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COQ7 pathogenetic variants cause primary CoQ 10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ 10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ 10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ 10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ 10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis., (© 2024. The Author(s).)

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE., (© 2024. The Author(s).)

Purpose: To describe the neuroanatomical correlates of unilateral congenital isolated oculomotor palsy by means of high-resolution MRI., Methods: Children with a clinical diagnosis of congenital isolated oculomotr palsy and with a high-resolution MRI acquisition targeted on the orbits and cranial nerves were selected and included in the study. An experienced pediatric neuroradiologist evaluated all the exams, assessing the integrity and morphology of extraocular muscles, oculomotor, trochlear and abducens nerves as well as optic nerves and globes. Clinical data and ophthalmologic evaluations were also collected., Results: Six children (age range: 1-16 years; males: 3) were selected. All patients showed, on the affected side (left:right = 5:1), anomalies of the III nerve and extraocular muscles innervated by the pathological nerve. One patient had complete nerve agenesis, two patients showed a diffuse thinning of the nerve, from the brainstem to the orbit and 3 patients showed a distal thinning of the oculomotor nerve, starting at the level of the cavernous sinus. In all cases atrophy of corresponding muscles was noticed, but the involvement of the affected muscles varied with the nervous pattern of injury., Conclusions: High-resolution MRI represents a valuable tool for the diagnosis of III nerve anomalies in unilateral congenital IOP, showing different patterns of nerve involvement and muscular atrophy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Summary: We report a very rare complication from metastatic breast cancer of right-sided blindness and ophthalmoplegia in a 70-year-old female. Cavernous sinus syndrome, superior orbital fissure syndrome and complicated sinusitis were considered in the differential diagnosis but involvement of cranial nerves II, III, IV, VI and the ophthalmic division of V were consistent with an orbital apex syndrome. She had been diagnosed with breast carcinoma 10 years previously. This report highlights the correct clinical and diagnostic pathway with computed tomography (CT) scan of the brain and paranasal sinuses to evaluate for the presence and extent of pathology and biopsy route for any causative mass. In this patient, the mass in the right parasellar region and orbital apex with extension into the sphenoid sinus was amenable to transsphenoidal biopsy which showed features suggestive of metastatic breast carcinoma. She was treated with palliative whole brain radiotherapy without resolution of symptoms., (Copyright© Authors.)

Introduction: The aim of the study was to investigate the clinical characteristics of isolated oculomotor paralysis (OP) cases caused by pure midbrain infarction (MI) with pupil sparing., Material and Methods: Patients with pure MI and pontine infarction (PI) at our hospital were included in this study. We compared the blood pressure and lipid levels between the two groups. And the clinical data and imaging features were summarized., Results: In total, 33 and 35 patients were included in the MI and PI groups, respectively. There was no significant difference in the distribution of age (64.9 ±10.0 vs. 65.1 ±10.8 years, p = 0.927) and males (84.8% vs. 74.3%, p = 0.282) between the MI and PI groups, respectively. The pure MI group had a comparable level of serum lipoprotein and cardiovascular risk factors compared with the PI group except for a lower proportion of hypertension (57.6% vs. 85.7%, p = 0.010). The majority (72.7%) of culprit lesions in the pure MI group was located in the paramedian area of the midbrain, and the ocular muscle palsies mostly involved the medial rectus (75.8%)., Conclusions: The Chinese patients with OP caused by pure MI were mainly characterized with rapidly progressive symptoms, multiple cerebrovascular risk factors, and typical MRI signs. Further efforts should be made in the differential diagnosis of this atypical midbrain syndrome.

Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct subtypes. Advances in molecular genetics have revealed numerous pathogenic causes of PEO, originally heralded in 1988 by the detection of single large-scale deletions of mitochondrial DNA (mtDNA) in skeletal muscle of people with PEO and Kearns-Sayre syndrome. Since then, multiple point variants of mtDNA and nuclear genes have been identified to cause mitochondrial PEO and PEO-plus syndromes, including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO). Intriguingly, many of those nuclear DNA pathogenic variants impair maintenance of the mitochondrial genome causing downstream mtDNA multiple deletions and depletion. In addition, numerous genetic causes of nonmitochondrial PEO have been identified., Competing Interests: Declaration of interests MH is a paid consultant to Modis Therapeutics, a wholly owned subsidiary of Zogenix/UCB, and Entrada Therapeutics. These relationships are de minimus for Columbia University Medical Center. Columbia University has patents for deoxynucleotide and deoxynucleoside therapies for mitochondrial DNA depletion syndrome, which is licensed by Modis Therapeutics; this relationship is monitored by an unconflicted external academic researcher. Received honoraria from the AAN and PlatformQ for speaking activities and research support from Modis Therapeutics and Entrada Therapeutics., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multi-system disorder caused by several homozygous or compound heterozygous mutations, mostly in the nuclear gene of TYMP. Our current knowledge on the underlying pathology of the disease is derived through the study of about 200 cases of different ethnicities. Clinical presentations include severe cachexia, weakness, ptosis, diplopia, abdominal cramps or digestive tract disorders, hearing impairment, and paresthesia.Herein, we aim to present five novel mutations of the nuclear gene of TYMP in six Iranian patients diagnosed with MNGIE. In our population, age at the time of diagnosis was 18 to 49 years, while the onset of the symptoms varied from 13 to 20 years. We detected two pathogenic non-frameshift nonsense premature stop codon mutations (c.1013C > A, and c.130C > T), one variant of uncertain significance (VUS) non-frameshift missense mutation (c.345G > T), one likely pathogenic frameshift insertion (c.801_802insCGCG), and one likely benign homozygous non-frameshift deletion (c.1176_1187del) from two siblings. Our findings also confirm the autosomal recessive inheritance pattern of MNGIE in the Iranian population. The lack of knowledge in the area of nuclear gene-modifier genes shadows the genotype-phenotype relationships of MNGIE., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype-phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm 2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE. NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.

Background: Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and non-progressive restrictive ophthalmoplegia. CFEOM1 is a stereotypical phenotype with isolated bilateral ptosis, bilateral ophthalmoplegia, absent upgaze, and globe infraduction. CFEOM3 is a more variable phenotype that can include unilateral disease, absent ptosis, residual upgaze, and/or orthotropia. Most cases of CFEOM1 result from recurrent heterozygous KIF21A missense mutations and less commonly from recurrent heterozygous TUBB3 missense mutations. While most cases of CFEOM3 result from recurrent heterozygous TUBB3 missense mutations, several pedigrees harbored pathogenic variants in KIF21A . Here, we asked if Lebanese pedigrees with CFEOM3 harbor pathogenic variants in TUBB3 or KIF21A. Materials and Methods: Families affected with congenital cranial dysinnervation disorders were prospectively recruited from the American University of Beirut pediatric ophthalmology clinic and included two probands with CFEOM. KIF21A hotspot exons and TUBB3 coding sequence were sequenced. Available family members were sequenced for co-segregation analysis. Results: Both families were found to have CFEOM3 and to harbor pathogenic variants in KIF21A (OMIM 608283). A simplex proband with CFEOM3 from a consanguineous Iraqi family harbored a de novo heterozygous KIF21A c.2860 C > T variant (p.R954W); this variant accounts for the majority of reported KIF21A mutations but is typically implicated in CFEOM1. A Lebanese father with CFEOM3 and his son with CFEOM1 segregated a heterozygous KIF21A c.2830 G > C variant (p.E944Q), previously reported in an individual with CFEOM1. Conclusions: These results support prior reports of KIF21A mutations as a rare cause of CFEOM3. These families are Middle Eastern or Chinese, supporting a genetic modifier in these populations.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3 . Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A , TUBB3 , and TUBB2B . Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls ( p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Dysfunction of the third cranial nerve can be provoked by a number of different conditions. An isolated cranial neuropathy as a first clinical sign of a non-Hodgkin lymphoma is very infrequent. We represent here an atypical case of lymphoblastic lymphoma revealed by an isolated third cranial nerve palsy. The patient was managed by alternating cycles of cyclophosphamide, vincristine, and prednisone. She made a full recovery with a complete resolution of the symptomatology.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation., (© 2020 American Academy of Neurology.)

