Publications by authors named "Kathryn J Swoboda"

124 Publications

Natural history of 10-meter walk/run test performance in spinal muscular atrophy: A longitudinal analysis.

Neuromuscul Disord 2021 Aug 24. Epub 2021 Aug 24.

Department of Neurology and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States.

As trials and treatments for spinal muscular atrophy (SMA) rapidly evolve, understanding the natural history and potential utility of the 10-meter walk/run test (10MWRT) in ambulant individuals is critical. Study aims were to: 1) establish change over time and across age for 10MWRT time in an untreated natural history cohort of young, ambulatory participants with SMA and 2) identify relations between 10MWRT time and age, SMA type, SMN2 copy number and anthropometrics. Untreated individuals (n = 56) age 2 to 21 years who were enrolled in a long-term natural history study between 2005 and 2014 and met inclusion criteria were included. Linear mixed effects models were used to assess changes in 10MWRT time with age and associations with SMA type, SMN2 copy number, and body mass. SMA type 3b (versus 3a), SMN2 copy number 4 (versus 3) and lower body mass were associated with faster 10MWRT. 10MWRT performance improved between 3 and 8 years of age, was stable between 9 and 10, and gradually declined from 11 to 18. Findings provide the first longitudinal natural history report of 10MWRT time in young individuals with SMA and offer a critical foundation for interpreting childhood change in short distance walking speed with pharmacologic treatment.
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http://dx.doi.org/10.1016/j.nmd.2021.08.010DOI Listing
August 2021

Implications of circulating neurofilamentsfor spinal muscular atrophytreatment early in life: A case series.

Mol Ther Methods Clin Dev 2021 Dec 30;23:524-538. Epub 2021 Oct 30.

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

This longitudinal cohort study aimed to determine whether circulating neurofilaments (NFs) can monitor response to molecular therapies in newborns with spinal muscular atrophy (SMA; NCT02831296). We applied a mixed-effect model to examine differences in serum NF levels among healthy control infants (n = 13), untreated SMA infants (n = 68), and SMA infants who received the genetic therapies nusinersen and/or onasemnogene abeparvovec (n = 22). Increased NF levels were inversely associated with copy number. SMA infants treated with either nusinersen or onasemnogene abeparvovec achieved important motor milestones not observed in the untreated cohort. NF levels declined more rapidly in the nusinersen cohort as compared with the untreated cohort. Unexpectedly, those receiving onasemnogene abeparvovec monotherapy showed a significant rise in NF levels regardless of copy number. In contrast, symptomatic SMA infants who received nusinersen, followed by onasemnogene abeparvovec within a short interval after, did not show an elevation in NF levels. While NF cannot be used as the single marker to predict outcomes, the elevated NF levels observed with onasemnogene abeparvovec and its absence in infants treated first with nusinersen may indicate a protective effect of co-therapy during a critical period of vulnerability to acute denervation.
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http://dx.doi.org/10.1016/j.omtm.2021.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605296PMC
December 2021

Cancer-induced muscle atrophy is determined by intrinsic muscle oxidative capacity.

FASEB J 2021 07;35(7):e21714

School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.

We tested the hypothesis that cancer cachexia progression would induce oxidative post-translational modifications (Ox-PTMs) associated with skeletal muscle wasting, with different responses in muscles with the prevalence of glycolytic and oxidative fibers. We used cysteine-specific isotopic coded affinity tags (OxICAT) and gel-free mass spectrometry analysis to investigate the cysteine Ox-PTMs profile in the proteome of both plantaris (glycolytic) and soleus (oxidative) muscles in tumor-bearing and control rats. Histological analysis revealed muscle atrophy in type II fibers in plantaris muscle, with no changes in plantaris type I fibers and no differences in both soleus type I and II fibers in tumor-bearing rats when compared to healthy controls. Tumor progression altered the Ox-PTMs profile in both plantaris and soleus. However, pathway analysis including the differentially oxidized proteins revealed tricarboxylic acid cycle and oxidative phosphorylation as main affected pathways in plantaris muscle from tumor-bearing rats, while the same analysis did not show main metabolic pathways affected in the soleus muscle. In addition, cancer progression affected several metabolic parameters such as ATP levels and markers of oxidative stress associated with muscle atrophy in plantaris muscle, but not in soleus. However, isolated soleus from tumor-bearing rats had a reduced force production capacity when compared to controls. These novel findings demonstrate that tumor-bearing rats have severe muscle atrophy exclusively in glycolytic fibers. Cancer progression is associated with cysteine Ox-PTMs in the skeletal muscle, but these modifications affect different pathways in a glycolytic muscle compared to an oxidative muscle, indicating that intrinsic muscle oxidative capacity determines the response to cancer cachectic effects.
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http://dx.doi.org/10.1096/fj.202100263RDOI Listing
July 2021

Massachusetts' Findings from Statewide Newborn Screening for Spinal Muscular Atrophy.

