Nusinersen Initiation After Onset of Weakness Does Not Prevent Progression of Hip Instability.

BACKGROUND: We report changes in the natural history of hip instability with nusinersen treatment among patients with spinal muscular atrophy (SMA) type II after onset of weakness, historically wheelchair-bound but now potentially ambulatory in the era of disease-modifying therapy. METHODS: Patients with genetically confirmed diagnoses of SMA type II who received intrathecal nusinersen from January 1, 2018, to June 30, 2022, were screened for inclusion. Patients with less than 6 months of follow-up, or prior hip surgeries were excluded. Primary clinical outcome measures included scores from Hammersmith motor functional scale expanded (HMFSE), revised upper limb module (RULM), 6-minute walk test (6MWT), and ambulatory status. Radiographic outcomes, including Reimer migration index, the presence of scoliosis, and pelvic obliquity, were also assessed. Secondary outcomes involved comparisons with a historical cohort of SMA type II patients treated at our institution who never received nusinersen. RESULTS: Twenty hips from 5 boys and 5 girls were included in the analysis, with a mean follow-up of 3 years and 8 months. The median age at time of nusinersen initiation was 6.8 years old, ranging between 2.5 and 10.3 years. All patients developed lower limb motor weakness before nusinersen initiation. After treatment with nusinersen, 1 previously stable hip (5%) developed subluxation, 15 hips (75%) remain subluxated, 3 hips (15%) remain dislocated, and 1 hip (5%) remained stable, with a statistically significant difference between the pretreatment and posttreatment groups ( P <0.01). Six patients (60%) were ambulatory at latest follow-up. Six patients (60%) had improved ambulatory ability; 2 had static ambulatory ability (20%); and 2 had deterioration in their walking ability. The median HFMSE score improved from 18.5 (range 0 to 46) to 22 (range 0 to 49) ( P =0.813), whereas the median RULM score improved from 17 (range 2 to 28) to 21.5 (range 5 to 37), which was statistically significant ( P =0.007). CONCLUSIONS: Hip instability persists despite treatment with nusinersen among patients with SMA type II who received nusinersen after onset of lower limb weakness. LEVEL OF EVIDENCE: Therapeutic Level IV.

Clinical characteristics of unvaccinated or incompletely vaccinated children with neurological manifestations due to SARS-CoV-2 Omicron infection.

Omicron generally causes milder disease than previous strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially in fully vaccinated individuals. However, incompletely vaccinated children may develop Omicron-related complications such as those affecting the central nervous system. To characterize the spectrum of clinical manifestations of neuro-COVID and to identify potential biomarkers associated with clinical outcomes, we recruited 15 children hospitalized for Omicron-related neurological manifestations in three hospitals in Hong Kong (9 boys and 6 girls aged 1-13 years). All were unvaccinated or incompletely vaccinated. Fourteen (93.3%) were admitted for convulsion, including benign febrile seizure (n = 7), complex febrile seizure (n = 2), seizure with fever (n = 3), and recurrent breakthrough seizure (n = 2), and the remaining nonconvulsive patient developed encephalopathic state with impaired consciousness. None of the seven children with benign febrile seizure and six of eight children with other neurological manifestations had residual deficits at 9-month follow-up. SARS-CoV-2 RNA was undetectable in the cerebrospinal fluid (CSF) specimens of seven patients who underwent lumbar puncture. Spike-and-wave/sharp waves affecting the frontal lobes were detected in four of seven (57.1%) patients who underwent electroencephalogram. Children with Omicron-related neurological manifestations had significantly higher blood levels of IL-6 (p < 0.001) and CHI3L1 (p = 0.022) than healthy controls, and higher CSF levels of IL-6 (p = 0.002) than children with non-COVID-19-related febrile illnesses. Higher CSF-to-blood ratios of IL-8 and CHI3L1 were associated with longer length of stay, whereas higher ratios of IL-6 and IL-8 were associated with higher blood tau level. The role of CSF:blood ratio of IL-6, IL-8, and CHI3L1 as prognostic markers for neuro-COVID should be further evaluated.

