Anne Rutkowski

University of California, Los Angeles, Los Angeles, California, United States

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Publications (9)22.92 Total impact

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    ABSTRACT: Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical as well genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis.
    Neuromuscular Disorders 01/2014; · 3.46 Impact Factor
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    ABSTRACT: The congenital muscular dystrophies (CMDs) comprise a heterogeneous group of heritable muscle disorders with often difficult to interpret muscle pathology, making them challenging to diagnose. Serial Sanger sequencing of suspected CMD genes, while the current molecular diagnostic method of choice, can be slow and expensive. A comprehensive panel test for simultaneous screening of mutations in all known CMD-associated genes would be a more effective diagnostic strategy. Thus, the CMDs are a model disorder group for development and validation of next-generation sequencing (NGS) strategies for diagnostic and clinical care applications. Using a highly multiplexed PCR-based target enrichment method (RainDance) in conjunction with NGS, we performed mutation detection in all CMD genes of 26 samples and compared the results with Sanger sequencing. The RainDance NGS panel showed great consistency in coverage depth, on-target efficiency, versatility of mutation detection, and genotype concordance with Sanger sequencing, demonstrating the test's appropriateness for clinical use. Compared to single tests, a higher diagnostic yield was observed by panel implementation. The panel's limitation is the amplification failure of select gene-specific exons which require Sanger sequencing for test completion. Successful validation and application of the CMD NGS panel to improve the diagnostic yield in a clinical laboratory was shown.
    PLoS ONE 01/2013; 8(1):e53083. · 3.73 Impact Factor
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    ABSTRACT: Congenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients. dy(2J) mice were treated with vehicle, 0.1 mg/kg or 1 mg/kg of omigapil daily via oral gavage over 17.5 weeks. Untreated age matched BL6 mice were used as controls. Functional, behavioral and histological measurements were collected. dy(2J) mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy(2J) mice (396 to 402 vs. 371 breaths per minute, p<0.03) and similar to control mice. There were no statistical differences in normalized forelimb grip strength between dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups. At 30-33 weeks of age, dy(2J) mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy(2J) mice showed normal cardiac systolic function throughout the trial. dy(2J) mice had significantly lower hindlimb maximal (p<0.001) and specific force (p<0.002) compared to the control group at the end of the trial. There were no statistically significant differences in maximal or specific force among treatments. dy(2J) mice treated with 0.1 mg/kg/day omigapil showed decreased percent fibrosis in both gastrocnemius (p<0.03) and diaphragm (p<0.001) compared to vehicle, and in diaphragm (p<0.013) when compared to 1 mg/kg/day omigapil treated mice. Omigapil treated dy(2J) mice demonstrated decreased apoptosis. Omigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.
    PLoS ONE 01/2013; 8(6):e65468. · 3.73 Impact Factor
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    ABSTRACT: The Myomatrix 2012 conference held April 22-24th, 2012 at the University of Nevada, Reno convened 73 international participants to discuss the dynamic relationship between muscle and its matrix in muscular dystrophy with a specific focus on congenital muscular dystrophy. Seven sessions over 2½ days defined three central themes: (1) the role of extracellular matrix proteins and compartments in development and specifically in congenital muscular dystrophy (CMD) (2) the role of extracellular matrix signaling and adhesion to membrane receptors and (3) the balance and interplay between inflammation and fibrosis as drivers of altered matrix stiffness, impaired regeneration and progressive dystrophy. This report highlights major conference findings and the translational roadmap as defined by conference attendees.
    Neuromuscular Disorders 07/2012; · 3.46 Impact Factor
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    ABSTRACT: Sequencing individual genes by Sanger sequencing is a time-consuming and costly approach to resolve clinically heterogeneous genetic disorders. Panel testing offers the ability to efficiently and cost-effectively screen all of the genes for a particular genetic disorder. We assessed the analytical sensitivity and specificity of two different enrichment technologies, solution-based hybridization and microdroplet-based PCR target enrichment, in conjunction with next-generation sequencing (NGS), to identify mutations in 321 exons representing 12 different genes involved with congenital muscular dystrophies. Congenital muscular dystrophies present diagnostic challenges due to phenotypic variability, lack of standard access to and inherent difficulties with muscle immunohistochemical stains, and a general lack of clinician awareness. NGS results were analyzed across several parameters, including sequencing metrics and genotype concordance with Sanger sequencing. Genotyping data showed that both enrichment technologies produced suitable calls for use in clinical laboratories. However, microdroplet-based PCR target enrichment is more appropriate for a clinical laboratory, due to excellent sequence specificity and uniformity, reproducibility, high coverage of the target exons, and the ability to distinguish the active gene versus known pseudogenes. Regardless of the method, exons with highly repetitive and high GC regions are not well enriched and require Sanger sequencing for completeness. Our study demonstrates the successful application of targeted sequencing in conjunction with NGS to screen for mutations in hundreds of exons in a genetically heterogeneous human disorder.
    The Journal of molecular diagnostics: JMD 03/2012; 14(3):233-46. · 3.48 Impact Factor
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    Neuromuscular Disorders 06/2011; 21(7):513-22. · 3.46 Impact Factor
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    ABSTRACT: Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.
    Journal of child neurology 11/2010; 25(12):1559-81. · 1.59 Impact Factor
