Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is a central nervous system (CNS) inflammatory disease characterized by contrast-enhanced MRI findings of salt-and-pepper-like lesions predominantly affecting the brainstem and cerebellum. We report two patients with CLIPPERS-like brain MRI findings who carried the same missense UNC13D variant in one allele along with deleterious variants in the opposite allele. Patient 1, a 23-year-old female, presented at 15 years of age with neurological symptoms and an MRI showing spontaneously resolving, contrast-enhancing lesions in the cerebellum. At age 16, the patient experienced an episode with systemic manifestations followed by recurrent CNS lesions that responded to steroid therapy. At age 22, the patient developed punctate to nodular contrast-enhancing lesions in the brainstem, cerebellum, and cerebrum, findings consistent with CLIPPERS. Patient 2, an 18-year-old female, presented at age 11 with ataxia and dysarthria, and an MRI showing multiple contrast-enhancing lesions in the cerebellum and brainstem, consistent with CLIPPERS MRI findings. Cerebellar biopsy revealed perivascular CD4+ T-lymphocyte infiltration, and the patient responded to steroid therapy, leading to an initial diagnosis of CLIPPERS. These patients were suspected of having inborn errors of immunity and were identified to have compound heterozygous UNC13D variants along with downregulated Munc13-4 protein. Both patients underwent allogeneic hematopoietic cell transplantation, with patient 1 remaining neurologically stable for two years post-transplantation, while patient 2 experienced a post-transplant relapse requiring steroid therapy. These cases highlight that biallelic variants in the UNC13D gene may cause CNS-predominant inflammation that mimics CLIPPERS.

Objective To evaluate the efficacy and safety of diazepam nasal spray (tradename: SPYDIA in Japan, VALTOCO® in the US) following single (Part 1) and multiple (Part 2) dose administrations in pediatric epilepsy patients. Methods Patients aged 6–17 years with status epilepticus (SE) or at risk for progression to SE despite stable antiseizure medication were eligible. In Part 1, a single intranasal dose (5, 10, or 15 mg) was administered immediately after the onset of a prespecified convulsive seizure. The primary endpoint was the responder rate (seizures ceasing within 10 min post-dose without recurrence for 30 min) in this part. In Part 2, multiple doses were administered for up to 24 weeks to assess efficacy and safety. Results From November 2022 and January 2024, 22 participants were enrolled in Part 1; 16 were treated. The responder rate was 62.5% (10/16; 95% CI, 35.4–84.8), with the lower CI limit exceeding the 30% threshold. In Part 2, 14 participants treated 91 seizures; 71.4% ceased within 10 min without recurrence for 12 h. Overall, 18 participants received diazepam nasal spray; 14 (77.8%) experienced treatment-emergent adverse events (TEAEs). No TEAEs led to discontinuation, and all treatment-related TEAEs were mild. Treatment satisfaction (“very” or “fairly” satisfied) was reported by 15/16 (93.8%) and 15/17 (88.2%) participants in Parts 1 and 2, respectively. Conclusion These findings support the favorable efficacy and safety profiles of diazepam nasal spray as a rescue therapy in pediatric patients with or at risk for SE.

Leigh syndrome (LS), characterized by progressive impairment and necrosis of the bilateral basal ganglia and brainstem structures, is the most prevalent mitochondrial disorder in children. Among the genetic causes of LS, the m.10191T>C variant in the mitochondrial complex I subunit gene MT-ND3 (NC_012920.1) is recognized as one of the most common. This variant is associated with a broad clinical spectrum, ranging from infantile lethality to adult-onset symptoms. Due to multisystem involvement, clinical manifestations are diverse, and treatment remains challenging. We present two patients with LS carrying the m.10191T>C variant of the MT-ND3 gene. Despite the severe clinical features and early disease onset, both patients demonstrated prolonged survival. Both patients exhibited psychomotor regression, and magnetic resonance imaging findings were indicative of bilateral basal ganglia and brainstem involvement. Subsequently, each patient developed rectal bleeding accompanied by elevated fecal calprotectin levels, which are indicative of intestinal inflammation. They also developed marked systemic edema and pleural effusions, which were exacerbated by infectious episodes and consistent with capillary leak syndrome. To the best of our knowledge, this is the first report describing severe capillary leak syndrome attributable to mitochondrial dysfunction in vascular endothelial cells. The observed rectal bleeding may reflect mitochondrial impairment within the intestinal wall. These findings extend the phenotypic spectrum of the m.10191T>C variant in LS.