A pilot study of an integrated, personalized, respiratory and motor telerehabilitation program for pediatric patients with hereditary neuromuscular disorders.

INTRODUCTION: Telerehabilitation provides physical training to patients through telecommunication networks. We examined the feasibility, safety, and efficacy of an integrated, personalized, respiratory and motor telerehabilitation program for pediatric patients with hereditary neuromuscular disorders (NMDs). METHODS: Stable pediatric patients were recruited for a 16-week home training program with personalized pulmonary, upper and lower limb exercises. Patients reviewed instructional videos at home and attended bi-weekly follow-ups through video or audio calls, text messages, or emails. The primary outcomes were respiratory function, Medical Research Council (MRC) grading, hand/pinch strength, 6-minute walk test, and Pediatric Quality-of-Life Inventory 3.0 Neuromuscular Module survey. The secondary outcomes were study compliance and user feedback. RESULTS: Patients with spinal muscular atrophy (n = 4), congenital myasthenic syndrome (n = 2), and Duchenne muscular dystrophy (n = 2) completed the program. The median weekly exercise time was 101.3 min (range: 30.0-266.9). No extra face-to-face physiotherapy sessions were requested by the patients. No adverse events were reported. After the study, patients showed improvements in maximal expiratory pressure (35.0 vs. 47.5 cm H2O, p = .028) and maintained their MRC grade, hand/pinch strength, and walking distance. Patients also reported improvements in the Pediatric Quality-of-Life Inventory 3.0 Neuromuscular Module survey score (74.5 vs. 87.0, p = .036). Patients rated the overall program highly (mean: 4.00/5.00) and recommended it as a standard of care (mean: 4.38/5.00). DISCUSSION: Our telerehabilitation program was feasible, safe, and possibly effective for this pilot cohort of stable pediatric patients with hereditary NMDs. Larger-scale studies for longer periods are warranted to confirm the results.

Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients.

BACKGROUND: LMNA-related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation. METHODS: The clinical presentations of patients with LMNA-related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism. RESULTS: Eighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known LMNA mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology. CONCLUSIONS: Our detailed clinical and genetic analysis of 84 patients with LMNA-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.

Prevalence and healthcare utilization of rare neurological diseases in Hong Kong: 2014-2018.

BACKGROUND: There has been increasing attention focused on the epidemiology of rare diseases (RDs) in recent years. Rare neurological diseases (RNDs) constitute a significant proportion of RDs; however, relevant research is still lacking. METHODS: A list of ICD-10 codes corresponding to RNDs was compiled using adaptations from the Orphanet Classification of Rare Diseases, and classified into rare epilepsy, movement-related, neurocutaneous, neuroimmune, neurometabolic and neurodegenerative, neuromuscular and other RNDs. Using the Clinical Data Analysis and Reporting System, which holds public hospital healthcare records of Hong Kong anonymously, we calculated the prevalence and healthcare utilization of RND patients between 2014 and 2018. The list of RNDs was also used to review relevant pharmacological trials within the International Clinical Trials Registry Platform between 2009 and 2018. RESULTS: The prevalence of RNDs in Hong Kong is 3.6 in 1,000 individuals. Patients with RNDs had frequent emergency department, outpatient and inpatient healthcare utilization. The average annual cost per patient is estimated at HKD 182,075 (€ 19,688). Different categories of RNDs showed different patterns of healthcare utilization. Moreover, there were only 677 RND-related pharmacological trials during the study period, and no trial was found for 78% of RNDs. CONCLUSIONS: This is one of the first population studies on the prevalence and healthcare utilization patterns of RNDs, with comprehensive reviews of RND-related pharmacological research. It shows high healthcare utilization rates among patients with RNDs, as well as a wide research gap in many RNDs. We call for better attention and tailored healthcare for these patients.

