Heterozygous variants in TUBB encoding one of β-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) ...and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.
Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare ...heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.
Purpose In patients with parkinsonism, the precise mechanism of impaired voluntary cough remains poorly understood. This study used the flow–volume curve to clarify whether disordered voluntary cough ...reflects the freezing phenomenon. Subjects and Methods Case 1 was a 58-year-old female who had been suffering from progressive supranuclear palsy-pure akinesia with gait freezing. Case 2 was a 59-year-old female who had advanced juvenile parkinsonism. The subjects were asked to take a deep inspiration to the total lung capacity and then cough more than five times through the face mask into the spirometer without intervening inspirations between the coughing efforts. Results Hesitation in cough initiation (case 2), decreased peak cough flow (case 1), and rounding of the first spike (cases 1 and 2) were observed. In addition, movements of the spike wave at a lower lung volume became progressively smaller and faster (cases 1 and 2). Conclusion These clinical manifestations in our patients are similar to those observed in the freezing phenomenon. However, to date, the concept of cough freezing has been underrecognized in clinical practice. From the present study, it could be hypothesized that the freezing phenomenon can occur in voluntary cough as well as in gait, speech, and writing.
Purpose This study used an accelerometer placed close to the center of gravity to quantitatively investigate whether unexpected gait initiation aggravates start hesitation (freezing of gait in gait ...initiation). Subject and Methods The subject was a 53-year-old female who had been suffering from juvenile parkinsonism since she was aged 21 years. An alternating-treatment design was used to compare acceleration characteristics under two gait initiation conditions, which were 1) deliberate gait initiation and 2) gait initiation on a sudden “go” verbal command (sudden gait initiation), in the “on” state of the medication cycle. Results In six out of eight sessions, a combination of reduced peak positive anterior accelerations and large power percentage in the high frequency band was consistently observed in the sudden gait initiation compared with deliberate gait initiation. In the other two sessions, although a large acceleration just after the “go” signal was observed, subsequent acceleration signals were blocked by sudden gait initiation. Conclusion The results suggest that, even in the “on” state, start hesitation is apparent without increased reliance on frontal cortical attentional mechanisms to compensate for impaired automaticity. In advanced juvenile parkinsonism, sudden gait initiation may be an effective paradigm as a provoking test for start hesitation.
Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA ...patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.
Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.
Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA–S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.
A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.
Aggressive immunosuppressive therapies have been proposed to treat primary angiitis of the central nervous system (PACNS). Here, we report the first successfully stabilized case of childhood, ...small-vessel PACNS with intravenous immunoglobulin (IVIG) therapy.
A 12-year-old boy was admitted to our hospital complaining of recurrent headaches and upper-left homonymous quadrantanopia, since the age of 11 years. Brain computed tomography scans revealed fine calcification in the right temporal and occipital lobes. Brain magnetic resonance imaging scans revealed white matter lesions, with gadolinium enhancement, which waxed, waned, and migrated for 1 year, without immunomodulatory therapies. A cerebrospinal fluid study showed pleocytosis (12 cells per µl). No clinical or serological findings suggested systemic inflammation or vasculitis. Brain angiography was unremarkable. Brain biopsy revealed thickened and hyalinized small vessels, with intramural infiltration of inflammatory cells, which confirmed the diagnosis of small-vessel PACNS. Because the patient developed surgical site infection following biopsy, the administration of monthly IVIG (2 g/kg) was prescribed, instead of immunosuppressive agents. After IVIG therapy, the patient remained stable, except for a single episode of mild radiological exacerbation at 16 months, which occurred when the IVIG interval was expanded. Oral prednisone was added and gradually tapered. At 50 months, his intellectual abilities and motor functions were normal, although he showed residual upper-left homonymous quadrantanopia and post-exercise headache. A temporary headache, associated with the immunoglobulin infusion, was resolved by slowing the infusion rate. PACNS should be treated aggressively to improve prognosis. However, when immunosuppressants are contraindicated, IVIG may be an alternative therapeutic option.
Coffin-Lowry syndrome is a rare X-linked disease, caused by loss-of-function mutations in the RPS6KA3 gene. Patients exhibit severe intellectual disability with characteristic dysmorphism. As there ...are no specific laboratory findings to support the diagnosis of Coffin-Lowry syndrome, it may be difficult to diagnose—especially in young children, where the characteristic craniofacial features are less discernible.
Here we report on a 2-year-old boy with Coffin-Lowry syndrome with a novel missense mutation in the RPS6KA3 gene. On magnetic resonance imaging, his brain exhibited periventricular signal abnormalities with multiple small cystic lesions. These findings may aid in diagnosis of Coffin-Lowry syndrome.
Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired ...by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia.
Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period.
Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases.
Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.
•Epileptic-dyskinetic encephalopathies are rare epileptic disorders characterized by EOEE with involuntary movement.•The presence of involuntary movements in patients with EOEE caused by gene ...variants may be a key diagnostic symptom.•Genetic diagnosis is useful and may provide a reference for treatment selection.
Epileptic-dyskinetic encephalopathies are rare epilepsies characterized by early-onset epileptic encephalopathies (EOEEs) with involuntary movement. Herein, we investigated the impact of gene variants in epileptic-dyskinetic encephalopathies. Four independent patients from four families who exhibited involuntary movements were recruited from Tokyo Metropolitan Neurological Hospital. The inclusion criteria were as follows: onset within 1 year after birth, frequent seizures, severe developmental delay and accompanying involuntary movements.
We detected four genetic mutations, including STXBP1, GNAO1, CYFIP2, and SCN8A variants. The involuntary movements were drug-resistant. However, pallidal electrocoagulation followed by gabapentin were partially effective in treating chorea and ballismus of the extremities in patients with GNAO1 variants, and perampanel partially suppressed seizures and involuntary movements in one patient with a SCN8A variant. Movement disorders are common to many neurodevelopmental disorders, including a variety of EOEEs. Although we could not establish a definitive correlation using genetic variants in patients with EOEE and movement disorders, involuntary movements in patients with EOEEs may be a key diagnostic finding. The usage of genetic variants could prove beneficial in the future as more patients are investigated with epileptic-dyskinetic encephalopathies.
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