Developmental stuttering is a common childhood condition characterized by disfluencies in speech, such as blocks, prolongations, and repetitions. While most children who stutter do so only transiently, there are some for whom stuttering persists into adulthood. Rare-variant screens in families including multiple relatives with persistent stuttering have so far identified six genes carrying putative pathogenic variants hypothesized to act in a monogenic fashion. Here, we applied a complementary study design, searching instead for de novo variants in exomes of 85 independent parent-child trios, each with a child with transient or persistent stuttering. Exome sequencing analysis yielded a pathogenic variant in SPTBN1 as well as likely pathogenic variants in PRPF8, TRIO, and ZBTB7A - four genes previously implicated in neurodevelopmental disorders with or without speech problems. Our results also highlighted two further genes of interest for stuttering: FLT3 and IREB2. We used extensive bioinformatic approaches to investigate overlaps in brain-related processes among the twelve genes associated with monogenic forms of stuttering. Analyses of gene-expression datasets of the developing and adult human brain, and data from a genome-wide association study of human brain structural connectivity, did not find links of monogenic stuttering to specific brain processes. Overall, our results provide the first direct genetic link between stuttering and other neurodevelopmental disorders, including speech delay and aphasia. In addition, we systematically demonstrate a dissimilarity in biological pathways associated with the genes thus far implicated in monogenic forms of stuttering, indicating heterogeneity in the etiological basis of this condition. Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. Symptomatic individuals experience hypoketotic hypoglycemia in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or during intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. Untreated severe hypoglycemic episodes can be accompanied by seizures, vomiting, lethargy, coma, and death. Metabolic decompensation during these episodes can result in elevated liver transaminases and hyperammonemia. Individuals with MCAD deficiency who have experienced the effects of uncontrolled metabolic decompensation are also at risk for chronic myopathy. Early identification and avoidance of prolonged fasting can ameliorate these findings. However, children with MCAD deficiency are at risk for obesity after initiation of treatment due to the frequency of feeding. The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in ACADM by molecular genetic testing OR by significantly reduced activity of MCAD activity in blood or cultured skin fibroblasts. Because of its relatively high sensitivity, ACADM molecular genetic testing can obviate the need for enzymatic testing, which is available only in limited academic centers. Treatment of manifestations: For routine daily treatment, fasting should be avoided and may require frequent feeding (every 2-3 hours) in infancy, overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch to maintain blood glucose levels during sleep. A normal, healthy diet containing no more than 30% of total energy from fat is recommended. All individuals with MCAD deficiency should avoid skipping meals and weight loss diets that recommend fasting. Prolonged or intense exercise should be covered by adequate carbohydrate intake and hydration. Intravenous glucose is recommended for surgical procedures that require several hours of fasting. Weight control measures such as regular education about proper nutrition and recommended physical exercise should be discussed to help avoid obesity. Standard treatment for developmental delay / aphasia, attention-deficit/hyperactivity disorder, and muscle weakness. For acute inpatient treatment, IV administration of glucose should be initiated immediately with 10% dextrose with appropriate electrolytes at a rate of 1.5 times maintenance rate or at 10-12 mg glucose/kg/minute to achieve and maintain a blood glucose level higher than 5 mmol/L, or between 120 and 170 mg/dL. Address electrolyte and pH imbalances with intravenous fluid management and initiate appropriate treatment for what triggered the metabolic stress. Surveillance: Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician should be involved to ensure proper nutrition in terms of quality and quantity. Affected infants should be seen in team clinic in two to three months, then every six to 12 months if otherwise clinically well; however, the frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers. Routine assessments for growth, acquisition of developmental milestones, neurobehavioral issues, and secondary carnitine deficiency are recommended. Agents/circumstances to avoid: Hypoglycemia; infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat; popular high-fat/low-carbohydrate diets; alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), which can elicit metabolic decompensation; aspirin. Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs and offspring of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures. Pregnancy management: Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnant women with MCAD deficiency. MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for MCAD deficiency are possible. Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. The clinical diagnosis of FHM can be established in a proband: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or second-degree relative with similar attacks that fulfill the diagnostic criteria for hemiplegic migraine. The molecular diagnosis can be established in a proband by identification of a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2, or SCN1A. Treatment of manifestations: A trial of acetazolamide for individuals with CACNA1A-FHM or a trial of prophylactic migraine medications (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, anti-seizure medications) for all FHM types may be warranted for frequent attacks. Anti-seizure treatment may be necessary for seizures, which are prevalent in ATP1A2-FHM. Corticosteroids in children with cerebral edema to reduce life-threatening manifestations. Surveillance: Neurologic evaluation to assess change in attack frequency and/or seizures, development of movement disorder, developmental delay, and/or learning disability annually or more frequently for worsening symptoms. Agents/circumstances to avoid: Vasoconstricting agents because of the risk of stroke; cerebral angiography as it may precipitate a severe attack. FHM and simplex hemiplegic migraine caused by a heterozygous ATP1A2, CACNA1A, PRRT2, or SCN1A pathogenic variant are inherited in an autosomal dominant manner. Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent. Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a de novo pathogenic variant or a pathogenic variant inherited from an asymptomatic parent. Each child of an individual with FHM has a 50% chance of inheriting the pathogenic variant. Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