Bone microarchitectural alterations in boys with Duchenne muscular dystrophy on long-term glucocorticoid treatment.

INTRODUCTION: Osteoporosis is a major health issue in boys with Duchenne muscular dystrophy (DMD). Data on the specific bone deficits and microarchitectural alterations in children with DMD were limited. This study aimed to assess the bone microarchitectural alterations in boys with DMD on long-term glucocorticoid using high-resolution peripheral quantitative computed tomography (HR-pQCT). MATERIALS AND METHODS: This was a cross-sectional, case-control study. Boys with DMD older than 5 years with no prior history of symptomatic fracture and had been on long-term glucocorticoid treatment were recruited from a single tertiary centre. For each participant, three gender- and age-matched controls were selected randomly from an existing HR-pQCT database of healthy individuals. RESULTS: Nine boys with DMD at a median age of 9.3 years were included. Three were found to have asymptomatic vertebral compression fracture. The HR-pQCT findings of these nine boys were compared with 27 healthy controls. Trabecular microstructure indices at the distal radius were significantly lower but the cortical vBMD was significantly higher in the DMD boys when compared with healthy controls. CONCLUSION: Lower microarchitectural measurement of trabecular bones, but higher cortical vBMD, was observed in DMD boys on long-term oral glucocorticoid. The results from this study provide preliminary, yet important insights into the bone microarchitecture of this group of patients.

A case report of complement C4B deficiency in a patient with steroid and IVIG-refractory anti-NMDA receptor encephalitis.

BACKGROUND: Complement C4A or C4B deficiency has never been reported in autoantibody-associated encephalitides patient. Here we present a case of anti-N-methyl- D-aspartate (NMDA) receptor encephalitis associated with homozygous C4B deficiency, who did not respond to intravenous immunoglobulin and pulse methylprednisolone but plasmapheresis and rituximab. CASE PRESENTATION: A fourteen-year-old boy presented to our unit with subacute onset of behavioral changes and confusion, and was later confirmed to be anti-NMDA receptor encephalitis. He was initially managed with intravenous immunoglobulin (IVIG) and pulse methylprednisolone but did not achieve any clinical improvement. Seven sessions of plasmapheresis was commenced with remarkable improvement after the second session, and was followed by four doses of rituximab. His neurological and cognitive functioning gradually returned to baseline. Immunological investigations demonstrated persistently low C4 levels below 8 mg/dL. A more in-depth complement analysis of the patient and his family showed that he has homozygous C4B deficiency. Genetic analysis revealed that the index patient has homozygous deficiency in complement C4B and he carries one non-functioning mutant C4B gene inherited from his mother. CONCLUSIONS: Low levels of serum C4 correlate with reduced functions of the classical and lectin pathways, leading to the impairment of immune-complexes removal. Plasmapheresis ameliorates complement deficiency and removes the offending immune-complexes leading to clinical improvement that was not achieved by IVIG and steroids. We postulate that serum C4 levels may serve as a biomarker for the need of plasmapheresis upfront rather than only after non-response to steroid and IVIG in treating anti-NMDA-receptor encephalitis.

Neurocognitive function, performance status, and quality of life in pediatric intracranial germ cell tumor survivors.

BACKGROUND: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. METHODS: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. Intracranial GCT survivors in Hong Kong aged ≥ 6 years who received cranial irradiation in the past 15 years were recruited. Neurocognitive function and performance status were assessed by the Hong Kong Wechsler Intelligence scale and Karnofsky/Lansky performance scales (KPS), respectively. Quality of life was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales. A chart review was performed for tumor characteristics and complications related to the tumor and its treatment. RESULTS: Twenty-five intracranial GCT survivors were recruited. Longer length of time since treatment was associated with lower IQ scores. Larger tumor size was associated with lower KPS scores. Hemiparesis, poor manual dexterity, and complications with multi-organ involvement were associated with significantly lower KPS scores. Higher irradiation dosage was associated with lower PedsQL physical scores. CONCLUSIONS: The majority of GCT survivors had average intellectual functioning, satisfactory performance status and relatively good quality of life, except in the physical aspect. Comprehensive evaluation and long-term follow-up of GCT survivors are essential to provide timely support and improve long-term outcomes.

Treatment of Symptomatic Spinal Muscular Atrophy with Nusinersen: A Prospective Longitudinal Study on Scoliosis Progression.

Background: Nusinersen treatment has demonstrated efficacy in improving clinical outcomes for spinal muscular atrophy (SMA), yet its impact on scoliosis progression remains unclear. Objective: This study aimed to assess the progression of scoliosis in pediatric patients with SMA undergoing nusinersen treatment. Methods: In this prospective study, data were systematically collected from Hong Kong pediatric SMA patients receiving nusinersen between 2018 and 2023. All patients had longitudinal radiographic studies pre-nusinersen, and at half-yearly or yearly intervals during treatment based on the scoliosis severity. Motor function evaluations were conducted pre-nusinersen, and after starting treatment at 6- and 12-month intervals. Results: Twenty-three patients ((SMA type 1 (SMA1) = 8, SMA type 2 (SMA2) = 7, SMA type 3 (SMA3) = 8)) with a median age of 5.8 years (range: 0.4-17.5 years) at nusinersen initiation, and median follow-up duration of 3.4 years (range: 1.1-5.2 years) were included. During the study period, motor scores remained stable or improved in 83% of patients. However, scoliosis progressed across all subtypes, with mean annual progression rates of 5.2, 11.9, and 3.6 degrees in SMA1, SMA2, and SMA3 respectively. Patients initiating nusinersen between ages 5 and 11 years exhibited the most rapid progression, with rates of 11.8, 16.5, and 7.3 degrees per year in SMA1, SMA2, and SMA3 respectively. Positive correlations were observed between the difference in CHOP-INTEND score post-nusinersen and scoliosis progression in SMA1 (rs = 0.741, p = 0.041). Conversely, negative correlations were found between the difference in HFMSE score post-nusinersen and scoliosis progression in SMA2 (rs =-0.890, p = 0.012) and SMA3 (rs =-0.777, p = 0.028). Conclusions: This study reveals that nusinersen treatment in symptomatic pediatric SMA patients with motor improvement is linked to increased scoliosis progression in SMA1, whereas it is associated with decreased progression in SMA2 and SMA3. Age, baseline Cobb angle, and motor milestone improvement are influential factors in scoliosis progression.

Bone Health Status of Children with Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a group of rare, inherited neuromuscular disorders. Bone health is often a neglected issue in children with SMA. This study aimed to evaluate the bone health status of children with SMA in Hong Kong. METHODS: This retrospective study included children with SMA who were managed in the Neuromuscular Disorder Clinics of 2 quaternary centers in Hong Kong. Bone health status was assessed by fracture history, bone mineral density (BMD) measured by dual energy X-ray absorptiometry, and serum 25-hydroxy-vitamin D (25[OH]D) level. RESULTS: Thirty-two children were included (males, 12). The median age was 10.8 years. BMD assessments were performed in 17 patients (SMA type 1=2, type 2=8, type 3=7). Low BMD was observed in 16 out of 17 patients. Four had a history of long bone fractures and were started on bisphosphonates. SMA types, age at last visit, sex, ambulation, and 25(OH)D level were not associated with fracture history or BMD Z-scores. Only one fulfilled the 2019 International Society for Clinical Densitometry (ISCD) pediatric definition of osteoporosis, with both low BMD and a history of clinically significant fracture. CONCLUSIONS: Children with SMA on disease-modifying treatments commonly had Low BMD and a history of fractures, but osteoporosis was uncommon according to the 2019 ISCD pediatric definition. A special definition of osteoporosis may be needed for this high-risk group.

