[Show abstract][Hide abstract] ABSTRACT: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency in human arylsulfatase A (hASA). We recently reported that ependymal cells and the choroid plexus are selectively transduced by intracerebroventricular (ICV) injection of adeno-associated virus serotype 1 (AAV1) vector and serve as a biological reservoir for the secretion of lysosomal enzymes into the cerebrospinal fluid (CSF). In the present study, we examined the feasibility of this AAV-mediated gene therapy to treat MLD model mice. Preliminary experiments showed that the hASA level in the CSF after ICV injection of self-complementary (sc) AAV1 was much higher than in mice injected with single-stranded AAV1 or scAAV9. However, when 18-week-old MLD mice were treated with ICV injection of scAAV1, the concentration of hASA in the CSF gradually decreased and was not detectable at 12 weeks after injection, probably due to the development of anti-hASA antibodies. As a result, the sulfatide levels in brain tissues of treated MLD mice were only slightly reduced compared with those of untreated MLD mice. These results suggest that this approach is potentially promising for treating MLD, but that controlling the immune response appears to be crucial for long-term expression of therapeutic proteins in the CSF.
[Show abstract][Hide abstract] ABSTRACT: Glycine encephalopathy (GCE) is a rare autosomal recessive disorder caused by defects in the glycine cleavage complex. Here we report a patient with GCE and elevated level of glycine in both the serum and the cerebrospinal fluid. Trio-based whole-exome sequencing identified novel compound heterozygous mutations (c.738-2A>G and c.929T>C (p.Met310Thr)) in LIAS. To date, three homozygous mutations have been reported in LIAS. All previously reported GCE patients also show elevated level of serum glycine. Our data further supports LIAS mutations as a genetic cause for GCE.Journal of Human Genetics advance online publication, 25 June 2015; doi:10.1038/jhg.2015.72.
Journal of Human Genetics 06/2015; DOI:10.1038/jhg.2015.72 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial dysfunction. LS is characterised by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter or spinal cord on T2-weighted MRI. LS is a genetically heterogeneous disease, and to date mutations in approximately 40 genes related to mitochondrial function have been linked to the disorder.
We investigated a pair of female monozygotic twins diagnosed with LS from consanguineous healthy parents of Indian origin. Their common clinical features included optic atrophy, ophthalmoplegia, spastic paraparesis and mild intellectual disability. High-blood lactate and high-intensity signal in the brainstem on T2-weighted MRI were consistent with a clinical diagnosis of LS. To identify the genetic cause of their condition, we performed whole exome sequencing.
We identified a homozygous nonsense mutation in C12orf65 (NM_001143905; c.346delG, p.V116*) in the affected twins. Interestingly, the identical mutation was previously reported in an Indian family with Charcot-Marie Tooth disease type 6, which displayed some overlapping clinical features with the twins.
We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers.
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Journal of neurology, neurosurgery, and psychiatry 05/2015; DOI:10.1136/jnnp-2014-310084 · 5.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.92.
European journal of human genetics: EJHG 05/2015; DOI:10.1038/ejhg.2015.92 · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background It is important to clarify the characteristic traits of the cognitive functions of Kabuki syndrome patients in order to choose appropriate pedagogical techniques.
Methods The cognitive functions in seven participants with Kabuki syndrome were investigated using the Kaufmann assessment battery for children test, the Benton facial recognition test and Theory of Mind test, with some copying tasks of two and three dimensional line drawing figures. The results were compared to those of seven Williams syndrome participants.
Results The findings indicated disparities among cognitive areas in the Kabuki syndrome participants with stronger subtest “number recall” than the subtest “gestalt closure” in the Kaufmann assessment battery for children test (p<0.05). The disparities were compatible as previously described. The difficulties in copying the line drawing figures suggested a dorsal pathway dysfunction similar to that in Williams syndrome patients, but further longitudinal observation is needed. In the Kabuki syndrome participants, four of five participants who could perform the Theory of Mind test could pass the test, whereas only two out of six in the Williams syndrome patients could do so. The discrepancies between the results of the Benton facial recognition test and Theory of Mind test were the opposite of those in the Williams syndrome patients, in spite of anecdotal observations of similar tendencies in social interaction.
Conclusion Kabuki syndrome is another disease that shows disparities among cognitive functions. Investigating this syndrome may help us to understand the mechanisms of human cognitive function.
European Journal of Paediatric Neurology 05/2015; 19(Suppl 2):S76. DOI:10.1016/S1090-3798(15)30252-X · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We encountered a 5-year-old girl who had short-lasting, severe, unilateral temporal headaches with ipsilateral lacrimation, nasal congestion and rhinorrhoea, and facial flushing after severe attacks. Family history revealed similar short-lasting, severe headaches in an older brother, younger sister, mother, maternal aunt, and maternal grandfather's brother.
We performed routine laboratory examinations and electrophysiological and radiological studies for three children, and whole-exome sequencing to determine the genetic causality in this family.
Focal hyperperfusion of the right trigeminal root entry zone was seen during a right-sided attack in one child, while left-sided temporal headache attacks were provoked by bilateral electrical stimulation of the upper extremities in another. We identified a novel SCN9A mutation (NM_002977: c.5218G>C, p.Val1740Leu) in all affected family members, but not in any of the unaffected members. SCN9A encodes the voltage-gated sodium-channel type IX alpha subunit known as Nav1.7.
