Renal coloboma syndrome/dominant optic atrophy with severe retinal atrophy and de novo digenic mutations in PAX2 and OPA1.

Renal coloboma syndrome (RCS) and dominant optic atrophy are mainly caused by heterozygous mutations in PAX2 and OPA1, respectively. We describe a patient with digenic mutations in PAX2 and OPA1. A female infant was born without perinatal abnormalities. Magnetic resonance imaging at 4 months of age showed bilateral microphthalmia and optic nerve hypoplasia. Appropriate body size was present at 2 years of age, and mental development was favorable. Color fundus photography revealed severe retinal atrophy in both eyes. Electroretinography showed slight responses in the right eye, but no responses in the left eye, suggesting a high risk of blindness. Urinalysis results were normal, creatinine-based estimated glomerular filtration rate was 63.5 mL/min/1.73 m2, and ultrasonography showed bilateral hypoplastic kidneys. Whole exome sequencing revealed de novo frameshift mutations in PAX2 and OPA1. Both variants were classified as pathogenic (PVS1, PS2, PM2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Genetic testing for ocular diseases should be considered for patients with suspected RCS and a high risk of total blindness.

An unusual case of oral surgical management in a patient with isovaleric acidemia and schizophrenia: A case report.

Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. In addition to technical complications, different comorbidities also present a complex range of concerning factors/challenges, which can increase the incidence of morbidity and mortality associated with surgery. IVA, a congenital error of metabolism, is a rare organic acidemia with a predisposition towards acute acidosis and life-threatening metabolic decompensation during stressful conditions, such as prolonged fasting and surgery. In addition, schizophrenia, a major neurological disorder, can result in manifestation of severe dental or periodontal conditions, including pericoronitis. The condition is associated with significant risk factors of postoperative complications, such as dangerous behaviors and adverse interactions between antipsychotic drugs and anesthetic agents. A case of comorbid dental disease with two coexisting chronic and life-threatening medical conditions, one of which is rare, is an unusual encounter in oral/dental surgery that is seldomly published. Moreover, implementing a safe and effective surgical intervention in such patients requires several informed considerations. However, only a few reported experiences or guidelines exist, reporting appropriate perioperative management strategies to minimize risks. Hence, in this case report, our experience of managing one of these rare encounters of a 20-year-old man who suffered from bilaterally partially erupted third molars, associated with chronic pericoronitis and dental caries of both the maxilla wisdom teeth with coexisting IVA and schizophrenia comorbidities is described. Additionally, the presentation and anticipated complications of the comorbid disorders of the patient are briefly reviewed. In this case, the pericoronitis and dental caries were treated by surgically removing the impacted third molars and the antagonist maxilla wisdom teeth under regional anesthesia and application of antibiotics for 3 days. The patient recovered without any postoperative complications after 1 year of follow-up.

Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.

We describe the case of a male patient with orofaciodigital (OFD) syndrome type XVI with a homozygous variant of TMEM107 (p.Phe106del) and the additional findings of tibial dysplasia, which is a pivotal finding of OFD syndrome type IV. His family history included two fetuses with anencephaly with or without cleft lip/palate and polydactyly with no genetic information. Careful attention should be given to the interpretation of this rare pattern.

A severe case of status dystonicus caused by a de novo KMT2B missense mutation.

Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and repeated infections. GPi-DBS is considered to be an effective treatment for patients with KMT2B mutations, and genetic diagnosis is important before progression to status dystonicus.

A novel homozygous missense SLC25A20 mutation in three CACT-deficient patients: clinical and autopsy data.

Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in mitochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.

Hereditary leiomyomatosis and renal cell cancer (HLRCC): A case report.

Hereditary leiomyomatosis and renal cell cancer is a rare, inherited disease caused by mutations in the fumarate hydratase gene. It is characterized by cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer. We present the case of a 42-year-old woman with a heterozygous missense mutation (p.M195T) in the fumarate hydratase gene. Although the patient did not have cutaneous leiomyoma and she had no family history of hereditary leiomyomatosis and renal cell cancer, the presence of early onset symptomatic uterine leiomyoma and type 2 papillary renal cell cancer confirmed the diagnosis of hereditary leiomyomatosis and renal cell cancer.

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

A novel nonsense SMC1A mutation in a patient with intractable epilepsy and cardiac malformation.

Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with SMC1A-associated CdLS with a novel SMC1A truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.

Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future.

