Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes.

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

Advantage of a higher position of the tracheostoma with glottic closure for preventing complications related to tracheostomy tube: a retrospective cohort study.

BACKGROUND: Surgery to prevent aspiration has complications related to tracheostomy tube, such as the trachea-brachiocephalic artery fistula. Glottic closure procedure makes tracheostoma at a position higher than the first ring of the trachea and theoretically has a potential to prevent such complications owing to a longer distance between the tip of tracheostomy tube and the tracheal membrane adjacent to the brachiocephalic artery. Our aim is to evaluate the safety of glottic closure in neurologically impaired patients by comparing outcomes with laryngotracheal separation. METHODS: This study is a single-center retrospective study from 2004 to 2019, using data of 15 and 12 patients who underwent glottic closure (GC) and laryngotracheal separation (LTS). The primary outcome was the incidence of postoperative complications induced by tracheostomy tube placement and adjustment of the tracheostomy tube position to prevent these complications, such as by converting to a length-adjustable tube and/or placing gauze between the skin and tube flange. Additionally, we analyzed the anatomical relationship between the tracheostomy tube tip and brachiocephalic artery and measured the distance between them using postoperative CT images. RESULTS: No patients in either group had trachea-brachiocephalic artery fistula. Erosion or granuloma formation occurred in 1 patient (7%) and 4 patients (33%) in the GC and LTS groups, respectively. Adjustment of the tracheostomy tube was needed in 2 patients (13%) and 6 patients (50%) in the GC and LTS groups. CT revealed a higher proportion of patients with the tracheostomy tube tip superior to the brachiocephalic artery in GC than LTS group. The mean tracheostoma-brachiocephalic artery distance was 40.8 and 32.4 mm in the GC and LTS groups. CONCLUSIONS: Glottic closure reduces the risk of postoperative complications related to a tracheostomy tube. This may be due to the higher position of the tracheostoma at the level of the cricoid cartilage, increasing the distance between the tracheostoma and brachiocephalic artery.

Efficacy of high-flow nasal cannula therapy in bedridden patients.

BACKGROUND: A growing number of studies have demonstrated the efficacy of high-flow nasal cannula therapy (HFNC) for treating children with acute respiratory distress. However, it remains unknown whether HFNC is effective in bedridden patients with acute respiratory distress. METHOD: We retrospectively reviewed the medical records of bedridden patients with acute respiratory distress who were treated with HFNC using a home ventilator in continuous positive airway pressure mode at our center between March 2014 and August 2016. We assessed heart rate, respiratory rate, oxygen saturation measured using a pulse oximeter, the partial pressure of venous carbon dioxide, or the transcutaneous partial pressure of carbon dioxide, and symptoms of respiratory distress before and after the initiation of HFNC. RESULTS: During the 2-year-study period, 25 patients were treated with HFNC. The patients' mean heart rate, respiratory rate, oxygen saturation measured using a pulse oximeter, and pressure of venous carbon dioxide/the transcutaneous partial pressure of carbon dioxide values improved significantly (P < 0.05). Symptoms of respiratory distress were considerably ameliorated at 1-3 h after the HFNC initiation, except in two patients. In these two patients, the HFNC was replaced with non-invasive positive pressure ventilation. Non-invasive positive pressure was also required at 16 to 168 h after the initiation of HFNC in five of the 28 episodes in which the patient was initially responsive to HFNC, as the patients' respiratory symptoms gradually deteriorated. CONCLUSION: Performing HFNC with a home ventilator in continuous positive airway pressure mode is effective at treating bedridden patients with acute respiratory distress. However, it is essential that the HFNC can be switched to non-invasive positive pressure if needed.

Ketogenic diet for refractory epilepsy with MEHMO syndrome: Caution for acute necrotizing pancreatitis.