Int J Neonatal Screen 2021 May 23;7(2). Epub 2021 May 23.

New England Newborn Screening Program, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Massachusetts began newborn screening (NBS) for Spinal Muscular Atrophy (SMA) following the availability of new treatment options. The New England Newborn Screening Program developed, validated, and implemented a screening algorithm for the detection of SMA-affected infants who show absent Exon 7 by Real-Time™ quantitative PCR (qPCR). We screened 179,467 neonates and identified 9 SMA-affected infants, all of whom were referred to a specialist by day of life 6 (average and median 4 days of life). Another ten hybrids were observed but never referred. The nine referred infants who were confirmed to have SMA were entered into treatment protocols. Early data show that some SMA-affected children have remained asymptomatic and are meeting developmental milestones and some have mild to moderate delays. The Massachusetts experience demonstrates that SMA NBS is feasible, can be implemented on a population basis, and helps engage infants for early treatment to maximize benefit.
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http://dx.doi.org/10.3390/ijns7020026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162354PMC
May 2021

Increased systemic HSP70B levels in spinal muscular atrophy infants.

Ann Clin Transl Neurol 2021 07 15;8(7):1495-1501. Epub 2021 May 15.

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Despite newly available treatments for spinal muscular atrophy (SMA), novel circulating biomarkers are still critically necessary to track SMA progression and therapeutic response. To identify potential biomarkers, we performed whole-blood RNA sequencing analysis in SMA type 1 subjects under 1 year old and age-matched healthy controls. Our analysis revealed the Heat Shock Protein Family A Member 7 (HSPA7)/heat shock 70kDa protein 7 (HSP70B) as a novel candidate biomarker to track SMA progression early in life. Changes in circulating HSP70B protein levels were associated with changes in circulating neurofilament levels in SMA newborns and infants. Future studies will determine whether HSP70B levels respond to molecular therapies.
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http://dx.doi.org/10.1002/acn3.51377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283166PMC
July 2021

Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec.

Mol Ther Methods Clin Dev 2021 Jun 24;21:76-82. Epub 2021 Feb 24.

Center for Gene Therapy, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.

Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human gene. We report anti-adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti-adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti-adeno-associated virus serotype 9 antibody titers >1:50.
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http://dx.doi.org/10.1016/j.omtm.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973120PMC
June 2021

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA.

Sci Transl Med 2021 01;13(578)

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.
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http://dx.doi.org/10.1126/scitranslmed.abb6871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208236PMC
January 2021

Detection of SMN1 to SMN2 gene conversion events and partial SMN1 gene deletions using array digital PCR.

Neurogenetics 2021 03 7;22(1):53-64. Epub 2021 Jan 7.

Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutations of survival motor neuron 1 (SMN1) but retention of one or more copies of the paralog SMN2. Within the SMA population, there is substantial variation in SMN2 copy number (CN); in general, those individuals with SMA who have a high SMN2 CN have a milder disease. Because SMN2 functions as a disease modifier, its accurate CN determination may have clinical relevance. In this study, we describe the development of array digital PCR (dPCR) to quantify SMN1 and SMN2 CNs in DNA samples using probes that can distinguish the single nucleotide difference between SMN1 and SMN2 in exon 8. This set of dPCR assays can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 CN and disease severity. We can detect SMN1-SMN2 gene conversion events in DNA samples by comparing CNs at exon 7 and exon 8. Partial deletions of SMN1 can also be detected with dPCR by comparing CNs at exon 7 or exon 8 with those at intron 1. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 CNs from SMA samples as well as identify gene conversion events and partial deletions of SMN1.
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http://dx.doi.org/10.1007/s10048-020-00630-5DOI Listing
March 2021

Unusual inclusions in cerebrospinal fluid macrophages of spinal muscular atrophy patients treated with nusinersen.

Int J Lab Hematol 2021 06 17;43(3):e104-e106. Epub 2020 Nov 17.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1111/ijlh.13392DOI Listing
June 2021

A novel pathogenic variant in DYNC1H1 causes various upper and lower motor neuron anomalies.

