Adult-onset hypoxaemia, diffuse lung lesions, and pulmonary hypertension in cobalamin C defect: a case report

Abstract Background Cobalamin C (cbl-C) defect is an inherited autosomal recessive disorder that commonly affects the central nervous system of infants. Severe pulmonary hypertension (PH) and diffuse lung lesions are unusual clinical manifestations, especially among adults. Case summary A 25-year-old man with hypoxaemia, diffuse lung lesions, and PH, suddenly developed nausea, vomiting, headache, and worsening of dyspnoea. Metabolic screening showed elevated serum levels of methylmalonic acid and homocysteine, and genetic testing revealed MMACHC gene mutations. He was eventually diagnosed with severe PH secondary to cbl-C defect and was successfully managed with vitamin B12, betaine, L-carnitine, folate, as well as ambrisentan and sildenafil. Discussion cbl-C is a rare cause of PH and can present with severe PH and diffuse lung lesions in adults. Given that the condition is treatable, a careful metabolic screening should be considered when a diagnosis of PH is made.

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Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity

Endocrinology ◽

10.1210/en.2016-1680 ◽

2016 ◽

Vol 158 (2) ◽

pp. 419-430 ◽

Cited By ~ 11

Author(s):

Zhaofei Wu ◽

M. Elena Martinez ◽

Donald L. St. Germain ◽

Arturo Hernandez

Keyword(s):

Energy Balance ◽

Elevated Serum ◽

Serum Levels ◽

Leptin Resistance ◽

Melanocortin System ◽

White Adipocyte ◽

Pituitary Thyroid Axis ◽

Thyroid Axis ◽

The Central Nervous System ◽

Type 3

Abstract The role of thyroid hormones (THs) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice as a result of defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3−/− brain is opposite that of the serum, exhibiting enhanced levels of TH action. Because the brain, particularly the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3−/− mice and determine whether it is associated with hypothalamic abnormalities. Here we show that Dio3−/− mice of both sexes exhibit decreased adiposity, reduced brown and white adipocyte size, and enhanced fat loss in response to triiodothyronine (T3) treatment. They also exhibit increased TH action in the hypothalamus, with abnormal expression and T3 sensitivity of genes integral to the leptin-melanocortin system, including Agrp, Npy, Pomc, and Mc4r. The normal to elevated serum levels of leptin, and elevated and repressed expression of Agrp and Pomc, respectively, suggest a profile of leptin resistance. Interestingly, Dio3−/− mice also display elevated locomotor activity and increased energy expenditure. This occurs in association with expanded nighttime activity periods, suggesting a disrupted circadian rhythm. We conclude that DIO3-mediated regulation of TH action in the central nervous system influences multiple critical determinants of energy balance. Those influences may partially compensate each other, with the result likely contributing to the decreased adiposity observed in Dio3−/− mice.

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Pulmonary hypertension with diffuse lung lesions in cobalamin C defect

Pediatrics International ◽

10.1111/ped.13971 ◽

2019 ◽

Vol 61 (10) ◽

pp. 1062-1063

Author(s):

Hiroyuki Yoshizawa ◽

Keiji Nogami ◽

Hiroaki Yaoi ◽

Midori Shima

Keyword(s):

Pulmonary Hypertension ◽

Lung Lesions ◽

Diffuse Lung

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Analysis of genotype-phenotype correlation in Walker-Warburg syndrome with a novel CRPPA mutation in different clinical manifestations

European Journal of Ophthalmology ◽

10.1177/11206721211016306 ◽

2021 ◽

pp. 112067212110163

Author(s):

Nurettin Bayram ◽

Ayşe Kaçar Bayram ◽

Hüseyin Per ◽

Hakan Gümüş ◽

Cemal Ozsaygili ◽

...

Keyword(s):

Phenotypic Variability ◽

Congenital Muscular Dystrophy ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Autosomal Recessive Disorder ◽