Background: Mutations in SQSTM1 gene have been recently identified as a rare cause of progressive childhood neurodegenerative disorder. So far, only 25 patients from 10 unrelated families were reported., Methods and Results: We report on the first Tunisian case of an 11-year-old girl with cerebellar ataxia, chorea and ophthalmoparesis. Brain MRI was normal. Whole-exome sequencing revealed a homozygous mutation c.823&#95;824del(p.Ser275Phefs*17) in SQSTM1 gene (GenBank: NM&#95;003900.4)., Conclusion: By pooling our data to the data of literature, we delineated the phenotypic spectrum and stressed on genetic heterogeneity of this rare neurodegenerative disease., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: Distal arthrogryposis type 5D (DA5D) is an autosomal recessive disease. The clinical symptoms include contractures of the joints of limbs, especially camptodactyly of the hands and/or feet, unilateral ptosis, a round-shaped face, arched eyebrows, and micrognathia, without ophthalmoplegia. ECEL1 is a DA5D causative gene that encodes a membrane-bound metalloprotease. ECEL1 plays important roles in the final axonal arborization of motor nerves in limb skeletal muscles and neuromuscular junction formation during prenatal development., Methods: A DA5D family with webbing of the elbows and fingers was recruited. We performed whole-exome sequencing (WES) and filtered mutations by disease-causing genes of arthrogryposis multiplex congenita (AMC). Mutational analysis and cosegregation confirmation were then performed., Results: We identified novel compound heterozygous mutations of ECEL1 (NM&#95;004826: c.69C>A, p.C23∗ and c.1810G>A, p.G604R) in the proband., Conclusions: We detected causative mutations in a DA5D family, expanding the spectrum of known ECEL1 mutations and contributing to the clinical diagnosis of DA5D., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Jie-Yuan Jin et al.)

Background: Wieacker-Wolff syndrome (WWS) is a congenital X-linked neuromuscular disorder, which was firstly reported in 1985. Zinc finger C4H2-type containing (ZC4H2) gene has been found to be associated with the disease pathogenesis. However, the underlying mechanism remains elusive., Methods: Whole-exome sequencing was performed to identify the mutations. Expression plasmids were constructed and cell culture and immune-biochemical assays were used to examine the effects of the mutation., Results: We reported a female patient with classical symptoms of WWS and discovered a novel nonsense heterozygous mutation (p.R67X; c.199C>T) in ZC4H2 gene in the patient but not in her parents. The mutation resulted in a 66 amino-acid truncated ZC4H2 protein. The mutation is located in the key helix domain and it altered the subcellular locations of the mutant ZC4H2 protein. X-chromosome inactivation (XCI) pattern analysis revealed that the XCI ratio of the proband was 22:78., Conclusion: Female heterozygous carriers with nonsense mutation with a truncated ZC4H2 protein could lead to the pathogenesis of Wieacker-Wolff syndrome and our study provides a potential new target for the disease treatment., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Titin, encoded by the gene TTN, is one of the main sarcomere components. It is involved in not only maintaining the structure of cardiac and skeletal muscles, but also in their development, extensibility, elasticity, and signaling events. Congenital titinopathy increasingly appears an important and common form of axial predominant congenital myopathy. The pathophysiological role of TTN in congenital titinopathy and pediatric heart diseases is yet to be explored. Here, we delineate the phenotype of two female siblings who developed severe congenital multi-minicore disease without cardiac involvement. Genetic investigation by whole exome sequencing demonstrated compound heterozygous TTN mutations (c.15496+1G>A, p.5166&#95;5258del; c.18597&#95;18598insC, p.Thr6200Hisfs*15), corresponding to the Ig domain of the proximal I-band. Aberrant splicing causing exon skipping was verified by in vitro minigene analysis. Our results suggest that TTN mutations affecting the Ig domain of the proximal I-band may be a cause of severe congenital defect in skeletal muscles without severe cardiac involvement, thereby providing evidence for the hypothesis that congenital titinopathy patients carrying biallelic N2BA only mutations are at lower cardiac risk than those with other combinations of mutations. Meanwhile, this study confirm the hypothesis on recessive truncating variants of TTN experimentally and thus support earlier reported genotype-phenotype correlations., (Copyright © 2019. Published by Elsevier B.V.)