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    ABSTRACT: Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. Muscle weakness may improve, worsen, or stabilize in the short term; however, with time progressive weakness and joint contractures, spinal deformities, and respiratory compromise may affect quality of life and life span. The main CMD subtypes, grouped by involved protein function and gene in which causative mutations occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutations in POMT1, POMT2, FKTN, FKRP, LARGE, and POMGNT1), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). Several less known CMD subtypes have been reported in a limited number of individuals. Cognitive impairment ranging from intellectual disability to mild cognitive delay, structural brain and/or eye abnormalities, and seizures are found almost exclusively in the dystroglycanopathies while white matter abnormalities without major cognitive involvement tend to be seen in the laminin alpha-2-deficient subtype. The diagnosis of congenital muscular dystrophy relies on clinical findings, brain and muscle imaging, muscle biopsy histology (dystrophic features without the hallmarks of the structural changes seen in the congenital myopathies), muscle and/or skin immunohistochemical staining, and molecular genetic testing. The congenital muscular dystrophies are inherited in an autosomal recessive manner with the exception of collagen VI-deficient CMD which may be inherited in an autosomal recessive or an autosomal dominant manner and LMNA-related CMD (L-CMD) which is inherited in an autosomal dominant manner with all cases to date caused by de novo mutation. In autosomal recessive subtypes, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carriers are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known. In autosomal dominant subtypes, the offspring of affected individuals have a 50% chance of being affected. The risk to sibs of an individual with an apparently de novo mutation is low, but not zero because of the possibility of germline mosaicism in one of the parents. Prenatal testing for pregnancies at increased risk is possible for families in which the disease-causing mutation has been identified. Treatment of manifestations: Treatment tailored to an individual’s needs is best managed by a multidisciplinary team. Speech therapy and swallowing studies are used to evaluate those with feeding difficulties and/or possible aspiration. Interventions may be needed for inadequate weight gain and poor feeding. Aspiration pneumonia and/or respiratory insufficiency may require assisted cough devices, supplemental oxygen, noninvasive ventilation, and/or mechanical ventilation via tracheostomy. Physical therapy focuses on stretching exercises of the spine and limbs and to prevent contractures, and positive pressure devices or ventilation to promote mobility of the thoracic cage. Splints, braces and surgical intervention are used to prevent and treat spinal and limb contractures and deformities; these and other assistive devices may help posture, ambulation, and mobility. Epilepsy, behavior problems, and/or intellectual disability require specific treatment and interventions. Vaccinations, early treatment of pulmonary infections, and attention to oral hygiene and care are important aspects of routine care. With support for their physical disabilities the vast majority of children with CMD who have normal cognitive development benefit socially and educationally from mainstreaming into regular educational facilities. The multidisciplinary team can provide social and emotional support for patients and caregivers. Surveillance: Routine monitoring of feeding and weight gain, respiratory function, strength, and mobility; annual or biannual monitoring for orthopedic and pulmonary complications; cardiac monitoring for those with CMD subtypes involving a risk for cardiomyopathy. Those with CMD subtypes with central nervous system involvement require surveillance for possible seizures and/or behavioral problems.
    01/1993;
  • Susana Quijano-Roy, Susan Sparks, Anne Rutkowski
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    ABSTRACT: The clinical manifestations of LAMA2-related muscular dystrophy (LAMA2 MD) range from severe, early-onset congenital muscular dystrophy (CMD) – referred to as early-onset LAMA2-related muscular dystrophy (LAMA2 MD) in this GeneReview – to mild, later childhood-onset limb-girdle type muscular dystrophy – referred to here as late-onset LAMA2-related muscular dystrophy (LAMA2 MD). Children with early-onset LAMA2 MD have profound hypotonia with muscle weakness evident at birth or within the first six months of life, poor spontaneous movements with contractures of the large joints, and weak cry often associated with respiratory failure. Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections are typical. Progressive scoliosis starting in childhood is common. Seizures and, less often, cardiac involvement can occur. Typically, individuals with early-onset LAMA2 MD do not achieve independent ambulation. Intellect is usually normal. Those with limb-girdle type muscular dystrophy have later onset of proximal muscle weakness and delayed motor milestones, but achieve independent ambulation; they may develop a rigid spine syndrome with joint contractures. Progressive respiratory insufficiency and scoliosis can occur. Diagnosis of LAMA2 MD is based on: clinical findings; elevated serum CK concentration; specific abnormal white matter signal on T2-weighted MRI by age one year; complete or partial laminin α2 deficiency on immunohistochemical (IHC) staining of muscle and/or skin; and biallelic mutation of LAMA2, the gene encoding the laminin subunit alpha-2. Treatment of manifestations: For infants and children with early-onset LAMA2 MD, multidisciplinary care may include: supplemental feeding and gastrostomy; cough assistance, followed by noninvasive ventilation support (intermittent positive pressure breathing [IPPB] or bilevel ventilation) for respiratory insufficiency; physical therapy and casts, splints, or orthotics for joint contractures; trunk orthotics or braces and spinal fusion as needed for scoliosis. Seizures are treated in a routine manner. Those with late-onset laminin α2 deficiency benefit from regular physical therapy to stretch the joints and spine and may need care for progressive respiratory insufficiency and joint and/or spinal deformities. Surveillance: Early-onset LAMA2 MD: During the first five years biannual follow up by: a dietician/gastroenterologist to assess nutritional intake and swallowing; a pulmonologist to assess respiratory function; a physical therapist to assess strength and joint range of motion; and an orthopedist to assess the spine. After age five years at least annual follow up is recommended if the disease course is stable. In the absence of cardiac symptoms, evaluation by a cardiologist including electrocardiogram and echocardiogram at age five years, ten years, and then every two years is recommended. Late-onset LAMA2 MD: Follow up with a pulmonologist, cardiologist, and physical therapist. Agents/circumstances to avoid: (1) Succinylcholine during induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities; (2) statin, cholesterol-lowering medication because of risk of muscle damage. LAMA2-related muscular dystrophy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.