BACKGROUND: The MEHMO (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome, which is caused by a hemizygous variant in the EIF2S3 gene on chromosome Xp22, is associated with significant morbidity and mortality. Refractory epileptic seizures and glucose dysregulation are characteristic manifestations of the MEHMO syndrome, which can often diminish patients' quality of life. CASE: A 5-year-old boy was referred to our hospital because of profound intellectual disability, micropenis, cryptorchidism, central hypothyroidism, and microcephaly. He had neonatal hypoglycemia at birth and later experienced refractory epileptic seizures and developed obesity and insulin-dependent diabetes. A diagnosis of MEHMO syndrome was established on the basis of the patient's clinical manifestations and de novo novel missense variant in the EIF2S3 gene (NM_001415.3:c.805 T > G) that was detected through whole-exome analysis. Although the patient's refractory seizures and diabetes had been well controlled with a combination of ketogenic diet (KD) therapy and insulin therapy, acute fatal necrotizing pancreatitis occurred at the age of 68 months. Moreover, despite intensive care, his condition rapidly deteriorated to multiple organ failure and acute respiratory distress syndrome, resulting in death. CONCLUSION: The pathophysiology of glucose intolerance in MEHMO syndrome remains to be elucidated; however, recent studies have suggested that EIF2S3 gene variants could lead to glucose dysregulation and ß-cell damage in the pancreas. We suspect that in the present case, KD therapy led to an abnormal load on the beta cells that were damaged owing to eIF2γ dysfunction. Therefore, the adverse effects of KD in patients with MEHMO syndrome should be considered.

Risk Factors for Cerebral Infarction in Duchenne Muscular Dystrophy: Review With our 2 Cases.

BACKGROUND: Although the incidence of cerebral infarction is higher in Duchenne muscular dystrophy (.75 per 100) than in the general population (7.5-11.4 per 100 000), only 18 cases have been reported, and prevention and management guidelines for infarction in this disorder remain lacking. PATIENTS AND METHODS: We encountered 2 cases of Duchenne muscular dystrophy with cerebral infarction. To clarify risk factors for such infarction in Duchenne muscular dystrophy, we reviewed 20 cases, including our 2 patients. RESULTS: Age at onset of infarction ranged from 4 to 31 years (n = 19). Most patients were 16-21 years old (14 of 19; 73.7%). Eighteen patients (90%) had dilated cardiomyopathy (DCM), showing a higher frequency than in the age-matched general Duchenne muscular dystrophy population. Left ventricular ejection fraction (LVEF) ranged from 10.2% to 42% (median, 20%; n = 9). Detectable cardiac thrombus and atrial fibrillation were rare (2 of 17; 11.8%, and 1 of 17; 5.9%, respectively). CONCLUSIONS: Presence of DCM with low LVEF seems to be the strongest risk factor for cerebral infarction in Duchenne muscular dystrophy.

Cumulative jerk as an outcome measure in nonambulatory Duchenne muscular dystrophy.

OBJECTIVES: Quantitative or semiquantitative outcome measures for patients with Duchenne muscular dystrophy (DMD) are important, as they can be objective indicators of the natural history of DMD; these measures also aid in the evaluation of the efficacy of various treatments. However, the most widely used standard outcome measures in patients with DMD, such as the North Star Ambulatory Assessment and the 6-min walk test, cannot be applied after patients have become nonambulatory. We evaluated the utility and reliability of accelerometric analysis of motor activity in nonambulatory patients with DMD. METHODS: We measured the motor activity of the upper extremity in 7 nonambulatory patients with DMD, by using an accelerometer attached at the wrist of the dominant arm. To eliminate gravitational acceleration, we measured the changes in acceleration between measurements. The root of the sum of squared values of the changes per unit time in the 3 axes of the accelerometer was defined as a jerk. The total sum of the jerk values obtained at a measurement frequency of 15.625 Hz for 8 h was defined as the cumulative sum of jerks (Cj). RESULTS: The Cj values had significant and very strong or strong correlations with the Brooke Upper Extremity Scale (rs = -0.973; p = 0.00023) and the arm function scores for the DMD Functional Ability Self-Assessment Tool (rs = 0.810, p = 0.027). The values also had a very strong or strong correlation with the elbow flexion strength (nondominant arm: r = 0.931, p = 0.002; dominant arm: r = 0.750, p = 0.052). CONCLUSION: Cj assessment is a useful method to evaluate motor activities in nonambulatory patients with DMD.

Successful use of non-invasive positive pressure ventilation in a patient with the severe form of X-linked myotubular myopathy.

The severity of X-linked myotubular myopathy (XLMTM) ranges from mild to severe, depending on the level of ventilatory support required. Patients with the severe form of XLMTM usually die within the first year of life due to respiratory failure. Most survivors need tracheostomies, and there has only been one report about the use of non-invasive positive pressure ventilation (NPPV) in patients with the severe form of XLMTM because of the severity of the associated respiratory failure. We successfully applied NPPV with high-span positive inspiratory pressure (PIP) in a patient with the severe form of XLMTM, who also had secondary pectus excavatum. About a year after the initiation of NPPV with high-span PIP, the patient's pectus excavatum had improved. As the patient's pectus excavatum improved, his respiratory disturbance was ameliorated, and the frequency of respiratory infections gradually decreased. NPPV might be the first-choice respiratory management strategy for patients with XLMTM.

