Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy.

Facioscapulohumeral dystrophy (FSHD) has a unique genetic aetiology resulting in partial chromatin relaxation of the D4Z4 macrosatellite repeat array on 4qter. This D4Z4 chromatin relaxation facilitates inappropriate expression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded by a retrogene that is embedded within the distal region of the D4Z4 repeat array. In the European population, the D4Z4 repeat array is usually organized in a single array that ranges between 8 and 100 units. D4Z4 chromatin relaxation and DUX4 derepression in FSHD is most often caused by repeat array contraction to 1-10 units (FSHD1) or by a digenic mechanism requiring pathogenic variants in a D4Z4 chromatin repressor like SMCHD1, combined with a repeat array between 8 and 20 units (FSHD2). With a prevalence of 1.5% in the European population, in cis duplications of the D4Z4 repeat array, where two adjacent D4Z4 arrays are interrupted by a spacer sequence, are relatively common but their relationship to FSHD is not well understood. In cis duplication alleles were shown to be pathogenic in FSHD2 patients; however, there is inconsistent evidence for the necessity of an SMCHD1 mutation for disease development. To explore the pathogenic nature of these alleles we compared in cis duplication alleles in FSHD patients with or without pathogenic SMCHD1 variant. For both groups we showed duplication-allele-specific DUX4 expression. We studied these alleles in detail using pulsed-field gel electrophoresis-based Southern blotting and molecular combing, emphasizing the challenges in the characterization of these rearrangements. Nanopore sequencing was instrumental to study the composition and methylation of the duplicated D4Z4 repeat arrays and to identify the breakpoints and the spacer sequence between the arrays. By comparing the composition of the D4Z4 repeat array of in cis duplication alleles in both groups, we found that specific combinations of proximal and distal repeat array sizes determine their pathogenicity. Supported by our algorithm to predict pathogenicity, diagnostic laboratories should now be furnished to accurately interpret these in cis D4Z4 repeat array duplications, alleles that can easily be missed in routine settings.

Nerve enlargement in patients with Noonan syndrome: A retrospective cohort study.

Noonan syndrome (NS) is an autosomal dominant condition characterized by facial dysmorphism, congenital heart disease, development delay, growth retardation and lymphatic disease. It is caused by germline pathogenic variants in genes encoding proteins in the Ras/mitogen-activated protein kinase signaling pathway. Nerve enlargement is not generally considered as a feature of NS, although some cases have been reported. High-resolution nerve ultrasound enables detailed anatomical assessment of peripheral nerves and can show enlarged nerves. This retrospective cohort study aims to describe the sonographic findings of patients with NS performed during a 1-year time period. Data on the degree of enlargement, the relation to increasing age, pain in extremities, genotype on the gene level and clinical features were collected. Twenty-nine of 93 patients visiting the NS Center of Expertise of the Radboud University Medical Center Nijmegen underwent high-resolution ultrasound. In 24 patients (83%) nerve enlargement was found. Most of them experienced pain. We observed a weak correlation with increasing age and the degree of nerve enlargement but no association with pain, genotype at the gene level or clinical features. This study shows that patients with NS have a high predisposition for sonographic nerve enlargement and that the majority experience pain.

Predicting non-response to intraglandular botulinum neurotoxin A injections for drooling in children with neurodevelopmental disabilities.