Allogenic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for a selected group of patients with mucopolysaccharidoses (MPS), including those with MPS types I, II, IVA, VI, and VII. Early diagnosis and timely referral to an expert in MPS are critical, followed by a complete examination and evaluation by a multidisciplinary team, including a transplantation physician. Treatment recommendations for MPS are based on multiple biological, sociological, and financial factors, including type of MPS, clinical severity, prognosis, present clinical signs and symptoms (disease stage), age at onset, rate of progression, family factors and expectations, financial burden, feasibility, availability, risks and benefits of available therapies such as HSCT, enzyme replacement therapy (ERT), surgical interventions, and other supportive care. International collaboration and data review are critical to evaluating the therapeutic efficacy and adverse effects of HSCT for MPS. Collaborative efforts to assess HSCT for MPS have been ongoing since the first attempt at HSCT in a patient with MPS reported in 1981. The accumulation of data since then has made it possible to identify early outcomes (ie, transplantation outcomes) and long-term disease-specific outcomes resulting from HSCT. The recent identification of predictive factors and the development of innovative regimens have significantly improved the outcomes of both engraftment failure and transplantation-related mortality. Assessment of long-term outcomes has considered a variety of factors, including type of MPS, type of graft, age at transplantation, and stage of disease progression, among others. Studies on long-term outcomes are considered a key factor in the use of HSCT in patients with MPS. These studies have shown the effects and limitations of HSCT on improving disease manifestations and quality of life. In this review, we summarize the efficacy, side effects, risks, and cost of HSCT for each type of MPS.

Mild prominence of the Sylvian fissure in a Bainbridge-Ropers syndrome patient with a novel frameshift variant in ASXL3.

A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS.

Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH).

The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.

Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease.

In this study, we describe a Japanese family with progressive hearing loss and macrothrombocytopenia. Using next-generation and Sanger sequencing analyses, we identified a heterozygous variant in exon 27 of the DIAPH1 gene (NM_005219), c.3637C>T, p.R1213X. All patients in the family had sensorineural hearing loss and macrothrombocytopenia. None of the patients exhibited a tendency to bleed. No pathogenic variants were found in the MYH9 gene. Hearing loss began with high-frequency loss during early childhood and progressed to severe hearing loss involving all frequencies. Analyses of the mean platelet volume and platelet distribution width indicated that the macrothrombocytopenia is progressive in patients with DIAPH1 related disease.There are no reports describing progressive macrothrombocytopenia in patients with pathogenic variants of DIAPH1. Thus, progressive macrothrombocytopenia may be a novel feature of deafness patients with pathogenic variants in DIAPH1.

A new mutation found in newborn screening for Fabry disease evaluated by plasma globotriaosylsphingosine levels.

A pilot study of newborn screening for Fabry disease was performed in Okinawa, Japan. A total of 2,443 neonates were screened using dried blood spot samples over 7 years starting in 2007. Of 13 neonates determined to have low α-galactosidase A (GLA) activity, one boy had a new missense mutation, p.G144D of the GLA gene. This mutation was considered to be a late-onset type, as evaluated based on plasma globotriaosylsphingosine levels and family history.

Isovaleric acidemia: Therapeutic response to supplementation with glycine, l-carnitine, or both in combination and a 10-year follow-up case study.

Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. METHODS: We evaluated the patient with IVA beginning at 5 years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600 mg leucine with glycine alone (250 mg/kg/day), l-carnitine alone (100 mg/kg/day), or both glycine and l-carnitine for four days each. RESULTS: (Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200 mg/kg/day) and l-carnitine (100 mg/kg/day) supplementation at 5 years of age, doses were gradually reduced to 111.7 mg/kg/day and 55.8 mg/kg/day, respectively, at 15 years of age. His mind and body had developed without any sequelae. DISCUSSION: We concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.

Activity of daily living for Morquio A syndrome.

The aim of this study was to evaluate the activity of daily living (ADL) and surgical interventions in patients with mucopolysaccharidosis IVA (MPS IVA). The factor(s) that affect ADL are age, clinical phenotypes, surgical interventions, therapeutic effect, and body mass index. The ADL questionnaire comprises three domains: "Movement," "Movement with cognition," and "Cognition." Each domain has four subcategories rated on a 5-point scale based on the level of assistance. The questionnaire was collected from 145 healthy controls and 82 patients with MPS IVA. The patient cohort consisted of 63 severe and 17 attenuated phenotypes (2 were undefined); 4 patients treated with hematopoietic stem cell transplantation (HSCT), 33 patients treated with enzyme replacement therapy (ERT) for more than a year, and 45 untreated patients. MPS IVA patients show a decline in ADL scores after 10years of age. Patients with a severe phenotype have a lower ADL score than healthy control subjects, and lower scores than patients with an attenuated phenotype in domains of "Movement" and "Movement with cognition." Patients, who underwent HSCT and were followed up for over 10years, had higher ADL scores and fewer surgical interventions than untreated patients. ADL scores for ERT patients (2.5years follow-up on average) were similar with the-age-matched controls below 10years of age, but declined in older patients. Surgical frequency was higher for severe phenotypic patients than attenuated ones. Surgical frequency for patients treated with ERT was not decreased compared to untreated patients. In conclusion, we have shown the utility of the proposed ADL questionnaire and frequency of surgical interventions in patients with MPS IVA to evaluate the clinical severity and therapeutic efficacy compared with age-matched controls.