Ketogenic diet using a Japanese ketogenic milk for patients with epilepsy: A multi-institutional study.

BACKGROUND: In Japan, Meiji 817-B (M817-B), a powdered ketogenic milk, has been available since the ketogenic diet was introduced to infants and tube-fed children with medication-resistant epilepsy in the 1980s. METHODS: We retrospectively evaluated the efficacy, tolerability, and side effects of the ketogenic diet using M817-B as the main source of daily food intake for patients with epilepsy by sending questionnaires to the members of a subcommittee of the Japan Epilepsy Society that focuses on the proper use of M817-B. RESULTS: A total of 42 patients were enrolled. Age at the initiation of the diet therapy ranged from 3 to 244 months (median, 32.5 months). Thirty-four patients were fed via tube, and the remaining 8 were fed orally. About 93% of patients were able to continue the diet for 1 month, 74% for 3 months, and 64% for 6 months. The median period of continuation was 16 months. One patient was able to continue as long as 7 years. The ketogenic ratio was maintained at about 3.0. The seizure-free rate and responder (>50% seizure reduction) rate were about 10% and 30-40%, respectively during the 12 months on the diet. Mean serum beta-hydroxybutyrate increased to almost 4 mM at 1 month and was maintained during the diet period. Side effects, which required discontinuation of the diet therapy, occurred in 11 of 42 patients and included hypertonia, weight loss, vomiting, hypoglycemia, metabolic acidosis, and hypokalemia. CONCLUSION: M817-B could be used long-term with demonstrated efficacy in seizure reduction, although there are some side effects that may require cessation of the diet therapy.

Left ventricular noncompaction cardiomyopathy in a patient with trisomy 13: A report and review of the literature.

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent trabecular meshwork, and it is thought to result from arrest of the normal compaction process during embryogenesis. Patients with LVNC may be asymptomatic or have symptoms ranging from heart failure to stroke, life-threatening arrhythmias, or sudden death. The frequency of LVNC in children has increased with longer clinical courses. About 80% of patients with trisomy 13 have a congenital cardiac abnormality, but a clinical description of LVNC with trisomy 13 is lacking because of its poor prognosis and lack of awareness about LVNC. We described a patient with trisomy 13 who was diagnosed with LVNC-dilated phenotype and died suddenly, as well as two additional patients with LVNC. All three patients had chronic heart failure without congenital heart disease and were treated with diuretics. To manage trisomy 13 with or without congenital heart disease, cardiac disease such as LVNC may present at any ages, and therefore cardiac evaluation should be considered as a part of their appropriate management.

Familial acute necrotizing encephalopathy without RANBP2 mutation: Poor outcome.

Most childhood cases of acute necrotizing encephalopathy (ANE) involve neither family history nor recurrence. ANE occasionally occurs, however, as a familial disorder or recurs in Caucasian patients. A mutation of RAN-binding protein 2 (RANBP2) has been discovered in more than one half of familial or recurrent ANE patients. In contrast, there has been no report of this mutation in East Asia. Here, we report the first sibling cases of typical ANE in Japan, with poor outcome. DNA analysis of genes associated with ANE or other encephalopathies, including RANBP2 and carnitine palmitoyl transferase II (CPT2), indicated neither mutations nor disease-related polymorphisms. On literature review, recurrent or familial ANE without the RANBP2 mutation has a more severe outcome and greater predilection for male sex than that with the RANBP2 mutation. This suggests that there are unknown gene mutations linked to ANE.

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.

OBJECTIVE: Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. METHODS: This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. RESULTS: High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. INTERPRETATION: Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.

[Enteral nutrition ameliorated superior mesenteric artery syndrome in a patient with Duchenne muscular dystrophy].