Serum Levels ◽

High Serum ◽

Congenital Glaucoma ◽

Cerebellar Dysplasia ◽

Ocular Manifestations

Purpose: Walker-Warburg syndrome (WWS) is a rare autosomal recessive disorder characterized by congenital muscular dystrophy and severe brain and eye malformations. This study aims to analyze genotype-phenotype correlations in WWS with a novel cytidine diphosphate-l-ribitol pyrophosphorylase A ( CRPPA) mutation in different clinical manifestations. Case description: We report a girl with a presentation of multiple brain and ocular anomalies. Her ophthalmological evaluation showed a shallow anterior chamber, cortical cataract, iris hypoplasia, persistent hyperplastic primary vitreous in the right eye, punctate cataract, iris hypoplasia, primary congenital glaucoma, and a widespread loss of fundus pigmentation in the left eye. She was hypotonic, and her deep tendon reflexes were absent. Laboratory investigations showed high serum levels of serum creatine kinase. Brain magnetic resonance imaging demonstrated hydrocephalus, agenesis of the corpus callosum, retrocerebellar cyst, cerebellar dysplasia and hypoplasia, cobblestone lissencephaly, and hypoplastic brainstem. Whole exome sequencing revealed a novel homozygous nonsense mutation in the first exon of the CRPPA gene (NM_001101426.4, c.217G>T, p.Glu73Ter). Conclusions: The study findings expand the phenotypic variability of the ocular manifestations in the CRPPA gene-related WWS. Iris hypoplasia can be a part of clinical manifestations of the CRPPA gene-related WWS. The uncovering of the genes associated with ocular features can provide preventative methods, early diagnosis, and improved therapeutic strategies.

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Elevated Serum Levels of Soluble CD163 in Polymyositis and Dermatomyositis: Associated with Macrophage Infiltration in Muscle Tissue

The Journal of Rheumatology ◽

10.3899/jrheum.141307 ◽

2015 ◽

Vol 42 (6) ◽

pp. 979-987 ◽

Cited By ~ 18

Author(s):

Qing-Lin Peng ◽

Yin-Li Zhang ◽

Xiao-Ming Shu ◽

Han-Bo Yang ◽

Lu Zhang ◽

...

Keyword(s):

Muscle Tissue ◽

Laboratory Data ◽

Elevated Serum ◽

Clinical Manifestations ◽

Serum Levels ◽

High Serum ◽

Macrophage Infiltration ◽

Healthy Controls ◽

Soluble Cd163 ◽

Cell Counts

Objective.To investigate serum levels of soluble CD163 (sCD163) in patients with polymyositis (PM) and dermatomyositis (DM), and to correlate these to clinical manifestations and laboratory data.Methods.Serum levels of sCD163 were detected in 24 patients with PM, 84 patients with DM, and 46 healthy controls by using the ELISA method. Immunohistochemistry staining of macrophage infiltration in muscle tissue using anti-CD163 monoclonal antibody was conducted on muscle biopsy specimens from 13 patients with PM and 17 with DM.Results.Serum levels of sCD163 were significantly increased in patients compared with healthy controls (p < 0.001). Patients with interstitial lung disease (ILD) had statistically higher sCD163 levels than patients without ILD (p < 0.001). High serum sCD163 levels were associated with increased incidence of antinuclear antibody (p < 0.05), higher serum levels of immunoglobulin G (p < 0.01) and immunoglobulin A (p < 0.05), and increased erythrocyte sedimentation rates (p < 0.01). Serum sCD163 levels were inversely correlated with CD3+ T cell counts in peripheral blood of patients (r = −0.306, p < 0.01). Cross-sectional assessment and longitudinal study revealed a significant correlation between serum sCD163 levels and disease activity. Patients with high serum sCD163 levels showed a higher incidence of CD163+ macrophage infiltration in muscle tissue than patients with normal sCD163 levels (chi-square value = 10.804, p < 0.01).Conclusion.Serum levels of sCD163 were significantly elevated and correlated with disease severity in patients with PM/DM, suggesting serum sCD163 as a promising biomarker in the disease evaluation of PM/DM. Our finding of elevated serum sCD163 levels associated with muscle macrophage infiltration highlights the role activated macrophage plays in the pathogenesis of PM/DM.

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Two Siblings with Kaufman Oculocerebrofacial Syndrome Resembling Oculoauriculovertebral Spectrum

Molecular Syndromology ◽

10.1159/000513078 ◽

2021 ◽

Vol 12 (2) ◽

pp. 106-111

Author(s):

Gizem Ürel-Demir ◽

Büşra Aydın ◽

Beren Karaosmanoğlu ◽

Özlem Akgün-Doğan ◽

Ekim Zihni Taşkıran ◽

...

Keyword(s):

