Genome sequencing adds an important diagnostic tool for patients with unsolved or atypical phenotypes. Here we describe the diagnostic journey in a patient with an atypical progressive course of riboflavin and thiamine responsive neurodegeneration, who is finally diagnosed with SMA through genome sequencing. The patient is a 28-year-old female presenting at age 4 years with fever, nausea, vomiting and leg pain, followed by itchy lesions on the soles of the feet, burning pain, frequent falls, and foot drop. At age 6-7 years, she developed progressive lower and then upper extremity weakness with loss of independent ambulation at age 10 years. She had scoliosis surgery at age 14 years and developed sudden respiratory failure requiring full-time ventilation via tracheostomy at age 19 years. She had progressive tongue and facial fasciculations with a dramatic response to high dose riboflavin and thiamine supplementation. Family history was significant for an undiagnosed older brother who passed away at age 7 years, who presented with a fever episode at age 2 years followed by progressive difficulty in walking and steppage gait. EMG and muscle biopsy revealed chronic neurogenic changes. Testing for SMN (RT-PCR) was negative. Repeat-SMN testing (MLPA) revealed heterozygous carrier status for the common SMN exon 7 deletion. Three independent WES studies were unrevealing. Research-based genome sequencing with an SMA centric re-analysis tool identified a novel missense variant c.809G>T p.(Ser270Ile) in SMN1, which was previously not recognized as located in SMN1. While exome sequencing did not allow the position of this variant to be unambiguously resolved between SMN1 and SMN2, genome sequencing did unambiguously position the variant on SMN1 via phasing with intronic sequence differences between SMN1 & SMN2. SMN2 copy number was 1. The parental data enabled a determination of compound heterozygosity. Location of intragenic mutations in SMN1 are expected to contribute to clinical severity. In the era of diseases modifying treatments, WGS, followed by direct gene sequencing, ended this diagnostic odyssey lasting more than two decades.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, acquired, treatable, immune-mediated disease. Autoimmune nodopathies due to antibodies against proteins of the paranode and node of Ranvier (neurofascin 186, neurofascin 155, contactin 1, and contactin-associated protein 1) represent a subgroup characterized by distinct clinical phenotype and treatment response. A 7-year-old girl with a known diagnosis of achromatopsia and mild expressive language delay presented with progressive symmetric lower extremity weakness over a period of 6 weeks. At presentation, she had bilateral upward gaze restriction, muscle strength was MRC grade 4 in lower limbs and grade 3 in bilateral ankle dorsiflexion. Tendon reflexes were absent. Electromyography (EMG) revealed motor and sensory demyelinating polyneuropathy with axonal involvement. Spinal magnetic resonance imaging showed contrast enhancement of the cauda equina roots. CSF protein concentration was 384 mg/dL (N: 15–45), with normal white blood cell count and glucose concentration. Treatment with IVIg and IV methylprednisolone (30 mg/kg/d for 5 days) was ineffective. She lost the ability of independent walking. Anti-contactin 1 and contactin-associated protein 1 (Caspr1) antibodies were positive in the serum. She was subsequently started on rituximab 750mg/m2 every week for the 1st month and then once every 6 months. The patient has received 4 doses of rituximab treatment so far. At the last visit she was able to stand independently for short periods. To our knowledge, this is the second description of a contactin 1-associated CIDP in the pediatric age group. The first patient had a Guillain-Barre syndrome like presentation, recurrent attacks, diagnosed with CIDP within a year, had a good response to rituximab and stable course, and diagnosed at age 5 years based on the analysis of archived serum and CSF samples. Shared clues were predominant motor involvement, demyelination and early axonal involvement, poor response to streoids and IVIg. Further characterization of pediatric patients may help to define clusters within the autoimmune nodopathies. Nodal/paranodal antibody testing should be considered in pediatric patients for optimizing treatment strategies.

