Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME): three new cases and review of the mutational spectrum.

BACKGROUND: Spinal muscular atrophy (SMA) could be classified as 5q and non-5q, based on the chromosomal location of causative genes. A rare form of non-5q SMA is an autosomal-recessive condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by myoclonic and generalized seizures with progressive neurological deterioration. SMA-PME is a clinically heterogeneous disorder that arises from biallelic pathogenic variants in ASAH1 gene. METHODS: Following clinical and primary laboratory assessments, whole-exome sequencing was performed to detect the disease-causing variants in three cases of SMA-PME from different families. Also, Multiplex ligation-dependent probe amplification (MLPA) was employed for determining the copy numbers of SMN1 and SMN2 genes to rule out 5q SMA. RESULTS: Exome sequencing revealed two different homozygous missense mutations (c.109 C > A [p.Pro37Thr] or c.125 C > T [p.Thr42Met]) in exon 2 of the ASAH1 gene in the affected members of the families. Sanger sequencing of the other family members showed the expected heterozygous carriers. In addition, no clinically relevant variant was identified in patients by MLPA. CONCLUSION: This study describes two different ASAH1 mutations and the clinical picture of 3 SMA-PME patients. In addition, previously reported mutations have been reviewed. This study could help to fortify the database of this rare disease with more clinical and genomic data.

An open-label phase 1 clinical trial of the allogeneic side population adipose-derived mesenchymal stem cells in SMA type 1 patients.

INTRODUCTION: Spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder of alpha motor neurons of spinal cord associated with progressive muscle weakness and hypotonia, is the most common genetic cause of infant mortality. Although there is few promising treatment for SMA, but the field of translational research is active in it, and stem cell-based therapy clinical trials or case studies are ongoing. Combination of different therapeutic approaches for noncurative treatments may increase their effectiveness and compliance of patients. We present a phase 1 clinical trial in patients with SMA1 who received side population adipose-derived mesenchymal stem cells (SPADMSCs). METHODS: The intervention group received three intrathecal administrations of escalating doses of SPADMSCs and followed until 24 months or the survival time. The safety analysis was assessed by controlling the side effects and efficacy evaluations performed by the Hammersmith Infant Neurological Examination (HINE), Ballard score, and electrodiagnostic (EDX) evaluation. These evaluations were performed before intervention and at the end of the follow-up. RESULTS: The treatment was safe and well tolerated, without any adverse event related to the stem cell administration. One of the patients in the intervention group was alive after 24 months of study follow-up. He is a non-sitter 62-month-old boy with appropriate weight gain and need for noninvasive ventilation (NIV) for about 8 h per day. Clinical scores, need for supportive ventilation, and number of hospitalizations were not meaningful parameters in the response of patients in the intervention and control groups. All five patients in the intervention group showed significant improvement in the motor amplitude response of the tibial nerve (0.56mV; p: 0.029). CONCLUSION: This study showed that SPADMSCs therapy is tolerable and safe with promising efficacy in SMA I. Probably same as other treatment strategies, early intervention will increase its efficacy and prepare time for more injections. We suggest EDX evaluation for the follow-up of treatment efficacy.

Short-term Efficacy of Ultrasonographic Guidance for Intra-articular Corticosteroid Injection in Hallux Rigidus: A Single-Blind Randomized Controlled Trial.

