Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy: An Emerging Cause of Meningoencephalomyelitis in Children and Adolescents.

Introduction: We describe 5 children with GFAP astrocytopathy with the goal of further characterizing this rare form of meningoencephalomyelitis. Methods: Retrospective chart review of patients diagnosed with GFAP astrocytopathy between 2019 and 2021. Results: Patients were 8-17 years old, and all were male. Fever, headache, and vomiting were common presenting symptoms, and weakness, tremor, and ataxia were common initial examination findings. Initial magnetic resonance imaging (MRI) showed spinal cord abnormalities in 2 patients and leptomeningeal enhancement in 1. Most patients had cerebral spinal fluid pleocytosis, and all screened negative for malignancy. Three patients progressed to coma, and all were treated with immunosuppressant therapy. By discharge, all patients had improved over their clinical nadir, although none had returned to baseline. Discussion: GFAP astrocytopathy is a recently recognized cause of meningoencephalomyelitis in children. Here, we expand our understanding of this entity with the goal of aiding those treating children with GFAP astrocytopathy.

A Postmortem MRI Study of Cerebrovascular Disease and Iron Content at End-Stage of Fragile X-Associated Tremor/Ataxia Syndrome.

Brain changes at the end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy and iron content, and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases, among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus and frontoparietal white matter, and significant atrophy in the cerebellar white matter, red nucleus and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus and amygdala, that were independent from a highly correlated number of regions with ICH and iron content in subcortical nuclei. Post-hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus and amygdala in FXTAS cases compared to controls, after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former being marked by demyelination/iron depletion and atrophy, and the latter by ICH and iron accumulation in basal ganglia.

[Immune-Mediated Cerebellar Ataxias].

Autoimmune mechanisms affect the cerebellum leading to the development of cerebellar ataxias (CAs), which are termed immune-mediated cerebellar ataxias (IMCAs). IMCAs have diverse etiologies. Gluten ataxia (GA), post-infectious cerebellitis (PIC), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamate decarboxylase 65 antibody-associated CA (anti-GAD ataxia), and primary autoimmune cerebellar ataxia (PACA). In addition to these well-established entities, CAs are associated with autoimmunity against ion channels and their related proteins, synaptic adhesion proteins, transmitter receptors, glial cells, and brainstem antigens. Cell-mediated mechanisms are assumed to be involved in PCD, whereas accumulating evidence shows that anti-GAD antibodies decrease gamma-aminobutyric acid (GABA) release to elicit functional synaptic deficits. The therapeutic benefits of immunotherapies vary depending on the etiology. Early intervention is recommended when the cerebellar reserve, abilities for compensation and restoration of pathologies are preserved.

Extracellular Vesicles From Hyperammonemic Rats Induce Neuroinflammation in Cerebellum of Normal Rats: Role of Increased TNFα Content.

Hyperammonemia plays a main role in the neurological impairment in cirrhotic patients with hepatic encephalopathy. Rats with chronic hyperammonemia reproduce the motor incoordination of patients with minimal hepatic encephalopathy, which is due to enhanced GABAergic neurotransmission in cerebellum as a consequence of neuroinflammation. Extracellular vesicles (EVs) could play a key role in the transmission of peripheral alterations to the brain to induce neuroinflammation and neurological impairment in hyperammonemia and hepatic encephalopathy. EVs from plasma of hyperammonemic rats (HA-EVs) injected to normal rats induce neuroinflammation and motor incoordination, but the underlying mechanisms remain unclear. The aim of this work was to advance in the understanding of these mechanisms. To do this we used an ex vivo system. Cerebellar slices from normal rats were treated ex vivo with HA-EVs. The aims were: 1) assess if HA-EVs induce microglia and astrocytes activation and neuroinflammation in cerebellar slices of normal rats, 2) assess if this is associated with activation of the TNFR1-NF-kB-glutaminase-GAT3 pathway, 3) assess if the TNFR1-CCL2-BDNF-TrkB pathway is activated by HA-EVs and 4) assess if the increased TNFα levels in HA-EVs are responsible for the above effects and if they are prevented by blocking the action of TNFα. Our results show that ex vivo treatment of cerebellar slices from control rats with extracellular vesicles from hyperammonemic rats induce glial activation, neuroinflammation and enhance GABAergic neurotransmission, reproducing the effects induced by hyperammonemia in vivo. Moreover, we identify in detail key underlying mechanisms. HA-EVs induce the activation of both the TNFR1-CCL2-BDNF-TrkB-KCC2 pathway and the TNFR1-NF-kB-glutaminase-GAT3 pathway. Activation of these pathways enhances GABAergic neurotransmission in cerebellum, which is responsible for the induction of motor incoordination by HA-EVs. The data also show that the increased levels of TNFα in HA-EVs are responsible for the above effects and that the activation of both pathways is prevented by blocking the action of TNFα. This opens new therapeutic options to improve motor incoordination in hyperammonemia and also in cirrhotic patients with hepatic encephalopathy and likely in other pathologies in which altered cargo of extracellular vesicles contribute to the propagation of the pathology.

Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation.

Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212-PLD3 relationship is important for Purkinje cell survival.

Primary Ovarian Failure in Addition to Classical Clinical Features of Coats Plus Syndrome in a Female Carrying 2 Truncating Variants of CTC1.

Coats plus syndrome is an autosomal recessive multisystemic and pleiotropic disorder affecting the eyes, brain, bone, and gastrointestinal tract, usually caused by compound heterozygous variants of the conserved telomere maintenance component 1 gene (CTC1), involved in telomere homeostasis and replication. So far, most reported patients are compound heterozygous for a truncating mutation and a missense variant. The phenotype is believed to result from telomere dysfunction, with accumulation of DNA damage, cellular senescence, and stem cell depletion. Here, we report a 23-year-old female with prenatal and postnatal growth retardation, microcephaly, osteopenia, recurrent fractures, intracranial calcification, leukodystrophy, parenchymal brain cysts, bicuspid aortic valve, and primary ovarian failure. She carries a previously reported maternally inherited pathogenic variant in exon 5 (c.724_727del, p.(Lys242Leufs*41)) and a novel, paternally inherited splice site variant (c.1617+5G>T; p.(Lys480Asnfs*17)) in intron 9. CTC1 transcript analysis showed that the latter resulted in skipping of exon 9. A trace of transcripts was normally spliced resulting in the presence of a low level of wild-type CTC1 transcripts. We speculate that ovarian failure is caused by telomere shortening or chromosome cohesion failure in oocytes and granulosa cells, with early decrease in follicular reserve. This is the first patient carrying 2 truncating CTC1 variants and the first presenting primary ovarian failure.

Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a limited expansion of CGG repeats in the FMR1 gene. Degeneration of neurons in FXTAS cell models can be triggered by accumulation of polyglycine protein (FMRpolyG), a by-product of translation initiated upstream to the repeats. Specific aims of our work included testing if naphthyridine-based molecules could (i) block FMRpolyG synthesis by binding to CGG repeats in RNA, (ii) reverse pathological alterations in affected cells and (iii) preserve the content of FMRP, translated from the same FMR1 mRNA. We demonstrate that cyclic mismatch binding ligand CMBL4c binds to RNA structure formed by CGG repeats and attenuates translation of FMRpolyG and formation of nuclear inclusions in cells transfected with vectors expressing RNA with expanded CGG repeats. Moreover, our results indicate that CMBL4c delivery can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed. We also show that CMBL4c-driven FMRpolyG loss is accompanied by partial FMRP reduction. As complete loss of FMRP induces FXS in children, future experiments should aim at evaluation of CMBL4c therapeutic intervention in differentiated tissues, in which FMRpolyG translation inhibition might outweigh adverse effects related to FMRP depletion.

SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.