Eur J Med Genet 2020 Dec 16;63(12):104063. Epub 2020 Sep 16.

ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories and Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA; Clinical Genomics Program, GeneDx, MD, USA. Electronic address:

Objective: To perform genotype-phenotype, clinical and molecular analysis in a large 3-generation family with autosomal dominant congenital spinal muscular atrophy.

Methods: Using a combined genetic approach including whole genome scanning, next generation sequencing-based multigene panel, whole genome sequencing, and targeted variant Sanger sequencing, we studied the proband and multiple affected individuals of this family who presented bilateral proximal lower limb muscle weakness and atrophy.

Results: We identified a novel heterozygous variant, c.1826T > C; p.Ile609Thr, in the DYNC1H1 gene localized within the common haplotype in the 14q32.3 chromosomal region which cosegregated with disease in this large family. Within the family, affected individuals were found to have a wide array of clinical variability. Although some individuals presented the typical lower motor neuron phenotype with areflexia and denervation, others presented with muscle weakness and atrophy, hyperreflexia, and absence of denervation suggesting a predominant upper motor neuron disease. In addition, some affected individuals presented with an intermediate phenotype characterized by hyperreflexia and denervation, expressing a combination of lower and upper motor neuron defects.

Conclusion: Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family.
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http://dx.doi.org/10.1016/j.ejmg.2020.104063DOI Listing
December 2020

Stander Use in Spinal Muscular Atrophy: Results From a Large Natural History Database.

Pediatr Phys Ther 2020 07;32(3):235-241

Department of Physical Therapy (Dr Townsend), School of Health and Rehabilitation Sciences, MGH Institute of Health Professions, Boston, Massachusetts; Center for Genomic Medicine and Department of Neurology (Drs Townsend, Simeone, and Swoboda and Mr Zhang), Massachusetts General Hospital, Boston, Massachusetts; Department of Physical Therapy and Human Movement Sciences and Department of Pediatrics (Dr Krosschell), Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Purpose: The purpose of this study was to describe stander use in a natural history cohort of drug therapy-naïve children with spinal muscular atrophy (SMA) who are not walking and identify factors associated with consistent stander use.

Methods: Data from 397 children with SMA types 1 and 2 characterized the prevalence and frequency of stander use. Predictors of consistent stander use explored were SMA type, survival motor neuron 2 gene (SMN2) copy number, respiratory support, and motor performance.

Results: Prevalence of consistent stander use was 13% in type 1 and 68% in type 2. SMA type, SMN2 copy number, respiratory support, and head rotation control each predicted consistent stander use.

Conclusions: Findings characterize stander use in children with SMA who are not walking, address important safety considerations, identify factors that may inform physical therapists' clinical decision-making related to standing program prescription, and provide guidance for future prospective studies.
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http://dx.doi.org/10.1097/PEP.0000000000000713DOI Listing
July 2020

Whole-blood dysregulation of actin-cytoskeleton pathway in adult spinal muscular atrophy patients.

Ann Clin Transl Neurol 2020 07 17;7(7):1158-1165. Epub 2020 Jun 17.

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Objective: Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age- and gender-matched controls (n = 34).

Methods: We performed the first large-scale whole blood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes.

Results: The primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton," and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patient-derived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first-degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation.

Interpretation: Our findings from whole blood and patient-derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.
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http://dx.doi.org/10.1002/acn3.51092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359125PMC
July 2020

Whole blood survival motor neuron protein levels correlate with severity of denervation in spinal muscular atrophy.

Muscle Nerve 2020 09 2;62(3):351-357. Epub 2020 Jul 2.

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Introduction: We sought to determine whether survival motor neuron (SMN) protein blood levels correlate with denervation and SMN2 copies in spinal muscular atrophy (SMA).

Methods: Using a mixed-effect model, we tested associations between SMN levels, compound muscle action potential (CMAP), and SMN2 copies in a cohort of 74 patients with SMA. We analyzed a subset of 19 of these patients plus four additional patients who had been treated with received gene therapy to examine SMN trajectories early in life.

Results: Patients with SMA who had lower CMAP values had lower circulating SMN levels (P = .04). Survival motor neuron protein levels were different between patients with two and three SMN2 copies (P < .0001) and between symptomatic and presymptomatic patients (P < .0001), with the highest levels after birth and progressive decline over the first 3 years. Neither nusinersen nor gene therapy clearly altered SMN levels.

