Yusuke Takezawa

FDG-PET study of patients with Leigh syndrome

We conducted a [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) study in five patients (median age 11 (range 4-13) years) with Leigh syndrome to evaluate its usefulness for understanding the functional brain dysfunction in this disease and in future drug trials. Four patients were found to have reported mitochondrial DNA gene mutations. The brain T2-weighted magnetic resonance imaging (MRI) showed high-intensity areas in the putamen bilaterally in five patients, caudate bilaterally in four, thalamus bilaterally in two, and brainstem in one. Cerebellar atrophy was observed in older two patients. For disease control, seven age-matched epilepsy patients who had normal MRI and FDG-PET studies were selected. For semiquantitative analysis of the lesions with decreased (18)F-FDG uptake, the mean standard uptake value (SUV) was calculated in regions of interest (ROIs) placed in each brain structure. We compared the SUV of nine segments (the frontal, temporal, parietal, and occipital lobes, thalami, basal ganglia, mid-brain, pons, and cerebellum) between patients with Leigh syndrome and controls. The glucose uptake was decreased significantly in the cerebellum and basal ganglia, which could explain the ataxia and dystonia in patients with Leigh syndrome. Although this study had some limitations, FDG-PET might be useful for evaluating the brain dysfunction and treatment efficacy of new drugs in patients with Leigh syndrome. Further study with more patients using advanced methods to quantify glucose uptake is needed before drawing a conclusion.

Outcome of hemiplegic cerebral palsy born at term depends on its etiology

OBJECTIVES To elucidate the etiology and its relationship to the outcomes of hemiplegic cerebral palsy (HCP). PARTICIPANTS AND METHODS MR images and outcomes of 156 children with HCP born at term and older than three years were investigated in two major centers for cerebral palsy in Japan. Etiologies were classified into perinatal ischemic stroke (PIS), cerebral dysgenesis (CD), and others. PIS was divided into periventricular venous infarction (PVI) and two types of arterial infarction; middle cerebral artery infarction (MCAI) and deep gray matter infarction (DGMI). Initial signs and the time of presentation were investigated among the three types of PIS. As functional outcomes, laterality of paresis, age at initial walk, affected hands function, intellectual development, and occurrence of epilepsy were compared among all the four types. RESULTS ETIOLOGY PIS was found in 106 children (68%), while CD accounted for 28 (18%). Among PIS, venous infarction was more common than arterial infarction (62:44). OUTCOMES PVI revealed later presentation of motor asymmetry and more involvement of lower extremity as the initial sign among PIS groups. Only MCAI showed right-side predominance in laterality of paresis. DGMI related to better intellectual development and PVI showed lower occurrence of epilepsy, while there was no significant difference in affected hands function among the four groups. PIS groups showed significantly earlier attainment of independent walk, better intellectual development, and lower occurrence of epilepsy than CD. CONCLUSIONS PVI was the most common cause of HCP born at term, and the etiology closely related to the initial signs of hemiplegia and overall outcomes.

Genomic analysis identifies masqueraders of full-term cerebral palsy

Cerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full‐term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders.

A novel mutation in the proteolytic domain of LONP1 causes atypical CODAS syndrome

Cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in LONP1. It is characterized by intellectual disability, cataracts, delayed tooth eruption, malformed auricles and skeletal abnormalities. We performed whole-exome sequencing on a 12-year-old Japanese male with severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia with motor regression and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on T2-weighted images. We detected compound heterozygous mutation in LONP1. One allele contained a paternally inherited frameshift mutation (p.Ser100Glnfs*46). The other allele contained a maternally inherited missense mutation (p.Arg786Trp), which was predicted to be pathogenic by web-based prediction tools. The two mutations were not found in Exome Variant Server or our 575 in-house control exomes. Some features were not consistent with CODAS syndrome but overlapped with Marinesco–Sjögren syndrome, a multisystem disorder caused by a mutation in SIL1. An atypical mutation site may result in atypical presentation of the LONP1 mutation.