Sterile α motif domain-containing protein 9-like (SAMD9L) is encoded by a hallmark interferon-induced gene with a role in controlling virus replication that is not well understood. Here, we analyze SAMD9L function from the perspective of human mutations causing neonatal-onset severe autoinflammatory disease. Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations, p.Asn885Thrfs*6 and p.Lys878Serfs*13. These frameshift mutations truncate the SAMD9L protein within a domain a region of homology to the nucleotide-binding and oligomerization domain (NOD) of APAF1, ∼80 amino acids C-terminal to the Walker B motif. Single-cell analysis of human cells expressing green fluorescent protein (GFP)-SAMD9L fusion proteins revealed that enforced expression of wild-type SAMD9L repressed translation of red fluorescent protein messenger RNA and globally repressed endogenous protein translation, cell autonomously and in proportion to the level of GFP-SAMD9L in each cell. The children's truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell, as did a missense Arg986Cys mutation reported recurrently as causing ataxia pancytopenia syndrome. Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection.

Clinical spectrum of individuals with de novo EBF3 variants or deletions.

Hypotonia, ataxia and delayed development syndrome (HADDS) (MIM#617330) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in EBF3 (MIM; 607,407), which is located on chromosome 10q26, and was first reported in 2017. To date, missense, nonsense and frameshift variants have been reported as causes of HADDS, and EBF3 pathogenic variants have been predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. It was also reported that total deletion of EBF3 associated with a 10q26.3 microdeletion also causes HADDS symptoms, supporting the concept that HADDS results from haploinsufficiency of EBF3. Here, we report eight unrelated individuals with heterozygous pathogenic variants of EBF3 or haploinsufficiency of EBF3 due to 10q26 deletion, who exhibit clinical findings including craniofacial features of HADDS. In a detailed examination of clinical manifestations in this study, revealed that neurogenic bladder was diagnosed in infancy (the median 6.5 months), was more frequent than previously reported, and required cystostomy in all but one case. For psychomotor delay, it was also found that their motor/skills values were significantly lower than their cognition/adaptation values (p = 0.0016; paired t-test). Therefore, that HADDS is a recognizable syndrome that shares its characteristic facial features, and that neurogenic bladder diagnosed in infancy and psychomotor delay with marked delay in motor/skills are noteworthy findings in the diagnosis and management of individuals with HADDS.

CT myelographic diagnosis of ligamentum flavum hypertrophy in a Warmblood Gelding with progressive ataxia.

An 8-year-old Warmblood gelding presented with a history of progressive ataxia for 6 weeks. Intra- and intervertebral ratios measured from lateral radiographs of the cervical spine were within normal limits. Computed tomographic myelography of the cervical spine revealed focal compression of the dorsal and the ventral contrast column as well as a ventral displacement of the spinal cord within the spinal canal due to a bulging of soft tissue attenuating material in the dorsal half of the intervertebral junction of C6 and C7. Post-mortem histopathological examination confirmed chondroid metaplasia of the ligamentum flavum at C6-C7.

Secondary CoQ10 deficiency, bioenergetics unbalance in disease and aging.

Coenzyme Q10 (CoQ10 ) deficiency is a rare disease characterized by a decreased accumulation of CoQ10 in cell membranes. Considering that CoQ10 synthesis and most of its functions are carried out in mitochondria, CoQ10 deficiency cases are usually considered a mitochondrial disease. A relevant feature of CoQ10 deficiency is that it is the only mitochondrial disease with a successful therapy available, the CoQ10 supplementation. Defects in components of the synthesis machinery caused by mutations in COQ genes generate the primary deficiency of CoQ10 . Mutations in genes that are not directly related to the synthesis machinery cause secondary deficiency. Cases of CoQ10 deficiency without genetic origin are also considered a secondary deficiency. Both types of deficiency can lead to similar clinical manifestations, but the knowledge about primary deficiency is deeper than secondary. However, secondary deficiency cases may be underestimated since many of their clinical manifestations are shared with other pathologies. This review shows the current state of secondary CoQ10 deficiency, which could be even more relevant than primary deficiency for clinical activity. The analysis covers the fundamental features of CoQ10 deficiency, which are necessary to understand the biological and clinical differences between primary and secondary CoQ10 deficiencies. Further, a more in-depth analysis of CoQ10 secondary deficiency was undertaken to consider its origins, introduce a new way of classification, and include aging as a form of secondary deficiency.