AIM: To develop robust multivariable prediction models for non-response to (1) submandibular botulinum neurotoxin A (BoNT-A) injections and (2) concurrent submandibular and parotid (four-gland) injections, to guide treatment decisions for drooling in children with neurodevelopmental disabilities, including cerebral palsy. METHOD: This was a retrospective cohort study including 262 children (155 males/107 females, median age 7 years 11 months [IQR 5 years 1 month], range 4 years 0 months - 17 years 11 months) receiving submandibular injections and 74 children (52 males/22 females, median age 7 years 7 months [IQR 4 years 3 months], range 4 years 9 months - 18 years 8 months) receiving four-gland injections. Multivariable logistic regression analyses were used to estimate associations between candidate predictors and non-response 8 weeks after injection. RESULTS: Ninety-six children (37%) were non-responders to submandibular injections, for which developmental age was the strongest predictor (adjusted odds ratio [aOR] 2.13; 95% confidence interval [CI] 1.02-4.45 for developmental age <4 years or 4-6 years with IQ <70). Other characteristics that showed a trend towards an increased risk of non-response were diagnosis, sex, and head position. Thirty-four children (46%) were non-responders to four-gland injections, for which tongue protrusion (aOR 3.10; 95% CI 1.14-8.43) seemed most predictive, whereas multiple preceding submandibular injections (aOR 0.34; 95% CI 0.10-1.16) showed a trend towards being protective. Predictors were, however, unstable across different definitions of non-response and both models (i.e. submandibular and four-gland) had insufficient discriminative ability. INTERPRETATION: Potential predictors of non-response to BoNT-A injections were identified. Nevertheless, the developed prediction models seemed inadequate for guidance of treatment decisions. WHAT THIS PAPER ADDS: Developmental age seemed most predictive of non-response to submandibular botulinum neurotoxin A injections. Non-response to concurrent submandibular and parotid injections was best predicted by tongue protrusion and number of previous injections. Multivariable prediction models including these clinical characteristics were unable to discriminate well. Predictors differed when non-response was defined using alternative outcome measures.

Comparing the evidence for botulinum neurotoxin injections in paediatric anterior drooling: a scoping review.

Paediatric anterior drooling has a major impact on the daily lives of children and caregivers. Intraglandular botulinum neurotoxin type-A (BoNT-A) injections are considered an effective treatment to diminish drooling. However, there is no international consensus on which major salivary glands should be injected to obtain optimal treatment effect while minimizing the risk of side effects. This scoping review aimed to explore the evidence for submandibular BoNT-A injections and concurrent submandibular and parotid (i.e. four-gland) injections, respectively, and assess whether outcomes could be compared across studies to improve decision making regarding the optimal initial BoNT-A treatment approach for paediatric anterior drooling. PubMed, Embase, and Web of Science were searched to identify relevant studies (until October 1, 2023) on submandibular or four-gland BoNT-A injections for the treatment of anterior drooling in children with neurodevelopmental disabilities. Similarities and differences in treatment, patient, outcome, and follow-up characteristics were assessed. Twenty-eight papers were identified; 7 reporting on submandibular injections and 21 on four-gland injections. No major differences in treatment procedures or timing of follow-up were found. However, patient characteristics were poorly reported, there was great variety in outcome measurement, and the assessment of side effects was not clearly described.   Conclusion: This review highlights heterogeneity in outcome measures and patient population descriptors among studies on paediatric BoNT-A injections, limiting the ability to compare treatment effectiveness between submandibular and four-gland injections. These findings emphasize the need for more extensive and uniform reporting of patient characteristics and the implementation of a core outcome measurement set to allow for comparison of results between studies and facilitate the optimization of clinical practice guidelines. What is Known: • There is no international consensus on which salivary glands to initially inject with BoNT-A to treat paediatric drooling. What is New: • Concluding on the optimal initial BoNT-A treatment based on literature is currently infeasible. There is considerable heterogeneity in outcome measures used to quantify anterior drooling.and clinical characteristics of children treated with intraglandular BoNT-A are generally insufficiently reported. • Consensus-based sets of outcome measures and patient characteristics should be developed and implemented.

Interdisciplinary assessment and treatment of paediatric drooling: two decades of experience by the Nijmegen saliva control team reflected in a stepwise algorithm.