Motor imagery (MI) ability has been studied extensively in healthy children and more recently in developmental coordination problems and cerebral palsy. It is a representation of the action of planning, execution and modulation of movement in the absence of any evident motor output. The aim of this study was to investigate the effects of telerehabilitation-based motor imagery (Tele-MI) training on MI ability and motor function in children with Duchenne Muscular Dystrophy (DMD). This prospective, randomized controlled study included 23 children with DMD and 12 healthy children aged 7-15 years. The children with DMD were randomized into two; considering the age, corticosteroid use and the functional status as study (n=12) and control (n=11) groups. The study group received Tele-MI training and telerehabilitation-based physical therapy program (Tele-PTP) while the control group received only Tele-PTP for 8 weeks. MI ability was assessed by the Kinesthetic and Visual Imagery Questionnaire-10 (KVIQ-10) and motor function by Motor Function Measure (MFM) before and after the training. DMD and healthy subjects were similar in terms of demographics (p>0.05). KVIQ-10 scores of the DMD population (visual: 17.30±4.69, kinestehic: 13.04±4.01, total: 30.35±7.46) were significantly lower than the healthy peers (visual: 20.25±3.01, kinesthetic: 18.08±4.68, total: 38.33±5.87; p=0.003). In the within group analysis, significant improvements were determined in the KVIQ-10 total score (p=0.003) and MFM scores (p=0.026) only in the study group (p<0.05). Between groups, KVIQ-10 total score was improved in study group after the intervention (p=0.014). This study showed that MI training improved MI ability and motor function in children with DMD. Although functional improvements were achieved by Tele-MI training, it was not superior to Tele-PTP. Development and evolution of MI ability in pediatric neuromuscular diseases requires further research.

Optimizing the diagnosis of neuromuscular disorders (NMDs) requires an iterative clinical/genomic approach. Despite advanced genomic sequencing technologies, it is estimated that about half of the patients do not receive a confirmed molecular diagnosis after initial genetic work-up. Here we evaluated 66 index patients with pediatric neuromuscular disorders of unknown genetic etiology recruited from a tertiary neuromuscular center in Turkey, in whom initial exome sequencing (ES) had been unrevealing. Diagnostic algorithm included singleton, trio or quartet research-based ES followed by clinical phenotype reassessment-driven prioritization of data analysis and the addition of bioinformatic pipelines that include copy number variants and short tandem repeat analysis followed by genome sequencing (GS), RNA sequencing and/or target gene sequencing. At data cut-off, ES sequencing for 42/66 of the cohort was completed including repeat ES for all, in combination with GS (n= 5) and RNAseq (n= 4). Interim diagnostic yield was 31/42 (73.8%) which included ES and CNV analysis (n= 1); ES and direct gene sequencing (n= 1); ES and mitochondrial filter (n= 1); ES and SMA Finder (n= 1); GS and gene sequencing (n= 1); GS and RNAseq (n= 1); GS, RNAseq and CNV analysis (n= 3) were diagnostic pathways. Several candidates, including novel candidate genes for the undiagnosed group, are in further analysis (n= 11). The initial analysis of our highly selected cohort highlights the value of an iterative phenotype driven approach to research-based sequencing data analyses with the integration of additional bioinformatics approaches to improve the genetic diagnostic yield.

ACTA1 encodes skeletal muscle α‐actin, the principal muscle actin isoform and the central component of sarcomeric thin filaments necessary for producing skeletal muscle contraction. Heterozygous pathogenic variants in ACTA1 cause myopathy with histopathologic features ranging from nemaline rods or actin aggregates to non-specific myopathic findings and a clinical spectrum ranging from severe congenital weakness and respiratory failure to a milder childhood or adult-onset myopathy. Cardiac involvement is not a commonly recognized feature of ACTA1-related disease as the predominant cardiac actin isoform is encoded by ACTC1, separate from skeletal actin.Nonetheless, there have been rare reports in the literature of cardiomyopathy related to ACTA1. To add to these observations and establish ACTA1 as a causative cardiac disease gene, we present the clinical, genetic, and histopathologic data collected for 25 patients with ACTA1-related cardiomyopathy (CM), representing the largest single cohort to date. This series includes four novel ACTA1 variants not previously reported in either skeletal or cardiac myopathy and 13 novel cardiac variants with previously reported ACTA1-myopathy without any associated cardiac phenotype. The present study comprises 18 dilated cardiomyopathy (DCM), four hypertrophic cardiomyopathy (HCM), one mixed DCM/HCM, and two other classified CM. There is also emergence of isolated congenital fiber type disproportion (CFTD) as the predominant histopathologic feature in patients with ACTA1-CM. Among patients in this series, we have identified two emerging groups with seemingly dichotomous phenotypes, namely those with neonatal-onset profoundly severe congenital myopathy with associated early-onset HCM and those with childhood or adult-onset mild skeletal myopathy with rigid spine and severe, rapidly progressive DCM often necessitating transplantation. Recognizing the possibility of ACTA1-related cardiac involvement is critical to promoting investigation into the pathophysiologic underpinnings of this disease.