Ectopic expression of CGG-repeats alters ovarian response to gonadotropins and leads to infertility in a murine FMR1 premutation model.

Women heterozygous for an expansion of CGG repeats in the 5'UTR of FMR1 risk developing fragile X-associated primary ovarian insufficiency (FXPOI) and/or tremor and ataxia syndrome (FXTAS). We show that expanded CGGs, independent of FMR1, are sufficient to drive ovarian insufficiency and that expression of CGG-containing mRNAs alone or in conjunction with a polyglycine-containing peptide translated from these RNAs contribute to dysfunction. Heterozygous females from two mouse lines expressing either CGG RNA-only (RNA-only) or CGG RNA and the polyglycine product FMRpolyG (FMRpolyG+RNA) were used to assess ovarian function in aging animals. The expression of FMRpolyG+RNA led to early cessation of breeding, ovulation and transcriptomic changes affecting cholesterol and steroid hormone biosynthesis. Females expressing CGG RNA-only did not exhibit decreased progeny during natural breeding, but their ovarian transcriptomes were enriched for alterations in cholesterol and lipid biosynthesis. The enrichment of CGG RNA-only ovaries for differentially expressed genes related to cholesterol processing provided a link to the ovarian cysts observed in both CGG-expressing lines. Early changes in transcriptome profiles led us to measure ovarian function in prepubertal females that revealed deficiencies in ovulatory responses to gonadotropins. These include impairments in cumulus expansion and resumption of oocyte meiosis, as well as reduced ovulated oocyte number. Cumulatively, we demonstrated the sufficiency of ectopically expressed CGG repeats to lead to ovarian insufficiency and that co-expression of CGG-RNA and FMRpolyG lead to premature cessation of breeding. However, the expression of CGG RNA-alone was sufficient to lead to ovarian dysfunction by impairing responses to hormonal stimulation.

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by impaired communication skills, ataxia, motor and balance deficits, intellectual disabilities, and seizures. The genetic cause of AS is the neuronal loss of UBE3A expression in the brain. A novel approach, described here, is a stem cell gene therapy which uses lentivector-transduced hematopoietic stem and progenitor cells to deliver functional UBE3A to affected cells. We have demonstrated both the prevention and reversal of AS phenotypes upon transplantation and engraftment of human CD34+ cells transduced with a Ube3a lentivector in a novel immunodeficient Ube3amat-/pat+ IL2rg-/y mouse model of AS. A significant improvement in motor and cognitive behavioral assays as well as normalized delta power measured by electroencephalogram was observed in neonates and adults transplanted with the gene modified cells. Human hematopoietic profiles observed in the lymphoid organs by detection of human immune cells were normal. Expression of UBE3A was detected in the brains of the adult treatment group following immunohistochemical staining illustrating engraftment of the gene-modified cells expressing UBE3A in the brain. As demonstrated with our data, this stem cell gene therapy approach offers a promising treatment strategy for AS, not requiring a critical treatment window.

Neuroblastoma With Opsoclonus-Myoclonus-Ataxia Syndrome: Role of Chemotherapy in the Management: Experience From a Tertiary Care Center in a Resource-limited Setting.