Anterior and posterior drooling are prevalent comorbidities in children with neurodevelopmental disabilities. Considering the heterogeneity of the patient population and the multifactorial aetiology of drooling, an interdisciplinary and individualised treatment approach is indispensable. However, no tool for stepwise decision-making in the treatment of paediatric drooling has been developed previously. Within the Radboudumc Amalia Children's Hospital, care for children with anterior and/or posterior drooling secondary to neurodevelopmental disabilities is coordinated by a saliva control team with healthcare professionals from six disciplines. In alignment with international literature, published guidelines, and evidence gained from two decades of experience and research by our team, this paper proposes an algorithm reflecting the assessment and treatment approach applied in our clinic. First, directions are provided to decide on the necessity of saliva control treatment, taking type of drooling, the child's age, and the severity and impact of drooling into account. Second, the algorithm offers guidance on the choice between available treatment options, highlighting the importance of accounting for child characteristics and child and caregiver preferences in clinical (shared) decision-making. CONCLUSIONS: With this algorithm, we aim to emphasise the importance of repeated stepwise decision-making in the assessment and treatment of drooling in children during their childhood, encouraging healthcare professionals to apply a holistic approach. WHAT IS KNOWN: • Children with anterior or posterior drooling secondary to neurodevelopmental disabilities comprise a heterogeneous group, necessitating an individualised treatment approach. • No stepwise decision-making tool is available for the treatment of paediatric drooling. WHAT IS NEW: • Deciding on the necessity of saliva control treatment should be a conscious process, based on type of drooling, age, and drooling severity and impact. • Type of drooling, age, cognition, oral motor skills, self-awareness, posture, diagnosis, and child/caregiver preferences need to be considered to decide on the optimal treatment.

Hypertrophic neuropathy: a possible cause of pain in children with Noonan syndrome and related disorders.

This study is aimed at describing the findings of high-resolution nerve ultrasound in children with Noonan syndrome (NS) and related disorders experiencing pain in their legs. This retrospective cohort study was conducted in the NS expert center of the Radboud University Medical Center in the Netherlands. Patients were eligible if they were younger than 18 years, clinically and genetically diagnosed with NS or a NS related disorder, and experienced pain in their legs. Anamneses and physical examination were performed in all children. In addition, high-resolution nerve ultrasound was used to assess nerve hypertrophy and, if needed, complemented spinal magnetic resonance imaging was performed. Over a period of 6 months, four children, three with NS and one child with NS with multiple lentigines, who experienced pain of their legs were eligible for inclusion. Muscle weakness was found in two of them. High-resolution nerve ultrasound showed (localized) hypertrophic neuropathy in all patients. One child underwent additional spinal magnetic resonance imaging, which showed profound thickening of the nerve roots and plexus.  Conclusion: In the four children included with a NS and related disorders, pain was concomitant with nerve hypertrophy, which suggests an association between these two findings. The use of high-resolution nerve ultrasound and spinal magnetic resonance imaging might result in better understanding of the nature of this pain and the possible association to nerve hypertrophy in patients with NS and related disorders. What is Known: • Children with Noonan syndrome and related disorders may report pain in their legs, which is often interpreted as growing pain. • Some adults with Noonan syndrome and related disorders have hypertrophic neuropathy as a possible cause of neuropathic pain. What is New: • This is the first study using high-resolution nerve ultrasound in children with Noonan syndrome and related disorders experiencing pain in their legs. • Hypertrophic neuropathy was diagnosed as possible cause of pain in four children with Noonan syndrome and related disorders.

Recognising symptoms of congenital myasthenic syndromes in children: A guide for paediatricians.

AIM: Congenital myasthenic syndromes (CMS) are a rare and diverse group of treatable neuromuscular transmission disorders. Diagnosis is often substantially delayed. This study aimed to identify common symptoms of CMS in children and their manifestation to aid diagnosis and early intervention. METHODS: We performed a retrospective cohort study, including 18 children (median age 13 years, range 9 years 5 months-18 years 0 month) with CMS. Data on CMS symptoms and their manifestation were extracted from patients' charts and supplemented with parental telephone interviews. Descriptive analyses were used to identify common symptoms. RESULTS: A median diagnostic delay of 4 years and 7 months (interquartile range: 51 months) was observed. Proximal muscle weakness (100%), ptosis (89%), clumsy gait (82%), difficulty eating solid foods (78%) and recurrent respiratory tract infections (72%) were most common in these patients. Symptoms mostly co-occurred and frequently had a fluctuating character, aggravated by infections or fatigue. CONCLUSION: Early referral to diagnose CMS is crucial to enable timely initiation of treatment. Heightened attention to a combination of symptoms related to muscle weakness, rather than individual symptoms, should support paediatricians in flagging these neuromuscular disorders. Medical history taking should be tailored to parents' perceptions, asking questions about recognisable symptoms of muscle weakness.