Ataluren is conditionally approved for nmDMD, in boys ≥ 5 years of age on steroid treatment with a 6-minute walk test (6MWT) ≥ 300m in Turkey. Our aim was to assess demographics and long-term motor functional outcomes of nmDMD patients. Among 45 patients with nmDMD, 26 males aged ≥ 5 years, with a follow-up period of at least 12 months were included. The 6MWT at baseline and every 6 months was the primary outcome measure. Time to rise from the floor, to climb and descend 4 standard-sized stairs, 10 m walk were secondary outcome measures. The median age at presentation was 36 (6-95) months. Presenting complaints were incidentally detected high serum creatine kinase (n=11, 42.3%), abnormal gait pattern and difficulty climbing stairs (n=9, 34.5%), motor developmental delay (n=2, 7.7%), motor and language developmental delay (n=1, 3.8%) and family history (n=3, 11.5%). The median age at clinical diagnosis was 44.5 (11-72) months. Clinically, 61.5% (n= 16) were diagnosed ≤ 4 years of age. The median age at genetic diagnosis, initiation of steroids and ataluren were; 65 (18-124), 60.5 (36-105.9) and 78.5 (60-126) months, respectively. Treatment was discontinued in 13 patients. Median duration of follow-up and Ataluren treatment were; 87.5 (25-149), 34.5 (7-76) months, respectively. At the last visit, 21 patients were ambulatory, and 5 patients were non-ambulatory. There was a significant difference in ambulatory vs non-ambulatory patients at the 1st year and the last assessments in terms of 6 MWT compared to the baseline (p=0.004, p=0.007, respectively). A significant negative correlation was found between the age of onset of Ataluren and the peak 6 MWT distances (rho=-0.456, p=0.019). Among the time function tests, the most significant increase was seen in stand from a sit position. Early diagnosis and initiation of treatment in combination with standards of care are effective in gaining and maintaining motor functions in nmDMD at a real-world setting.

Congenital myasthenic syndromes (CMS) are a heterogenous group of inherited disorders due to impaired neuromuscular transmission and fatigable weakness. Monitoring and measuring fatigue and fatigability in CMS is challenging especially in the pediatric age group, in the rare diseases setting and even with small number of patients within different genetic subgroups. The aim of this study was to determine whether the 6-minute walk test (6 MWT) predicts muscular fatigability in children with CMS. Eight children (4 males, 4 females), [COLQ, n= 5; CHRNE, n= 2; CHAT, n= 1] with a mean age of 11.75±3.54 years were retrospectively analyzed. Treatment regime included mono-or combination therapy including salbutamol, pridostigmin, ephedrine and 3,4-diaminopyridine. The distance and walking speed of each minute for 6 MWT were determined. Wilcoxon Signed Rank Test was used to compare the mean distance and walking speed in the 6 MWT. Body mass index of children was 17.78±5.98 kg/m2. The mean distance and walking speed of 6 MWT were 463.38±132.59 m and 1.29±0.37 m/s. There was no difference between the first minutes and the last minutes, between the first 2 and the last 2 minutes during 6 MWT in terms of distance and speed (p>0.05). The 6MWT which is suggested as an outcome measure for fatigability across neuromuscular diseases, did not provide additional evidence to predict muscular fatigue in CMS. This observation in this small series highlights the need for multidimensional assessment of fatigue and fatigability, combining validated questionnaires and objective measures of function with remote monitoring techniques and wearable devices.