The abdominal complications of Duchenne muscular dystrophy (DMD) include acute gastric dilatation, superior mesenteric artery (SMA) syndrome, ileus and constipation. We report herein a patient with DMD in whom SMA syndrome was successfully treated with enteral tube nutrition. The patient was a 16-year-old boy diagnosed with DMD at 2 years. Steroid therapy was started at 5 years, and he was unable to walk and was wheelchair-bound at 11 years. Lordoscoliosis progressed after the age of 14 years. Noninvasive mechanical ventilation was introduced due to respiratory impairment at 15 years. During 8 months with respiratory impairment, his body weight decreased from 40.3 kg to 33.4 kg. He was referred to our hospital for vomiting and hematemesis. Radiographic studies indicated a diagnosis of SMA syndrome. Enteral nutrition with a nasojejunal tube successfully treated SMA syndrome for 5 months and his body weight increased from 32.7 kg to 36.1 kg. Gastrostomy was subsequently performed and no recurrence was evident. SMA syndrome is caused by compression of the third part of the duodenum at the angle between the aorta and SMA. The conditions for duodenal vascular compression are weight loss resulting in depletion of the retroperitoneal fat and progressive lordosis. The reasons for SMA syndrome with our patient were weight loss and progressive lordoscoliosis. A conservative approach with enteral nutrition promoted weight gain, increasing retroperitoneal fat. Enteral nutrition should be considered for the treatment of SMA syndrome as a complication of DMD.

ALDH18A1-related cutis laxa syndrome with cyclic vomiting.

Cutis laxa (CL) syndromes are connective tissue disorders characterized by redundant, sagging, inelastic and wrinkled skin, with organ involvement. Here, we describe a patient with ALDH18A1-related CL who developed cyclic vomiting. The patient was a 12-year-old boy who presented with poor postnatal growth, hypotonia, short stature, joint hyperlaxity, microcephaly, strabismus, bilateral cataracts, facial dysmorphism and severe mental retardation. Bone radiographs showed osteopenia and osteoporosis, and magnetic resonance angiography showed marked kinking and tortuosity of the brain vessels. These findings were clinically compatible with ALDH18A1-related CL. Molecular analysis revealed a de novo heterozygous mutation (p.R138Q) in ALDH18A1. No mutations were found in PYCR1 gene. The patient developed cyclic vomiting with decreased blood levels of ornithine, citrulline, arginine and proline without hyperammonemia and other hypoaminoacidemias were also found. ALDH18A1 encodes Δ(1)-pyrroline-5-carboxylate synthase, which is related to the biosynthesis of ornithine, citrulline, arginine, and proline. Cyclic vomiting has never been reported in other ALDH18A1-related CL patients. This is the first case report of ALDH18A1-related CL with cyclic vomiting associated with amino acid abnormalities.

Effects and limits of acute noninvasive positive pressure ventilation in children with severe motor and intellectual disabilities with pneumonia/bronchitis.

Objective: We have frequently applied noninvasive positive pressure ventilation (NPPV) to treat acute respiratory failure in children with severe motor and intellectual disabilities. We investigated the features and causes of conditions requiring endotracheal intubation. We aimed to determine whether phlegm expulsion using appropriate breathing physiotherapy with NPPV could avoid the need for endotracheal intubation in such patients. Methods: Between December 2010 and November 2012, 21 children with 51 episodes of acute respiratory failure were placed on NPPV at our hospital. We investigated the ratio, background, and causes of conditions requiring endotracheal intubation. Results: Pneumonia and bronchitis caused 30 and 21 episodes of respiratory failure, respectively. Respiratory infection required endotracheal intubation in 8 of 30 episodes of pneumonia, and in none of the 21 episodes of bronchitis. Respiratory infections were caused by upper airway obstruction with large amounts of secretion (n=4), lower airway obstruction due to atelectasis (n=3) and a combination of both (n=1). The frequency of breathing physiotherapy was significantly higher for all patients who required assistance with active phlegm expulsion than in those who did not (p=0.006). More patients on endotracheal intubation also required phlegm aspiration compared with other patients (p=0.019). Conclusion: We applied NPPV to acute respiratory failure in children with severe motor and intellectual disabilities. This allowed 84% of them to avoid endotracheal intubation. Acute respiratory failure did not improve in any patient who required endotracheal intubation, but we also used NPPV with breathing physiotherapy and postural drainage. Assistance with phlegm expulsion is hampered in children with severe motor and intellectual disabilities due to conditions such as thoracic deformations, joint contracture and glossoptosis. We consider that assistance with phlegm expulsion using appropriate breathing physiotherapy with NPPV is very important for such patients.

A patient with Joubert syndrome who developed sleep-related breathing disorder at 15 years of age.