Dysphagia limit in children with cerebral palsy aged 4 to 12 years.

AIM: To assess the dysphagia limit in children with cerebral palsy (CP) according to Eating and Drinking Ability Classification System (EDACS) level, sex, and age compared to typically developing children. METHOD: Seventy-seven children with CP (54 males, 23 females; mean age 7y 6mo, SD 2y 2mo, age range 4-12y) were assessed with the Maximum Volume Water Swallow Test. Median dysphagia limit in the CP group was compared with data of typically developing children. RESULTS: The dysphagia limit of children with CP differed significantly (p<0.001) from typically developing children. The latter showed a threefold higher median dysphagia limit (22mL) compared to children with CP in EDACS level I (7mL). The higher the EDACS level, the lower the dysphagia limit in children with CP. EDACS level explained 55% of the variance in the dysphagia limit of the CP group. INTERPRETATION: Where children with CP in EDACS levels IV and V showed that their capacity met the level of their performance, children in EDACS level I had the ability to perform a maximum capacity task, but still had a threefold lower median dysphagia limit than typically developing children. Establishment of the dysphagia limit should be part of general swallowing assessment in children with CP.

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands.

Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study.

BACKGROUND: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness. METHODS: LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient's age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed. DISCUSSION: Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up. CONCLUSION: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD. TRIAL REGISTRATION: This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017-3911) and is registered at ClinicalTrial.gov ( NCT04478981 ).

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Posterior drooling in children with cerebral palsy and other neurodevelopmental disorders.

AIM: To evaluate the effect of botulinum neurotoxin A (BoNT-A) injections, submandibular gland excision (SMGE), and bilateral submandibular duct ligation (2DL) for the control of posterior drooling in children with neurological impairment. METHOD: In a retrospective cohort, children with neurological impairment (e.g. cerebral palsy) treated between 2000 and 2016 were identified. Mean age at time of surgery was 9 years (range 1-21y). The primary outcome was posterior drooling severity by a visual analogue scale (VAS; 0-10) at baseline, 8-weeks, and 32-weeks follow-up. The secondary outcome was lower respiratory tract infections during the follow-up period. RESULTS: Ninety-two patients (out of 475; 47 males, 45 females) were identified. They were undergoing three different treatments: BoNT-A (n=63), SMGE (n=16), and 2DL (n=13). A significant reduction in VAS over time was observed in the total group of 92 patients. After SMGE, VAS decreased significantly from 6.82 (SD 3.40) at baseline to 2.29 (SD 1.93) at 8 weeks, and 2.17 (SD 2.58) at 32 weeks (F[2.34]=11.618, p<0.001). There was no significant decrease after both BoNT-A and 2-DL. INTERPRETATION: Posterior drooling is an unfamiliar, potentially life-threatening condition that is treatable with medication, BoNT-A injections, or surgery. Although all treatments reduced signs and symptoms of posterior drooling, there is a greater effect after SMGE compared to BoNT-A and 2-DL. What this paper adds Submandibular gland excision has better results for posterior drooling than botulinum toxin A or submandibular duct ligation.

Changes in severity and impact of drooling after submandibular gland botulinum neurotoxin A injections in children with neurodevelopmental disabilities.