Discussion: These data provide evidence that whole blood SMN levels correlate with SMN2 copy number and severity of denervation.
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http://dx.doi.org/10.1002/mus.26995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496476PMC
September 2020

Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN.

Mol Metab 2020 09 11;39:101012. Epub 2020 May 11.

School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil. Electronic address:

Objective: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia.

Methods: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats.

Results: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity.

Conclusions: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia.
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http://dx.doi.org/10.1016/j.molmet.2020.101012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283151PMC
September 2020

Neuronal modeling of alternating hemiplegia of childhood reveals transcriptional compensation and replicates a trigger-induced phenotype.

Neurobiol Dis 2020 07 27;141:104881. Epub 2020 Apr 27.

Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA. Electronic address:

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by heterozygous de novo missense mutations in the ATP1A3 gene that encodes the neuronal specific α3 subunit of the Na,K-ATPase (NKA) pump. Mechanisms underlying patient episodes including environmental triggers remain poorly understood, and there are no empirically proven treatments for AHC. In this study, we generated patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls for the E815K ATP1A3 mutation that causes the most phenotypically severe form of AHC. Using an in vitro iPSC-derived cortical neuron disease model, we found elevated levels of ATP1A3 mRNA in AHC lines compared to controls, without significant perturbations in protein expression. Microelectrode array analyses demonstrated that in cortical neuronal cultures, ATP1A3 iPSC-derived neurons displayed less overall activity than neurons differentiated from isogenic mutation-corrected and unrelated control cell lines. However, induction of cellular stress by elevated temperature revealed a hyperactivity phenotype following heat stress in ATP1A3 neurons compared to control lines. Treatment with flunarizine, a drug commonly used to prevent AHC episodes, did not impact this stress-triggered phenotype. These findings support the use of iPSC-derived neuronal cultures for studying complex neurodevelopmental conditions such as AHC and provide a platform for mechanistic discovery in a human disease model.
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http://dx.doi.org/10.1016/j.nbd.2020.104881DOI Listing
July 2020

Prospective Cohort Study of Nusinersen Treatment in Adults with Spinal Muscular Atrophy.

J Neuromuscul Dis 2020 ;7(3):257-268

Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Background: The impact of nusinersen therapy on outcomes in adults with Spinal Muscular Atrophy (SMA) remains uncertain.

Objective: To demonstrate whether nusinersen therapy, at currently prescribed doses, can stabilize or improve motor function in adults with SMA using existing outcome measures.

Methods: A single-center prospective cohort study of 6 adults with SMA type 3, with inclusion/exclusion criteria intended to optimize the ability to demonstrate change using established outcome measures. Primary outcomes were the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Measure (RULM). Secondary outcomes were the PedsQL Fatigue scale, the SMA Functional Rating Scale (SMAFRS), and the 6-minute and 10-meter walk tests (6 MWT and 10 MWT). Estimates of change in HFMSE and RULM mean scores across visits were calculated using a linear mixed effects model. Change from baseline was used for other outcome measures.

Results: HFMSE and RULM scores over 12 months were stable or improved in all participants, with a mean increase of 2 points in each. Other measures showed high intra-individual variability. Adverse events related to the primary diagnosis, including injury and infection, significantly impacted the ability to reliably perform walk tests in the four ambulatory participants.

Conclusions: HFMSE and RULM show potential as responsive outcome measures of motor function in ambulatory and non-ambulatory adults with SMA type 3. A time-dependent accrual of benefit of nusinersen on motor function was apparent in this cohort. More sensitive alternative measures of quality of life, fatigue, exercise tolerance, stability and ADLs are clearly needed for adults with SMA.
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http://dx.doi.org/10.3233/JND-190453DOI Listing
March 2021

Serum creatinine is a biomarker of progressive denervation in spinal muscular atrophy.

Neurology 2020 03 27;94(9):e921-e931. Epub 2019 Dec 27.

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston.

Objective: Identifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA.

Methods: We examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 () copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE).

Results: Patients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93-2.49; < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52-1.82; < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31-1.58; < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 copies had 1.8-fold (95% CI 1.57-2.11; < 0.0001) higher Crn levels compared to patients with SMA with 2 copies and 1.4-fold (95% CI 1.24-1.58; < 0.0001) higher Crn levels compared to patients with SMA with 3 copies. Patients with SMA with 3 copies had 1.4-fold (95% CI 1.21-1.56; < 0.0001) higher Crn levels than patients with SMA with 2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters ( < 0.0001) and positive associations between Crn and maximum CMAP ( < 0.0001) and between Crn and MUNE ( < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, copies, HFMS, CMAP, and MUNE.

