitive discharges of a motor unit typically attributable to a demyelinating condition. We report a 12-year-old girl with unilateral trigeminal myokymia who presented with involuntary jaw movements. Electromyography demonstrated unilateral rhythmic myokymic discharges in the left masseter and temporalis muscles at a rate of 3.5 Hz. Abnormal jaw movements spontaneously resolved over 8 months without treatment or residual deficits. The pathophysiology of myokymic discharges is discussed.
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http://dx.doi.org/10.1177/08830738030180081201DOI Listing
August 2003

CMT4A: identification of a Hispanic GDAP1 founder mutation.

Ann Neurol 2003 Mar;53(3):400-5

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Mutations of the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause autosomal recessive Charcot-Marie-Tooth disease type 4A. We report four additional families with recessive mutations (487C-->T, Q163X; 359G-->A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina.
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http://dx.doi.org/10.1002/ana.10505DOI Listing
March 2003

Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.

Ann Neurol 2003 Mar;53(3):354-65

Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.
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http://dx.doi.org/10.1002/ana.10466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744322PMC
March 2003

Lumbar spinal stenosis causing congenital clubfoot.

J Child Neurol 2002 Jan;17(1):72-4

Department of Neurology, University of Texas-Houston Medical School, 77030, USA.

Congenital lumbar spinal stenosis is believed to rarely cause neurologic symptoms during childhood. We present a 16-year-old boy with bilateral congenital clubfeet surgically corrected by tendo Achillis releases at 2 years of age who presented with progressive, bilateral footdrop. Magnetic resonance imaging of his lumbosacral spine showed severe spinal stenosis at the L3-5 vertebrae. Congenital lumbar spinal stenosis is probably an under-recognized cause of lower extremity neurologic abnormalities, including clubfoot deformity. Magnetic resonance imaging has made this eminently treatable disorder easier to recognize.
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http://dx.doi.org/10.1177/088307380201700122DOI Listing
January 2002

Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.

Ann Neurol 2002 Feb;51(2):190-201

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.
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http://dx.doi.org/10.1002/ana.10089DOI Listing
February 2002