Joubert syndrome is characterized by neonatal breathing disorders that are thought to improve with age, but recent findings indicate that sleep-related breathing disorders can occur even after infancy. A 15-year-old boy who had a breathing disorder during the neonatal period developed mental retardation and hypotonia. He was diagnosed with Joubert syndrome based on the clinical course and molar tooth sign on brain MRI at 9 years of age. Daytime sleepiness developed at 15 years of age. An interview and the results of sleep questionnaires (Epworth sleepiness scale, Pediatric sleep questionnaire and Pittsburgh sleep quality index), indicated that the patient had daytime sleepiness and a sleep-related breathing disorder. Overnight polysomnography showed central apnea with an apnea hypopnea index of 16, indicating that the patient had central sleep apnea syndrome. After nighttime oxygen therapy at home for one month, the sleep questionnaires showed improved daytime sleepiness and the sleep-related breathing disorder. The improvement persisted for over 12 months thereafter. Sleep-related breathing disorders could be indicated by non-specific complaints such as daytime sleepiness and lead to appropriate therapies. Such disorders should be considered as a complication of Joubert syndrome even after infancy.

Severe acute abdomen caused by symptomatic Meckel's diverticulum in three children with trisomy 18.

Meckel's diverticulum (MD) is the most prevalent congenital anomaly of the gastrointestinal tract and often presents a diagnostic challenge. Patients with trisomy 18 frequently have MD, but the poor prognosis and lack of consensus regarding management for neonates has meant that precise information on the clinical manifestations in infants and children with MD is lacking. We describe the cases of three children with trisomy 18 who developed symptomatic MD. Intussusception was diagnosed in Patient 1, intestinal volvulus in Patient 2, and gastrointestinal bleeding in Patient 3. All three patients underwent surgical treatment and only the Patient 1 died due to pulmonary hypertensive crisis. The other two patients experienced no further episodes of abdominal symptoms. In patients with trisomy 18, although consideration of postoperative complications and prognosis after surgical treatment is necessary, symptomatic MD should carry a high index of suspicion in patients presenting with acute abdomen.

[Effectiveness of continuous infusion of tizanidine (Ternelin) via a feeding tube for patients with the mixed type of tetraplegia].

OBJECTIVE: Severe muscle hypertonia in patients with the mixed type of tetraplegia may be associated with significant deterioration in the quality of life of the patients. Intermittent use of oral muscle relaxant drugs, for example, Tizanidine (Ternelin), which is a fast-acting muscle relaxant, can provide relief from the severe hypertonia in these patients, but only for short durations. METHODS: We conducted a retrospective study of the effect of continuous infusion of tizanidine via a feeding tube on the severe systemic muscle hypertonia in patients with the mixed type of tetraplegia. We mixed tizanidine with milk or other enteral nutrients and administered the mixture via a naso-duodenal tube at a constant infusion rate several hours to 5 patients with the mixed type of tetraplegia showing severe uncontrolled systemic hypertonia under intermittent treatment with oral muscle relaxant drugs. RESULTS: Significant relief from the systemic muscle hypertonia was obtained in 4 of the 5 patients with improvement of the quality of life of the patients, e. g., they could get adequate sleep. There were no serious side effects in any of the cases. CONCLUSION: We consider that continuous infusion of tizanidine via a feeding tube would be useful for the treatment of severe systemic hypertonia in patients in whom the symptom cannot be adequately controlled by intermittent use of oral muscle relaxant drugs.

[A family with creatine transporter deficiency diagnosed with urinary creatine/creatinine ratio and the family history: the third Japanese familial case].

Creatine transporter deficiency (CRTR-D) is an X-linked disorder characterized by hypotonia, developmental delay, and seizures. We report the third Japanese family with CRTR-D. The proband was an 8-year-old boy who presented with hypotonia, severe intellectual disability and two episodes of seizures associated with/without fever. Among 7 siblings (4 males, 3 females), the eldest brother had severe intellectual disability, epilepsy, and sudden death at 17 years of age, while 18-year-old third elder brother had severe intellectual disability, autism, and drug-resistant epilepsy. The proband's urinary creatine/creatinine ratio was increased. A reduced creatine peak on brain magnetic resonance spectroscopy and a known pathogenic mutation in the SLC6A8 gene (c.1661 C > T;p.Pro554Leu) confirmed the diagnosis of CRTR-D. The same mutation was found in the third elder brother. Their mother was a heterozygote. Symptoms of CRTR-D are non-specific. Urinary creatine/creatinine ratio should be measured in patients with hypotonia, developmental delay, seizure and autism whose family history indicates an X-linked inheritance.

Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.

OBJECTIVE: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. METHOD: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. RESULTS: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. CONCLUSION: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.