Hesitancy, reactogenicity and immunogenicity of the mRNA and whole-virus inactivated Covid-19 vaccines in pediatric neuromuscular diseases.

The mRNA-based BNT162b2 and inactivated whole-virus CoronaVac are two widely used COVID-19 vaccines that confer immune protection to healthy individuals. However, hesitancy toward COVID-19 vaccination appeared to be common for patients with neuromuscular diseases (NMDs) due to the paucity of data on the safety and efficacy in this high-risk patient population. Therefore, we examined the underlying factors associated with vaccine hesitancy across time for NMDs and assessed the reactogenicity and immunogenicity of these two vaccines. Patients aged 8-18 years with no cognitive delay were invited to complete surveys in January and April 2022. Patients aged 2-21 years were enrolled for COVID-19 vaccination between June 2021 and April 2022, and they recorded adverse reactions (ARs) for 7 days after vaccination. Peripheral blood was obtained before and within 49 days after vaccination to measure serological antibody responses compared to healthy children and adolescents. Forty-one patients completed vaccine hesitancy surveys for both timepoints, while 22 joined the reactogenicity and immunogenicity arm of the study. Two or more family members vaccinated against COVID-19 was positively associated with intention of vaccination (odds ratio 11.7, 95% CI 1.81-75.1, p = .010). Pain at the injection site, fatigue, and myalgia were the commonest ARs. Most ARs were mild (75.5%, n = 71/94). All 19 patients seroconverted against the wildtype SARS-CoV-2 after two doses of either vaccine, similar to 280 healthy counterparts. There was lower neutralization against the Omicron BA.1 variant. BNT162b2 and CoronaVac were safe and immunogenic for patients with NMDs, even in those on low-dose corticosteroids.

Guillain-Barré syndrome in children - High occurrence of Miller Fisher syndrome in East Asian region.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare acquired immune-mediated polyneuropathy. Updated population-based data concerning paediatric GBS is needed. METHODS: Paediatric patients aged below 18 years diagnosed with GBS between 2009 and 2018 in all 11 paediatric departments in Hong Kong were identified from the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. The collected data from medical health records were reviewed by paediatric neurologist from each department. Estimated incidence of paediatric GBS was calculated. We also compared our findings with other paediatric GBS studies in Asia. RESULTS: 63 subjects of paediatric GBS were identified, giving an estimated annual incidence of 0.62 per 100,000 population. Half of the subjects had acute inflammatory demyelinating polyneuropathy (AIDP) (n = 31; 49.2%), one quarter had Miller Fisher Syndrome (MFS) (n = 16; 25.4%), one-fifth had axonal types of GBS (n = 12; 19.0%), and four were unclassified. Paediatric subjects with axonal subtypes of GBS compared to the other 2 subtypes, had significantly higher intensive care unit (ICU) admission rates (p = 0.001) and longest length of stay (p = 0.009). With immunomodulating therapy, complete recovery was highest in those with MFS (100%), followed by AIDP (87.1%) and axonal GBS (75%). Our study also confirms a higher MFS rate for paediatric GBS in East Asia region and our study has the highest MFS rate (25.4%). CONCLUSION: Our population-based 10-year paediatric GBS study provides updated evidence on estimated incidence, healthcare burden and motor outcome of each subtype of paediatric GBS and confirmed a higher occurrence of paediatric MFS in East Asia.

Clinical Spectrum and Burden of Influenza-Associated Neurological Complications in Hospitalised Paediatric Patients.