Children with neuroblastoma (NB) and opsoclonus-myoclonus-ataxia syndrome (OMAS) have a favorable oncologic outcome and overall survival. In contrast, despite intensive multidrug immunomodulation, the neurologic outcome is complicated by the relapsing nature of the neurologic symptoms and long-term neurobehavioral sequelae. Being associated with low-risk NB, there exists an ambiguity in the current literature regarding the administration of chemotherapy in these children. We reviewed our archives for children with NB-OMAS over a 22-year (January 1996 to January 2018) period. Eighteen children (10 female) with a median age at diagnosis of 23 months had NB-OMAS and were included. They had stage 1 (9/18; 50%), 2 (1/18; 5.5%), 3 (7/18; 39%), and 4 (1/18; 5.5%) disease according to the International Neuroblastoma Staging System. Multimodality therapy included surgery (16/18; 89%), chemotherapy (11/18; 61%), and immunomodulatory therapy (10/18; 55%). Complete oncologic remission was achieved in all children. Relapse of OMAS and presence of neurologic sequelae were observed in 1 (5.5%) and 5 (28%) cases, respectively. Presence of neurologic sequelae was significantly associated with low-tumor stage (P=0.036) and treatment without chemotherapy (P=0.003). Chemotherapy administration was the only variable significantly predicting a favorable neurologic outcome (95% confidence interval: 0.26-1.40, P=0.01). To conclude, our study including a limited cohort of patients highlights a favorable neurologic outcome associated with chemotherapy administration in children with NB-OMAS. However, further studies with larger sample size need to be conducted before drawing any definite conclusions.

Case Report: Encephalitis Caused by Balamuthia mandrillaris in a 3-Year-Old Iranian Girl.

It is about half a century since free-living amoebae were recognized as pathogenic organisms, but there is still much we should learn about these rare fatal human infectious agents. A recently introduced causative agent of granulomatous amoebic encephalitis, Balamuthia mandrillaris, has been reported in a limited number of countries around the world. A 3-year-old girl was referred to our tertiary hospital because of inability to establish a proper diagnosis. She had been experiencing neurologic complaints including ataxia, altered level of consciousness, dizziness, seizure, and left-sided hemiparesis. The patient's history, physical examination results, and laboratory investigations had led to a wide differential diagnosis. Computed tomography (CT) scan and magnetic resonance imaging analyses revealed multiple mass lesions. As a result, the patient underwent an intraoperative frozen section biopsy of the brain lesion. The frozen section study showed numerous cells with amoeba-like appearances in the background of mixed inflammatory cells. Medications for free-living amoebic meningoencephalitis were administered. PCR assay demonstrated B. mandrillaris as the pathogenic amoeba. Unfortunately, the patient died 14 days after her admission. To our knowledge, this is the first report of B. mandrillaris meningoencephalitis in the Middle East and the first time we have captured the organism during a frozen-section study.

Ophthalmic phenotypes associated with biallelic loss-of-function PCDH12 variants.

Individuals carrying biallelic loss-of-function mutations in PCDH12 have been reported with three different conditions: the diencephalic-mesencephalic junction dysplasia syndrome 1 (DMJDS1), a disorder characterized by global developmental delay, microcephaly, dystonia, and a midbrain malformation at the diencephalic-mesencephalic junction; cerebral palsy combined with a neurodevelopmental disorder; and cerebellar ataxia with retinopathy. We report an additional patient carrying a homozygous PCDH12 frameshift, whose anamnesis combines the most recurrent DMJDS1 clinical features, that is, global developmental delay, microcephaly, and ataxia, with exudative vitreoretinopathy. This case and previously published DMJDS1 patients presenting with nonspecific visual impairments and ophthalmic disorders suggest that ophthalmic alterations are an integral part of clinical features associated with PCDH12 loss-of-function.

Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease.

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.

Clinico-pathological and Molecular Spectrum of Mitochondrial Polymerase γ Mutations in a Cohort from India.