Recognition of distinctive patterns of muscle involvement on imaging studies as part of "deep phenotyping" is a helpful tool in the diagnostic pathway of patients with rare neuromuscular disease. Describe whole-body muscle MRI findings in a patient with a novel biallelic homozygous missense variant (c.801G>A, p.Asn267Lys) in PAX7 (NM_002584.2). An 8-year-old Turkish girl, with a history of decreased intrauterine movements, polyhdramniosis, low birth weight, ptosis and cyanosis at birth, presented at the age of 4 years-4 months with abnormal gait. Course was progressive and complicated with weakness involving axial, truncal and proximal muscle groups, swallowing difficulties, scoliosis and nocturnal hypoventilation syndrome. Parents were first cousins, family history was otherwise non-contributory. Physical examination revealed asthenic phenotype, bilateral ptosis, bulbous nose, high arched palate, retrognathia, and myopathic face. Neck was tilted to the right side with limited lateral neck rotations on both sides. She had scoliosis, inability to flex the knees, knee and foot ankle contractures at the right side, and bilateral achilles tendon contractures bilaterally. She had upper and lower extremity proximal > distal weakness. Serum CK level and initial muscle biopsy evaluation at the age of 4 years-4 months from vastus lateralis showed very mild variation in fiber size with the preservation of normal polygonal structure of muscle fibers. Immunohistochemical staining with oxidative enzymes (NADH, SDH, COX, COX-SDH) showed uneven staining in very few fibers. SDH and COX stainings were normal. Distribution of Type 1 and Type 2 fibers were normal on ATPase staining. Spectrin, collagen 6, Laminin-211, dystrophin and sarcoglycan stainings were normal. Whole-body MRI at 6 years and 3 months of age revealed atrophy of bilateral sternocleidomastoid, paraspinal, gluteal, and thigh muscles, as well as mild thoracolumbar dextroscoliosis. Paraspinal muscle involvement comprised erector spinae at lumbar, thoracic and neck levels, and iliopsoas muscles on both sides. One and a half years later, MRI of both thighs showed marked atrophy of the adductor muscle groups and sartorius along with atrophy of the quadriceps and semitendinosus muscles on both sides. No edema or increased diffusion was identified. The pattern of fatty replacement resembled rough-textured brush strokes. Re-evaluation of the muscle biopsy showed absence of PAX7-positive cells. To our knowledge, this is the first description of whole-body MRI imaging in a patient with PAX7-CM. Selective sternocleidomastoid, paraspinal and thigh muscle involvement will further help to differentiate early-onset myopathies within the emerging group of "primary satellite-cellopathies", which includes biallelic PAX7 variants. Recognition of distinctive patterns of muscle involvement on imaging studies as part of "deep phenotyping" is a helpful tool in the diagnostic pathway of patients with rare neuromuscular disease. Describe whole-body muscle MRI findings in a patient with a novel biallelic homozygous missense variant (c.801G>A, p.Asn267Lys) in PAX7 (NM_002584.2). An 8-year-old Turkish girl, with a history of decreased intrauterine movements, polyhdramniosis, low birth weight, ptosis and cyanosis at birth, presented at the age of 4 years-4 months with abnormal gait. Course was progressive and complicated with weakness involving axial, truncal and proximal muscle groups, swallowing difficulties, scoliosis and nocturnal hypoventilation syndrome. Parents were first cousins, family history was otherwise non-contributory. Physical examination revealed asthenic phenotype, bilateral ptosis, bulbous nose, high arched palate, retrognathia, and myopathic face. Neck was tilted to the right side with limited lateral neck rotations on both sides. She had scoliosis, inability to flex the knees, knee and foot ankle contractures at the right side, and bilateral achilles tendon contractures bilaterally. She had upper and lower extremity proximal > distal weakness. Serum CK level and initial muscle biopsy evaluation at the age of 4 years-4 months from vastus lateralis showed very mild variation in fiber size with the preservation of normal polygonal structure of muscle fibers. Immunohistochemical staining with oxidative enzymes (NADH, SDH, COX, COX-SDH) showed uneven staining in very few fibers. SDH and COX stainings were normal. Distribution of Type 1 and Type 2 fibers were normal on ATPase staining. Spectrin, collagen 6, Laminin-211, dystrophin and sarcoglycan stainings were normal. Whole-body MRI at 6 years and 3 months of age revealed atrophy of bilateral sternocleidomastoid, paraspinal, gluteal, and thigh muscles, as well as mild thoracolumbar dextroscoliosis. Paraspinal muscle involvement comprised erector spinae at lumbar, thoracic and neck levels, and iliopsoas muscles on both sides. One and a half years later, MRI of both thighs showed marked atrophy of the adductor muscle groups and sartorius along with atrophy of the quadriceps and semitendinosus muscles on both sides. No edema or increased diffusion was identified. The pattern of fatty replacement resembled rough-textured brush strokes. Re-evaluation of the muscle biopsy showed absence of PAX7-positive cells. To our knowledge, this is the first description of whole-body MRI imaging in a patient with PAX7-CM. Selective sternocleidomastoid, paraspinal and thigh muscle involvement will further help to differentiate early-onset myopathies within the emerging group of "primary satellite-cellopathies", which includes biallelic PAX7 variants.