BACKGROUND: Influenza is one of the most common causes of acute respiratory tract infections around the world. Influenza viruses can cause seasonal epidemics. There remains limited information on the impact of both seasonal influenza A and influenza B related hospitalisations from neurological complications in paediatric populations in Asia. OBJECTIVES: To examine both the clinical spectrum and healthcare burden of influenza-associated neurological complications (IANCs) within the paediatric population of Hong Kong. METHODS: We conducted a population-based retrospective study to identify all paediatric patients (<18 years) admitted to a public hospital in Hong Kong with a confirmed influenza A or B infection between 2014 and 2018 using the Clinical Data Analysis and Reporting System of the Hospital Authority. The clinical spectrum of the paediatric patients with IANCs was studied. The clinical burden of paediatric influenza patients with IANCs were compared to paediatric influenza patients without neurological complications. RESULTS: A total of 28,016 children admitted to the paediatric wards diagnosed to have influenza A or B infection were identified, accounting for 5.7% (28,016/489,955) of total paediatric admissions. 67.3% had influenza A and 32.7% had influenza B, and 8.9% had IANCs. The mean annual incidence of IANCs in children was 57 per 100,000 population. The spectrum of IANCs in our paediatric patients included febrile seizures (80.6%), myositis (11.4%), seizures with fever (5.4%), influenza-associated encephalitis/encephalopathy (IAE) (2.6%) and rarely Guillain-Barré syndrome (0.04%). Most paediatric patients with IANCs (85.5%) presented at a young age of <6 years. Paediatric patients with IANCs had significant longer hospital stays (p < 0.001), higher percentages of mechanical ventilation use (p < 0.05) and PICU admissions (p < 0.001), and higher mortality rates (p < 0.001) compared to those without neurological complications. Amongst those with IANCs, IAE was the sole cause of all seven reported mortalities. CONCLUSIONS: Seasonal influenza A & B is a common cause of hospitalisation for paediatric patients in Hong Kong. We found neurological complications from influenza A and B caused a significantly higher clinical burden compared to those without neurological complications. Children in younger age groups (<6 years old) are at highest risk and thus increasing vaccination coverage to this age group is recommended.

Deep learning-based thigh muscle segmentation for reproducible fat fraction quantification using fat-water decomposition MRI.

BACKGROUND: Time-efficient and accurate whole volume thigh muscle segmentation is a major challenge in moving from qualitative assessment of thigh muscle MRI to more quantitative methods. This study developed an automated whole thigh muscle segmentation method using deep learning for reproducible fat fraction quantification on fat-water decomposition MRI. RESULTS: This study was performed using a public reference database (Dataset 1, 25 scans) and a local clinical dataset (Dataset 2, 21 scans). A U-net was trained using 23 scans (16 from Dataset 1, seven from Dataset 2) to automatically segment four functional muscle groups: quadriceps femoris, sartorius, gracilis and hamstring. The segmentation accuracy was evaluated on an independent testing set (3 × 3 repeated scans in Dataset 1 and four scans in Dataset 2). The average Dice coefficients between manual and automated segmentation were > 0.85. The average percent difference (absolute) in volume was 7.57%, and the average difference (absolute) in mean fat fraction (meanFF) was 0.17%. The reproducibility in meanFF was calculated using intraclass correlation coefficients (ICCs) for the repeated scans, and automated segmentation produced overall higher ICCs than manual segmentation (0.921 vs. 0.902). A preliminary quantitative analysis was performed using two-sample t test to detect possible differences in meanFF between 14 normal and 14 abnormal (with fat infiltration) thighs in Dataset 2 using automated segmentation, and significantly higher meanFF was detected in abnormal thighs. CONCLUSIONS: This automated thigh muscle segmentation exhibits excellent accuracy and higher reproducibility in fat fraction estimation compared to manual segmentation, which can be further used for quantifying fat infiltration in thigh muscles.

Generation of genomic-integration-free human induced pluripotent stem cells and the derived cardiomyocytes of X-linked dilated cardiomyopathy from DMD gene mutation.

We derived an integration-free induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a 23-year-old male patient. This patient carries a 5' splice site point mutation in intron 1 (c.31+1G>A) of the dystrophin gene, a mutation associated with X-linked dilated cardiomyopathy (XLDCM). Sendai virus was used to reprogram the PBMCs and deliver OCT3/4, SOX2, c-MYC, and KLF4 factors. The iPSC line (HKUi002-A) generated preserved the mutation, expressed common pluripotency markers, differentiated into three germ layers in vivo, and exhibited a normal karyotype. Further differentiation into cardiomyocytes enables the study of the disease mechanisms of XLDCM.