Polymerase γ catalytic subunit (POLG), a nuclear gene, encodes the enzyme responsible for mitochondrial DNA (mtDNA) replication. POLG mutations are a major cause of inherited mitochondrial diseases. They present with varied phenotypes, age of onset, and severity. Reports on POLG mutations from India are limited. Hence, this study aimed to describe the clinico-pathological and molecular observations of POLG mutations. A total of 446 patients with clinical diagnosis of mitochondrial disorders were sequenced for all exons and intron-exon boundaries of POLG. Of these, 19 (4.26%) patients (M:F: 10:9) had POLG mutations. The age of onset ranged from 5 to 55 years with an overlapping phenotypic spectrum. Ptosis, peripheral neuropathy, seizures, and ataxia were the common neurological features observed. The most common clinical phenotype was chronic progressive external ophthalmoplegia (CPEO) and CPEO plus (n = 14). Muscle biopsy showed characteristic features of mitochondrial myopathy in fourteen patients (14/19) and respiratory chain enzyme deficiency in eleven patients (11/19). Multiple mtDNA deletions were seen in 47.36% (9/19) patients. Eight pathogenic POLG variations including two novel variations (p.G132R and p.V1106A) were identified. The common pathogenic mutation identified was p.L304R, being present in eight patients (42.1%) predominantly in the younger age group followed by p.W748S in four patients (21%). To the best of our knowledge, this is the first extensive study from India, highlights the clinico-pathological and molecular spectrum of POLG mutations.

The Sphincter of O'Beirne-Part 2: Report of a Case of Chronic Constipation with Autonomous Dyssynergia.

BACKGROUND: Chronic constipation can have one or more of many etiologies, and a diagnosis based on symptoms is not sufficient as a basis for treatment, in particular surgery. AIM: To investigate the cause of chronic constipation in a patient with complete absence of spontaneous bowel movements. METHODS: High-resolution colonic manometry was performed to assess motor functions of the colon, rectum, the sphincter of O'Beirne and the anal sphincters. RESULTS: Normal colonic motor patterns were observed, even at baseline, but a prominent high-pressure zone at the rectosigmoid junction, the sphincter of O'Beirne, was consistently present. In response to high-amplitude propagating pressure waves (HAPWs) that were not consciously perceived, the sphincter and the anal sphincters would not relax and paradoxically contract, identified as autonomous dyssynergia. Rectal bisacodyl evoked marked HAPW activity with complete relaxation of the sphincter of O'Beirne and the anal sphincters, indicating that all neural pathways to generate the coloanal reflex were intact but had low sensitivity to physiological stimuli. A retrograde propagating cyclic motor pattern initiated at the sphincter of O'Beirne, likely contributing to failure of content to move into the rectum. CONCLUSIONS: Chronic constipation without the presence of spontaneous bowel movements can be associated with normal colonic motor patterns but a highly exaggerated pressure at the rectosigmoid junction: the sphincter of O'Beirne, and failure of this sphincter and the anal sphincters to relax associated with propulsive motor patterns. The sphincter of O'Beirne can be an important part of the pathophysiology of chronic constipation.

Ophthalmic findings and a novel CTC1 gene mutation in coats plus syndrome: a case report.

BACKGROUND: Coats plus syndrome is a rare multisystem disorder, and is also a telomere-related disorder caused by CTC1 gene mutation. We reported ophthalmic findings in a Chinese child with genetically confirmed Coats plus syndrome. MATERIALS AND METHODS: The comprehensive ophthalmic findings were presented, as well as treatment history and systemic manifestations. In addition, genetic testing was performed to confirm the diagnosis. RESULTS: Examination under anesthesia showed notable retinal vasculopathy, including vascular tortuosity and dilation, abnormal vascular anastomosis, retinal telangiectasias and mild exudation, extensive peripheral avascularity, as well as the presence of retinal neovascularization. The patient developed vitreous hemorrhage and tractional retinal detachment, and then underwent vitrectomy. Meanwhile, the patient was noted to have growth retardation and leukoencephalopathy. Gene testing identified a compound heterozygous mutation in CTC1 gene: a novel splicing site mutation (c.33 + 1 G > T) and a deletion mutation (c.2954_2956del, p.C985del), which were inherited from his mother and father, respectively. CONCLUSIONS: The present report expanded the genotype and phenotype spectrum of CTC1 gene associated with Coats plus syndrome.