Scoliosis, vitamin D deficiency and osteopenia due to immobilization as well as loss of muscle tone to the bone which may lead to fractures complicate SMA. Our aim is to evaluate bone health in patients with SMA. Thirty-two patients with a history of either scoliosis and/or bone fracture, followed at our center between 2017-2022 with the diagnosis of SMA type 1, 2 and 3 were retrospectively evaluated. Age of fracture, nature of the event causing fracture, localization, serum calcium, phosphorus, alkaline phosphatase, and vitamin D levels, whether there was scoliosis or not and DEXA were assessed. There were 8 patients (25%) with SMA type 1, 20 patients (62.5%) with SMA type 2, and 2 patients (6.3%) with SMA type 3. The median age of the patients was 12 (4,7-19,3) years. Two patients diagnosed with SMA type 3 were transformed to SMA type 2 during follow-up. Thirty patients (93.8%) were treated with nusinersen. One of them died before completing loading doses. One patient has not received disease-modifying therapy yet. The median follow-up period of the patients receiving nusinersen was 47 (19-65) months. Eight patients were lost to follow-up. Scoliosis was almost universal in the cohort (n=31; 96.9%), and 8/31 (25.8%) were operated. Growth-friendly surgery (n= 4), definitive fusion (n= 4) were the preferred techniques. Six patients were operated prior to nusinersen treatment. There was a progression in 15 out of 18 patients (83.3%) who had scoliosis before treatment. 4 patients didn't have scoliosis before treatment and two of them developed scoliosis under treatment in three and 14 months. Six patients were operated before the treatment; thus, assessment of scoliosis progression was not appropriate. Eight patients (4 girls, 4 boys) (25%) had 10 fractures. The median age at the time of the first fracture was 5.3 (1.9-15.9) years. The fractures occurred before the treatment protocol in five patients. The most common localization was the distal femur. Fractures occurred with trauma (n= 4), during physical therapy (n= 2), and dressing (n=1). Serum calcium, phosphorus and alkaline phosphatase levels were within the normal range for age for all patients. Vitamin D levels were available for 23 (71.9%) of the patients. Vitamin D levels showed deficiency in 3 (13%), and insufficiency in 10 (43.5%) patients. DEXA was performed in 13 patients; the median of L1-4 bone mineral density z score adjusted for height was -1.9 (-3.6 – 0.1). Pamidronate treatment was administered to 3 (9.3%) of the patients for osteoporosis and vertebral fracture. Twenty-six (81.3%) patients were attending physiotherapy regularly. This study shows that scoliosis is almost universal and bone fractures can complicate the course despite disease modifying therapies and physiotherapy. Considering the immobility, osteopenia, and extraneuronal phenotypes of SMA, endocrinological evaluation should be part of follow-up. Scoliosis, vitamin D deficiency and osteopenia due to immobilization as well as loss of muscle tone to the bone which may lead to fractures complicate SMA. Our aim is to evaluate bone health in patients with SMA. Thirty-two patients with a history of either scoliosis and/or bone fracture, followed at our center between 2017-2022 with the diagnosis of SMA type 1, 2 and 3 were retrospectively evaluated. Age of fracture, nature of the event causing fracture, localization, serum calcium, phosphorus, alkaline phosphatase, and vitamin D levels, whether there was scoliosis or not and DEXA were assessed. There were 8 patients (25%) with SMA type 1, 20 patients (62.5%) with SMA type 2, and 2 patients (6.3%) with SMA type 3. The median age of the patients was 12 (4,7-19,3) years. Two patients diagnosed with SMA type 3 were transformed to SMA type 2 during follow-up. Thirty patients (93.8%) were treated with nusinersen. One of them died before completing loading doses. One patient has not received disease-modifying therapy yet. The median follow-up period of the patients receiving nusinersen was 47 (19-65) months. Eight patients were lost to follow-up. Scoliosis was almost universal in the cohort (n=31; 96.9%), and 8/31 (25.8%) were operated. Growth-friendly surgery (n= 4), definitive fusion (n= 4) were the preferred techniques. Six patients were operated prior to nusinersen treatment. There was a progression in 15 out of 18 patients (83.3%) who had scoliosis before treatment. 4 patients didn't have scoliosis before treatment and two of them developed scoliosis under treatment in three and 14 months. Six patients were operated before the treatment; thus, assessment of scoliosis progression was not appropriate. Eight patients (4 girls, 4 boys) (25%) had 10 fractures. The median age at the time of the first fracture was 5.3 (1.9-15.9) years. The fractures occurred before the treatment protocol in five patients. The most common localization was the distal femur. Fractures occurred with trauma (n= 4), during physical therapy (n= 2), and dressing (n=1). Serum calcium, phosphorus and alkaline phosphatase levels were within the normal range for age for all patients. Vitamin D levels were available for 23 (71.9%) of the patients. Vitamin D levels showed deficiency in 3 (13%), and insufficiency in 10 (43.5%) patients. DEXA was performed in 13 patients; the median of L1-4 bone mineral density z score adjusted for height was -1.9 (-3.6 – 0.1). Pamidronate treatment was administered to 3 (9.3%) of the patients for osteoporosis and vertebral fracture. Twenty-six (81.3%) patients were attending physiotherapy regularly. This study shows that scoliosis is almost universal and bone fractures can complicate the course despite disease modifying therapies and physiotherapy. Considering the immobility, osteopenia, and extraneuronal phenotypes of SMA, endocrinological evaluation should be part of follow-up.