The aim of this study was to reach consensus among researchers, clinicians, and service managers on the most important outcomes of cognitive-communication treatments for children and adolescents (ages 5-18 years) with traumatic brain injury, in the postacute stage of rehabilitation and beyond. This is an international three-round e-Delphi study. In Round 1, participants answered three open-ended questions, generating important treatment outcomes at three stages of development (5-11, 12-15, and > 15-18 years). Results were analyzed using qualitative content analysis and combined with outcomes from a previous scoping review. In Rounds 2-3, outcome importance was ranked on a 9-point scale. Consensus was defined a priori with outcomes rated as being "essential" (7-9) by at least 70% of respondents and rated 1-3 by less than 15% of respondents. Consensus outcomes were linked to the International Classification of Functioning, Disability and Health (ICF). A total of 360 outcomes met consensus for all age groups. For 5- to 11-year-old children, important outcomes linked almost equally to the Body Functions (n = 52, 13.1%) and Activity/Participation (n = 50, 12.6%) components of the ICF. Outcomes of "successful start to school," "return to school," and "school functioning" were uniquely important. For older children and adolescents, outcomes linked to the Activity/Participation component of the ICF most frequently (12-15 years: n = 62, 15.6%; > 15-18 years: n = 73, 18.4%). For older cohorts, unique outcomes of "emotional safety," "employment," and "life skill development" met consensus. Participants consider many outcomes, spanning most of the ICF, to be important for children and adolescents with cognitive-communication disorders (CCDs). As children and adolescents age, the importance of ICF components shifts, and distinct outcomes emerge, highlighting the necessity of developmentally relevant rehabilitation. The broad range of outcomes reaching consensus reflects pediatric CCD complexity and the need for holistic, person-centered care. Future research should explore the priorities of children and adolescents with CCDs and their families.

Patient experience for people with aphasia/families in acute care is frequently reported as negative, with communication barriers contributing to adverse events and significant long-term physical and psychosocial sequelae. Although the effectiveness of providing supported communication training and resources for health care providers in the stroke system is well documented, there is less evidence of implementation strategies for sustainable system change. This paper describes an implementation process targeting two specific areas: 1) improving Stroke Team communication with patients with aphasia, and 2) helping the Stroke Team provide support to families. The project aimed for practical sustainable solutions with potential contribution toward the development of an implementation practice model adaptable for other acute stroke contexts. The project was designed to create a communicatively accessible acute care hospital unit for people with aphasia. The process involved a collaboration between a Stroke Team covering two units/wards led by nurse managers (19 participants), and a community-based Aphasia Team with expertise in Supported Conversation for Adults with Aphasia (SCA™) - an evidence-based method to reduce language barriers and increase communicative access for people with aphasia. Development was loosely guided by the integrated knowledge translation (iKT) model, and information regarding the implementation process was gathered in developmental fashion over several years. Examples of outcomes related to the two target areas include provision of accessible information about aphasia to patients as well as development of two new products - a short virtual SCA™ eLearning module relevant to acute care, and a pamphlet for families on how to keep conversation alive. Potential strategies for sustaining a focus on aphasia and communicative access emerged as part of the implementation process. This implementation journey allowed for a deeper understanding of the competing demands of the acute care context and highlighted the need for further work on sustainability of communicative access interventions for stroke patients with aphasia and their families.

To evaluate the clinical spectrum associated with ATP1A2 variants in Chinese children with hemiplegia, migraines, encephalopathy or seizures. Sixteen children (12 males and 4 females), including ten patients with ATP1A2 variants whose cases had been published previously, were identified using next-generation sequencing. Fifteen patients had FHM2 (familial hemiplegic migraine type 2), including three who had AHC (alternating hemiplegia of childhood) and one who had drug-resistant focal epilepsy. Thirteen patients had DD (developmental delay). The onset of febrile seizures, which occurred between 5 months and 2 years 5 months (median 1 year 3 months) was earlier than the onset of HM (hemiplegic migraine), which occurred between 1 year 5 months and 13 years (median 3 years 11 months). Disturbance of consciousness subsided first, at 40 h to 9 days (median 4.5 days); hemiplegia and aphasia were resolved slowly, taking 30 min to 6 months (median 17.5 days) for the former and 24 h to over 1 year (median 14.5 days) for the latter. Cranial MRI showed edema in the cerebral hemispheres, mainly the left hemisphereacute attacks. All thirteen FHM2 patients recovered to baseline in 30 min to 6 months. Fifteen patients had between 1 and 7 (median 2) total attacks between the baseline and follow-up timepoints. We report twelve missense variants, including a novel variant ATP1A2 variant, p.G855E. The known genotypic and phenotypic spectra of Chinese patients with ATP1A2-related disorders were further expanded. Recurrent febrile seizures and DD combined with paroxysmal hemiplegia and encephalopathy should raise the clinical suspicion of FHM2. The avoidance of triggers and thus the prevention of attacks may be the most effective therapy for FHM2.

Microdeletion in the 16p11.2 loci lead to a distinct neurodevelopmental disorder with intellectual disability and autism spectrum disorder in addition to dysmorphia, macrocephaly, and increased body mass index. One of the deleted genes in this region is PRRT2 which codes for proline-rich transmembrane protein 2. Heterozygous variants in PRRT2 cause four distinct neurological disorders including benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD), PKD with infantile convulsions, and familial hemiplegic migraine (FHM). A 13-year-old male with a known history of 16p11.2 deletion and resultant cognitive delay presented with sudden onset of headache, left-sided weakness, facial droop, and aphasia concerning for acute ischemic stroke. Magnetic resonance imaging of the brain was performed urgently which did not reveal any acute processes and his presentation met criteria for hemiplegic migraine. There have been reports of PKD and BFIE in this microdeletion syndrome; however, our proband is the first case that presented with FHM related to haploinsufficiency of PRRT2. This report highlights the importance of counseling patient families regarding acute paroxysmal presentations in this syndrome.