BACKGROUND AND OBJECTIVES: The influence of the age at which complete corpus callosotomy (CC) surgery is performed on seizure outcomes remains unclear. This study aimed to evaluate the age-dependent aspects of long-term seizure outcomes after complete CC. METHODS: We reviewed 41 patients who underwent one-stage complete CC. Seizure outcomes were analyzed for age at epilepsy onset and at complete CC, focal MRI abnormality, and etiology. RESULTS: The median age was 7 months at epilepsy onset and 93 months at complete CC. The median follow-up duration was 67 months. Sixteen patients had focal MRI lesions and 4 had only general atrophy. Etiology was identified in 20 patients. For overall seizure outcomes (N = 41), complete seizure freedom was achieved in 5 patients, excellent seizure reduction (>80%) in 11, good (50%-80%) in 5, and poor (<50%) in 20. Freedom was correlated with younger age at complete CC and unknown etiology (P ≤ .05). Freedom was only achieved in patients aged younger than 7 years. Worthwhile (≥50%, freedom, excellent, and good) and not worthwhile (<50%, poor) overall seizure reduction showed no statistical difference in age at complete CC. No related factor was found for worthwhile overall seizure reduction. For drop attack outcomes (N = 31), freedom was achieved in 22 cases, excellent in 5, and poor in 4. Freedom was correlated with younger age at complete CC (P < .05) although freedom was achieved in 4 of 7 patients older than 20 years. Age at complete CC showed no statistical difference between worthwhile (≥50%) and not worthwhile (<50%) drop attack reduction. Worthwhile drop attack reduction was correlated with unknown etiology (P < .05). Complications were mild and transient. CONCLUSION: Complete CC is an excellent surgical option based on favorable seizure outcomes and acceptable complications in our present study.

OBJECTIVE:Surgery for peri-rolandic epilepsy requires appropriate consideration to balance the functional risk of postoperative motor deficit and seizure outcome. Based on voxel-based morphometric analysis, the authors hypothesized that cortical damage and ischemic subcortical damage related to surgery could affect postoperative motor deterioration. METHODS:Sixteen patients with peri-rolandic epilepsy who underwent resective surgery at a single institution were retrospectively investigated. Their imaging findings, postoperative seizure outcomes, and postoperative neurological deteriorations in motor function, as well as duration, were analyzed. Using the standardized MRI data of each case, the authors examined the surgically resected area on high-resolution 3D MR images and the high-intensity area on diffusion-weighted images, which were converted to voxel data. These voxel data were superimposed on a standard brain image for neuroimaging assessment. Postoperative motor deterioration of the orofacial region, upper limb, or lower limb was noted as no, transient, or permanent deterioration and analyzed in relation to the surgically resected area and subcortical damage. Univariate analysis of the clinical factors was conducted between cases with permanent upper- and/or lower-limb motor deterioration and those with no or transient deterioration. RESULTS:The mean follow-up period was 28 months. Ten patients (62.5%) achieved Engel class I. Fourteen patients (87.5%) experienced postoperative motor deteriorations in the following areas (no/transient/permanent): orofacial (11/5/0), upper limb (9/5/2), and lower limb (9/3/4). All cases with orofacial motor deterioration underwent cortical resection of the inferior third of the peri-rolandic cortex. Cortical resection of the precentral gyrus only, in contrast to both the precentral and postcentral gyri, was not associated with permanent upper- and/or lower-limb motor deterioration. Cortical resection involving the postcentral gyrus was significantly associated with permanent upper- and/or lower-limb motor deterioration in 4 cases (25.0%). Surgically related perforating artery injury caused ischemic subcortical damage, which was significantly associated with postoperative transient or permanent motor deterioration by extending to the corticospinal tract (CST). CONCLUSIONS:Postoperative motor deterioration for peri-rolandic epilepsy was related to both the resected cortex and ischemic subcortical damage. In peri-rolandic epilepsy, cortical resection of the precentral gyrus might not necessarily cause permanent upper- and/or lower-limb motor deterioration because of the functional reserve in other peri-rolandic areas outside the epileptic focus. On the other hand, cortical resection of the postcentral gyrus could cause permanent upper- and/or lower-limb motor deterioration because of injury to the vasculature, which is crucial for the descending motor pathway in the CST.