Autosomal Recessive ◽

Clinical Manifestations ◽

Gene Mutations ◽

Autosomal Recessive Disorder ◽

Pathogenic Mutation ◽

Genetic Alterations ◽

High Rate ◽

Facial Features ◽

Psychomotor Delay ◽

Oculoauriculovertebral Spectrum

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental manifestations due to <i>UBE3B</i> gene mutations. The vast majority of the affected individuals exhibit microcephaly, eye abnormalities, and typical facial gestalt including blepharophimosis, ptosis, telecanthus, upslanting palpebral fissures, dysplastic ears, and micrognathia. We encountered 2 siblings in whom severe psychomotor delay, distinctive facial features, hearing loss, and respiratory distress were observed. Some clinical manifestations of the patients, including epibulbar dermoid, microtia, and multiple preauricular tags, were reminiscent of the oculoauriculovertebral spectrum. However, 2 affected siblings exhibited a similar clinical picture consisting of microcephaly, severe developmental and cognitive disabilities, failure to thrive, and dysmorphic features, which were not fully consistent with oculoauriculovertebral spectrum. Also, hypoplastic nails, considered as a core manifestation of Coffin-Siris syndrome, were present in our patients. Therefore, whole-exome sequencing was carried out in order to identify the underlying genetic alterations, contributing to the complex phenotype shared by the 2 siblings. A homozygous pathogenic mutation was found in both affected siblings in the <i>UBE3B</i> gene which caused Kaufman oculocerebrofacial syndrome. Kaufman oculocerebrofacial syndrome should be considered among the autosomal recessive causes of blepharophimosis-mental retardation syndromes, particularly in populations with a high rate of consanguineous marriages, even if there are dysmorphic facial features that are not typically associated with the phenotype.

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A unique case of ectopic pancreas presenting as jejunal malignance

Journal of Surgical Case Reports ◽

10.1093/jscr/rjz217 ◽

2019 ◽

Vol 2019 (7) ◽

Cited By ~ 1

Author(s):

Peng Zhang ◽

Mojin Wang ◽

Lifen Bai ◽

Wen Zhuang

Keyword(s):

Histopathological Examination ◽

Epigastric Pain ◽

Elevated Serum ◽

Clinical Manifestations ◽

Serum Levels ◽

Carbohydrate Antigen ◽

Ectopic Pancreas ◽

Proximal Jejunum ◽

Normal Ranges ◽

Serum Cea

AbstractEctopic pancreas is defined as pancreatic tissues having no anatomic or vascular connections with the orthotopic pancreas. It is difficult for clinicians to diagnose this disease without performing a histopathological examination because it lacks specific clinical manifestations. This case report is of a 46-year-old woman who presented with epigastric pain. She had elevated serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 72-4 (CA72-4). Abdominal contrast-enhanced computed tomography (CT) revealed a persistently enhanced mass in the proximal jejunum, which was confirmed as ectopic pancreas via histopathological examination. Her serum CEA and CA72-4 levels were restored to normal ranges after resecting the jejunal ectopic pancreas. This is the first reported case of ectopic pancreas causing an elevation in serum CEA and CA-724 levels; this report supports the metaplasia theory and suggests that jejunal masses should be cautiously diagnosed for avoiding unnecessary concerns among patients and their families.

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Encephalopathy Associated with Severe Cytomegalovirus Infection in an Immunocompetent Young Woman

Case Reports in Infectious Diseases ◽

10.1155/2021/5589739 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Syuichi Tetsuka ◽

Tomohiro Suzuki ◽

Tomoko Ogawa ◽

Ritsuo Hashimoto ◽

Hiroyuki Kato

Keyword(s):

Young Adults ◽

Medial Temporal Lobe ◽

Elevated Serum ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Serum Levels ◽

Cmv Infection ◽

Steroid Pulse ◽

Intravenous Acyclovir ◽

Pp65 Antigenemia

Primary cytomegalovirus (CMV) infection in healthy young adults is usually an asymptomatic or mononucleosis-like syndrome, whereas in immunocompromised patients, CMV can cause significant disease. In this study, we report an unusual case of primary CMV infection wherein the patient, an immunocompetent 21-year-old woman, presented severe encephalopathy, acute hepatitis, retinitis, and reactivation of latent Epstein–Barr virus. She developed confusion, high fever, headache, and tonic-clonic seizures. Brain magnetic resonance imaging showed high-intensity lesions in the medial temporal lobe and basal ganglia. Liver dysfunction was observed, and abdominal computed tomography revealed splenohepatomegaly. After fundus findings, the patient was diagnosed with CMV retinitis. Upon admission, she was treated with intravenous acyclovir and steroid pulse therapy. Considering both her serious clinical condition and elevated serum levels of interleukin-6, we speculated that her condition was similar to cytokine-storm-induced encephalopathy. On day 2 after admission, she showed prompt recovery from these clinical manifestations. Since blood CMV pp65 antigenemia was found to be positive, we administered ganciclovir for 2 weeks. On the basis of her clinical manifestations and the presence of blood CMV DNA and CMV pp65 antigenemia along with IgM kinetics, we finally diagnosed this patient with severe primary CMV infection. She left our hospital without sequelae 20 days after admission. The incidence of severe CMV disease in immunocompetent young adults might be higher than previously recognized. Noninvasive testing for CMV (such as CMV pp65 antigenemia and CMV DNAemia) is widely available and can help early diagnosis. Short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy in the early stages of primary CMV infection. Considering such a background, clinicians should keep severe primary CMV infection in mind as a differential diagnosis in the clinical setting.

