Polyglucosan body myopathy-1 (PGBM1) is an extremely rare glycogen storage diseases that leads to muscle weakness and cardiomyopathy due to the accumulation of polyglucosan bodies. The clinical ...presentation appears to be partially dependent on the genetic mutation, but no clear genotype/phenotype correlation is currently possible.
We describe a 7 year old patient, who initially presented with recurrent vomiting and respiratory infections until her first year of life. Diagnostic workup revealed an achalasia and the whole exome sequencing revealed an homozygous RBCK1 (RANBP2-type and C3HC4-type zinc finger containing 1) variant (c.896_899delAGTG) located in exon 7 (mid-domain), which has also been described in 4 patients with PGBM1.
The unusual presentation with gastrointestinal and respiratory symptoms before the development of progressive muscle weakness expands the phenotype of this disease.
•Polyglucosan body myopathy-1 (PGBM1) is an extremely rare glycogen storage diseases.•An accumulation of polyglucosan bodies leads to muscle weakness and cardiomyopathy.•The patient initially presented with respiratory symptoms and failure to thrive.•More patients are needed for a more accurate genotype-phenotype correlation.
Zusammenfassung
Seit einiger Zeit stehen für die Behandlung der spinalen Muskelatrophie (SMA) Medikamente mit unterschiedlichen Wirkmechanismen zur Verfügung, die den Verlauf der Erkrankung erheblich ...beeinflussen können. Unbehandelt ist diese neuromuskuläre Erkrankung immer progredient und führt bei der schwersten Verlaufsform SMA Typ 1 meist innerhalb von 24 Monaten zum Tod. Der genetische Defekt liegt auf dem Survival-motor-neuron-1-Gen (SMN1-Gen). Dies führt zu einem Verlust von SMN1-Protein und damit zum Untergang von Motoneuronen. Bei allen Patienten liegt das SMN2-Gen, das nur etwa 10 % funktionstüchtiges Protein bilden kann, in unterschiedlicher Kopienanzahl vor und beeinflusst den klinischen Schweregrad der Erkrankung, wobei fließende Übergänge zwischen den einzelnen Typen zu beobachten sind. Das erste für die SMA zugelassene Medikament ist Spinraza®, ein Antisense-Oligonukleotid, das intrathekal verabreicht wird, das mRNA-Splicing verändert und so zu einer vermehrten Produktion von SMN2-Protein führt. Das zweite zugelassene Medikament ist Zolgensma®. Dabei handelt es sich um eine Genersatztherapie, bei der das SMN1-Gen mittels eines Virusvektors als Einmalinfusion in den Körper eingebracht wird, um dann funktionierendes SMN-Protein zu bilden. Kurz vor der Zulassung steht außerdem Risdiplam®, dies ist ein sogenanntes „small molecule“ und setzt wie Spinraza® am SMN2-Gen an. Der Vorteil besteht in der Möglichkeit der oralen Einnahme. In allen Studien zu diesen Medikamenten wurde gezeigt, dass ein möglichst früher, am besten präsymptomatischer Beginn die besten Ergebnisse in den motorischen Scores für die Patienten erbrachte. Ein Neugeborenen-Screening könnte die betroffenen Kinder noch vor Symptombeginn detektieren.
OBJECTIVE:To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS).
METHODS:Clinical course, MRI, MOG-abs, AQP4-abs, and CSF ...cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study.
RESULTS:Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%.
CONCLUSIONS:Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.
Background
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are ...available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted.
Methods
We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria.
Results
Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0–4.3) in Austria. The most frequent genetic etiology was
CHRNE
(
n
= 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in
DOK7
(
n
= 4),
RAPSN
(
n
= 3),
COLQ
(
n
= 2),
GMPPB
(
n
= 2),
CHAT
(
n
= 1),
COL13A1
(
n
= 1),
MUSK
(
n
= 1) and
AGRN
(
n
= 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients.
Conclusions
Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype–phenotype correlations that may help to improve the diagnostic approach and patient management.
Adeno-associated viruses (AAV) are well-suited to serve as gene transfer vectors. Onasemnogene abeparvovec uses AAV9 as virus vector. Previous exposure to wild-type AAVs or placental transfer of ...maternal AAV antibodies, however, can trigger an immune response to the vector virus which may limit the therapeutic effectiveness of gene transfer and impact safety. We present the case of a female patient with spinal muscular atrophy (SMA) and three survival motor neuron 2 (SMN2) gene copies. The infant had elevated titers of AAV9 antibodies at diagnosis at 9 days of age. Being presymptomatic at diagnosis, it was decided to retest the patient's AAV9 antibody titer at two-weekly intervals. Six weeks after initial diagnosis, a titer of 1:12.5 allowed treatment with onasemnogene abeparvovec. The presented case demonstrates that, provided the number of SMN2 gene copies and the absence of symptoms allow, onasemnogene abeparvovec therapy is feasible in patients with initially exclusionary AAV9 antibody titers of >1:50.
Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic ...findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (
n
= 36) or neuromyelitis optica spectrum disorder (
n
= 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (
n
= 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset.
Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse ...myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC).
We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission.
Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p < 0.001) and compared to all other groups (p < 0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups.
Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities.
•Leukocyte and differential counts show differences between pediatric patients with MOGAD, AQP4-ab positive NMOSD and MS.•Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio differ between the groups and between acute attack/remission.•These parameters might help clinicians to evaluate disease activity and even distinguish between different disease entities.
Abstract Background Facial nerve paralysis is a common disease in children. Most of the patients show complete recovery. This single-center cohort study exclusively included pediatric patients to ...investigate the outcome of all patients with facial nerve palsy. Methods Hospital records of all the patients admitted to the Children's Hospital in Linz between January 2005 and December 2010 with facial nerve paralysis were reviewed. Patients with peripheral facial nerve palsy were invited for clinical reevaluation between July 2011 and October 2011. The House-Brackmann score was used for reassessment. Results Fifty-six patients agreed to return for an additional clinical reevaluation. Study participants were divided in two groups according to their House-Brackmann scores: group 1 (n = 44), with a score <2 were considered good outcomes, and group 2 (n = 12), with a score ≥2 showed persistent mild to moderate dysfunction of the facial nerve and were considered moderate outcomes. The most important finding was the difference of the reported time to remission ( P = 0.003) between the groups. Conclusion The results of this study indicate that facial paralysis in children is not as benign as supposed. It is suggested that patients and their guardians be informed that a slight face asymmetry may persist, but functional recovery in general is excellent.
New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic ...neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD).
To describe systematically the CSF profile in children with MOG-EM.
Cytological and biochemical findings (including white cell counts WCC and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster MRZ reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively.
Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age.
MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.
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