AIMS: To examine changes in objective and subjective drooling severity measures after submandibular botulinum neurotoxin A injection in children with neurodevelopmental disabilities, explore their relationship, and evaluate if clinically relevant responses relate to changes in the impact of drooling. METHOD: This longitudinal, observational cohort study involved 160 children (92 males, 68 females; 3-17y, mean 9y 1mo, SD 3y 6mo) treated between 2000 and 2012 at the Radboud University Medical Center, Nijmegen, the Netherlands. Repeated measures analysis of variance was used to compare the 5-minute Drooling Quotient (DQ5) and Visual Analogue Scale (VAS) for drooling severity pretreatment and posttreatment, and Pearson's rho to assess their association. A parent questionnaire was used to assess drooling impact in responders (defined as ≥50% reduction in DQ5 and/or ≥2 SD reduction in VAS for drooling severity 8wks postintervention) and non-responders. RESULTS: One hundred and twelve children (70%) were responders. Their mean VAS for drooling severity and DQ5 scores were significantly lower 32 weeks postintervention compared to baseline. At baseline, the VAS for drooling severity-DQ5 relationship was 'weak' (rs =0.15, p=0.060), whereas it was 'fair' at 8 weeks (rs =0.43, p=0.000) and 32 weeks (rs =0.30, p=0.000). For responders, a significant change was found regarding the impact of drooling on daily care and social interactions at 8 weeks after intervention; most of these effects were maintained at 32 weeks. INTERPRETATION: A clinically relevant response based on a combination of objective and subjective measures of drooling severity was accompanied by positive changes regarding the impact of drooling on daily care and social interactions. WHAT THIS PAPER ADDS: Botulinum neurotoxin A injection into the submandibular glands reduced drooling severity in 70% of children with neurodevelopmental disabilities. Objective (5-minute Drooling Quotient) and subjective (Visual Analogue Scale for drooling severity) measures correlated 8 and 32 weeks after treatment. Objective and subjective measures complemented each other when changes in drooling severity were assessed. Reduced drooling severity was accompanied by positive changes with regard to the impact of drooling.

Submandibular duct ligation after botulinum neurotoxin A treatment of drooling in children with cerebral palsy.

AIM: To assess: (1) the effect on drooling of bilateral submandibular duct ligation as surgical therapy after the administration of submandibular botulinum neurotoxin A (BoNT-A) for excessive drooling and (2) the predictive value of treatment success with BoNT-A on treatment success after bilateral submandibular duct ligation. METHOD: This was a within-participant retrospective observational study in which 29 children with severe drooling (15 males, 14 females) received BoNT-A treatment at a mean age of 9 years 6 months (SD 2y 5mo), followed by bilateral submandibular duct ligation at a mean age of 10 years 11 months (SD 2y 4mo). Fifteen children were diagnosed with cerebral palsy (CP), with 12 children classified in Gross Motor Function Classification System levels IV and V. The 14 children without CP had non-progressive developmental disorders. The primary drooling severity outcomes were the Visual Analogue Scale (VAS; subjective assessment) and drooling quotient (objective assessment). Measurements were taken before each intervention and again at 8 and 32 weeks. RESULTS: The VAS was significantly lower after bilateral submandibular duct ligation at follow-up compared to BoNT-A treatment (mean difference -33, p≤0.001; 95% confidence interval [CI]=-43.3 to -22.9). The mean drooling quotient did not significantly differ between BoNT-A treatment and bilateral submandibular duct ligation at follow-up (3.3, p=0.457; 95% CI=-4.35 to 9.62) or between 8 and 32 weeks (4.7, p=0.188; 95% CI=-2.31 to 11.65). INTERPRETATION: BoNT-A treatment and bilateral submandibular duct ligation are both effective treatment modalities for drooling. At 32-week follow-up, subjective drooling severity after bilateral submandibular duct ligation was significantly lower compared to previous BoNT-A injections in participants. However, treatment success with BoNT-A is no precursor to achieving success with bilateral submandibular duct ligation. WHAT THIS PAPER ADDS: Bilateral submandibular duct ligation is an effective therapy for drooling after treatment with botulinum neurotoxin A (BoNT-A). Treatment success with BoNT-A is not a predictor of successful therapy with bilateral submandibular duct ligation.