In myasthenia gravis autoantibodies target components of the neuromuscular junction causing variable degrees of weakness. In most cases, autoantibodies trigger complement-mediated endplate damage and extraocular muscles may be most susceptible. A proportion of MG cases develop treatment-resistant ophthalmoplegia. We reviewed publications spanning 65 years reporting the histopathological findings in the muscles and extraocular muscles of myasthenic patients to determine whether pathological changes in extraocular muscles differ from non-ocular muscles. As extraocular muscles represent a unique muscle allotype we also compared their histopathology in myasthenia to those in strabismus. We found that in myasthenia gravis, the non-ocular muscles frequently demonstrate neurogenic changes regardless of myasthenic serotype. Mitochondrial stress/damage was also frequent in myasthenic muscles and possibly more evident in muscle-specific kinase antibody-positive MG. Although myasthenia-associated paralysed extraocular muscles demonstrated prominent fibro-fatty replacement and mitochondrial alterations, these features appeared commonly in paralysed extraocular muscles of any cause. We postulate that extraocular muscles may be more susceptible than limb muscles to poor contractility as a consequence of myasthenia, resulting in a cascade of atrophy signaling pathways and altered mitochondrial homeostasis which contribute to the tipping point in developing treatment-resistant myasthenic ophthalmoplegia. Early strategies to improve force generation in extraocular muscles are critical., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Especially in acute onset of ophthalmoplegia, efficient neuroradiological evaluation is necessary to assist differential diagnosis, clinical course, and treatment options., Methods: Different manifestations of ophthalmoplegia are explained and illustrated by characteristic neuroradiological and clinical findings., Results: To present those ophthalmoplegic disorders in a clear manner, this review refers to different neuroanatomical structures and compartments. From neuroophthalmological point of view, diseases going ahead with ophthalmoplegia can be divided into (1) efferent infranuclear/peripheral disturbances involving oculomotor cranial nerves, (2) conjugate gaze abnormalities due to internuclear or supranuclear lesions, and (3) diseases of the extraocular eye muscles or their impairment due to intraorbital pathologies., Conclusion: The knowledge of the relationship between neurological findings in ophthalmoplegia and involved neuroanatomical structures is crucial, and neuroradiology can be focused on circumscribed anatomical regions, using optimized investigation protocols.

Objective: To retrospectively evaluate the clinical signs, imaging findings, and outcome of feline internal ophthalmoparesis/ophthalmoplegia., Procedure: Medical records were reviewed from 2008 to 2015. Inclusion criteria included cats that presented with internal ophthalmoparesis/ophthalmoplegia, underwent diagnostic imaging, and had follow-up information available., Results: Twelve cases of feline internal ophthalmoparesis/ophthalmoplegia were identified. Nine cats were unilaterally affected, and three cats were bilaterally affected. Affected cats had a median age of 10.54 years (range 5.75 to 13.17), and both sexes of varying breeds were affected (nine males; three females). Clinical signs including abnormal mental status (n = 9; 75%) and additional neurologic abnormalities (n = 10; 83%) were observed. Magnetic resonance imaging and/or computed tomography (MRI/CT) of the head were performed in ten cats, revealing a mass lesion in all cases with varying locations. Multicentric lymphoma was diagnosed in two cats via abdominal ultrasound and cytology. All twelve cats were euthanized due to deterioration of clinical signs and/or quality-of-life concerns. Median time from diagnosis to euthanasia was 3.5 days (range 0 to 80 days)., Conclusions: Feline internal ophthalmoparesis/ophthalmoplegia rarely presents as the sole clinical sign in a referral hospital. Advanced imaging (MRI/CT) may be necessary to reach a definitive diagnosis in these cases. However, abdominal ultrasound would be advocated in cats with systemic clinical signs as a less expensive and less invasive diagnostic test to further investigate the possible etiology of internal ophthalmoparesis/ophthalmoplegia prior to advanced imaging. Feline cases with internal ophthalmoparesis/ophthalmoplegia associated with other intracranial signs and/or systemic clinical signs have a poor prognosis., (© 2017 American College of Veterinary Ophthalmologists.)

Given that eye movement control can be framed as an inferential process, how are the requisite forces generated to produce anticipated or desired fixation? Starting from a generative model based on simple Newtonian equations of motion, we derive a variational solution to this problem and illustrate the plausibility of its implementation in the oculomotor brainstem. We show, through simulation, that the Bayesian filtering equations that implement 'planning as inference' can generate both saccadic and smooth pursuit eye movements. Crucially, the associated message passing maps well onto the known connectivity and neuroanatomy of the brainstem - and the changes in these messages over time are strikingly similar to single unit recordings of neurons in the corresponding nuclei. Furthermore, we show that simulated lesions to axonal pathways reproduce eye movement patterns of neurological patients with damage to these tracts., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Eight-and-a-half syndrome is a rare condition that is described as a combination of one-and-a-half syndrome and an ipsilateral facial nucleus lesion. We present a clinical case of occurrence of eight-and-a-half syndrome that was caused by a demyelinating lesion in the dorsal pontine tegmentum. A 44-year-old man presented to the hospital with a subacute onset of horizontal diplopia and left-sided facial weakness. MRI revealed a T2 hyperintense lesion in his dorsal pons, which was consistent with a demyelinating pathology. Treatment with intravenous steroids showed significant improvement in his symptoms. In our case, it occurred due to a suspected demyelinating lesion that was this patient's first and only demyelinating event, leaving him with a diagnosis of clinically isolated syndrome. His responsiveness to steroids represents the first case report of an adult patient presenting with an eight-and-a-half syndrome secondary to a suspected demyelinating pathology., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Competing Interests: Competing interests: None declared.

