Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities.

Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.

Long-term clinical observation of patients with heterozygous KIF1A variants.

KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation.

Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan.

PURPOSE: Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency. METHODS: This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023. RESULTS: We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in three out of four patients. Transient transaminitis was the most common symptom (23.1%). All the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM_138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency. CONCLUSIONS: GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.

A case of 49,XXXYY followed-up from infancy to adulthood with review of literature.

49,XXXYY is an extremely rare sex chromosomal aneuploidy (SCA), with only seven cases reported worldwide to date. Among these cases, only three have been documented into adulthood. Moreover, no cases of 49,XXXYY have been reported in Japan. This SCA has been identified in two scenarios: in vitro fertilization and abortion. Similar to 47,XXY, this aneuploidy is a type of Klinefelter syndrome. Aneuploidy of the X chromosome can lead to various progressive complications due to excess X chromosomes. Herein, we present the case of a Japanese man with 49,XXXYY. He exhibited developmental delays and external genitalia abnormalities since early infancy but was not closely monitored for these symptoms until the age of 3 years old. At that time, a chromosome test revealed his karyotype to be 49,XXXYY. Subsequent examinations were conducted due to various symptoms, including delayed motor development, intellectual disability, facial dysmorphisms, forearm deformities, hip dysplasia, cryptorchidism, micropenis, primary hypogonadism, and essential tremor. Since reaching puberty, he has undergone testosterone replacement therapy for primary hypogonadism, experiencing no complications related to androgen deficiency to date. He has maintained normal lipid and glucose metabolism, as well as bone density, for a prolonged period. There are no other reports on the long-term effects of testosterone treatment for the SCA. Appropriate testosterone replacement therapy is recommended for individuals with 49,XXXYY to prevent complications. This report will contribute to an enhanced understanding of the 49,XXXYY phenotype, aiding in the diagnosis, treatment, and genetic counseling of future cases.

Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease.

Background: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA syndrome), and Kawasaki disease (KD) are both considered to be disorders of the innate immune system, and the potential role of inflammasome activation in the immunopathogenesis of both diseases has been previously described. Case presentation: Herein, we report the clinical courses of three patients who presented a rare combination of PFAPA syndrome and KD. Two patients who presented KD later developed the PFAPA syndrome, of whom one developed recurrent KD 2 years after the initial diagnosis. The third patient developed KD one year after the onset of PFAPA syndrome. The presence of both of these conditions within individual patients, combined with the knowledge that inflammasome activation is involved in both PFAPA syndrome and KD, suggests a shared background of inflammatory dysregulation. To elucidate the mechanism underlying shared inflammatory dysregulation, we investigated the roles of Nod-like receptors (NLRs) and their downstream inflammasome-related genes. All the patients had a frameshift variant in CARD8 (CARD8-FS). A previous study demonstrated a higher frequency of CARD8-FS, whose product loses CARD8 activity and activates the NLRP3 inflammasome, in patients with the PFAPA syndrome. Additionally, the NLRP3 inflammasome is known to be activated in patients with KD. Together, these results suggest that the CARD8-FS variant may also be essential in KD pathogenesis. As such, we analyzed the CARD8 variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population. Conclusions: We report the clinical courses of three patients with a rare combination of PFAPA syndrome and KD. All the patients had the CARD8-FS variant. However, we could not find a difference in the variant frequency between patients with KD and the general Japanese population. As the frequency of KD is much higher than that of PFAPA among Japanese patients, and the cause of KD is multifactorial, it is possible that only a small portion of patients with KD harbor CARD8-FS as a causative gene.

Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population.

Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12-35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.

Treatment of ZC4H2 Variant-Associated Spastic Paraplegia with Selective Dorsal Rhizotomy and Intensive Postoperative Rehabilitation: A Case Report.

Selective dorsal rhizotomy (SDR) has been used to treat children with spastic cerebral palsy (CP), and its beneficial effect on quality of life and ambulation has been confirmed in long-term follow-up studies. However, the role of SDR in the treatment of spasticity in patients with hereditary spastic paraplegia (HSP) and related disorders is not well-established. Here, we report the first patient with the ZC4H2 variant who underwent SDR to treat spastic paraplegia. Abnormal gait was discovered during a regular checkup at the age of 3 years and 9 months, and she was diagnosed with spastic paraplegia. She was heterozygous for the ZC4H2 variant and underwent SDR at the age of 5 years and 11 months, which alleviated the spasticity. The patient underwent inpatient postoperative rehabilitation for 4 months and continued outpatient physiotherapy after discharge. The Gross Motor Function Measure-88 score and maximum walking speed decreased transiently 1 month postoperatively, but gradually recovered, and continuously improved 6 months postoperatively. SDR and postoperative intensive rehabilitation were effective in improving motor and walking functions up to 6 months after surgery, although long-term follow-up is needed to draw conclusions.