Detailed analysis of 26 cases of 1q partial duplication/triplication syndrome.

Partial 1q trisomy syndrome is a rare disorder. Because unbalanced chromosomal translocations often occur with 1q trisomy, it is difficult to determine whether patient symptoms are related to 1q trisomy or other chromosomal abnormalities. The present study evaluated genotype-phenotype correlations of 26 cases diagnosed with 1q partial trisomy syndrome. DNA microarray was used to investigate the duplication/triplication region of 16 cases. Although there was no overlapping region common to all 26 cases, the 1q41-qter region was frequently involved. One case diagnosed as a pure interstitial trisomy of chromosome 1q by G-banded karyotype analysis was instead found to be a pure partial tetrasomy by CytoScan HD Array. In four 1q trisomy syndrome cases involving translocation, the translocated partner chromosome could not be detected by DNA microarray analyzes despite G-banded karyotype analysis, because there were a limited number of probes available for the partner region. DNA microarray and G-banded karyotyping techniques were therefore shown to be compensatory diagnostic tools that should be used by clinicians who suspect chromosomal abnormalities. It is important to continue recruiting affected patients and observe and monitor their symptoms to reveal genotype-phenotype correlations and to fully understand their prognosis and identify causal regions of symptoms.

SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements.

Intellectual disability (ID) is a heterogeneous condition affecting 2-3% of the population, often associated with multiple congenital anomalies (MCA). The genetic cause remains largely unexplained for most cases. To investigate the causes of ID/MCA of unknown etiology in the Japanese population, 645 subjects have been recruited for the screening of pathogenic copy-number variants (CNVs). Two screenings using bacterial artificial chromosome (BAC) arrays were previously performed, which identified pathogenic CNVs in 133 cases (20.6%; Hayashi et al., J. Hum. Genet., 2011). Here, we present the findings of the third screening using a single-nucleotide polymorphism (SNP) array, performed in 450 negative cases from our previous report. Pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical significance had been previously established. Among the 22 cases, we identified PPFIA2 as a novel candidate gene for ID. Analysis of copy-neutral loss of heterozygosity (CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had been mostly identified in the two previous screenings.

Hematopoietic stem cell transplantation for Morquio A syndrome.

Morquio A syndrome features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio A has been described. We conducted HSCT for 4 cases with Morquio A (age at HSCT: 4-15years, mean 10.5years) and followed them at least 10years (range 11-28years; mean 19years). Current age ranged between 25 and 36years of age (mean 29.5years). All cases had a successful full engraftment of allogeneic bone marrow transplantation without serious GVHD. Transplanted bone marrow derived from HLA-identical siblings (three cases) or HLA-identical unrelated donor. The levels of the enzyme activity in the recipient's lymphocytes reached the levels of donors' enzyme activities within two years after HSCT. For the successive over 10years post-BMT, GALNS activity in lymphocytes was maintained at the same level as the donors. Except one case who had osteotomy in both legs one year later post BMT, other three cases had no orthopedic surgical intervention. All cases remained ambulatory, and three of them could walk over 400m. Activity of daily living (ADL) in patients with HSCT was better than untreated patients. The patient who underwent HSCT at four years of age showed the best ADL score. In conclusion, the long-term study of HSCT has demonstrated therapeutic effect in amelioration of progression of the disease in respiratory function, ADL, and biochemical findings, suggesting that HSCT is a therapeutic option for patients with Morquio A.

Progressive hip joint subluxation in Saul-Wilson syndrome.

Saul-Wilson syndrome (SWS) is a rare congenital skeletal syndrome characterized by postnatal onset of short stature, relative microcephaly, frontal bossing, prominent eyes with shallow orbits, midface hypoplasia, cataract, and generalized skeletal changes, including spondylar dysplasia, overtubulation of the long bones with metaphyseal flaring and megaepiphyses, coxa valga, elbow deformity, and brachydactyly. We describe a boy with the overall clinical and radiological features fitting the characteristics of SWS, although cataract, elbow deformity, and overt brachydactyly were not seen. He presented with painful hip joint due to hip subluxation in late childhood, which exacerbated with age and ultimately, required surgical intervention. Awareness of this orthopedic complication in SWS is essential in the management of patients with SWS.