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

OBJECTIVE: Facioscapulohumeral dystrophy (FSHD) is one of the most frequent heritable muscular dystrophies, with a large variety in age at onset and disease severity. The natural history and molecular characteristics of FSHD in childhood are incompletely understood. Our objective is to clinically and genetically characterize FSHD in childhood. METHODS: We performed a nationwide, single-investigator, natural history study on FSHD in childhood. RESULTS: Multiple-source recruitment resulted in 32 patients with FSHD (0-17 years), leading to an estimated prevalence of 1 in 100,000 children in The Netherlands. This series of 32 children with FSHD revealed a heterogeneous phenotype and genotype in childhood. The phenotypic hallmarks of FSHD in childhood are: facial weakness with normal or only mildly affected motor performance, decreased functional exercise capacity (6-minute walk test), lumbar hyperlordosis, and increased echo intensity on muscle ultrasonography. In addition, pain and fatigue were frequent and patients experienced a lower quality of life compared to healthy peers. In contrast to the literature on early-onset FSHD, systemic features such as hearing loss and retinal and cardiac abnormalities were infrequent and subclinical, and epilepsy and intellectual disability were absent. Genotypically, patients had a mean D4Z4 repeat array of 5 units (range, 2-9), and 14% of the mutations were de novo. INTERPRETATION: FSHD in childhood is more prevalent than previously known and the genotype resembles classic FSHD. Importantly, FSHD mainly affects functional exercise capacity and quality of life in children. As such, these results are paramount for counseling, clinical management, and stratification in clinical research. Ann Neurol 2018;84:635-645.

Submandibular gland botulinum neurotoxin A injection for predicting the outcome of submandibular duct relocation in drooling: a retrospective cohort study.

AIM: This study evaluated whether the effect of submandibular gland botulinum neurotoxin A (BoNT-A) injection can predict the outcome of submandibular duct relocation with sublingual gland excision (SMDR) in children with drooling. Furthermore, we compared the effectiveness of both procedures. METHOD: A retrospective cohort study was performed in 42 children and adolescents (25 males, 17 females; mean [SD] age at BoNT-A injection 11y [4], range 4-20y; mean [SD] age at SMDR 15y [4], range 7-23y) with cerebral palsy or another non-progressive developmental disability who had undergone both BoNT-A injection and SMDR for drooling. Main outcomes were the drooling quotient and the visual analogue scale (VAS) on drooling severity at 8 weeks and 32 weeks follow-up. RESULTS: Failure or success of previous BoNT-A injections had no influence on success of consecutive SMDR. Relative change in main outcomes showed no significant relation between BoNT-A injection and SMDR for any follow-up measurement. After 8 weeks, SMDR was more successful than BoNT-A injection in diminishing VAS (VAS 80.0% vs 54.3%; drooling quotient 56.2% vs 51.0%). After 32 weeks, both drooling quotient (64.3% vs 29.5%) and VAS (75.7% vs 37.1%) showed significantly higher proportions of success for SMDR. INTERPRETATION: The effect of submandibular BoNT-A injection does not predict subsequent SMDR success in drooling. Furthermore, SMDR has a larger and longer-lasting positive effect on drooling than BoNT-A injections. WHAT THIS PAPER ADDS: Submandibular botulinum neurotoxin A (BoNT-A) injection effect does not predict submandibular duct relocation with sublingual gland excision outcome. Submandibular duct relocation is more effective and more permanent than BoNT-A injection.

