Objective
The cyclin‐dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) ...provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure‐free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones.
Methods
This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit.
Results
Ninety‐two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0‐11.0). Eighty‐one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor‐tonic‐spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty‐three percent of patients experienced a seizure‐free period ranging from 1 to >12 months, but only 6% were still seizure‐free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia.
Significance
The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset ...refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.
Centronuclear myopathies (CNMs) are characterized by muscle weakness and increased numbers of central nuclei within myofibers. X-linked myotubular myopathy, the most common severe form of CNM, is ...caused by mutations in MTM1, encoding myotubularin (MTM1), a lipid phosphatase. To increase our understanding of MTM1 function, we conducted a yeast two-hybrid screen to identify MTM1-interacting proteins. Striated muscle preferentially expressed protein kinase (SPEG), the product of SPEG complex locus (SPEG), was identified as an MTM1-interacting protein, confirmed by immunoprecipitation and immunofluorescence studies. SPEG knockout has been previously associated with severe dilated cardiomyopathy in a mouse model. Using whole-exome sequencing, we identified three unrelated CNM-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. SPEG was markedly reduced or absent in two individuals whose muscle was available for immunofluorescence and immunoblot studies. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. Our results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy.
OBJECTIVE:To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and ...hypotonia, using next-generation sequencing of whole exomes and genomes.
METHODS:Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest.
RESULTS:Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations.
CONCLUSIONS:Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.
ABSTRACT
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
Objective
The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease‐modifying therapeutics are ...currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments.
Method
Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two syndrome‐specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters.
Results
At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT‐related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow‐up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level.
Interpretation
The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790–802
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.
Aim
To delineate the speech and language phenotype of a cohort of individuals with FOXP1‐related disorder.
Method
We administered a standardized test battery to examine speech and oral motor ...function, receptive and expressive language, non‐verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together with speech and language findings.
Results
Twenty‐nine patients (17 females, 12 males; mean age 9y 6mo; median age 8y range 2y 7mo–33y; SD 6y 5mo) with pathogenic FOXP1 variants (14 truncating, three missense, three splice site, one in‐frame deletion, eight cytogenic deletions; 28 out of 29 were de novo variants) were studied. All had atypical speech, with 21 being verbal and eight minimally verbal. All verbal patients had dysarthric and apraxic features, with phonological deficits in most (14 out of 16). Language scores were low overall. In the 21 individuals who carried truncating or splice site variants and small deletions, expressive abilities were relatively preserved compared with comprehension.
Interpretation
FOXP1‐related disorder is characterized by a complex speech and language phenotype with prominent dysarthria, broader motor planning and programming deficits, and linguistic‐based phonological errors. Diagnosis of the speech phenotype associated with FOXP1‐related dysfunction will inform early targeted therapy.
What this paper adds
Individuals with FOXP1‐related disorder have a complex speech and language phenotype.
Dysarthria, which impairs intelligibility, is the dominant feature of the speech profile.
No participants were receiving speech therapy for dysarthria, but were good candidates for therapy
Features of speech apraxia occur alongside persistent phonological errors.
Language abilities are low overall; however, expressive language is a relative strength.
What this paper adds
Individuals with FOXP1‐related disorder have a complex speech and language phenotype.
Dysarthria, which impairs intelligibility, is the dominant feature of the speech profile.
No participants were receiving speech therapy for dysarthria, but were good candidates for therapy
Features of speech apraxia occur alongside persistent phonological errors.
Language abilities are low overall; however, expressive language is a relative strength.
CDKL5 Deficiency Disorder (CDD) is a rare X-linked monogenic developmental encephalopathy that is estimated to affect 1:42,000 live births. CDD is caused by pathogenic variants in the CDKL5 gene and ...is observed in both male and female patients. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from fibroblasts of six unrelated CDD patients—three males and three females. These patients are clinically diagnosed to present with classic CDD phenotypes, including refractory epilepsy and global developmental delay, and are being followed in a longitudinal clinical study.
Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously ...demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies.
Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study.
As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome.
There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.
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