Unraveling the genetics of the paralytic strabismus syndromes known as congenital cranial dysinnervation disorders (CCDDs) is both informing physicians and their patients and broadening our understanding of development of the ocular motor system. Genetic mutations underlying ocular CCDDs alter either motor neuron specification or motor nerve development, and highlight the importance of modulations of cell signaling, cytoskeletal transport, and microtubule dynamics for axon growth and guidance. Here we review recent advances in our understanding of two CCDDs, congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome (DRS), and discuss what they have taught us about mechanisms of axon guidance and selective vulnerability. CFEOM presents with congenital ptosis and restricted eye movements, and can be caused by heterozygous missense mutations in the kinesin motor protein KIF21A or in the β-tubulin isotypes TUBB3 or TUBB2B. CFEOM-causing mutations in these genes alter protein function and result in axon growth and guidance defects. DRS presents with inability to abduct one or both eyes. It can be caused by decreased function of several transcription factors critical for abducens motor neuron identity, including MAFB, or by heterozygous missense mutations in CHN1, which encodes α2-chimaerin, a Rac-GAP GTPase that affects cytoskeletal dynamics. Examination of the orbital innervation in mice lacking Mafb has established that the stereotypical misinnervation of the lateral rectus by fibers of the oculomotor nerve in DRS is secondary to absence of the abducens nerve. Studies of a CHN1 mouse model have begun to elucidate mechanisms of selective vulnerability in the nervous system., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This case report presents a patient diagnosed with Tolosa-Hunt syndrome (THS) after an extensive neuro-diagnostic and neuroimaging evaluation. Diagnostic work-up included thorough physical and neurological examination, complete laboratory serum assessments, neuroendocrine and immunohistochemistry analysis, cerebrospinal fluid analysis, neurophysiology assessment, ophthalmologist examination and neuroimaging. Th e most important diagnostic tool in deriving the diagnosis of THS was neuroimaging evaluation that included baseline and follow-up cranial contrast enhanced magnetic resonance imaging (MRI). Baseline cranial contrast enhanced MRI detected a nonspecific inflammatory granulomatous lesion in the right cavernous sinus extending basally towards the right trigeminal cave (Meckel's cave) and anteriorly towards the apex of the right orbit. Systemic intravenous high-dose corticosteroid therapy was administered for 3 consecutive days and then tapered down to lower oral steroid doses. Following therapy, the patient experienced complete regression of symptoms. Follow-up cranial contrast enhanced MRI showed significant regression of inflammatory lesion in the area of right cavernous sinus, thus verifying the efficacy of the treatment applied. This paper shows that an extensive diagnostic schedule for THS must be conducted prior to therapeutic treatment, for the possibility of alternative diagnosis. Patients suspected of having THS require careful evaluation, appropriate treatment, and follow-up.

Individuals with inclusion body myopathy type 3 (IBM3) display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K) in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in decreased in vitro motility, reduced muscle power output and focal myofibrillar disorganization similar to that seen in individuals with IBM3., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Congenital fibrosis of the extraocular muscles (CFEOM) is a hereditary ocular disease and can be classified into three subtypes. The aim of the present study was to determine the genetic basis and describe the clinical phenotype of CFEOM type 1 and 3. Two Chinese families with CFEOM type 1 and 3 were identified. The patients and their family members were subjected to comprehensive ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination, assessment of palpebral fissure size, levator function, ocular motility, and cover and forced duction tests. Genomic DNA was extracted from the leukocytes of venous blood samples collected from the two families and from 200 unrelated control subjects from the same population. Coding exons of the KIF21A gene were amplified using polymerase chain reaction analysis and sequenced directly in the two probands. The detected mutations were further analyzed in all available family members and the unrelated control subjects. A heterozygous mutation, c.2860C>T (p.R954W), in KIF21A was identified in the two families, and this was cosegregated with the presence of the diseases in the two families, however, it was absent in the 200 normal control subjects. Among the three affected family members with CFEOM1, differences were observed with regard to the presence of aberrant eye movement. The results indicated that, in the patients with CFEOM1 and CFEOM3, the disease was caused by the same KIF21A gene mutation. The KIF21A gene may be a major disease‑causing gene for Chinese patients with CFEOM3. Phenotypic heterogeneity was observed in the patients with CFEOM1.