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Porphyria cutanea tarda in a patient on chronic ambulatory peritoneal dialysis.

Journal of the American Society of Nephrology ◽

10.1681/asn.v73397 ◽

1996 ◽

Vol 7 (3) ◽

pp. 397-402

Author(s):

J C Ruggian ◽

S Fishbane ◽

F J Demento ◽

J K Maesaka ◽

G L Frei

Keyword(s):

Peritoneal Dialysis ◽

Porphyria Cutanea Tarda ◽

Esrd Patient ◽

Elevated Serum ◽

Clinical Manifestations ◽

Serum Levels ◽

Hemodialysis Patients ◽

Uroporphyrinogen Decarboxylase ◽

Hepatic Iron Overload ◽

Proper Diagnosis

Porphyria cutanea tarda is a disorder of heme biosynthesis resulting from a defect or deficiency in the enzyme uroporphyrinogen decarboxylase. Heme precursors accumulate in the blood, urine, stool, and skin, where exposure to sunlight results in the clinical manifestations. Porphyria cutanea tarda has been described in adult hemodialysis patients. The pathogenesis of porphyria cutanea tarda in this population is thought to be related to the inability of hemodialysis to adequately clear porphyrin precursors, resulting in increased precursor serum levels, precursor skin deposition, and subsequent clinical manifestations. A proper diagnosis of porphyria cutanea tarda in hemodialysis patients requires fractionation of serum porphyrins. Normalization of the porphyrin profile and reversal of the dermal manifestations require the withdrawal of hepatotoxic agents and the reversal of hepatic iron overload. A case of porphyria cutanea tarda in an adult ESRD patient treated with continuous ambulatory peritoneal dialysis is described. In this patient, the disease was related to elevated serum levels of phenytoin, which had been administered for seizure disorder.

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Progressive Muscular Dystrophy in α-Sarcoglycan–deficient Mice

The Journal of Cell Biology ◽

10.1083/jcb.142.6.1461 ◽

1998 ◽

Vol 142 (6) ◽

pp. 1461-1471 ◽

Cited By ~ 253

Author(s):

Franck Duclos ◽

Volker Straub ◽

Steven A. Moore ◽

David P. Venzke ◽

Ron F. Hrstka ◽

...

Keyword(s):

Muscular Dystrophy ◽

Elevated Serum ◽

Autosomal Recessive Disorder ◽

Serum Levels ◽

Muscle Enzymes ◽

Progressive Muscular Dystrophy ◽

Muscle Necrosis ◽

Stable Association ◽

Deficient Mice ◽

Sarcolemmal Integrity

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the α-sarcoglycan gene. To determine how α-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed α-sarcoglycan– deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of α-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of α-dystroglycan association with membranes. In contrast, no change in the expression of ε-sarcoglycan (α-sarcoglycan homologue) was observed. Recombinant α-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan–sarcospan complex is requisite for stable association of α-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.

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Knobloch Syndrome in Siblings with Posterior Fossa Malformations Along with Cerebellar Midline Cleft Abnormality Caused by Biallelic COL18A1 Mutation: Case-Based Review

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721073 ◽

2020 ◽

Author(s):

Siddaramappa J. Patil ◽

Shruti Pande ◽

Jyoti Matalia ◽

Venkatraman Bhat ◽

Minal Kekatpure ◽

...

Keyword(s):

Posterior Fossa ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Later Life ◽

Facial Dysmorphism ◽

Ocular Manifestations ◽

Occipital Encephalocele ◽

Knobloch Syndrome ◽

Posterior Fossa Malformations ◽

Midline Cleft

AbstractKnobloch syndrome (KS) is an autosomal recessive disorder caused by biallelic pathogenic variants in COL18A1. KS clinically manifests with the typical eye findings (high myopia, vitreoretinal degeneration, retinal detachment, and lens subluxation), variable neurological findings (occipital encephalocele, polymicrogyria, cerebellar malformations, epilepsy, and intellectual disability), and the other uncommon clinical manifestations. Literature review of all KS patients (source PubMed) was done with special reference to cerebellar abnormalities. Here, we report two siblings with typical KS with posterior fossa malformations and novel cerebellar midline cleft abnormality analyzed by whole exome sequencing. Known pathogenic homozygous variant c.2908C > T; (p.Arg970Ter) in exon 26 of COL18A1 was found as a cause for KS. These two siblings presented with early-onset severe ocular manifestations, facial dysmorphism, and variable central nervous system manifestations along with novel cerebellar midline cleft abnormality. The presence or absence of structural brain malformations and genotypes does not absolutely predict cognitive functions in KS patients. However, the presence of posterior fossa abnormality may be predictive for the development of ataxia in later life and needs further studies.

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