INYECCIÓN DE NEUROTOXINA BOTULÍNICA A EN LA GLÁNDULA SUBMANDIBULAR PARA PREDECIR EL RESULTADO DE LA REUBICACIÓN DEL CONDUCTO SUBMANDIBULAR EN BABEO: UN ESTUDIO DE COHORTE RETROSPECTIVO: OBJETIVO: Este estudio evaluó si el efecto de la inyección de neurotoxina A botulínica submandibular (BoNT-A) puede predecir el resultado de la reubicación del conducto submandibular con escisión de la glándula sublingual (SMDR) en niños con babeo. Además, comparamos la efectividad de ambos procedimientos. MÉTODO: Se realizó un estudio de cohorte retrospectivo en 42 niños y adolescentes (25 varones, 17 mujeres; edad media [DE] en la inyección de BoNT-A 11 años [4], rango 4-20 años; edad media [SD] a SMDR 15 años [4] rango 7-23 años) con parálisis cerebral u otra discapacidad del desarrollo no progresiva que se haya sometido a una inyección de BoNT-A y SMDR para babear. Los resultados principales fueron el cociente de babeo y la escala analógica visual (VAS) en la severidad del babeo a las 8 semanas y 32 semanas de seguimiento. RESULTADOS: El fracaso o el éxito de las inyecciones anteriores de BoNT-A no tuvo influencia en el éxito de la SMDR consecutiva. El cambio relativo en los resultados principales no mostró una relación significativa entre la inyección de BoNT-A y SMDR para cualquier medición de seguimiento. Después de 8 semanas, SMDR fue más exitoso que la inyección de BoNT-A en la VAS disminuida (VAS 80,0% vs 54,3%; cociente de babeo 56,2% vs 51,0%). Después de 32 semanas, tanto el cociente de babeo (64,3% vs 29,5%) como el VAS (75,7% vs 37,1%) mostraron proporciones significativamente más altas de éxito para SMDR. INTERPRETACIÓN: El efecto de la inyección submandibular de BoNT-A no predice el éxito posterior de SMDR en el babeo. Además, el SMDR tiene un efecto positivo mayor y más duradero en el babeo que las inyecciones de BoNT-A.

INJEÇÃO DE NEUROTOXINA BOTULÍNICA NA GLÂNDULA SUBMANDIBULAR PARA PREDIÇÃO DO RESULTADO DA RELOCACÃO DO DUCTO SUBMANDIBULAR NA SIALORRÉIA: UM ESTUDO DE COORTE RETROSPECTIVO: OBJETIVO: Este estudo avaliou se o efeito da neurotoxina botulínica A (NTBo-A) na glândula submandibular pode predizer o resultado da relocação do ducto submandibular com excisão sublingual da glândula (RDSM) em crianças com sialorréia. Ainda, comparamos a efetividade de ambos os procedimentos. MÉTODO: Um estudo de coorte retrospectivo foi realizado em 42 crianças e adolescentes (25 do sexo masculino, 17 do sexo feminino; idade média [DP] no momento da injeção de NTBo-A 11a[4], variação de 4-20a; idade média [DP] no momento da RDSM 15a [4], variação de 7-23a) com paralisia cerebral ou outra desordem não-progressiva do desenvolvimento que passaram por injeção de NTBo-A e RDSM para sialorréia. Os principais desfechos foram o quociente de sialorréia e a escala visual análoga (EVA) sobre a severidade da sialorréia no acompanhamento de 8 e 32 semanas. RESULTADOS: A falha ou sucesso da NTBo-A prévia não teve influência no sucesso da RDSM consecutiva. A mudança relativa nos principais desfechos não mostrou nenhuma relação significativa entre a injeção de NTBo-A e a RDSM para nenhuma das medidas no acompanhamento. Após 8 semanas, a RDSM foi mais bem sucedida do que a NTBo-A na redução da EVA (EVA 80,0% vs 54,3%; quociente de sialorréia 56,2% vs 51,0%). Após 32 semanas, tanto o quociente de sialorréia (64,3% vs 29,5%) quanto a EVA (75,7% vs 37,1%) mostram proporções significativamente mais altas de sucesso para a RDSM. INTERPRETAÇÃO: O efeito da injeção submandibular de NTBo-A não prediz o sucesso da RDSM subsequente na sialorréia. Ainda, a RDSM tem efeito maior e mais duradouro na sialorréia do que injeções de NTBo-A.

Effectiveness of submandibular duct relocation in 91 children with excessive drooling: A prospective cohort study.

