This study aimed to elucidate the clinical characteristics of MECP2 duplication syndrome (MDS), particularly at initial presentation, and to provide clinical clues for the early diagnosis of this ...condition. We conducted a nationwide survey for MDS by sending questionnaires to 575 hospitals where board-certified pediatric neurologists were working and 195 residential hospitals for persons with severe motor and intellectual disabilities in Japan. This survey found 65 cases of MDS, and clinical data of 24 cases in which the diagnosis was genetically confirmed were analyzed. More than half of the patients (52%) had visited a hospital at least once during infancy due to symptoms associated with MDS, with a median age at the initial visit of 7 months. The symptoms that were frequently prevalent at the first visit were facial dysmorphic features, hypotonia, motor developmental delay, and recurrent infections. Dysmorphic features included small mouth, tented upper lip, tapered fingers, and hypertelorism. Other symptoms, including epilepsy, intellectual disabilities, autistic features, stereotypic movements, and gastrointestinal problems, generally appeared later with age. Some symptoms of MDS were found to be age-dependent and may not be noticeable in infancy. Recognition of these clinical characteristics may facilitate the early diagnosis and proper treatment of patients with MDS, improve their long-term outcomes, and help adapt appropriate genetic counseling.
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•The first nationwide MECP2 duplication syndrome (MDS) survey was conducted in Japan.•The median age of the patients with MDS at the first hospital visit was 7 months.•Some symptoms of MDS were age-dependent and may not be noticeable in infancy.•Facial dysmorphism, hypotonia, recurrent infections were common at the first visit.•Recognizing the clinical characteristics of MDS may facilitate the early diagnosis.
Abstract
In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic ...heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11–61 years). While symptom onset often occurred in early childhood median: 24 months, interquartile range (IQR) = 24, a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann–Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman’s rank correlation coefficient r = −0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.
Saffari et al. report a systematic cross-sectional analysis of clinical, radiographic, and molecular features of 44 patients with HSP-ZFYVE26 (SPG15); the largest cohort assembled to date. The analysis delineates early disease manifestations and identifies markers of disease severity.
Purpose: Silent magnetic resonance imaging (MRI) scans produce reduced acoustic noise and are considered more gentle for sedated children. The aim of this study was to compare the validity of T1- ...(T1W) and T2-weighted (T2W) silent sequences for myelination assessment in children with conventional spin-echo sequences.Materials and Methods: A total of 30 children (21 boys, 9 girls; age range: 1–83 months, mean age: 35.5 months, median age: 28.5 months) were examined using both silent and spin-echo sequences. Acoustic noise levels were analyzed and compared. The degree of myelination was qualitatively assessed via consensus, and T1W and T2W signal intensities were quantitatively measured by percent contrast.Results: Acoustic noise levels were significantly lower during silent sequences than during conventional sequences (P < 0.0001 for both T1W and T2W). Inter-method comparison indicated overall good to excellent agreement (T1W and T2W images, κ = 0.76 and 0.80, respectively); however, agreement was poor for cerebellar myelination on T1W images (κ = 0.14). The percent contrast of silent and conventional MRI sequences had a strong correlation (T1W, correlation coefficient CC = 0.76; T1W excluding the middle cerebellar peduncle, CC = 0.82; T2W, CC = 0.91).Conclusions: For brain MRI, silent sequences significantly reduced acoustic noise and provided diagnostic image quality for myelination evaluations; however, the two methods differed with respect to cerebellar delineation on T1W sequences.
Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by MECP2 mutations. We identified a de novo WDR45 mutation, which caused a subtype of neurodegeneration with brain iron ...accumulation, in a patient showing clinically typical RTT. The mutation (c.830+1G>A) led to aberrant splicing in lymphoblastoid cells. Sequential brain magnetic resonance imaging demonstrated that iron deposition in the globus pallidus and the substantia nigra was observed as early as at 11 years of age. Because the patient showed four of the main RTT diagnostic criteria, WDR45 should be investigated in patients with RTT without MECP2 mutations.
In glucose transporter 1 deficiency syndrome (Glut1DS), cerebrospinal fluid glucose (CSFG) and CSFG to blood glucose ratio (CBGR) show significant differences among groups classified by phenotype or ...genotype. The purpose of this study was to investigate the association between these biochemical parameters and Glut1DS severity.
The medical records of 45 patients who visited Osaka University Hospital between March 2004 and December 2021 were retrospectively examined. Neurological status was determined using the developmental quotient (DQ), assessed using the Kyoto Scale of Psychological Development 2001, and the Scale for the Assessment and Rating of Ataxia (SARA). CSF parameters included CSFG, CBGR, and CSF lactate (CSFL).
CSF was collected from 41 patients, and DQ and SARA were assessed in 24 and 27 patients, respectively. Simple regression analysis showed moderate associations between neurological status and biochemical parameters. CSFG resulted in a higher R2 than CBGR in these analyses. CSF parameters acquired during the first year of life were not comparable to those acquired later. CSFL was measured in 16 patients (DQ and SARA in 11 and 14 patients, respectively). Although simple regression analysis also showed moderate associations between neurological status and CSFG and CSFL, the multiple regression analysis for DQ and SARA resulted in strong associations through the use of a combination of CSFG and CSFL as explanatory variables.
