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OBJECTIVE:To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS:We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS:The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE:GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

Aim: To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile‐onset epilepsies. Method: We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile‐onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features. Wilcoxon rank‐sum tests and χ2 or Fisher's exact tests were performed for between‐cohort comparisons. Results: We identified 137 individuals with CDD (110 females, 80.3%; median age at last follow‐up 3 year 11 months) and 313 individuals with infantile‐onset epilepsies (156 females, 49.8%; median age at last follow‐up 5 years 2 months; 35% with genetic diagnosis). Features reported significantly more frequently in the CDD group than in the comparison cohort included developmental and epileptic encephalopathy (81% vs 66%), treatment‐resistant epilepsy (95% vs 71%), sequential seizures (46% vs 6%), epileptic spasms (66% vs 42%, with hypsarrhythmia in 30% vs 48%), regression (52% vs 29%), evolution to Lennox–Gastaut syndrome (23% vs 5%), diffuse hypotonia (72% vs 36%), stereotypies (69% vs 11%), paroxysmal movement disorders (29% vs 17%), cerebral visual impairment (94% vs 28%), and failure to thrive (38% vs 22%). Interpretation: CDD, compared with other suspected or confirmed genetic epilepsies presenting in the first year of life, is more often characterized by a combination of treatment‐resistant epilepsy, developmental and epileptic encephalopathy, sequential seizures, spasms without hypsarrhythmia, diffuse hypotonia, paroxysmal movement disorders, cerebral visual impairment, and failure to thrive. Defining core phenotypic characteristics will improve precision diagnosis and treatment. [ABSTRACT FROM AUTHOR]

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Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is caused by heterozygous or hemizygous variants in CDKL5 and is characterized by refractory epilepsy, cognitive and motor impairments, and cerebral visual impairment. CDKL5 has multiple transcripts, of which the longest transcripts, NM_003159 and NM_001037343, have been used historically in clinical laboratory testing. However, the transcript NM_001323289 is the most highly expressed in brain and contains 170 nucleotides at the 3′ end of its last exon that are noncoding in other transcripts. Two truncating variants in this region have been reported in association with a CDD phenotype. To clarify the significance and range of phenotypes associated with late truncating variants in this region of the predominant transcript in the brain, we report detailed information on two individuals, updated clinical information on a third individual, and a summary of published and unpublished individuals reported in ClinVar. The two new individuals (one male and one female) each had a relatively mild clinical presentation including periods of pharmaco‐responsive epilepsy, independent walking and limited purposeful communication skills. A previously reported male continued to have a severe phenotype. Overall, variants in this region demonstrate a range of clinical severity consistent with reports in CDD but with the potential for milder presentation. [ABSTRACT FROM AUTHOR]

Introduction: X-linked myotubular myopathy (XLMTM), characterized by severe hypotonia, weakness, respiratory distress, and early mortality, is rare and natural history studies are few.Methods: RECENSUS is a multicenter chart review of male XLMTM patients characterizing disease burden and unmet medical needs. Data were collected between September 2014 and June 2016.Results: Analysis included 112 patients at six clinical sites. Most recent patient age recorded was ≤18 months for 40 patients and >18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. Mortality was 44% (64% ≤18 months; 32% >18 months). Premature delivery occurred in 34/110 (31%) births. Nearly all patients (90%) required respiratory support at birth. In the first year of life, patients underwent an average of 3.7 surgeries and spent 35% of the year in the hospital.Discussion: XLMTM is associated with high mortality, disease burden, and healthcare utilization. Muscle Nerve 57: 550-560, 2018. [ABSTRACT FROM AUTHOR]

Objective: To measure the efficacy of mecasermin (recombinant human insulin‐like growth factor 1, rhIGF‐1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double‐blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF‐1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28‐week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory‐ and electroencephalography (EEG)‐based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation As in the phase 1 trial, rhIGF‐1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A -associated neurodevelopmental disorder and explore genotype-phenotype correlations. We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo , heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate. We reinforce the finding that certain RAB11A missense variants lead to intellectual disability and developmental delays. Other clinical features might include gait disturbances, hypotonia, magnetic resonance imaging abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Epilepsy seems to be less common and linked to variants outside the binding sites. Individuals with variants in the binding sites seem to have a more multisystemic, nonepileptic phenotype. Similar to other Rab-related disorders, RAB11A -associated neurodevelopmental disorder can also impact gait, tonus, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy seems to affect the minority of patients with variants outside the binding sites. [ABSTRACT FROM AUTHOR]

Background: CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy. While a subset of individuals is believed to experience comorbid behavioral disorders, none have reported well-defined affective disorders. Though there is a documented association between epilepsy and mood disorders, they may go undetected in the CDD population due to difficulty assessing mood in the presence of severe/profound intellectual disability and disease-related sleep dysregulation. We aimed to identify the clinical characteristics of an individual with CDD who presented with a mood disorder falling outside this expected behavioral phenotype., Case Presentation: We identified one 22-year-old female with CDD diagnosed with unspecified bipolar disorder at 18 years of age. Family history was noncontributory. At diagnosis, she had fluctuations in mood, characterized by periods of elated affect, increased energy and vocalizations, hypertonia, and insomnia lasting 3-4 days alternating with periods of depressed affect, irritability, hypotonia, and excessive sleep lasting for up to one month. She had experienced frequent mood swings and sleep dysregulation from early childhood, and by early adulthood the duration of "up" and "down" periods fell in the range specified in the DSM-5 bipolar disorder criteria. Trazodone and suvorexant did not alleviate sleep related symptoms. Her epilepsy was well controlled on lamotrigine monotherapy since early childhood. Though lamotrigine treatment has had no psychiatric benefit despite its known mood stabilizing properties, aripiprazole has been effective in reducing severity and frequency of fluctuations between hypomania and depression., Conclusions: While sleep and behavioral disorders fall within the expected phenotype for CDD, this is the first report of bipolar disorder. Careful attention to patterns of sleep and behavior that may indicate mood cycling in this population is required, particularly in the setting of limited communication and functional abilities.

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity., (© 2024 Wiley Periodicals LLC.)

Objective: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder., Methods: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients., Results: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder., Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124., (© 2018 American Neurological Association.)