Post-transplant human herpes virus 6 (HHV6) encephalitis can be followed by refractory epilepsy accompanied by intellectual decline after several months. However, such cases are extremely rare, and the disease mechanism remains elusive. We present the case of an eight-year-old boy who presented with epileptic encephalopathy 11 months after developing post-transplant acute limbic encephalitis (PALE) caused by HHV6. The patient developed multiple types of seizures, primarily characterized by epileptic spasms. Significant electroencephalographic (EEG) abnormalities were noted during the interictal period, along with regression of cognitive and language functions and progressive atrophy of the entire brain, including the hippocampus. He was managed with multiple antiepileptic drugs, although his seizures remained uncontrolled for one year after epilepsy onset. Herein, we summarized and analyzed the clinical features of the previously reported cases and the present case. The median time from the onset of HHV6 PALE to epilepsy was 11.5 months. Developmental regression or cognitive decline, multiple seizure types including tonic seizures, generalized slow waves, multifocal spike-wave activity on interictal EEG, brain changes such as hippocampal sclerosis, and poor seizure prognosis are common features. The disease was classified as epileptic encephalopathy following HHV6-related PALE (EE-PALE). This case not only provides additional evidence that EE-PALE is a distinct disease with consistent clinical features but is also expected to contribute to the identification of its pathogenesis and effective treatment.

IntroductionIt is hard to realize the extent of the expected postoperative neurological deficit for patients themselves. The provision of appropriate information can contribute not only to examining surgical indications but also to filling the gap between patient and expert expectations. We hypothesized that propofol infusion into the intracranial arteries (ssWada) could induce focal neurological symptoms with preserved wakefulness, enabling the patients to evaluate the postsurgical risk subjectively.MethodsPresurgical evaluation using ssWada was performed in 28 patients with drug-resistant epilepsy. Based on anatomical knowledge, propofol was super-selectively infused into the intracranial arteries including the M1, M2, and M3 segments of the middle cerebral artery (MCA), A2 segment of the anterior cerebral artery, and P2 segment of the posterior cerebral artery to evaluate the neurological and cognitive symptoms. We retrospectively analyzed a total of 107 infusion trials, including their target vessels, and elicited symptoms of motor weakness, sensory disturbance, language, unilateral hemispatial neglect (UHN), and hemianopsia. We evaluated preserved wakefulness which enabled subjective evaluations of the symptoms and comparison of the subjective experience to the objective findings, besides adverse effects during the procedure.ResultsPreserved wakefulness was found in 97.2% of all trials. Changes in neurological symptoms were positively evaluated for motor weakness in 51.4%, sensory disturbance in 5.6%, language in 48.6%, UHN in 22.4%, and hemianopsia in 32.7%. Six trials elicited seizures. Multivariate analysis showed significant correlations between symptom and infusion site of language and left side, language and MCA branches, motor weakness and A2 or M2 superior division, and hemianopsia and P2. Transient adverse effect was observed in 8 cases with 12 infusion trials (11.2 %).ConclusionThe ssWada could elicit focal neurological symptoms with preserved wakefulness. The methodology enables specific evaluation of risk for cortical resection and subjective evaluation of the expected outcome by the patients.

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.

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.