BACKGROUND: Multiple considerations should be taken before standardizing a clinical procedure such as efficacy, safety, or the cost. The aim of this study was to compare the effects of landmark-guided vs ultrasonography-guided intra-articular injection of corticosteroid into the first metatarsophalangeal joint cavity to reduce pain and dysfunction in patients with hallux rigidus. METHODS: We carried out a single-blind randomized controlled trial with 2 parallel arms in an outpatient clinic affiliated with a medical university. In total, 50 participants (35 women) with the mean (SD) age of 49.8 (10.3) years were randomly allocated to landmark-guided or ultrasonography-guided groups (each n = 25). Each patient received a single intra-articular injection of 40-mg methylprednisolone plus 1 mL lidocaine into the affected first metatarsophalangeal joint. The primary outcome was joint pain and the secondary outcome was the American Orthopaedic Foot & Ankle Society score. We measured the outcomes at baseline and 2 and 6 weeks after the intervention. RESULTS: Six weeks after the injections, there were no statistically significant differences between the study groups in pain reduction and increase in the American Orthopaedic Foot & Ankle Society scores (P = .131 and .241, respectively). We did not find any complications for the injections in both groups. There were statistically significant changes within each group in pain and the scores for the landmark (P < .001, and P = .007), and ultrasonography groups (both P < .001). CONCLUSION: Landmark guidance is as effective as ultrasonographic guidance for intra-articular injection in patients with hallux rigidus. A single intra-articular injection of 40 mg methylprednisolone plus 1 mL lidocaine is an efficient and safe therapeutic measure for decreasing joint pain and maintaining its function, at least for 6 weeks. LEVEL OF EVIDENCE: Level I, high-quality prospective randomized study.

Pharmacogenetic and Association Studies on the Influence of HLA Alleles and Rivastigmine on the Iranian Patients with Late-Onset Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB1*06:00/x, DRB1*04:00/x, DRB1*15:00/x, and B*07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB1*06:00/x genotype offers strong protection against AD (P = 0.0074), while B*07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer's disease (SAD) (P = 0.009). Interestingly, B*07:00/x genotype does not show any apparent associations with familial Alzheimer's disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB1*04:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB1*06:00/x and B*07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB1*06:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B*07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQß1 peptide containing positively charged AAs histidine30 and arginine55 and HLA class I ß chain containing negatively charges aspartic acid114 and glutamic acid45,152 in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.

The First Comprehensive Cohort of the Duchenne Muscular Dystrophy in Iranian Population: Mutation Spectrum of 314 Patients and Identifying Two Novel Nonsense Mutations.

Mutations in the dystrophin gene could cause Duchenne muscular dystrophy (DMD), which is the most common muscular disorder in pediatrics. Considering the growing evidence on appropriateness of gene therapies for DMD, precise genetic diagnosis seems essential. Hence, we conducted a study to determine mutational patterns in Iranian children with DMD. To detect all probable large mutations in the dystrophin gene, 314 DMD patients were evaluated using the multiplex ligation-dependent probe amplification (MLPA). Subjects who were MLPA-negative underwent the next generation sequencing (NGS) to identify potential point mutations. MLPA detected deletions (79.93%) and duplications (5.41%) along the dystrophin gene of 268 patients. Distribution of large mutations was heterogeneous and followed hotspot pattern throughout the gene. From 46 patients who were MLPA-negative, 43 exhibited point mutations including nonsense in 7.64%, frameshifts in 4.77%, splicing in 0.96%, and missense variations in 0.32% of participants. Most of the point mutations were located between exons 19 and 40. In three patients (1%), no mutation was found using either MLPA or NGS. Two subjects had novel nonsense mutations (L1675X and E1199X) in their dystrophin gene, which were considered as the possible reason for elimination of major domains of the gene. The results of this study provided invaluable information regarding the distribution of various large and small mutations in Iranian individuals with DMD. Besides, the novel nonsense mutations L1675X and E1199X were identified within the highly conserved residues, leading to elimination of significant domains of the dystrophin gene.

Neuralgic Amyotrophy with Cervical Root and Cranial Nerves Involvement in a Child.

Idiopathic neuralgic amyotrophy (INA) is a disorder presented with acute severe pain in the upper extremity, followed by muscle weakness, paralysis and atrophy. INA is rare in children and few reports are found in the literature. Here, we report a case of INA in an 8-yr old boy from Iran following pharyngitis.

A novel case report of spinal muscular atrophy with progressive myoclonic epilepsy from Iran.