The severity of Glut1DS can be predicted from CSF parameters. Glucose and lactate are independent contributors to the developmental and neurological status in Glut1DS.
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•Glucose transporter 1 deficiency syndrome severity is predictable.•Cerebrospinal fluid glucose correlates with the severity.•Cerebrospinal fluid lactate is another predictor of severity.•Parameters for prediction differ between older children and those <1 year of age.•Innate severity should be considered while evaluating ketogenic diet efficacy.
The COL4A1 (collagen Type 4 alpha1) pathogenic variant is associated with porencephaly and schizencephaly and accounts for approximately 20% of these patients. This gene variant leads to systemic ...microvasculopathy, which manifests as brain, ocular, renal, and muscular disorders. However, only a few patients with surgical interventions have been reported and the potential surgical risks are unknown. Here, we present the cases of two female patients between 7 and 8 years of age who were diagnosed with the COL4A1 variant and underwent laparoscopy‐assisted percutaneous endoscopic gastrostomy (LAPEG) for oral dysphagia. Their primary brain lesions were caused by porencephaly and paralysis, which are caused by multiple cerebral hemorrhages and infarctions, and both patients had refractory epileptic complications. Although LAPEG was successfully performed in both patients without any intraoperative complications, one patient developed alveolar hemorrhage postoperatively and required mechanical ventilation. Thus, careful perioperative management of patients with the COL4A1 variant is important.
In Japan, Meiji 817-B (M817-B), a powdered ketogenic milk, has been available since the ketogenic diet was introduced to infants and tube-fed children with medication-resistant epilepsy in the 1980s.
...We retrospectively evaluated the efficacy, tolerability, and side effects of the ketogenic diet using M817-B as the main source of daily food intake for patients with epilepsy by sending questionnaires to the members of a subcommittee of the Japan Epilepsy Society that focuses on the proper use of M817-B.
A total of 42 patients were enrolled. Age at the initiation of the diet therapy ranged from 3 to 244 months (median, 32.5 months). Thirty-four patients were fed via tube, and the remaining 8 were fed orally. About 93% of patients were able to continue the diet for 1 month, 74% for 3 months, and 64% for 6 months. The median period of continuation was 16 months. One patient was able to continue as long as 7 years. The ketogenic ratio was maintained at about 3.0. The seizure-free rate and responder (>50% seizure reduction) rate were about 10% and 30–40%, respectively during the 12 months on the diet. Mean serum beta-hydroxybutyrate increased to almost 4 mM at 1 month and was maintained during the diet period. Side effects, which required discontinuation of the diet therapy, occurred in 11 of 42 patients and included hypertonia, weight loss, vomiting, hypoglycemia, metabolic acidosis, and hypokalemia.
M817-B could be used long-term with demonstrated efficacy in seizure reduction, although there are some side effects that may require cessation of the diet therapy.
To establish an objective method of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) that can assist in the diagnosis of glucose transporter 1 deficiency syndrome (GLUT1-DS).
FDG-PET was ...performed in 8 patients with a mean age of 12.5 years (range, 2–22 years) with GLUT1-DS. Their PET findings were compared with those of 45 controls with a mean age of 11.2 years (range, 2–21 years) by statistical parametric mapping (SPM12, Welcome Neurological Institute). The controls had epilepsy of unknown etiology and normal MRI findings. The age-adjusted ratios of mean radioactivities in regions of interest (ROIs) of bilateral lenticular nuclei, thalami, and the whole cerebral cortex were also measured. The sensitivities and specificities of the ratios for the differential diagnosis of GLUT1-DS were also determined.
SPM showed significantly decreased uptake in bilateral thalami and increased uptake in bilateral lenticular nuclei in patients with GLUT1-DS. There were no areas in the cerebral cortex with significant differences between patients and controls. On ROI analysis, by setting the cut-off value of the age-adjusted lenticular nuclei/thalami radioactivity ratio to 1.54, patients with GLUT1-DS were differentiated from controls with sensitivity of 1.00 and specificity of 0.98.
The age-adjusted lenticular nuclei/thalami radioactivity ratio on PET can distinguish patients with GLUT1-DS from patients with epilepsy of unknown etiology with high sensitivity and specificity. It is important to pay attention to the metabolism of the lenticular nuclei and thalami on PET for the diagnosis of GLUT1-DS.
Familial hemiplegic migraine (FHM) is an inherited autosomal dominant disorder characterized by migraine with reversible hemiplegia. FHM1 is caused by variants in CACNA1A, encoding a P/Q type ...neuronal voltage-gated calcium channel α subunit, which is also associated with episodic ataxia type 2 (EA2). FHM2 is associated with ATP1A2, which codes for an Na+/K+-ATPase isoform 2 subunit.
We identified an FHM2 family, the mother and her daughter, with a novel variant in ATP1A2, p.Gly377Asp, located in a well-conserved P-type ATPase motif. Additionally, the mother harbored deletion in the CACNA1A, associated with EA2, but her daughter did not. The mother presented migraine with typical aura without motor deficit, whereas her daughter had migraine accompanied by recurrent motor deficit and altered consciousness. The additional CACNA1A deletion in the mother might serve as a modifier.
Our report emphasizes the importance of genetic analysis to diagnose neurological ion channel/transporter diseases.
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