Introduction:DYT-KMT2B is a rare childhood-onset, hereditary movement disorder typically characterized by lower-limb dystonia and subsequently spreads into the craniocervical and laryngeal muscles. Recently, KMT2B-encoding lysine (K)-specific histone methyltransferase 2B was identified as the causative gene for DYT-KMT2B, also known as DYT28. In addition to the fact that many physicians do not have sufficient experience or knowledge of hereditary dystonia, the clinical features of DYT-KMT2B overlap with those of other hereditary dystonia, and limited clinical biomarkers make the diagnosis difficult.Methods:Histone proteins were purified from the oral mucosa of patients with de novo KMT2B mutation causing premature stop codon, and then trimethylated fourth lysine residue of histone H3 (H3K4me3) which was catalyzed by KMT2B was analyzed by immunoblotting with specific antibody. We further analyzed the significance of H3K4me3 in patients with DYT-KMT2B using publicly available datasets.Results:H3K4me3 histone mark was markedly lower in the patient than in the control group. Additionally, a reanalysis of publicly available datasets concerning DNA methylation also demonstrated that KMT2B remained inactive in DYT-KMT2B.Discussion:Although only one case was studied due to the rarity of the disease, the reduction of H3K4me3 in the patient's biological sample supports the dysfunction of KMT2B in DYT-KMT2B. Together with informatics approaches, our results suggest that KMT2B haploinsufficiency contributes to the DYT-KMT2B pathogenic process.

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

Introduction: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy. Case report: The patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy. Conclusions: To our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4. (C) 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Incubation of L1210 murine leukemia cells in vitro with 10 μM of the bifunctional alkylating agent bis(2-chloroethyl)methylamine (nitrogen mustard, HN2) for 10 min brought about a fall of more than 99.9% in their ability to form colonies when the cells were suspended in 0.5% nutrient agar. Incubation with HN2 also inhibited the influx of the potassium congener 86Rb+ to exponentially proliferating L1210 cells in a concentration-dependent manner. This inhibition was specific and was accounted for by a reduction of a diuretic-sensitive component of 86Rb+ influx, identified in the preceding paper (Wilcock, C. and Hickman, J.A. (1988) Biochim. Biophys. Acta 946, 359–367) as being mediated by a Na+/K+/Cl− cotransporter. Inhibition by 10 μM HN2 was complete after a 3-h incubation. There was no inhibition at this time of the ouabain-sensitive component of 86Rb+ influx, mediated by Na+/K+-ATPase. After 3 h of incubation with 10 μM HN2 there was also no change in the membrane potential of the treated cells as measured by the distribution of the [3H]TPMP+, no decrease in cellular ATP concentration and no change in intracellular pH, and the ability of the cells to exclude the vital dye Trypan blue was not significantly different from control values. These effects of HN2, therefore, appeared to follow lethal damage, but precede cell death. In the stationary phase of L1210 cell growth, the component of HN2 and diuretic-sensitive K+ influx to L1210 cells was reduced, whilst the component constituting the HN2-insensitive ouabain-sensitive sodium pump was increased. The monofunctional alkylating agent MeHN1 (2-chloroethyldimethylamine) which cannot cross-link cellular targets and has no antitumour activity, did not inhibit 86Rb+ influx to L1210 cells when incubated at equimolar or equitoxic concentrations to HN2. Intracellular potassium concentration was maintained close to control values of 138 ± 10 mM in HN2-treated cells because of an approx. 35% fall in cell volume. The results suggest that the Na+/K+/Cl− cotransporter is a selectively inhibitable target for HN2, and the lesion is discussed with reference to the cytotoxic effects of this agent.

BACKGROUND: Recovery time after corpus callosotomy (CC) is known to be longer in elderly than in younger patients. OBJECTIVE: To evaluate the relationship between patient age and recovery time of activities of daily living (ADL) after 1-stage complete CC. METHODS: This study included 41 patients (22 women; aged 13 months-34 years, median 7 years) who underwent 1-stage complete CC for medically intractable seizures with drop attacks, infantile spasms, and/or bilaterally synchronized electroencephalographic discharges between August 2009 and April 2019. The timing of restart of competence in 5 ADL categories and surgical outcomes were recorded. RESULTS: Patients (1) restarted speech at 2.2 ± 1.3 (mean ± 2 standard deviations; range 1-5) days, (2) restarted replying with their own name on request at 5.5 ± 8.6 (2-33) days, (3) restarted oral intake at 1.6 ± 1.7 (1-11) days, (5) discontinued intravenous feeding at 6.0 ± 3.0 (2-16) days, and (5) restarted ambulation or wheelchair movement at 5.8 ± 3.4 (2-10) days. Younger patients showed significantly (P < .0223) earlier recovery of ambulation or wheelchair movement, but no age difference was found in the other 4 ADL categories. Overall seizure freedom was achieved in 5 patients, excellent (>80%) seizure reduction in 11, good (50%-80%) seizure reduction in 5, and poor (<50%) seizure reduction in 20. CONCLUSION: Early ADL recovery after 1-stage complete CC is favorable in both young and adult patients. These findings, with good surgical outcomes, will encourage more positive consideration of 1-stage complete CC in both pediatric and adult patients.