Biallelic GALM pathogenic variants cause a novel type of galactosemia

PurposeGalactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia.MethodsTrio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants.ResultsThe highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins.ConclusionBiallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

Reply to: Avoid valproate in IARS2 mutations

We express our gratitude to Josef Finsterer et al. for writing a letter about our article on the clinical concerns. We understand their concern and would like to respond as follows. First, valproic acid was induced as initial treatment for West syndrome, as explained in our report [1], followed by gradually discontinuing it over a few months as adrenocorticotropic hormone (ACTH) injection therapy starts to show effectiveness. Hence, we do not think that valproic acid could play the central role in worsening the phenotype of our patients. Second, as a clinical test for mitochondrial diseases, fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) have some inherent limitations, as mentioned by you [2]; however, this concern also applies to lactate/pyruvate examination [3]. At present, no clinical test has adequate power to diagnose mitochondrial diseases by itself. Thus, for the comprehensive diagnosis of mitochondrial diseases, we cannot help but consider such biomarkers, including FGF-21, GDF-15, and lactate/pyruvate, as useful despite several limitations. Finally, concerning the etiology of hypotonia presented in both of our patients, we conducted muscle biopsy in patient II-1 and detected no abnormality [1]. Then, we assumed that myogenic hypotonia might be contradictory. Conversely, as we did not perform nerve conduction study, we cannot confirm whether it was because of the peripheral nerve or the central nervous system (CNS). Nevertheless, we attribute their hypotonia to the CNS because other reported IARS2-related disorders without Leigh syndrome did not exhibit severe hypotonia, and some patients with Leigh syndrome reportedly presented hypotonia [4]. However, the mechanism of central hypotonia remains unclear [5]. We hope that these responses addressed your concerns adequately.

Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation

Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature.

Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome

BACKGROUND IARS2 encodes isoleucine-tRNA synthetase, which is aclass-1 amino acyl-tRNA synthetase. IARS2 mutations are reported to cause Leigh syndrome or cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysphasia syndrome (CAGSSS). To our knowledge, IARS2 mutations and diseases related to it have only been reported in three families. Here we report a case of two Japanese siblings with Leigh syndrome, some features of CAGSSS, and West syndrome that are found to have compound heterozygous novel IARS2 mutations. CASE REPORT A 7-month-old Japanese girl presented with infantile spasms. Brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy and hyperintensity in the bilateral basal ganglia. Three years later, her younger sister also presented with infantile spasms. MRI revealed diffuse brain atrophy and hyperintensity of the bilateral ganglia, suggesting Leigh syndrome. The siblings were identified with compound heterozygous missense mutations in IARS2, p.[(Phe227Ser)];[(Arg817His)]. CONCLUSION This is the first case study reporting Leigh syndrome concomitant with some features of CAGSSS in siblings with novel IARS2 mutations, thereby broadening the phenotypic spectrum of IARS2-related disorders. Further studies are warranted to elucidate the nature of these disorders.

Reply to: A genomic cause of cerebral palsy should not change the clinical classification

Dear Editor, We thank MacLennan et al. for their letter pertaining to our article on the interpretation that our patients with pathogenic variants are “masquerading as cerebral palsy.” We entirely agree with their comments that cerebral palsy is an umbrella diagnosis of nonprogressive disorders of the control of movement and posture, encompassing a heterogeneous group of etiologies, which infer no specific causation. In addition, we agree that if patients with genetic causes of clinically diagnosed cerebral palsy are eliminated, an artificial reduction will occur in the incidence of cerebral palsy. Moreover, removing genomic causes could disenfranchise patients and families from the support. At present, not all healthcare providers accurately comprehend the definition of cerebral palsy. In fact, in the draft and review process, some experts opined that our cohort did not fit into the cerebral palsy group because our cases neither exhibited “typical” nor “classical” cerebral palsy. Hence, for broader acceptance, we changed the expression from “cerebral palsy with pathogenic variants” to “masqueraders of cerebral palsy.” Because it has been revealed that several patients with cerebral palsy have more than anticipated genetic abnormalities (i.e., monogenic causative genes, susceptibility genes, and copy number variations), we believe that it is crucial to retain the umbrella clinical diagnosis of cerebral palsy with subclassifications by possible or likely cause, including neonatal asphyxia, infarction, and genetic abnormality, for the reasons suggested by them. We hope that their international cohort and subsequent analysis results in the elucidation of the underlying mechanisms of cerebral palsy and the optimization of therapeutic interventions.

Patchy white matter hyperintensity in ring chromosome 18 syndrome.

Ring chromosome 18 syndrome is a chromosomal abnormality in which partial deletions occur at both ends of chromosome 18, that is, distally on the short and long arms. Previously reported brain magnetic resonance imaging (MRI) abnormalities include diffuse hyperintensity in the white matter, which has been regarded as hypomyelination because the gene for myelin basic protein production is located on the long arm of chromosome 18. We report the case of a 14‐year‐old boy with ring chromosome 18 syndrome, whose MRI showed patchy asymmetrical T2 and fluid‐attenuated inversion‐recovery hyperintensities in the deep white matter as well as diffuse hypomyelination. These patchy lesions may indicate demyelination or gliosis rather than hypomyelination. This result differs from previous reports.