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is of special interest because the late-onset myopathic form of the disease is often dramatically riboflavin-responsive (RR). After our group's recent publication including 19 patients with RR-MADD, we continued to encounter late-diagnosed patients and aimed to describe the characteristics of the recent patients we diagnosed with RR-MADD. Patients diagnosed with RR-MADD since January 2019 were included. Clinical, laboratory and molecular genetic characteristics were evaluated retrospectively from hospital records. Three patients at the ages of 12 (P1, M), 13 (P2, F) and 16 (P3, F) years were diagnosed during the study period. The age at onset was 9-14 years. All had vomiting, fatigue, myalgia, proximal muscle weakness (with predominant involvement of neck extensors) and weight loss, but the main presenting complaints were diverse (vomiting, neck pain, and headache). Swallowing (P2) and breathing (P2, P3) difficulties were also present. Peak serum creatine kinase (CK) levels (359-1932 U/L; N≤ 145 U/L) were above the normal range, but P1 occasionally had normal CK. P1 also had hyperammonemia and significant lactic acidosis, but lactic acidosis was mild-moderate in P2 and P3. Urinary organic acid analysis revealed significant elevations of glutaric acid, 2-hydroxyglutaric acid, ethylmalonic acid, dicarboxylic acids and acylglycine derivatives and acylcarnitine profiling from dried blood spots showed elevated long-chain acylcarnitines in all patients, and medium-chain acylcarnitines in one. Treatment only with riboflavin (300 mg/d) and coenzyme Q10 (200 mg/d) resulted in complete resolution of symptoms in all patients within 2-7 days. Sequencing of ETFDH gene revealed homozygosity of the founder variant c.1130T>C (p.Leu377Pro) in P1 and P2, but was non-diagnostic in P3, for whom whole exome sequencing for the investigation of other MADD genes is underway. There is an overlap of these new patients with our previously reported RR-MADD cohort. Diverse, systemic and non-specific presentations, obscurity of myopathy are the key challenges defining diagnostic delay. Metabolic work-up of this treatable myopathy should be considered for preventing life-threatening complications and significant morbidity. Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is of special interest because the late-onset myopathic form of the disease is often dramatically riboflavin-responsive (RR). After our group's recent publication including 19 patients with RR-MADD, we continued to encounter late-diagnosed patients and aimed to describe the characteristics of the recent patients we diagnosed with RR-MADD. Patients diagnosed with RR-MADD since January 2019 were included. Clinical, laboratory and molecular genetic characteristics were evaluated retrospectively from hospital records. Three patients at the ages of 12 (P1, M), 13 (P2, F) and 16 (P3, F) years were diagnosed during the study period. The age at onset was 9-14 years. All had vomiting, fatigue, myalgia, proximal muscle weakness (with predominant involvement of neck extensors) and weight loss, but the main presenting complaints were diverse (vomiting, neck pain, and headache). Swallowing (P2) and breathing (P2, P3) difficulties were also present. Peak serum creatine kinase (CK) levels (359-1932 U/L; N≤ 145 U/L) were above the normal range, but P1 occasionally had normal CK. P1 also had hyperammonemia and significant lactic acidosis, but lactic acidosis was mild-moderate in P2 and P3. Urinary organic acid analysis revealed significant elevations of glutaric acid, 2-hydroxyglutaric acid, ethylmalonic acid, dicarboxylic acids and acylglycine derivatives and acylcarnitine profiling from dried blood spots showed elevated long-chain acylcarnitines in all patients, and medium-chain acylcarnitines in one. Treatment only with riboflavin (300 mg/d) and coenzyme Q10 (200 mg/d) resulted in complete resolution of symptoms in all patients within 2-7 days. Sequencing of ETFDH gene revealed homozygosity of the founder variant c.1130T>C (p.Leu377Pro) in P1 and P2, but was non-diagnostic in P3, for whom whole exome sequencing for the investigation of other MADD genes is underway. There is an overlap of these new patients with our previously reported RR-MADD cohort. Diverse, systemic and non-specific presentations, obscurity of myopathy are the key challenges defining diagnostic delay. Metabolic work-up of this treatable myopathy should be considered for preventing life-threatening complications and significant morbidity.

