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1.  SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet? 
Spinal muscular atrophy (SMA) remains one of the most common and lethal autosomal recessive diseases. Homozygous deletion of survival of motor neuron 1 (SMN1) and resulting SMN protein deficiency manifests predominantly with motor neuron degeneration; however, a wealth of emerging data supports a broader influence of SMN deficiency in disease pathogenesis. In this issue of the JCI, Kariya and colleagues demonstrate the relatively selective impact of SMN depletion on the distal motor unit using a series of SMN2-expressing transgenic mice in which constitutive SMN knockdown follows variable periods of normal development. Their observations provide further insights regarding the temporal requirements for SMN in mice, renewing speculation about when and where repletion of SMN is necessary for optimal outcomes in SMA patients.
PMCID: PMC3904635  PMID: 24463455
2.  Spinal Muscular Atrophy Genetic Counseling Access and Genetic Knowledge: Parents’ Perspectives 
Journal of Child Neurology  2007;22(8):1019-1026.
Spinal muscular atrophy is characterized by degeneration of α motor neurons in the anterior horns of the spinal cord, which leads to progressive symmetrical muscle weakness and atrophy. Spinal muscular atrophy is the leading fatal autosomal recessive disorder in infancy, and genetic counseling is an essential component of the care of families of these patients. However, little guidance is available in the published literature regarding the process and benefit of genetic counseling for families. Accordingly, the authors designed a questionnaire to assess parents’ knowledge of the disease, gauge their access to genetic counseling, and determine how parents use information gained from counseling to guide choices for future pregnancies. The questionnaire specifically targeted when genetic counseling was received, from whom, parental knowledge regarding spinal muscular atrophy genetics, parental choices regarding spinal muscular atrophy and their child, frequency of prenatal testing, perceived relevance of newborn screening, and opinions regarding the disease. Most families clearly received some type of genetic counseling. Yet how and from whom they received the information varied greatly, as did their genetic knowledge of spinal muscular atrophy. The highest percentage of families received counseling from neurologists, who may not be appropriately prepared to provide formal genetic counseling. Many respondents reported having a negative experience with genetic counseling, possibly because it occurred at the time of diagnosis or shortly afterward, a period of great emotional turmoil. These data suggest that a consistent approach for facilitating how and when genetic counseling is received is greatly needed.
PMCID: PMC3260047  PMID: 17761658
spinal muscular atrophy; genetic counseling; genetic testing; carrier testing; parents’ perspectives
3.  Perspectives on Clinical Trials in Spinal Muscular Atrophy 
Journal of Child Neurology  2007;22(8):957-966.
Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.
PMCID: PMC3260051  PMID: 17761650
spinal muscular atrophy; clinical trials; histone deacetylase inhibitors
4.  Of SMN in mice and men: a therapeutic opportunity 
The Journal of Clinical Investigation  2011;121(8):2978-2981.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that predominantly affects motor neurons, resulting in progressive muscular atrophy and weakness. SMA arises due to insufficient survival motor neuron (SMN) protein levels as a result of homozygous disruption of the SMN1 gene. SMN upregulation is a promising and potent treatment strategy for this currently incurable condition. In this issue of the JCI, two independent research groups report novel observations in mouse models of severe SMA that provide hope that this approach will afford meaningful benefit to individuals with SMA.
PMCID: PMC3148751  PMID: 21785213
5.  Spinal muscular atrophy type 1: Are proactive respiratory interventions associated with longer survival? 
Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading genetic cause of death in infancy and early childhood.
To determine whether the early initiation of noninvasive respiratory interventions is associated with longer survival.
Single-institution retrospective cohort study identified children with spinal muscular atrophy type 1 from January 1, 2002 to May 1, 2009 who were followed for 2.3 mean yrs.
Tertiary care children’s hospital and outpatient clinics in a vertically integrated healthcare system.
Patients or Other Participants
Forty-nine children with spinal muscular atrophy type 1 were grouped according to the level of respiratory support their caregivers chose within the first 3 months after diagnosis: proactive respiratory care (n = 26) and supportive care (n = 23).
Proactive respiratory care included bilevel non-invasive ventilation during sleep and twice a day cough assist while supportive respiratory care included suctioning, with or without supplemental oxygen.
Measurements and Main Results
Kaplan–Meier survival curves were assessed based on intention to treat. Children treated with early proactive respiratory support had statistically longer survival compared to supportive care (log rank 0.047); however, the adjusted hazard ratio for survival was not statistically different (2.44 [95% confidence interval 0.84–7.1]). Children in the proactive group were more likely to be hospitalized for respiratory insufficiency (83% vs. 46%) and had shortened time after diagnosis until first hospital admission for respiratory insufficiency (median 118 vs. 979 days).
Longer survival time with spinal muscular atrophy type 1 is associated with early, noninvasive respiratory care interventions after diagnosis.
PMCID: PMC4334579  PMID: 22198810
noninvasive ventilation; respiratory failure; spinal muscular atrophy; survival analysis
6.  Nutritional Practices at a Glance: Spinal Muscular Atrophy Type I Nutrition Survey Findings 
Journal of child neurology  2013;29(11):1467-1472.
Proactive nutritional management for children with spinal muscular atrophy type I can provide insight into improved spinal muscular atrophy care. This observational study consisted of a nutritional and medical history survey of children with spinal muscular atrophy type I collected in 2009-2011. Forty-four caregiver survey responses were evaluated using descriptive statistics. Average age of spinal muscular atrophy type I subjects was 5 years (5 mo-16 y). The subject cohort was composed of 22 males, 21 females, and 1 unreported. Nutrition support via feeding tube was utilized by 43 of 44 subjects. A majority of respondents reported using elemental or semi-elemental formula for subjects’ essential caloric intake (34 of 44). Formula intolerance issues were reported by many caregivers (27 of 44). Half of caregivers implemented dietary changes on their own or with guidance from other families; 15 caregivers consulted a registered dietitian. Survey responses and comments indicate need for evidence-based nutritional guidelines for spinal muscular atrophy.
PMCID: PMC4334580  PMID: 24097849
SMA nutrition; spinal muscular atrophy type I; elemental diet
7.  Motor Unit Number Estimation in Infants and Children with Spinal Muscular Atrophy 
Muscle & nerve  2002;25(3):445-447.
Spinal muscular atrophy (SMA) is a disease of lower motor neurons. Motor unit number estimation (MUNE) is an electrophysiologic method to estimate the number of motor neurons innervating a muscle group. We applied the multiple point stimulation technique to the ulnar nerve–hypothenar muscle group to study lower motor neuron loss in 14 SMA subjects, including those presymptomatic, and varying from newborn through 45 years of age. Preliminary data support the value of MUNE to help understand the time course of motor neuron loss in SMA.
PMCID: PMC4334581  PMID: 11870724
motor neuron disease; motor unit number estimation (MUNE); spinal muscular atrophy (SMA)
8.  Natural History of Denervation in SMA: Relation to Age, SMN2 Copy Number, and Function 
Annals of neurology  2005;57(5):704-712.
Denervation was assessed in 89 spinal muscular atrophy (SMA) 1, 2, and 3 subjects via motor unit number estimation (MUNE) and maximum compound motor action potential amplitude (CMAP) studies, and results correlated with SMN2 copy, age, and function. MUNE and maximum CMAP values were distinct among SMA subtypes (p < 0.05). Changes in MUNE and maximum CMAP values over time were dependent on age, SMA type, and SMN2 copy number. SMN2 copy number less than 3 correlated with lower MUNE and maximum CMAP values (p < 0.0001) and worse functional outcomes. As SMN2 copy number increases, so does functional status (p < 0.0001). Change in MUNE longitudinally over the time intervals examined in this study was not statistically significant for any SMA cohort. However, a decline in maximum CMAP over time was apparent in SMA2 subjects (p = 0.049). Age-dependent decline in MUNE and maximum CMAP was apparent in both SMA 1 (p < 0.0001) and SMA 2 (p < 0.0001) subjects, with age as an independent factor regardless of type. Maximum CMAP at the time of the initial assessment was most predictive of functional outcome (p < 0.0001). Prospective longitudinal studies in four prenatally diagnosed infants demonstrated significant progressive denervation in association with symptomatic onset or functional decline. These data highlight the potential value of such measures in increasing our understanding of pathophysiological factors involved in denervation in SMA.
PMCID: PMC4334582  PMID: 15852397
9.  Glucose Metabolism and Pancreatic Defects in Spinal Muscular Atrophy 
Annals of neurology  2012;72(2):256-268.
Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA.
Glucose metabolism and pancreas development were investigated in the Smn2B/− intermediate SMA mouse model and type I SMA patients.
Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing α cells at the expense of insulin-producing β cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children.
Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis.
PMCID: PMC4334584  PMID: 22926856
10.  Vitamin D Intake Is Inadequate in Spinal Muscular Atrophy Type I Cohort: Correlations With Bone Health 
Journal of child neurology  2013;29(3):374-380.
Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population.
PMCID: PMC4259287  PMID: 23334077
vitamin D; spinal muscular atrophy type I; bone mineral density; SMN1
11.  Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome 
Human mutation  2013;34(8):1066-1070.
Aicardi-Goutières syndrome (AGS) is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1 or ADAR1. Here we provide molecular, biochemical and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.
PMCID: PMC3714325  PMID: 23592335
Aicardi-Goutières syndrome; AGS; RNASEH2A; Synonymous mutations; splicing
12.  LTBP4 genotype predicts age of ambulatory loss in Duchenne Muscular Dystrophy 
Annals of neurology  2013;73(4):481-488.
Duchenne Muscular Dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-β binding protein 4, was previously discovered in a genomewide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort.
We analyzed nonsynonymous SNPs from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form “VTTT” and “IAAM” LTBP4 haplotypes.
Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to TGFβ displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4's role as regulator of TGFβ.
LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients.
PMCID: PMC4106425  PMID: 23440719
muscular dystrophy; genetic modifier; TGFβ
13.  Public Attitudes Regarding a Pilot Study of Newborn Screening for Spinal Muscular Atrophy 
A population-based pilot study of newborns screening for a rare genetic condition, spinal muscular atrophy (SMA), is being conducted with funding from the National Institutes of Health. The first component of the study is to assess the ethical, legal and social implications of population-based pilot studies with a focus on public engagement and parental decision-making for the proposed opt-out approach in this research. We conducted focus groups with members of the general public to ascertain attitudes about the pilot study and acceptability of an opt-out approach in two states, Colorado and Utah, where the pilot screening is being proposed (N = 70). We developed an informational video for the project and showed it to the groups prior to the discussion in order to inform participants about population-based research, newborn screening, permission/consent models, and SMA.
Results indicated support for the conduct of pilot studies that is consistent with the current standard of practice for similar population-based programs. There was support for an opt-out approach for parental decision-making; however there was limited parental knowledge about population-based research, newborn screening and SMA. In general, our participants considered this pilot study to be low risk and of potential benefit to infants and families. The majority of participants were supportive of an opt-out approach with information delivered through various avenues
PMCID: PMC3606635  PMID: 23443997
Newborn screening; population-based research; public health; spinal muscular atrophy; research ethics; focus groups
Muscle & nerve  2014;49(2):187-192.
An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults.
There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes.
Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months.
VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.
PMCID: PMC3888833  PMID: 23681940
15.  Alpha-Synuclein Loss in Spinal Muscular Atrophy 
Spinal muscular atrophy, the most prevalent hereditary motor neuron disease, is caused by mutations in the survival motor neuron (SMN) 1 gene. A significant reduction in the encoded SMN protein leads to the degeneration of motor neurons. However, the molecular events leading to this process are not well understood. The present study uses a previously developed neuronal cell culture model of spinal muscular atrophy for a multiplex transcriptome analysis. Furthermore, gene expression analysis was performed on in vitro cell cultures, as well as tissue samples of spinal muscular atrophy patients and transgenic mice. RNA and subsequent Western blot protein analyses suggest that low SMN levels are associated with significantly lower alpha-synuclein expression. Examination of two genes related to vesicular transport showed a similar though less dramatic decrease in expression. The 140-amino acid protein alpha-synuclein, dominant mutations of which have previously been associated with an autosomal dominant form of Parkinson's disease, is strongly expressed in select neurons of the brain. Although not well understood, the physiologic functions of alpha-synuclein have been linked to synaptic vesicular neurotransmitter release and neuroprotection, suggesting a possible contribution to Smn-deficient motor neuron pathology. Furthermore, alpha-synuclein may be a genetic modifier or biomarker of spinal muscular atrophy.
PMCID: PMC3918138  PMID: 20640532
Spinal muscular atrophy; Alpha-synuclein; Motor neuron disease; Survival motor neuron
Neuromuscular disorders : NMD  2008;18(6):453-459.
Mitochondrial DNA depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in mitochondrial nucleotide metabolism (POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1) and MPV17. Recently, mutations in The RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in 7 infants from 4 families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age.
We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at three months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months.
All three patients had lactic acidosis and severe depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exon 6, 8 and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.
PMCID: PMC3891825  PMID: 18504129
17.  Population Pharmacokinetics of Valproic Acid in Pediatric Patients With Epilepsy: Considerations for Dosing Spinal Muscular Atrophy Patients 
Journal of clinical pharmacology  2011;52(11):1676-1688.
Valproic acid (VPA) dosing strategies used in recent clinical trials in patients with spinal muscular atrophy (SMA) have utilized a paradigm of monitoring trough levels to estimate drug exposure with subsequent dose titration. The validity of this approach remains uncertain and could be improved by understanding sources of pharmacokinetic variability. A population pharmacokinetic analysis of VPA in pediatric patients with epilepsy was recently performed. The pooled data set included 52 subjects with epilepsy, ages 1 to 17 years, who received intravenous and/or various oral formulations. The data was best fit by a 2-compartment model; inclusion of age and weight reduced intersubject variability for clearance (41%), central volume (70%), and peripheral volume (42%) over the base model. The final model for clearance and volume parameters was clearance = 0.854 · (weight/70)0.75; central volume of distribution = 10.3 · (weight/70)1.0 · (age/8.5)−0.267; peripheral volume of distribution = 4.08 · (weight/70)1.0; and intercompartmental clearance = 5.34 · (weight/70)0.75. Application of the model to data from a clinical trial in SMA patients suggests altered kinetics, perhaps based on underlying physiologic differences such as alterations in lean body mass. Future studies in SMA should incorporate modeling and simulation techniques to support individualized dosing and further assess if additional patient-specific factors necessitate alternative dosing strategies.
PMCID: PMC3345311  PMID: 22167565
Pediatrics; valproic acid; pharmacokinetics; spinal muscular atrophy; SMA
18.  Observational study of caloric and nutrient intake, bone density, and body composition in infants and children with Spinal Muscular Atrophy type I 
Neuromuscular disorders : NMD  2012;22(11):966-973.
Clinical experience supports a critical role for nutrition in patients with spinal muscular atrophy (SMA). Three-day dietary intake records were analyzed for 156 visits in 47 SMA type I patients, 25 males and 22 females, ages 1 month-13 years (median 9.8 months) and compared to dietary reference intakes for gender and age along with anthropometric measures and dual-energy x-ray absorptiometry (DEXA) data. Using standardized growth curves, twelve patients met criteria for failure to thrive (FTT) with weight for age < 3rd percentile; eight met criteria based on weight for height. Percentage of body fat mass was not correlated with weight for height and weight for age across percentile categories. DEXA analysis further demonstrated that SMA type I children have higher fat mass and lower fat free mass than healthy peers (p<0.001). DEXA and dietary analysis indicates a strong correlation with magnesium intake and bone mineral density (r=0.65, p<0.001). Average caloric intake for 1–3 year olds was 68.8 ±15.8 kcal/kg - 67% of peers’ recommended intake. Children with SMA type I may have lower caloric requirements than healthy age-matched peers, increasing risk for over and undernourished states and deficiencies of critical nutrients. Standardized growth charts may overestimate FTT status in SMA type I.
PMCID: PMC3484247  PMID: 22832342
Spinal muscular atrophy type I; body composition; bone density; nutrient and caloric intake; dual-energy x-ray absorptiometry; growth status; nutrient deficiencies
19.  Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene 
Human mutation  2011;32(3):299-308.
Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.
PMCID: PMC3724403  PMID: 21972111
DMD; exon skipping; nonsense mutations; Becker muscular dystrophy; splicing motifs; dystrophin
20.  SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy 
PLoS ONE  2013;8(4):e60113.
Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).
BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.
12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.
Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.
PMCID: PMC3615018  PMID: 23565191
21.  De novo mutations in ATP1A3 cause alternating hemiplegia of childhood 
Heinzen, Erin L. | Swoboda, Kathryn J. | Hitomi, Yuki | Gurrieri, Fiorella | Nicole, Sophie | de Vries, Boukje | Tiziano, F. Danilo | Fontaine, Bertrand | Walley, Nicole M. | Heavin, Sinéad | Panagiotakaki, Eleni | Fiori, Stefania | Abiusi, Emanuela | Di Pietro, Lorena | Sweney, Matthew T. | Newcomb, Tara M. | Viollet, Louis | Huff, Chad | Jorde, Lynn B. | Reyna, Sandra P. | Murphy, Kelley J. | Shianna, Kevin V. | Gumbs, Curtis E. | Little, Latasha | Silver, Kenneth | Ptác̆ek, Louis J. | Haan, Joost | Ferrari, Michel D. | Bye, Ann M. | Herkes, Geoffrey K. | Whitelaw, Charlotte M. | Webb, David | Lynch, Bryan J. | Uldall, Peter | King, Mary D. | Scheffer, Ingrid E. | Neri, Giovanni | Arzimanoglou, Alexis | van den Maagdenberg, Arn M.J.M. | Sisodiya, Sanjay M. | Mikati, Mohamad A. | Goldstein, David B. | Nicole, Sophie | Gurrieri, Fiorella | Neri, Giovanni | de Vries, Boukje | Koelewijn, Stephany | Kamphorst, Jessica | Geilenkirchen, Marije | Pelzer, Nadine | Laan, Laura | Haan, Joost | Ferrari, Michel | van den Maagdenberg, Arn | Zucca, Claudio | Bassi, Maria Teresa | Franchini, Filippo | Vavassori, Rosaria | Giannotta, Melania | Gobbi, Giuseppe | Granata, Tiziana | Nardocci, Nardo | De Grandis, Elisa | Veneselli, Edvige | Stagnaro, Michela | Gurrieri, Fiorella | Neri, Giovanni | Vigevano, Federico | Panagiotakaki, Eleni | Oechsler, Claudia | Arzimanoglou, Alexis | Nicole, Sophie | Giannotta, Melania | Gobbi, Giuseppe | Ninan, Miriam | Neville, Brian | Ebinger, Friedrich | Fons, Carmen | Campistol, Jaume | Kemlink, David | Nevsimalova, Sona | Laan, Laura | Peeters-Scholte, Cacha | van den Maagdenberg, Arn | Casaer, Paul | Casari, Giorgio | Sange, Guenter | Spiel, Georg | Boneschi, Filippo Martinelli | Zucca, Claudio | Bassi, Maria Teresa | Schyns, Tsveta | Crawley, Francis | Poncelin, Dominique | Vavassori, Rosaria
Nature genetics  2012;44(9):1030-1034.
Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified de novo nonsynonymous mutations in ATP1A3 in all seven AHC patients. Subsequent sequence analysis of ATP1A3 in 98 additional patients revealed that 78% of AHC cases have a likely causal ATP1A3 mutation, including one inherited mutation in a familial case of AHC. Remarkably, six ATP1A3 mutations explain the majority of patients, including one observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene.
PMCID: PMC3442240  PMID: 22842232
22.  New Therapeutic Approaches to Spinal Muscular Atrophy 
Bench to bedside progress has been widely anticipated for a growing number of neurodegenerative disorders. Of these, spinal muscular atrophy (SMA) is perhaps the best poised to capitalize on advances in targeted therapeutics development over the next few years. Several laboratories have achieved compelling success in SMA animal models using sophisticated methods for targeted delivery, repair, or increased expression of the survival motor neuron protein, SMN. The clinical community is actively collaborating to identify, develop, and validate outcome measures and biomarkers in parallel with laboratory efforts. Innovative trial design and synergistic approaches to maximize proactive care in conjunction with treatment with one or more of the promising pharmacologic and biologic therapies currently in the pipeline will maximize our chances to achieve meaningful outcomes for patients. This review highlights recent promising scientific and clinical advances bringing us ever closer to effective treatment(s) for our patients with SMA.
PMCID: PMC3260050  PMID: 22134788
Spinal muscular atrophy; SMA; SMN1; SMN2; Therapeutics; Clinical trials; Sensory; Motor; AAV9; Gene therapy; Humans; Animal models; Motor neuron; Spinal cord circuitry; Anterior horn cell; Natural history; Outcomes; Phenotype; Review; RNA splicing; Preclinical
23.  A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites 
European Journal of Human Genetics  2011;19(10):1045-1051.
Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ∼1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ∼1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity.
PMCID: PMC3190247  PMID: 21610747
spinal muscular atrophy; Hutterites; founder population; haplotype; carrier frequency; carrier screening
24.  Reliability of the Modified Hammersmith Functional Motor Scale in Young Children with Spinal Muscular Atrophy 
Muscle & nerve  2011;44(2):246-251.
The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with SMA ≤ 30 months (mo) of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also explored.
Twenty-two children with SMA Type II [mean age=20mo; (SD)5mo; range = 9mo–30mo] were tested twice using the MHFMS. Twenty-five TD children [mean age = 18mo; (SD)7mo; range=9mo–30mo] were tested once.
The average difference between MHFMS scores for SMA children was 0.18 [1st assessment mean=12.8(SD 9.8); 2nd test mean=13.0(SD 8.8)]. Reliability was excellent (ICC1,3=0.96, SEM=1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean=39.2(SD1.2)] and achieved maximum test scores at 12 months of age.
MHFMS scores in young children with SMA Type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up.
PMCID: PMC3136587  PMID: 21698647
spinal muscular atrophy; test-retest reliability; Modified Hammersmith Functional Motor Scale; outcome; MHFMS
25.  Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study 
PLoS ONE  2012;7(4):e35462.
Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets.
To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches.
Materials and Methods:
A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2–12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures.
A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS.
In this cross-sectional study, “BforSMA” (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with disease progression, and assess potential impact on clinical trial design.
Trial Registry NCT00756821.
PMCID: PMC3338723  PMID: 22558154

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