Although extraocular muscles are commonly affected by myasthenia gravis (MG) at presentation, a treatment-resistant ophthalmoplegic complication of MG (OP-MG) occurs in younger patients with African-genetic ancestry. In MG, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some OP-MG cases because of relative deficiency of decay-accelerating factor/CD55. Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling. We screened the regulatory region of the transforming growth factor beta-1 (TGFB1) gene encoding the cytokine pivotal in muscle healing responses. We show the frequency of an African-specific polymorphism TGFB1 c.-387 T (rs11466316) among South Africans with African-genetic ancestry is higher than 1000 Genomes African controls (17.2% vs 4.8%; P<1 × 10(-7)), and associates with juvenile OP-MG (28%; P=0.043). Further, TGFB1 -387 C>T is functional because it represses the TGFB1 promoter construct basal activity by fivefold, and OP-MG fibroblasts (-387 C/T or T/T) have lower basal TGFB1 mRNA transcripts compared with controls (-387 C/C)(P=0.001). Co-transfections with Sp1 show less responsiveness of the -387 T promoter compared with wild-type -387 C (P=0.015). Our findings suggest that population-specific alleles may lower TGFB1 expression, thereby influencing OP-MG susceptibility by inhibiting extraocular muscle CD55 upregulation and/or altered endplate remodeling.

Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. It is unclear whether these inherited myopathies initiated by mutations in distinct classes of genes are etiologically related. Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila melanogaster homologs of human hnRNPA2B1 and DNAJB6, respectively. We introduced disease-homologous mutations to Hrb98DE, thus capturing mutation-dependent phenotypes in a genetically tractable model system. Ectopic expression of the disease-associated mutant form of hnRNPA2B1 or Hrb98DE in fly muscle resulted in progressive, age-dependent cytoplasmic inclusion pathology, as observed in humans with hnRNPA2B1-related myopathy. Cytoplasmic inclusions consisted of hnRNPA2B1 or Hrb98DE protein in association with the stress granule marker ROX8 and additional endogenous RNA-binding proteins (RBPs), suggesting that these pathological inclusions are related to stress granules. Notably, TDP-43 was also recruited to these cytoplasmic inclusions. Remarkably, overexpression of MRJ rescued this phenotype and suppressed the formation of cytoplasmic inclusions, whereas reduction of endogenous MRJ by a classical loss of function allele enhanced it. Moreover, wild-type, but not disease-associated, mutant forms of MRJ interacted with RBPs after heat shock and prevented their accumulation in aggregates. These results indicate both genetic and physical interactions between disease-linked RBPs and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations in hnRNPA2B1 and DNAJB6., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To test the validity of diffusion tensor imaging (DTI) measures of tissue injury by examining such measures in a white matter structure with well-defined function, the medial longitudinal fasciculus (MLF). Injury to the MLF underlies internuclear ophthalmoparesis (INO)., Methods: 40 MS patients with chronic INO and 15 healthy controls were examined under an IRB-approved protocol. Tissue integrity of the MLF was characterized by DTI parameters: longitudinal diffusivity (LD), transverse diffusivity (TD), mean diffusivity (MD) and fractional anisotropy (FA). Severity of INO was quantified by infrared oculography to measure versional disconjugacy index (VDI)., Results: LD was significantly lower in patients than in controls in the medulla-pons region of the MLF (p < 0.03). FA was also lower in patients in the same region (p < 0.0004). LD of the medulla-pons region correlated with VDI (R = -0.28, p < 0.05) as did FA in the midbrain section (R = 0.31, p < 0.02)., Conclusions: This study demonstrates that DTI measures of brain tissue injury can detect injury to a functionally relevant white matter pathway, and that such measures correlate with clinically accepted evaluation indices for INO. The results validate DTI as a useful imaging measure of tissue integrity.

Objective: Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements - saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy., Methods: Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses., Results: Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation., Interpretation: Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.

Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is a rare type of congenital myopathy. It is characterized by early onset of symptoms, mild proximal muscle weakness, hyporeflexia or areflexia, normal serum creatine kinase (CK) levels and myopathic electromyography finding, uniform type 1 fibers, and nonprogression. We report a 2-year-old boy who presented with congenital hypotonia, breathing and feeding difficulty, myopathic facies, proximal muscle weakness, ptosis, total external ophthalmoplegia and delayed motor developmental milestones. Normal serum muscle enzyme and short duration of motor unit potentials on electromyography were noted. Muscle biopsy showed uniformity of type 1 fibers (greater than 99%) and moderate variation in fiber size without specific structural abnormality. Total external ophthalmoplegia may be one of the important clinical manifestations of CNMDU1. It is important to recognize this disorder because it is nonprogressive in nature., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The term hereditary inclusion-body myopathies (HIBMs) defines a group of rare muscle disorders with autosomal recessive or dominant inheritance and presence of muscle fibers with rimmed vacuoles and collection of cytoplasmic or nuclear 15-21 nm diameter tubulofilaments as revealed by muscle biopsy. The most common form of HIBM is due to mutations of the GNE gene that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. This results in abnormal sialylation of glycoproteins that possibly leads to muscle fiber degeneration. Mutations of the valosin containing protein are instead responsible for hereditary inclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), with these three phenotypic features having a variable penetrance. IBMPFD probably represents a disorder of abnormal cellular trafficking of proteins and maturation of the autophagosome. HIBM with congenital joint contractures and external ophthalmoplegia is due to mutations of the Myosin Heavy Chain IIa gene that exerts a pathogenic effect through interference with filament assembly or functional defects in ATPase activity. This review illustrates the clinical and pathologic characteristics of HIBMs and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBN) and omnipause neurons (OPN) within the brainstem, both types of cells are highly active. Experimental lesions of EBN and OPN cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBN and OPN. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBN and OPN are ensheathed by perineuronal nets (PN), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PN, rather than to the neurons they support, could lead to neuronal dysfunction-such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PN., (© 2015 New York Academy of Sciences.)

Autosomal-dominant optic atrophy (ADOA) is the most common inherited optic neuropathy, due to mutations in the optic atrophy 1 gene (OPA1) in about 60%-80% of cases. At present, the clinical heterogeneity of patients carrying OPA1 variants renders genotype-phenotype correlations difficulty. Since 2005, when we published the first locus-specific database (LSDB) dedicated to OPA1, a large amount of new clinical and genetic knowledge has emerged, prompting us to update this database. We have used the Leiden Open-Source Variation Database to develop a clinico-biological database, aiming to add clinical phenotypes related to OPA1 variants. As a first step, we validated this new database by registering several patients previously reported in the literature, as well as new patients from our own institution. Contributors may now make online submissions of clinical and molecular descriptions of phenotypes due to OPA1 variants, including detailed ophthalmological and neurological data, with due respect to patient anonymity. The updated OPA1 LSDB (http://opa1.mitodyn.org/) should prove useful for molecular diagnoses, large-scale variant statistics, and genotype-phenotype correlations in ADOA studies., (© 2014 WILEY PERIODICALS, INC.)

"Eight-and-a-half" syndrome is "one-and-a-half" syndrome (conjugated horizontal gaze palsy and internuclear ophthalmoplegia) plus ipsilateral fascicular cranial nerve seventh palsy. This rare condition, particularly when isolated, is caused by circumscribed lesions of the pontine tegmentum involving the abducens nucleus, the ipsilateral medial longitudinal fasciculus, and the adjacent facial colliculus. Its recognition is therefore of considerable diagnostic value. We report a case of a 65-year-old man who presented with eight-and-a-half syndrome in which brain magnetic resonance imaging scan revealed a lacunar pontine infarction., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Primary paranasal sinus lymphoma is an uncommon malignancy that accounts for only 0.17% of all lymphomas and is often difficult to diagnose. Initially, tumors in this area cause very few symptoms and are at an advanced stage at the time of diagnosis. Ophthalmologic signs and symptoms occur early in the disease process because of close proximity of the orbit to the paranasal sinuses. We report on a case of primary malignant lymphoma of the sphenoid and ethmoid sinuses with involvement of the cavernous sinus, initially presenting with ophthalmologic signs and symptoms in association with cavernous sinus syndrome.

Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.