The objective is to evaluate outcome data of paediatric patients with SMA treated with nusinersen. Among 72 patients between 2017-2022, we evaluated 46 patients who at least completed the initial loading doses and first maintenance dose. Patients enrolled in clinical trials, early access program, and diagnosed through National Newborn Screening Program are excluded. Motor functions tests (CHOP-INTEND, HFMSE) at baseline and each dose after the loading doses were assessed. Spearman correlation test was used to evaluate the relationship between the motor functions and age of onset of treatment. 46 patients (19 girls, 27 boys) with SMA; SMA type 1 (n=18), type 2 (n= 15), type 3 (n= 13) were evaluated. At treatment initiation, median age of SMA type 1, type 2 and type 3 patients were 6.5 (1-123); 112 (50-178); 88 (31-190) months, respectively. Median follow-up duration was 37.7 (13-171) months for type 1, 134 (65-210) months for type 2, 73 (37-153) months for type 3. Median baseline CHOP-INTEND score was 23 (0-38) for type 1. Median HMFSE score was 4 (1-26) for type 2, 41 (17-62) for type 3. At last assessment, 2 patients walk independently, and 2 patients walk with support in SMA type 1 group. Three patients with type 3 lost ability of independent walking. At last assessment, median CHOP-INTEND score was 41 (3-64) for type 1, median HMFSE score was 8 (4-30) for type 2, and 48 (28-64) for type 3. Side-effects included proteinuria, thrombocytosis, intracranial hypotension in 10 patients and did not require cessation of treatment. There was a significant negative correlation between the motor functions of SMA type 1 patients whose age at onset of treatment was ≤18 months and >18 months (p=0.047, correlation coefficient=-0.379). A significant negative correlation was found between the age of onset of treatment and motor score in all SMA types (p<0.005, correlation coefficient=-0,529). At baseline, 8 patients (SMA type 1= 6; type 2= 2), and during follow-up 4 patients (SMA type 1= 2; type 2= 2) required ventilatory support. In SMA type 1, 2 patients required feeding with percutaneous gastrostomy and 1 patient with a nasogastric tube. Scoliosis developed in 3 patients with SMA type 1, 14 patients with SMA type 2 and 3 patients with SMA type 3 before treatment; and 8 patients with SMA type 1 and 3 patients with SMA type 3 under treatment. Scoliosis surgery was performed in 2 patients with SMA type 2. Six of the 18 patients with SMA type 1 had cognitive involvement and language delay, with autistic features accompanying 1 patient with type 1 and 1 patient with type 2 who also had epilepsy. In conclusion, this cohort represents a heterogeneous group of symptomatic paediatric SMA patients treated with nusinersen. Positive treatment effect was evident in all patients treated under the age of 18 months, irrespective of SMA type. This real-life data echoes that early initiation of treatment positively affects outcome, with gains in motor function and/or stabilization. Multidisciplinary care plays an ever-important role because of the mismatch in outcome parameters. The objective is to evaluate outcome data of paediatric patients with SMA treated with nusinersen. Among 72 patients between 2017-2022, we evaluated 46 patients who at least completed the initial loading doses and first maintenance dose. Patients enrolled in clinical trials, early access program, and diagnosed through National Newborn Screening Program are excluded. Motor functions tests (CHOP-INTEND, HFMSE) at baseline and each dose after the loading doses were assessed. Spearman correlation test was used to evaluate the relationship between the motor functions and age of onset of treatment. 