OBJECTIVE: To evaluate the effectiveness of submandibular duct relocation (SMDR) in drooling children with neurological disorders. DESIGN: Prospective cohort study. SETTING: Academic Outpatient Saliva Control Clinic. PARTICIPANTS: Ninety-one children suffering from moderate to severe drooling. MAIN OUTCOME MEASURES: Direct observational drooling quotient (DQ; 0-100) and caretaker Visual Analogue Scale (VAS; 0-100). Secondary outcome measures were drooling severity (DS) and frequency rating scales. RESULTS: The DQ at baseline, 8 and 32 weeks postoperatively was 26.4, 12.3 and 10.8, respectively. VAS score decreased from 80.1 at baseline to 28.3 and 37.0 at 8 and 32 weeks after surgery. Median DS at baseline, 8 and 32 weeks was 5, 3 and 4, whereas the drooling frequency median scores were 4, 2 and 2, respectively. Five children required prolonged intubation due to transient floor of the mouth swelling, two of whom developed a ventilator-associated pneumonia. Another child developed atelectasis with postoperative pneumonia. Two more children needed tube feeding because of postoperative eating difficulties for 3 days or suprapubic catheterisation for urinary retention. Children aged 12 years or older (OR = 3.41; P = 0.03) and those with adequate stability and position of the head (OR = 2.84; P = 0.09) appeared to benefit most from treatment. CONCLUSIONS: Submandibular duct relocation combined with excision of the sublingual glands appears to be relatively safe and effective in diminishing visible drooling in children with neurological disorders, particularly in children aged 12 years and older and those without a forward head posture.

Negative effects of submandibular botulinum neurotoxin A injections on oral motor function in children with drooling due to central nervous system disorders.

AIM: The aims of this study were: (1) to determine the incidence and nature of adverse effects on oral motor function after first injections of botulinum neurotoxin A (BoNT-A) in submandibular glands for excessive drooling in children with central nervous system disorders; and (2) to identify independent predictors of these adverse effects. METHOD: A cohort study involved 209 children (123 males, 86 females, aged 4-27y, median 8y 4mo), who received submandibular BoNT-A injections for drooling. Adverse effects were categorized into swallowing, eating, drinking, articulation, and other problems. Univariable logistic regression was used to study differences in patients with and without adverse effects. Possible predictors were identified using multivariable logistic regression. RESULTS: Transient adverse effects occurred in 33% of the 209 BoNT-A treatments. Almost 80% of these were mild, versus 8.7% severe. Approximately 54% of the adverse effects spontaneously resolved within 4 weeks; 3% still existed after 32 weeks. A diagnosis of cerebral palsy, higher range of BoNT-A dosage, and a pre-treatment drooling quotient <18% were found to be independent predictors of adverse effects. INTERPRETATION: Before using submandibular BoNT-A injections for drooling, potential adverse effects should be discussed. Oral motor function needs to be monitored, because existing dysphagia may be worsened. The identified clinical predictors could be helpful to optimize patient selection.

Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD).

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic individuals to severely affected patients with an early onset. An estimated 10% of FSHD patients have an early onset (onset before 10 years of age) and are traditionally classified as infantile FSHD. This subgroup is regarded as severely affected and extra-muscular symptoms, such as hearing loss and retinopathy, are frequently described. However, information on the prevalence, natural history and clinical management of early onset FSHD is currently lacking, thereby hampering adequate patient counselling and management. Therefore, a population-based prospective cohort study on FSHD in children is highly needed. METHODS/DESIGN: This explorative study aims to recruit all children (aged 0-17 years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The children will be assessed at baseline and at 2-year follow-up. The general aim of the study is the description of the clinical features and genetic characteristics of this paediatric cohort. The primary outcome is the motor function as measured by the Motor Function Measure. Secondary outcomes include quantitative and qualitative description of the clinical phenotype, muscle imaging, genotyping and prevalence estimations. The ultimate objective will be a thorough description of the natural history, predictors of disease severity and quality of life in children with FSHD. DISCUSSION: The results of this population-based study are vital for adequate patient management and clinical trial-readiness. Furthermore, this study is expected to provide additional insight in the epigenetic and environmental disease modifying factors. In addition to improve counselling, this could contribute to unravelling the aetiology of FSHD. TRIAL REGISTRATION: clinicaltrials.gov NCT02625662.

Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.

We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease.