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The article explains the various symptoms and causes of spinocerebellar ataxia type 31 (SCA31), an adult-onset autosomal-dominant neurodegenerative disorder. The numerous insertions containing the complex penta-nucleotide repeats including a long [(TGGAA).sub.n] stretch are shown to be highly associated with the onset of the disorder.

The mucopolysaccharidoses (MPS) are a genetically heterogenous group of enzyme deficiencies marked by accumulation of glycosaminoglycans in lysosomes leading to multisystem disease. Although significant therapeutic advances have been made for the MPS disorders, including recombinant enzyme replacement approaches, the neuronopathic features of MPS lack adequate treatment. Gene therapies, including adeno-associated virus vectors targeting the central nervous system, hold significant promise for this group of disorders. Optimal outcomes of all therapies will require early disease identification and treatment, ideally by newborn screening. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is a consequence of Duchenne muscular dystrophy (DMD). Suggested treatments include angiotensin-converting enzyme (ACE) inhibitors and/or β blockers (BBs), but few large series have been reported. We present 42 patients with DMD and cardiomyopathy treated with an ACE inhibitor or an ACE inhibitor plus a BB. Serial echocardiograms were recorded. Adequate ejection fractions (EFs) were obtained at initiation of therapy (EF <55%). ACE inhibitor dosage adjustments were made if a continued decrease in EF was noted. BB therapy was initiated when average heart rate on Holter monitoring exceeded 100 beats/min. Data were analyzed using paired t test and linear regression. Before ACE inhibition, patients (n = 22) demonstrated decreased EF over time (r2 = 0.23). At ACE inhibitor therapy initiation, mean age was 14.1 ± 4.6 years and mean EF was 44.2 ± 6.8%. BB therapy was used in 24 of 42 patients. Mean age for the ACE inhibitor + BB group was 15.7 ± 3.9 years. The 2 groups showed significant improvement (p <0.0001 for ACE inhibitor and ACE inhibitor plus BB) compared to the pretherapy group. No significant differences were noted between treatment groups. Patients with DMD demonstrated a gradual decrease in myocardial function. Treatment with ACE inhibitor or ACE inhibitor plus BB resulted in significant improvement compared to pretherapy. No significant difference occurred in EF improvement between treatment groups. In conclusion, treatment with ACE inhibitor or ACE inhibitor plus BB can delay progression of cardiomyopathy. [Copyright &y& Elsevier]

Abstract: 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 seven infants from four 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 3 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 exons 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. [Copyright &y& Elsevier]

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities.Methods: Patients with genetically confirmed SMA completed functional testing at each visit including the Neuromuscular GRO and other appropriate gross motor outcomes.Results: We enrolled 91 patients with SMA types 1 to 3 between 8 days and 32.1 years. The GRO utilizes a 0- to 2-point scale with scores in our cohort ranging from 1 to 95 points with no floor or ceiling effect. GRO scores were significantly different across functional categories (P < 0.001) and treatment status (P = 0.01) and correlated to other functional assessments (P ≤ 0.001). All patients were measured using the GRO, whereas traditional outcomes were only appropriate on 36% to 59% of our cohort.Conclusion: The Neuromuscular GRO quantifies function across the span of age and abilities included in our cohort, allowing for continuous longitudinal monitoring on one scale to reduce the burden of testing in our heterogeneous clinic population. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials targeting younger cohorts of boys with Duchenne muscular dystrophy are necessary as earlier intervention may maximize treatment effect. Boys with Duchenne muscular dystrophy often have gross motor delays very early in life, and although they gain skills, they are on a lower trajectory than typical peers. Quantifying the natural rate of motor maturation in Duchenne muscular dystrophy from an early age permits identification of deviations from the expected trajectory related to treatment effects.Methods: The purpose of our study was to define the natural history in boys aged from ≥3 to <8 years using the North Star Ambulatory Assessment (NSAA), 100-meter timed test (100m), 10-meter walk/run (10m), time to rise (Rise), and 4-stair climb (4SC). Assessments were completed as standard of care during regularly scheduled clinic visits.Results: One hundred sixty-two boys with DMD aged 3.1 to 7.9 years on glucocorticoids were evaluated using one or more of the following tests as appropriate for age: NSAA (N = 158; 3.1-7.9 years), 100m (N = 131; 3.4-7.9 years), 10m (N = 162; 3.1-7.9 years), Rise (N = 160; 3.1-7.9 years), and 4SC (N = 153; 3.1-7.9 years). Longitudinal data are presented by age in a subcohort (N = 64).Conclusions: Our study documents the baseline function of boys with DMD who are being treated with corticosteroids. These data will be useful to compare ongoing and future therapeutic intervention(s) for DMD. [ABSTRACT FROM AUTHOR]

The reading frame rule suggests that Duchenne muscular dystrophy (DMD) results from DMD mutations causing an out-of-frame transcript, whereas the milder Becker muscular dystrophy results from mutations causing an in-frame transcript. However, predicted nonsense mutations may instead result in altered splicing and an in-frame transcript. Here we report a 10-year-old boy with a predicted nonsense mutation in exon 42 who had a 6-minute walk time of 157% of that of age matched DMD controls, characterized as intermediate muscular dystrophy. RNA sequencing analysis from a muscle biopsy revealed only 6.0–9.8% of DMD transcripts were in-frame, excluding exon 42, and immunoblot demonstrated only 3.2% dystrophin protein expression. Another potential genetic modifier noted was homozygosity for the protective IAAM LTBP4 haplotype. This case suggests that very low levels of DMD exon skipping and dystrophin protein expression may result in amelioration of skeletal muscle weakness, a finding relevant to current dystrophin-restoring therapies. [ABSTRACT FROM AUTHOR]

Background: Individuals with Duchenne muscular dystrophy have an increased risk of long bone fractures. Such fractures are sometimes associated with brain dysfunction due to fat embolism syndrome, although this syndrome has seldom been documented in muscular dystrophy patients.Patient Description: We describe a child with Duchenne muscular dystrophy who developed fat embolism syndrome with neurological dysfunction following multiple long bone fractures. He experienced recurrent cerebral infarctions that probably resulted from embolization through a patent foramen ovale. The patent foramen ovale was closed by an occluder device in the cardiac catheterization laboratory, and he did not experience further infarctions.Conclusions: Fat embolism with ischemic cerebral infarction can occur in individuals with Duchenne muscular dystrophy following long bone fractures. In this setting it is important to identify and close atrial level shunts in order to prevent additional infarctions. [ABSTRACT FROM AUTHOR]

Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 1011 vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 1011 vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys. Patients: Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months. Results: Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05). Conclusion: Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure. [ABSTRACT FROM AUTHOR]

No treatment exists for facioscapulohumeral muscular dystrophy (FSHD), one of the most common inherited muscle diseases. Although FSHD can be debilitating, little effort has been made to develop targeted therapies. This lack of focus on targeted FSHD therapy perpetuated because the genes and pathways involved in the disorder were not understood. Now, more than 2 decades after efforts to decipher the root cause of FSHD began, this barrier to translation is finally lowering. Specifically, several recent studies support an FSHD pathogenesis model involving overexpression of the myopathic DUX4 gene. DUX4 inhibition has therefore emerged as a promising therapeutic strategy for FSHD. In this study, we tested a preclinical RNA interference (RNAi)-based DUX4 gene silencing approach as a prospective treatment for FSHD. We found that adeno-associated viral (AAV) vector-delivered therapeutic microRNAs corrected DUX4-associated myopathy in mouse muscle. These results provide proof-of-principle for RNAi therapy of FSHD through DUX4 inhibition. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to evaluate the spectrum of muscle involvement on Magnetic Resonance Imaging (MRI) in patients with collagen VI related disorders. Nineteen patients with genetically confirmed collagen VI related disorders, 10 with Bethlem myopathy and 9 with Ullrich congenital muscular dystrophy (CMD), had muscle MRI of their legs using T1 sequences through calves and thighs. In patients with Bethlem myopathy the vasti muscles appeared to be the most frequently and most strikingly affected thigh muscles, with a rim of abnormal signal at the periphery of each muscle and relative sparing of the central part. Another frequent finding was the presence of a peculiar involvement of the rectus femoris with a central area of abnormal signal within the muscle. Patients with Ullrich CMD had a more diffuse involvement of the thigh muscles with relative sparing of sartorius, gracilis and adductor longus. In 8 of the 9 patients with Ullrich CMD, we also observed the peripheral rim of the vastus lateralis and the central area in the rectus femoris observed in patients with Bethlem myopathy. At calf level the results were more variable but a significant proportion of patients with both Bethlem myopathy (8/10) and Ullrich CMD (6/9) showed a rim of abnormal signal at the periphery of soleus and gastrocnemii. Bethlem myopathy and Ullrich CMD patients have distinct patterns of muscle involvement on MRI with some overlap between the two forms. Our results suggest that muscle MR may be used, as an additional tool, to identify patients with collagen VI related disorders. This information is even more important in the patients with a typical Ullrich CMD clinical phenotype but with normal collagen expression of VI in muscle and/or skin. [Copyright &y& Elsevier]

Magnetic resonance imaging of a girl with giant axonal neuropathy revealed a progressive white matter disease. In close agreement with histopathological features reported previously, localized proton magnetic resonance spectroscopy at 9 and 12 years of age indicated a specific damage or loss of axons (reduced N-acetylaspartate and N-acetylaspartylglutamate) accompanied by acute demyelination (elevated choline-containing compounds, myo-inositol, and lactate) in white matter as well as a generalized proliferation of glial cells (elevated choline-containing compounds and myo-inositol) in both gray and white matter. [Copyright &y& Elsevier]

Abstract: We present a case of juvenile dermatomyositis with unusual histopathologic findings. The child presented with a course consistent with dermatomyositis, a diagnosis confirmed by finding reticulotubular aggregates in endothelial cells on electron microscopy. However, histopathology of his muscle biopsy revealed a striking pattern of glycogen accumulation, to an extent similar to that seen in glycogen storage diseases; this degree of accumulation could potentially confound histopathologic diagnosis. [Copyright &y& Elsevier]