46 patients (19 girls, 27 boys) with SMA; SMA type 1 (n=18), type 2 (n= 15), type 3 (n= 13) were evaluated. At treatment initiation, median age of SMA type 1, type 2 and type 3 patients were 6.5 (1-123); 112 (50-178); 88 (31-190) months, respectively. Median follow-up duration was 37.7 (13-171) months for type 1, 134 (65-210) months for type 2, 73 (37-153) months for type 3. Median baseline CHOP-INTEND score was 23 (0-38) for type 1. Median HMFSE score was 4 (1-26) for type 2, 41 (17-62) for type 3. At last assessment, 2 patients walk independently, and 2 patients walk with support in SMA type 1 group. Three patients with type 3 lost ability of independent walking. At last assessment, median CHOP-INTEND score was 41 (3-64) for type 1, median HMFSE score was 8 (4-30) for type 2, and 48 (28-64) for type 3. Side-effects included proteinuria, thrombocytosis, intracranial hypotension in 10 patients and did not require cessation of treatment. There was a significant negative correlation between the motor functions of SMA type 1 patients whose age at onset of treatment was ≤18 months and >18 months (p=0.047, correlation coefficient=-0.379). A significant negative correlation was found between the age of onset of treatment and motor score in all SMA types (p<0.005, correlation coefficient=-0,529). At baseline, 8 patients (SMA type 1= 6; type 2= 2), and during follow-up 4 patients (SMA type 1= 2; type 2= 2) required ventilatory support. In SMA type 1, 2 patients required feeding with percutaneous gastrostomy and 1 patient with a nasogastric tube. Scoliosis developed in 3 patients with SMA type 1, 14 patients with SMA type 2 and 3 patients with SMA type 3 before treatment; and 8 patients with SMA type 1 and 3 patients with SMA type 3 under treatment. Scoliosis surgery was performed in 2 patients with SMA type 2. Six of the 18 patients with SMA type 1 had cognitive involvement and language delay, with autistic features accompanying 1 patient with type 1 and 1 patient with type 2 who also had epilepsy. In conclusion, this cohort represents a heterogeneous group of symptomatic paediatric SMA patients treated with nusinersen. Positive treatment effect was evident in all patients treated under the age of 18 months, irrespective of SMA type. This real-life data echoes that early initiation of treatment positively affects outcome, with gains in motor function and/or stabilization. Multidisciplinary care plays an ever-important role because of the mismatch in outcome parameters.

Objective In 2017, a new set of criteria was proposed by EULAR/ACR to classify idiopathic inflammatory myopathies. Our aim was to validate the EULAR/ACR 2017 classification criteria in juvenile dermatomyositis (JDM) patients. Methods This study was carried out at Hacettepe University Children's Hospital Department of Paediatrics, Divisions of Rheumatology, Neurology and Paediatric Pathology Unit. Control patients included inborn errors of metabolism presenting with myopathy and/or rhabdomyolysis, idiopathic rhabdomyolysis, dystrophinopathies, neuromyotonia and systemic rheumatic disorders. Patients' data were collected retrospectively from patient files. Results Fifty-eight JDM patients (60.3% female) and 40 controls (32.5% female) were included in this study. When the probability cut-off was set at 55% as recommended, the sensitivity/specificity of the new criteria to diagnose JDM were 96.5%/85% in the total cohort, 95.8%/84.6% without the muscle biopsy data and 97%/85.7% with biopsy data. With the ROC curve analysis, the optimal probability cut-off for the whole cohort was found to be >62%; providing a sensitivity/specificity of 96.6% (95% CI: 88.1% to 99.6)/90% (95% CI: 76.3% to 97.2%), and >68.5% for the patients with muscle biopsy providing sensitivity/specificity of 97% (84.7-99.9%)/100% (76.8-100%), respectively. The new EULAR/ACR criteria were the most sensitive, however, the least specific compared to the Tanimoto criteria (sensitivity/specificity 64%/97.5%) and Bohan-Peter criteria (sensitivity/ specificity 74.1%/92.5%). Conclusion The new EULAR/ACR criteria performed favourably in our JDM cohort especially with the probability cut-off of >62%.

Fetal Akinesia Deformation Syndrome (FADS) ist der syndromale Sammelbegriff für Erkrankungen mit einem bilateralen arthrogrypotischen Phänotyp, aufgrund intrauteriner Minderbewegung. Die genetische Ätiologie der fetalen Akinesie ist ungenügend erforscht und stellt mit aktuell über 300 mit Arthrogrypose-assoziierten Genen eine diagnostische Herausforderung dar.