Noriko Miyake

Yokohama City University, Yokohama, Kanagawa, Japan

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Publications (195)794.32 Total impact

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    ABSTRACT: Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.Journal of Human Genetics advance online publication, 10 September 2015; doi:10.1038/jhg.2015.108.
    Journal of Human Genetics 09/2015; DOI:10.1038/jhg.2015.108 · 2.46 Impact Factor
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    ABSTRACT: The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRNS). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high frequency. NUP107 is ubiquitously expressed, including in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hamper NUP107 binding to NUP133 (nucleoporin 133 kDa) and NUP107 incorporation into NPCs in vitro. Zebrafish with nup107 knockdown generated by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, thereby mimicking the pathological changes seen in the kidneys of the SRNS individuals with NUP107 mutations. Considering the unique properties of the podocyte (highly differentiated foot-process architecture and slit membrane and the inability to regenerate), we propose a "podocyte-injury model" as the pathomechanism for SRNS due to biallelic NUP107 mutations.
    The American Journal of Human Genetics 09/2015; DOI:10.1016/j.ajhg.2015.08.013 · 10.93 Impact Factor
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    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.
    Scientific Reports 08/2015; 5. DOI:10.1038/srep13104 · 5.58 Impact Factor
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    ABSTRACT: KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
    Epilepsia 07/2015; 56(9). DOI:10.1111/epi.13072 · 4.57 Impact Factor
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    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 · 2.46 Impact Factor
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    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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of neurology, neurosurgery, and psychiatry 05/2015; DOI:10.1136/jnnp-2014-310084 · 6.81 Impact Factor
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    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 · 4.35 Impact Factor
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    ABSTRACT: Generalized hypertrichosis is a feature of several genetic disorders, and the nosology of these entities is still provisional. Recent studies have implicated chromosome 17q24.2-q24.3 microdeletion and the reciprocal microduplication in a very rare form of congenital generalized hypertrichosis terminalis (CGHT) with or without gingival hyperplasia. Here, we report on a 5-year-old Egyptian girl born to consanguineous parents. The girl presented with CGHT and gingival hyperplasia for whom we performed detailed clinical, pathological, and molecular studies. The girl had coarse facies characterized by bilateral epicanthic folds, thick and abundant eyelashes, a broad nose, full cheeks, and lips that constituted the distinctive facial features for this syndrome. Biopsy of the gingiva showed epithelial marked acanthosis and hyperkeratosis with hyperplastic thick collagen bundles and dense fibrosis in the underlying tissues. Array analysis indicated a 17q24.2-q24.3 chromosomal microdeletion. We validated this microdeletion by real-time quantitative PCR and confirmed a perfect co-segregation of the disease phenotype within the family. In summary, this study indicates that 17q24.2-q24.3 microdeletion caused CGHT with gingival hyperplasia and distinctive facies, which should be differentiated from the autosomal recessive type that lacks the distinctive facies. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2015; 167(10). DOI:10.1002/ajmg.a.37185 · 2.16 Impact Factor
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    ABSTRACT: Focal cortical dysplasia (FCD) Type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD Type IIb. We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD Type IIb, five with Type IIa, and six with Type I. We performed whole exome sequencing using paired samples from nine of the FCD Type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital PCR. The effect of MTOR mutations on mTOR kinase signaling was evaluated by immunohistochemistry and western blot analyses of brain samples and by in vitro transfection experiments. We identified four lesion-specific somatic MTOR mutations in six of 13 (46%) individuals with FCD Type IIb showing mutant allele rates of 1.11-9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD Type IIb brain tissues with MTOR mutations was clearly elevated compared with control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. We found low-prevalence somatic mutations in MTOR in FCD Type IIb, indicating that activating somatic mutations in MTOR cause FCD Type IIb. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 05/2015; 78(3). DOI:10.1002/ana.24444 · 9.98 Impact Factor
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    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 · 2.30 Impact Factor
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    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 · 2.80 Impact Factor
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    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; 60(7). DOI:10.1038/jhg.2015.35 · 2.46 Impact Factor
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    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.
    Epilepsia 04/2015; 56(6). DOI:10.1111/epi.12987 · 4.57 Impact Factor
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    ABSTRACT: Myoclonus-dystonia syndrome (MDS) is a rare autosomal-dominant movement disorder characterized by brief, frequently alcohol-responsive myoclonic jerks that begin in childhood or early adolescence, caused by mutations in the ε-sarcoglycan gene (SGCE). The patient was a 6-year-old boy. At 2 years 8 months, he had abnormal movement when he ran due to dystonia of his left leg. At 3 years 5 months, he exhibited dystonia and myoclonic movement of his arms when eating. Myoclonus was likely to develop when he felt anxiety or exhaustion. Genomic DNA showed a heterozygous mutation in SGCE (c.109 + 1 G > T). His father and uncle with the same mutation also experienced milder dystonia or myoclonic movements. SGCE mutation can cause a broad range of clinical symptoms between and within families. We should consider MDS as a differential diagnosis for patients with paroxysmal walking abnormalities and/or myoclonic movements. © 2015 Japan Pediatric Society.
    Pediatrics International 04/2015; 57(2):324-6. DOI:10.1111/ped.12613 · 0.73 Impact Factor
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    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. This article is protected by copyright. All rights reserved.
    Clinical Genetics 03/2015; DOI:10.1111/cge.12586 · 3.93 Impact Factor
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    ABSTRACT: 6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end-stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4-Mb duplication at 6p25.3-p25.1 with 32 protein-coding genes and a 220-Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non-coincidental complication. FOXC1, located within the 6.4-Mb duplicated region at 6p25.3-p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2015; 167(3):592-601. DOI:10.1002/ajmg.a.36942 · 2.16 Impact Factor
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    ABSTRACT: Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(5). DOI:10.1002/ajmg.a.36881 · 2.16 Impact Factor
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    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 · 2.46 Impact Factor
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    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-I 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-I but a normal peak GH on stimulation and an adequate increase in IGF-I on administration of recombinant human growth hormone (rhGH). A magnetic resonance imaging 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.
    Journal of Clinical Endocrinology &amp Metabolism 02/2015; 100(4):jc20143852. DOI:10.1210/jc.2014-3852 · 6.21 Impact Factor
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    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 · 2.46 Impact Factor

Publication Stats

2k Citations
794.32 Total Impact Points


  • 2006–2015
    • Yokohama City University
      Yokohama, Kanagawa, Japan
    • Japan Science and Technology Agency (JST)
      Edo, Tōkyō, Japan
  • 2005–2014
    • Nippon Medical School
      • Department of Biochemistry and Molecular Biology
      Edo, Tōkyō, Japan
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
  • 2011
    • Nippon Veterinary and Life Science University
      Edo, Tōkyō, Japan
  • 2007–2010
    • Juntendo University
      • • Department of Clinical Laboratory
      • • Department of Medicine
      Edo, Tōkyō, Japan
  • 2008
    • Health Sciences University of Hokkaido
      Tōbetsu, Hokkaidō, Japan
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2005–2008
    • Nagasaki University
      • • Department of Pediatrics
      • • Graduate School of Biomedical Sciences
      Nagasaki, Nagasaki, Japan
  • 2006–2007
    • Lund University
      • Department of Molecular Medicine and Gene Therapy
      Lund, Skåne, Sweden