Spinal muscular atrophy (SMA) is a disorder characterized by decreased motor function due to the muscle atrophy in the background of degenerated anterior horn cells and motor cells of lower cranial nerves nuclei. The most frequent form is inherited as an autosomal recessive trait resulting from mutations in the survival motor neuron gene (SMN-1). On the other hand, a rare variant of this condition, named progressive myoclonic epilepsy subtype (SMA-PME) occurs in the result of a mutation in N-acylsphingosine amidohydrolase-1 gene (ASAH-1). The latter gene is responsible for lysosomal acid-ceramidase production. SMA-PME has been characterized by a progressive muscle weakness from ages 3-7 years, accompanied by epilepsy, an intractable seizure, and sometimes sensorineural hearing loss. In this report, we have presented a 15-year old female patient with SMA-PME that was attended to neurology clinic for a new onset tremor, seizure and proximal weakness in all limbs. We identified a homozygous mutation in exon II on her ASAH-1 gene [c.173C>T (p. Thr58Met)]. Also, a modest reduction was found in ceramidase-activity. As was expected patient`s seizures did not respond to conventional therapies.

Overexpression of SMN2 Gene in Motoneuron-Like Cells Differentiated from Adipose-Derived Mesenchymal Stem Cells by Ponasterone A.

Cell therapy and stem cell transplantation strategies have provided potential therapeutic approaches for the treatment of neurological disorders. Adipose-derived mesenchymal stem cells (ADMSCs) are abundant adult stem cells with low immunogenicity, which can be used for allogeneic cell replacement therapies. Differentiation of ADMSCs into acetylcholine-secreting motoneurons (MNs) is a promising treatment for MN diseases, such as spinal muscular atrophy (SMA), which is associated with the level of SMN1 gene expression. The SMN2 gene plays an important role in MN disorders, as it can somewhat compensate for the lack of SMN1 expression in SMA patients. Although the differentiation potential of ADMSCs into MNs has been previously established, overexpression of SMN2 gene in a shorter period with a longer survival has yet to be elucidated. Ponasterone A (PNA), an ecdysteroid hormone activating the PI3K/Akt pathway, was studied as a new steroid to promote SMN2 overexpression in MNs differentiated from ADMSCs. After induction with retinoic acid, sonic hedgehog, forskolin, and PNA, MN phenotypes were differentiated from ADMSCs, and immunochemical staining, specific for ß-tubulin, neuron-specific enolase, and choline acetyltransferase, was performed. Also, the results of real-time PCR assay indicated nestin, Pax6, Nkx2.2, Hb9, Olig2, and SMN2 expression in the differentiated cells. After 2 weeks of treatment, cultures supplemented with PNA showed a longer survival and a 1.2-fold increase in the expression of SMN2 (an overall 5.6-fold increase; *P ≤ 0.05), as confirmed by the Western blot analysis. The PNA treatment increased the levels of ChAT, Isl1, Hb9, and Nkx2 expression in MN-like cells. Our findings highlight the role of PNA in the upregulation of SMN2 genes from MSC-derived MN-like cells, which may serve as a potential candidate in cellular therapy for SMA patients.

Wrist bone mineral density utility in diagnosing hip osteoporosis in postmenopausal women.

BACKGROUND: Osteoporosis is a common bone disease that increases with age. Wrist bone mineral density (BMD) has significant correlation with other skeletal sites and it could be used as a diagnostic method for osteoporosis. The purpose of this study was to evaluate the role of wrist BMD in diagnosing osteoporosis in postmenopausal women. METHODS: In this cross-sectional study, 99 postmenopausal women with mean age of 57 ± 6.9 (range 50-76) years were evaluated. BMD of nondominant wrist, lumbar spine (L2-L4) and femur bone using a dual-energy X-ray absorptiometry (DXA) device as well as lateral lumbosacral X-ray for degenerative joint disease (DJD) evaluation were measured. Mean T-score of wrist was lower than hip and lumbar area. RESULTS: Osteopenia and osteoporosis were observed in 40.4% and 59.6% in the wrist, 38.4% and 24.2% in the hip and 36.4% and 49.5% in lumbar-spine BMD measurements, respectively. There was positive correlation between wrist BMD with hip BMD (r = 0.468,p < 0.001) and lumbar BMD (r = 0.322, p = 0.001). DJD due to lumbosacral X-ray was reported in 84 cases (84.8%) including mild DJD in 45 (53.5%), moderate DJD in 33 (39.3%) and severe DJD in 6 (7.2%). CONCLUSIONS: Our results showed that wrist BMD has better accuracy than lumbar BMD in diagnosing osteoporosis in postmenopausal women.