Clinical practice with steroid therapy for Duchenne muscular dystrophy: An expert survey in Asia and Oceania.

BACKGROUND: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network. RESULTS: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed. CONCLUSIONS: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary.

Health-related quality of life in Chinese boys with Duchenne muscular dystrophy and their families.

This study aims to assess the family functioning and health-related quality of life (HRQOL) in Chinese boys with Duchenne muscular dystrophy (DMD) and their parents using Pediatric Quality-of-Life Family Impact Module (PedsQL FIM) and Pediatric Quality-of-Life Inventory (PedsQL) 4.0. Findings from 15 families with DMD were compared with 15 unaffected families. The HRQOL, as measured by the mean PedsQL 4.0 Generic Core Scale scores for the boys with DMD were significantly lower than those of age-matched healthy boys, for overall (p < 0.05, parent-report; p <0.001, self-report), physical (p < 0.001, parent-report and self-report), and social (p < 0.05, parent-report) functioning, but the emotional functioning is not affected. The parent-child concordance of our affected DMD families was generally in the moderate-to-good agreement range (intraclass correlation coefficients from 0.51 to 0.73), except for emotional (0.28) and social (0.31) functioning. The PedsQL FIM total score showed an inverse relationship with the affected child's age (correlation coefficient: -0.55; p < 0.01) and the disease stage (correlation coefficient: -0.63; p < 0.01) confirming that parental HRQOL and overall family functioning worsened as the child increased in age with advancing disease stage.

Selective dorsal rhizotomy in Hong Kong: multidimensional outcome measures.

We prospectively case series study evaluated the short-term effectiveness of selective dorsal rhizotomy plus physiotherapy. Twenty children with spastic cerebral palsy, selected for selective dorsal rhizotomy (mean age, 8.57 years; range, 5.96-11.18 years), were assessed before, and 6 and 12 months after, selective dorsal rhizotomy. Main outcome measures included the Modified Ashworth Scale, passive range of joint movement, the Gross Motor Function Measure, the Pediatric Evaluation of Disability Inventory, the Canadian Occupational Performance Measure, and three-dimensional gait analysis. The results confirmed that selective dorsal rhizotomy plus physiotherapy provided a statistically significant reduction of spasticity, functional improvements in mobility and self-care performance, and increased participation in social situations in our study group (85% exhibited normal intelligence, and 90% belonged to Gross Motor Function Classification System levels I-III). The Gross Motor Function Measure proved to be sensitive in documenting motor functional changes, except for children at Gross Motor Function Classification System level I. Instrumental three-dimensional gait analysis with kinematics and kinetics data analysis confirmed gait improvements in children of higher motor function. The Canadian Occupational Performance Measure indicated improvements in social participation.

A recurrent de novo DYNC1H1 tail domain mutation causes spinal muscular atrophy with lower extremity predominance, learning difficulties and mild brain abnormality.

We describe four unrelated patients with the same de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene. We found a high phenotype-genotype correlation with all four patients having early childhood-onset predominant lower limb muscle weakness and wasting which was slowly progressing and later-onset mild upper extremities proximal weakness. All four patients presented minor cognitive dysfunction with learning difficulty and developmental behavioural comorbidities with mild abnormalities in the brain MRI. The leg muscle MRI findings are highly consistent in DYN1CH1-related spinal muscular atrophy with lower limb predominance (SMALED) with relative sparing of biceps femoris and semitendinosus, and hypertrophy of adductor longus in the thighs; and sparing the anterior and medial muscles in the calves. This report provides important clinical evidence indicating the de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene is pathogenic causing SMALED. Muscle MRI is more specific than muscle biopsy in the diagnosis of SMALED.