Gain-of-function mutations in Nav1.7 are well known to cause paroxysmal extreme pain disorder (PEPD), a painful Na-channelopathy characterized by attacks of excruciating deep burning pain in the rectal, ocular, or jaw areas. The SCN9A mutation suggests that our patients had a phenotype of PEPD with a predominant symptom of short-lasting, severe, unilateral headache.
The Journal of Headache and Pain 04/2015; 16(1):35. DOI:10.1186/s10194-015-0519-3 · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Using whole exome sequencing, we confirmed a diagnosis of biotin-responsive basal ganglia disease (BBGD) accompanied by possible Kawasaki Disease. BBGD is an autosomal-recessive disease arising from a mutation of the SLC19A3 gene encoding the human thiamine transporter 2 protein, and usually manifests as subacute to acute encephalopathy. In this case, compound heterozygous mutations of SLC19A3, including a de novo mutation in one allele, was the cause of disease. Although a large number of genetic neural diseases have no efficient therapy, there are several treatable genetic diseases, including BBGD. However, to achieve better outcome and accurate diagnosis, therapeutic analysis and examination for disease confirmation should be done simultaneously. We encountered a case of possible Kawasaki disease, which had progressed to BBGD caused by an extremely rare genetic condition. Although the prevalence of BBGD is low, early recognition of this disease is important because effective improvement can be achieved by early biotin and thiamine supplementation.Journal of Human Genetics advance online publication, 16 April 2015; doi:10.1038/jhg.2015.35.
Journal of Human Genetics 04/2015; DOI:10.1038/jhg.2015.35 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations.Methods
Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl-d-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models.ResultsWe identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months of birth, including hyperkinetic movements in two patients (2/4, 50%), and seizures in two patients (2/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor.SignificanceClinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.
[Show abstract][Hide abstract] ABSTRACT: Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail.
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[Show abstract][Hide abstract] ABSTRACT: Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD.Journal of Human Genetics advance online publication, 19 February 2015; doi:10.1038/jhg.2015.13.
Journal of Human Genetics 02/2015; 60(5). DOI:10.1038/jhg.2015.13 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Ciliopathies are a group of rare conditions that present through a wide range of manifestations. Given the relative common occurrence of defects of the GH/IGF-1 axis in children with short stature and growth retardation, the association between ciliopathies and these defects needs further attention. Case: Our patient is a boy who was born at term and noted to have early growth retardation and weight gain within the first 18 months of life. Biochemical tests demonstrated low IGF-1 but a normal peak GH on stimulation and an adequate rise in IGF-1 on administration of rhGH. An MRI scan revealed pituitary hypoplasia and an ectopic posterior pituitary. His growth responded well to rhGH therapy. Subsequently he also developed a retinopathy of his rods and cones, metaphyseal dysplasia and hypertension with renal failure requiring renal replacement therapy. Whole exome sequencing demonstrated compound heterozygous mutations of IFT172, thus consistent with a ciliopathy. Conclusions: This is the first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood and was initially managed as a case of functional GH deficiency that responded to rhGH therapy. This case highlights the importance of ciliary function in pituitary development and the link between early onset growth failure and ciliopathies.
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs*48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.Journal of Human Genetics advance online publication, 5 February 2015; doi:10.1038/jhg.2015.7.
Journal of Human Genetics 02/2015; 60(4). DOI:10.1038/jhg.2015.7 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whole-exome sequencing (WES) is becoming a standard tool for detecting nucleotide changes, and determining whether WES data can be used for the detection of copy-number variations (CNVs) is of interest. To date, several algorithms have been developed for such analyses, although verification is needed to establish if they fit well for the appropriate purpose, depending on the characteristics of each algorithm. Here, we performed WES CNV analysis using the eXome Hidden Markov Model (XHMM). We validated its performance using 27 rare CNVs previously identified by microarray as positive controls, finding that the detection rate was 59%, or higher (89%) with three or more targets. XHMM can be effectively used, especially for the detection of >200 kb CNVs. XHMM may be useful for deletion breakpoint detection. Next, we applied XHMM to genetically unsolved patients, demonstrating successful identification of pathogenic CNVs: 1.5-1.9-Mb deletions involving NSD1 in patients with unknown overgrowth syndrome leading to the diagnosis of Sotos syndrome, and 6.4-Mb duplication involving MECP2 in affected brothers with late-onset spasm and progressive cerebral/cerebellar atrophy confirming the clinical suspect of MECP2 duplication syndrome. The possibility of an 'exome-first' approach for clinical genetic investigation may be considered to save the cost of multiple investigations.Journal of Human Genetics advance online publication, 22 January 2015; doi:10.1038/jhg.2014.124.
Journal of Human Genetics 01/2015; 60(4). DOI:10.1038/jhg.2014.124 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.Journal of Human Genetics advance online publication, 4 December 2014; doi:10.1038/jhg.2014.103.
Journal of Human Genetics 12/2014; 60(2). DOI:10.1038/jhg.2014.103 · 2.53 Impact Factor