Non-invasive positive pressure ventilation (NPPV) in children has recently increased worldwide and is used not only for neuromuscular diseases but for various other diseases. However, there have been ...few observational studies on long-term NPPV in children in Japan.
Based on medical records, we retrospectively evaluated patients aged ≤20 years who were initiated long-term NPPV at our hospital from January 2001 to December 2015.
A total of 53 patients on long-term NPPV were identified; 38 (72%) had severe motor and intellectual disabilities (SMID). Compared to those with non-neuromuscular diseases, those with neuromuscular diseases had significantly more planned initiations and less frequent use of oxygen. Regarding patient outcome, 34 patients continued NPPV (64%), and there were three discontinues (6%), seven tracheostomies (13%), and nine deaths (17%). The continuation rate was high among those with neuromuscular disorders (15/19 cases, 79%) and that of tracheotomy was high in those with metabolic/degenerative diseases (3/9 cases, 33%). Ten patients transitioned to adult care, accounting for 29% of the 34 continuing patients.
This is the first observational study on long-term NPPV use in children in Japan that examined outcomes in patients with a range of disorders. The initiation situation, management, and outcomes differed between patients with neuromuscular and non-neuronal muscular diseases. Long-term use of NPPV is possible in many cases, including children with SMID, but can be challenging to continue in patients with progressive diseases such as metabolic/degenerative diseases. Careful discussions regarding the management of each patient are necessary.
Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (
ITPR1
) have been identified in families with early-onset spinocerebellar ataxia type 29 (SCA29) and late-onset SCA15, but have not ...been found in sporadic infantile-onset cerebellar ataxia. We examined if mutations of
ITPR1
are also involved in sporadic infantile-onset SCA. Sixty patients with childhood-onset cerebellar atrophy of unknown etiology and their families were examined by whole-exome sequencing. We found de novo heterozygous
ITPR1
missense mutations in four unrelated patients with sporadic infantile-onset, nonprogressive cerebellar ataxia. Patients displayed nystagmus, tremor, and hypotonia from very early infancy. Nonprogressive ataxia, motor delay, and mild cognitive deficits were common clinical findings. Brain magnetic resonance imaging revealed slowly progressive cerebellar atrophy.
ITPR1
missense mutations cause infantile-onset cerebellar ataxia.
ITPR1
-related SCA includes sporadic infantile-onset cerebellar ataxia as well as SCA15 and SCA29.
Marked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases.
The influence of ...systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy.
A total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions.
Apart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.
Aminoacylation is the process of attaching amino acids to their cognate tRNA, and thus is essential for the translation of mRNA into protein. This direct interaction of tRNA with amino acids is ...catalyzed by aminoacyl-tRNA synthetases. Using whole-exome sequencing, we identified compound heterozygous mutations c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*) in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.
Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can ...lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in
FOLR1
,
C5orf42
,
POLG
,
TPP1
,
PEX16
, and de novo mutations in
CACNA1A
, and
ITPR1
. Patient 1A with
FOLR1
mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with
TPP1
mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with
PEX16
mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.
Alexander disease (AxD) is a neurodegenerative disease in astrocytes caused by a mutation in the gene encoding glial fibrillary acidic protein, GFAP. We herein present the case of a 12-year-old girl ...who showed intermittent exotropia at 3 years of age and central precocious puberty at 7 years of age. The periventricular and medulla oblongata showed high signal intensity on T2-weighted magnetic resonance imaging. The patient was diagnosed with AxD after direct sequencing revealing a de novo recurrent mutation, c.1246C>T (p.R416W) in GFAP. The transient expression of GFAPR416W in cells resulted in the significant formation of aggregates, which recapitulated the hallmark of AxD. We firstly utilized In Cell analyzer to prove the tendency of aggregate formation by mutants of GFAP.
Japanese Leigh syndrome case treated with EPI-743 Kouga, Takeshi; Takagi, Mariko; Miyauchi, Akihiko ...
Brain & development (Tokyo. 1979),
February 2018, 2018-Feb, 2018-02-00, 20180201, Letnik:
40, Številka:
2
Journal Article
Recenzirano
Leigh syndrome is a mitochondrial disease caused by respiratory chain deficiency, and there are no proven effective therapies. EPI-743 is a potent cellular oxidative stress protectant and results of ...clinical trials for mitochondrial diseases are accumulating.
At 5months, a girl presented with the scarce eye movement and diminished muscle tone. She was diagnosed with Leigh encephalopathy from blood and cerebrospinal fluid lactate elevation and MRI findings. Sequence analysis for mitochondrial DNA revealed a T10158C mutation in the mitochondrial encoded ND3 gene in complex I.
At 8months, succinate was prescribed expected to restore the electron transport chain system. After that her condition got worse and succinate was discontinued. Subsequent administration of EPI-743 improved her eye movement, fine motor movements of the extremities, and bowel movement. She is now 5years old. Although brain atrophy has progressed, she has still respiratory free time.
Our patient showed visible improvement with EPI-743 treatment and the only patient surviving after 4years. There is a possibility that EPI-743 is modifying the natural course of the syndrome.
Abstract Objective The objective of this study was to investigate stiripentol (STP) administration in cases of Dravet syndrome (DS) by comparing CYP2C19 allelic polymorphisms with the clinical ...effects of STP, including plasma concentrations of concomitant drugs and adverse effects of STP. Materials and methods Eleven cases of DS cases were included. Demographic and clinical characteristics of the cases (age at the study period, body weight, mean dose and plasma concentration of valproate acid (VPA)/clobazam (CLB) off and on STP, mean plasma concentration of norclobazam (N-CLB) off and on STP, degree of seizure reduction, and adverse effects of STP) were examined with each CYP2C19 polymorphism. Results There were 3 cases of DS with wild type, 6 with intermediate type, and 2 with poor type of CYP2C19 polymorphisms. The N-CLB concentration/CLB dose ratio and N-CLB/CLB concentration ratio off STP were significantly higher in poor metabolizers. Three (37%) of 8 cases showed no effectiveness of STP regardless of the N-CLB concentration increase, and 1 (33%) of 3 cases showed effectiveness of STP regardless of N-CLB concentration decrease. In total, 6 (54%) of 11 cases with DS had >50% reduction in seizure frequency without significant differences in CYP2C19 polymorphisms. Conclusion This study demonstrated an effect of CYP2C19 polymorphisms on STP administration in Japanese cases of DS. There were cases of seizure reduction regardless of N-CLB concentration decrease on STP, which suggests a significant anti-convulsant action of STP. N-CLB concentration decrease on STP was observed in 1 case with ketogenic diet and 2 cases with∗ 3 allelic polymorphisms of CYP2C19.
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