Conclusions: These findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.
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http://dx.doi.org/10.1212/WNL.0000000000008762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238944PMC
March 2020

Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study.

Neuromuscul Disord 2019 11 12;29(11):842-856. Epub 2019 Sep 12.

Biogen, Cambridge, MA, USA.

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.
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http://dx.doi.org/10.1016/j.nmd.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127286PMC
November 2019

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment.

J Clin Invest 2019 11;129(11):4817-4831

Department of Neuroscience and.

BACKGROUNDSpinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge of baseline and drug-induced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments.METHODSSMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies.RESULTSSMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels.CONCLUSIONSA normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs.FUNDINGSMA Foundation, SMART, NIH (R01-NS096770, R01-NS062869), Ionis Pharmaceuticals, and PTC Therapeutics. Biogen provided support for absolute real-time RT-PCR.
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http://dx.doi.org/10.1172/JCI124120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819103PMC
November 2019

Impaired kidney structure and function in spinal muscular atrophy.

Neurol Genet 2019 Oct 12;5(5):e353. Epub 2019 Aug 12.

Department of Neurology (F.C.N., J.J.S., A.W.M., P.N., A.J.J., R.Z., M.F., N.H., C.R.R.A., K.J.S.), Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA; Department of Pathology (I.R.), Massachusetts General Hospital, Boston, MA; Regenerative Medicine Program (M.-O.D., R.K.), Ottawa Hospital Research, Institute Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine (M.-O.D., R.K.), University of Ottawa, Canada; Centre for Neuromuscular Disease (M.-O.D., R.K.), University of Ottawa, Ottawa, Ontario, Canada; Division of Pediatric Nephrology (A.S.), Massachusetts General Hospital, Boston, MA; Department of Biology (N.H.), Federal University of São Carlos, Sorocaba, Sao Paulo, SP, Brazil; and Department of Medicine (R.K.), University of Ottawa, Ottawa, Ontario, Canada.

Objective: To determine changes in serum profiles and kidney tissues from patients with spinal muscular atrophy (SMA) type 1 compared with age- and sex-matched controls.

Methods: In this cohort study, we investigated renal structure and function in infants and children with SMA type 1 in comparison with age- and sex-matched controls.

Results: Patients with SMA had alterations in serum creatinine, cystatin C, sodium, glucose, and calcium concentrations, granular casts and crystals in urine, and nephrocalcinosis and fibrosis. Nephrotoxicity and polycystic kidney disease PCR arrays revealed multiple differentially expressed genes, and immunoblot analysis showed decreased calcium-sensing receptors and calbindin and increased insulin-like growth factor-binding proteins in kidneys from patients with SMA.

Conclusions: These findings demonstrate that patients with SMA type 1, in the absence of disease-modifying therapies, frequently manifest impaired renal function as a primary or secondary consequence of their disease. This study provides new insights into systemic contributions to SMA disease pathogenesis and the need to identify coadjuvant therapies.
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http://dx.doi.org/10.1212/NXG.0000000000000353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705648PMC
October 2019

Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies.

Neurology 2019 05 24;92(21):e2492-e2506. Epub 2019 Apr 24.

From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.

Objective: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).

Methods: Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.

Results: Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.

Conclusions: Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.

Clinicaltrialsgov Identifier: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).

Classification Of Evidence: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.
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http://dx.doi.org/10.1212/WNL.0000000000007527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541434PMC
May 2019

Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development.

Proc Natl Acad Sci U S A 2019 04 1;116(16):7793-7798. Epub 2019 Apr 1.

Chemical Biology and Therapeutics Science, Broad Institute of Harvard and MIT, Cambridge, MA 02142;

Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by the addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test-retest reliability (mean coefficient of variation, 13% in samples collected 8-11 wk apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, and will facilitate development of prion disease therapeutics with this mechanism of action.
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http://dx.doi.org/10.1073/pnas.1901947116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475435PMC
April 2019

Genotype-structure-phenotype relationships diverge in paralogs , , and .

Neurol Genet 2019 Feb 4;5(1):e303. Epub 2019 Feb 4.