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism that results from mutations in genes involved in molybdenum cofactor (Moco) biosynthesis. MoCD is characterized clinically by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. We report on a patient with an unusual late disease onset and mild phenotype, characterized by delayed development and a decline triggered by a febrile illness and a subsequent dystonic movement disorder. Magnetic resonance imaging showed abnormal signal intensities of the bilateral basal ganglia. Blood and urine chemistry tests demonstrated remarkably low serum and urinary uric acid levels. A urine sulfite test was positive. Specific diagnostic workup showed elevated levels of xanthine and hypoxanthine in serum with increased urinary sulfocysteine (SSC) levels. Genetic analysis revealed a homozygous missense mutation at c.1510C > T (p.504R > W) in exon 10 of the MOCS1 in isoform 7 (rs1387934803). At age 1 year 4 months, the patient was placed on a low protein diet to reduce cysteine load and accumulation of sulfite and SCC in tissues. At 3 months after introduction of protein restriction, the urine sulfite test became negative and the urine SCC level was decreased. After starting the protein restriction diet, dystonic movement improved, and the patient's course progressed without regression and seizures. Electroencephalogram findings were remarkably improved. This finding demonstrates that the dietary protein restriction suppresses disease progression in mild cases of MoCD and suggests the effectiveness of dietary therapy in MoCD.

Objective: Accurate estimation of the epileptogenic zone (EZ) is essential for favorable outcomes in epilepsy surgery. Conventional ictal electrocorticography (ECoG) onset is generally used to detect the EZ but is insufficient in achieving seizure-free outcomes. By contrast, high-frequency oscillations (HFOs) could be useful markers of the EZ. Hence, we aimed to detect the EZ using interictal spikes and investigated whether the onset area of interictal spike-related HFOs was within the EZ. Methods: The EZ is considered to be included in the resection area among patients with seizure-free outcomes after surgery. Using a complex demodulation technique, we developed a method to determine the onset channels of interictal spike-related ripples (HFOs of 80–200 Hz) and investigated whether they are within the resection area. Results: We retrospectively examined 12 serial patients who achieved seizure-free status after focal resection surgery. Using the method that we developed, we determined the onset channels of interictal spike-related ripples and found that for all 12 patients, they were among the resection channels. The onset frequencies of ripples were in the range of 80–150 Hz. However, the ictal onset channels (evaluated based on ictal ECoG patterns) and ripple onset channels coincided in only 3 of 12 patients. Conclusions: Determining the onset area of interictal spike-related ripples could facilitate EZ estimation. This simple method that utilizes interictal ECoG may aid in preoperative evaluation and improve epilepsy surgery outcomes.

Biallelic 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) variants were recently reported as a cause of progressive and incurable neurodegenerative diseases ranging from neonatal-onset leukoencephalopathy with severe neurodevelopmental delay to spastic paraplegia. Although the physiological function of HPDL remains unknown, its subcellular localization in the mitochondria has been reported. Here, we report a case of HPDL-related neurological disease that was clinically and neuroimaging compatible with Leigh syndrome, previously unreported, and was treated with a ketogenic diet.

We report on a 12-year-old female who developed osteosarcoma with tuberous sclerosis. Clinical sequencing of osteosarcoma tissues identified a somatic mutation in the TP53 gene and a novel germline mutation in the TSC2 gene. Pathological analysis of osteosarcoma tissue revealed increased phosphorylation of S6, a downstream target in the mTOR pathway. This is the first reported detection of a germline TSC2 mutation and somatic TP53 mutation in osteosarcoma with tuberous sclerosis. This case is unique and suggestive of a TSC2-dependent genetic pathway through mTOR signaling and a second-hit model for oncogenesis.