Upregulation of hepatic nuclear receptors in extremely preterm ovine fetuses undergoing artificial placenta therapy.

OBJECTIVE: Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses. This fetal model, resembling a "knockout placenta," lacks placental and maternal support, while maintaining a healthy extrauterine survival. METHODS: Six ovine fetuses at 95 ± 1 d gestational age (GA; term = ∼150 d)/∼600 g delivery weight were maintained on an APT platform for a period of 120 h (APT Group). Six age-matched, in utero control fetuses were delivered at 99-100 d GA (Control Group). Fetal liver tissue samples and blood samples were collected at delivery from both groups and assessed mRNA expression of NRs and target transporters involved in the hepatobiliary transport system using quantitative PCR. Data were tested for group differences with ANOVA (p < .05 deemed significant). RESULTS: mRNA expression of NRs was identified in both the placenta and the extremely preterm ovine fetal liver. The expression of HNF4α, LRH1, LXR, ESR1, PXR, CAR, and PPARα/γ were significantly elevated in the liver of the APT Group compared to the Control Group. Moreover, target transporters NTCP, OATP1B3, BSEP, and MRP4 were upregulated, whereas MRP2 and MRP3 were unchanged. Although there was no evidence of liver necrosis or apoptotic changes histologically, there was an impact in the fetal liver of the ATP group at the tissue level with a significant increase in TNFα mRNA, a cytokine involved in liver inflammation, and blood elevation of transaminases. CONCLUSION: A number of NRs in the fetal liver were significantly upregulated after loss of placental-maternal support. However, the expression of target transporter genes appeared to be insufficient to compensate role of the placenta and maternal liver and avoid fetal liver damage, potentially due to insufficient excretion of organic anions.

Artificial placenta support of extremely preterm ovine fetuses at the border of viability for up to 336 hours with maintenance of systemic circulation but reduced somatic and organ growth.

Introduction: Artificial placenta therapy (APT) is an experimental life support system to improve outcomes for extremely preterm infants (EPI) less than 1,000 g by obviating the need for pulmonary gas exchange. There are presently no long-term survival data for EPI supported with APT. To address this, we aimed to maintain 95d-GA (GA; term-150d) sheep fetuses for up to 2 weeks using our APT system. Methods: Pregnant ewes (n = 6) carrying singleton fetuses underwent surgical delivery at 95d GA. Fetuses were adapted to APT and maintained for up to 2 weeks with constant monitoring of key physiological parameters and extensive time-course blood and urine sampling, and ultrasound assessments. Six age-matched in-utero fetuses served as controls. Data were tested for group differences with ANOVA. Results: Six APT Group fetuses (100%) were adapted to APT successfully. The mean BW at the initiation of APT was 656 ± 42 g. Mean survival was 250 ± 72 h (Max 336 h) with systemic circulation and key physiological parameters maintained mostly within normal ranges. APT fetuses had active movements and urine output constantly exceeded infusion volume over the experiment. At delivery, there were no differences in BW (with edema in three APT group animals), brain weight, or femur length between APT and in-utero Control animals. Organ weights and humerus lengths were significantly reduced in the APT group (p < 0.05). Albumin, IGF-1, and phosphorus were significantly decreased in the APT group (p < 0.05). No cases of positive blood culture were detected. Conclusion: We report the longest use of APT to maintain extremely preterm fetuses to date. Fetal systemic circulation was maintained without infection, but growth was abnormal. This achievement suggests a need to focus not only on cardiovascular stability and health but also on the optimization of fetal growth and organ development. This new challenge will need to be overcome prior to the clinical translation of this technology.

High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses.

Context: Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated. Objective: We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses. Methods: Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq. Results: The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3ß-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89). Conclusion: Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.

A Case Series of Patients With MYBPC1 Gene Variants Featuring Undulating Tongue Movements as Myogenic Tremor.

Myosin-binding protein C1 (MYBPC1) encodes myosin-binding protein C, slow type (sMyBP-C), an accessory protein that regulates actomyosin cross-linking, stabilizes thick filaments, and modulates contractility in muscle sarcomeres and has recently been linked to myopathy with tremor. The clinical features of MYBPC1 mutations manifesting in early childhood bear some similarities to those of spinal muscular atrophy (SMA), such as hypotonia, involuntary movement of the tongue and limbs, and delayed motor development. The development of novel therapies for SMA has necessitated the importance of differentiating SMA from other diseases in the early infancy period. We report the characteristic tongue movements of MYBPC1 mutations, along with other clinical findings, such as positive deep tendon reflexes and normal peripheral nerve conduction velocity testing, which could help in considering other diseases as differential diagnoses.

Neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis: A case report with a novel missense variant of SCN1A.

Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome. CASE REPORT: We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia. CONCLUSION: Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A. The efficacy of sodium channel blocker was also discussed. Further exploration of the phenotype-genotype relationship of SCN1A variants may lead to better pharmacological treatments and family guidance.

A method for phenylalanine self-monitoring using phenylalanine ammonia-lyase and a pre-existing portable ammonia detection system.

Phenylketonuria is an inborn error of phenylalanine metabolism caused by a phenylalanine hydroxylase deficiency. To prevent the occurrence of neurological symptoms and maternal complications resulting from phenylketonuria, patients must adhere to a strict diet therapy, tetrahydrobiopterin supplementation, or pegvaliase injection to maintain blood phenylalanine levels within a recommended range throughout their lives. Therefore, monitoring blood phenylalanine levels is necessary to determine the recent metabolic status of phenylalanine in patients with PKU; however, there are no available instruments for individuals to monitor their own blood phenylalanine levels using whole fingertip blood. We developed a phenylalanine monitoring system (designated as PheCheck) that included a pre-existing portable ammonia detection device and phenylalanine ammonia-lyase, which converts phenylalanine to trans-cinnamic acid and ammonia. This system was able to remove 86.7% ± 0.03% of the ammonia contained in fingertip blood and successfully reduce background ammonia levels. A good correlation was found between the estimated plasma phenylalanine levels detected by PheCheck and plasma phenylalanine levels detected by high-performance liquid chromatography (R2 0.97). The entire PheCheck process for measuring blood phenylalanine takes only 20 min. PheCheck can lay the foundation for home phenylalanine monitoring with high feasibility because all the components are easily accessible. Further studies with a more user-friendly PheCheck optimized for practice are needed to improve blood phenylalanine control, reduce the burden on patients and/or caregivers, and prevent the sequelae associated with phenylketonuria.

Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility.

Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis.

Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor.

ANO3 encodes Anoctamin-3, also known as TMEM16C, a calcium-activated chloride channel. Heterozygous variants of ANO3 can cause dystonia 24, an adult-onset focal dystonia. Some pediatric cases have been reported, but most patients were intellectually normal with some exceptions. Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia. Trio exome sequencing identified a heterozygous de novo missense variant NM_031418.4:c.1809T>G, p.(Asn603Lys) in the ANO3 gene. Three cases with ANO3 variants and intellectual disability have been reported, including the present case. These variants were predicted to face in the same direction on the same alpha-helix (the transmembrane 4 domain), suggesting an association between these variants and childhood-onset movement disorder with intellectual disability. In pediatric cases with developmental delay and movement disorders such as tremor and ataxia, specific variants in the transmembrane 4 domain of ANO3 may be a cause, even in the absence of dystonia.

Novel POLE mutations identified in patients with IMAGE-I syndrome cause aberrant subcellular localisation and protein degradation in the nucleus.

BACKGROUND: DNA replisome is a molecular complex that plays indispensable roles in normal DNA replication. IMAGE-I syndrome is a DNA replisome-associated genetic disease caused by biallelic mutations in the gene encoding DNA polymerase epsilon catalytic subunit 1 (POLE). However, the underlying molecular mechanisms remain largely unresolved. METHODS: The clinical manifestations in two patients with IMAGE-I syndrome were characterised. Whole-exome sequencing was performed and altered mRNA splicing and protein levels of POLE were determined. Subcellular localisation, cell cycle analysis and DNA replication stress were assessed using fibroblasts and peripheral blood from the patients and transfected cell lines to determine the functional significance of POLE mutations. RESULTS: Both patients presented with growth retardation, adrenal insufficiency, immunodeficiency and complicated diffuse large B-cell lymphoma. We identified three novel POLE mutations: namely, a deep intronic mutation, c.1226+234G>A, common in both patients, and missense (c.2593T>G) and in-frame deletion (c.711_713del) mutations in each patient. The unique deep intronic mutation produced aberrantly spliced mRNAs. All mutants showed significantly reduced, but not null, protein levels. Notably, the mutants showed severely diminished nuclear localisation, which was rescued by proteasome inhibitor treatment. Functional analysis revealed impairment of cell cycle progression and increase in the expression of phospho-H2A histone family member X in both patients. CONCLUSION: These findings provide new insights regarding the mechanism via which POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression, a characteristic of DNA replisome-associated diseases.

Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2.

Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.