Department of Neurosurgery (K.J. Sweadner, E.A., J.T.P.), Center for Human Genetics Research (K.J. Swoboda), and Department of Neurology, (K.J. Swoboda, L.J.O.) Massachusetts General Hospital, Boston; and the Department of Neurology (A.B.), Wake Forest School of Medicine, Winston-Salem, NC.

Objective: We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases , , and .

Methods: Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology.

Results: Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in were absent from patient data. The known variants in fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites.

Conclusions: Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in that correlates with neurologic outcomes. The absence of "severe" pathogenic variants in patients predicts that they will manifest either in a different tissue or by death in utero and that new variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.
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http://dx.doi.org/10.1212/NXG.0000000000000303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384024PMC
February 2019

Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype.

Hum Genet 2019 Mar 20;138(3):241-256. Epub 2019 Feb 20.

Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by loss or mutation of the survival motor neuron 1 (SMN1) gene and retention of SMN2. We performed targeted capture and sequencing of the SMN2, CFTR, and PLS3 genes in 217 SMA patients. We identified a 6.3 kilobase deletion that occurred in both SMN1 and SMN2 (SMN1/2) and removed exons 7 and 8. The deletion junction was flanked by a 21 bp repeat that occurred 15 times in the SMN1/2 gene. We screened for its presence in 466 individuals with the known SMN1 and SMN2 copy numbers. In individuals with 1 SMN1 and 0 SMN2 copies, the deletion occurred in 63% of cases. We modeled the deletion junction frequency and determined that the deletion occurred in both SMN1 and SMN2. We have identified the first deletion junction where the deletion removes exons 7 and 8 of SMN1/2. As it occurred in SMN1, it is a pathogenic mutation. We called variants in the PLS3 and SMN2 genes, and tested for association with mild or severe exception patients. The variants A-44G, A-549G, and C-1897T in intron 6 of SMN2 were significantly associated with mild exception patients, but no PLS3 variants correlated with severity. The variants occurred in 14 out of 58 of our mild exception patients, indicating that mild exception patients with an intact SMN2 gene and without modifying variants occur. This sample set can be used in the association analysis of candidate genes outside of SMN2 that modify the SMA phenotype.
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http://dx.doi.org/10.1007/s00439-019-01983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503527PMC
March 2019

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Nat Commun 2018 11 5;9(1):4619. Epub 2018 Nov 5.

AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, 75013, France.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
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http://dx.doi.org/10.1038/s41467-018-06014-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218476PMC
November 2018

Harnessing the power of the patient perspective for rare disease therapeutics.

Neurology 2018 09 24;91(13):585-586. Epub 2018 Aug 24.

From the Center for Human Genomics, Massachusetts General Hospital Department of Neurology, Boston.

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http://dx.doi.org/10.1212/WNL.0000000000006230DOI Listing
September 2018

Recruitment & retention program for the NeuroNEXT SMA Biomarker Study: Super Babies for SMA!

Contemp Clin Trials Commun 2018 Sep 20;11:113-119. Epub 2018 Jul 20.

Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Background/aims: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible.

Methods: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study.

Results: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll.

Conclusions: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.
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http://dx.doi.org/10.1016/j.conctc.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072892PMC
September 2018

Novel Mutations Identified With Next-Generation Sequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical Phenotypes.

Child Neurol Open 2018 23;5:2329048X18789282. Epub 2018 Jul 23.

Pediatric Motor Disorders Research Program, Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.

Next-generation sequencing was performed for 2 families with an undiagnosed neurologic disease. Analysis revealed X-linked mutations in the () gene, which is associated with X-linked Pelizaeus-Merzbacher disease and Spastic Paraplegia type 2. In family A, the novel missense mutation c.617T>A (p.M206K) was hemizygous in the 2 affected male children and heterozygous in the mother. In family B, the novel frameshift mutation c.359_369del (p.G120fs) was hemizygous in the affected male child. Although mutations have been reported to cause an increasingly wide range of phenotypes inclusive of the dystonia, spastic paraparesis, motor neuronopathy, and leukodystrophy observed in our patients, atypical features included the cerebrospinal fluid deficiency of neurotransmitter and pterin metabolites and the delayed appearance of myelin abnormalities on neuroimaging studies. Next-generation sequencing studies provided a diagnosis for these families with complex leukodystrophy disease phenotypes, which expanded the spectrum of PLP1-associated leukodystrophy clinical phenotypes.
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http://dx.doi.org/10.1177/2329048X18789282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056774PMC
July 2018
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