Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.

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Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

10.1101/858696 ◽

2019 ◽

Author(s):

Francesca Mattioli ◽

Gaelle Hayot ◽

Nathalie Drouot ◽

Bertrand Isidor ◽

Jérémie Courraud ◽

...

Keyword(s):

Intellectual Disability ◽

Rna Binding ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Brain Mri ◽

Severe Form ◽

Neural Cells ◽

Loss Of Function ◽

Ataxic Gait ◽

Feeding Difficulties

ABSTRACTThe Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.

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Review for "Homozygous loss‐of‐function mutations in CCDC134 are responsible for a severe form of osteogenesis imperfecta"

10.1002/jbmr.4011/v1/review2 ◽

2019 ◽

Keyword(s):

Osteogenesis Imperfecta ◽

Severe Form ◽

Loss Of Function

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SAT-241 Pituitary Stalk Interruption Syndrome Presenting as Neonatal Hypotonia

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1366 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Nordie Anne Bilbao

Keyword(s):

Pituitary Gland ◽

Neonatal Period ◽

Hormone Replacement ◽

Brain Mri ◽

Rare Condition ◽

Pituitary Stalk ◽

Pituitary Hormone ◽

Thyroid Function Tests ◽

Acth Stimulation ◽

Central Hypothyroidism

Abstract Pituitary stalk interruption syndrome (PSIS) is a rare condition that include congenital anatomic abnormalities of the pituitary gland and hypopituitarism. There is a wide variety of clinical presentation, with the age at presentation encompassing from neonatal period to adulthood and including one or more pituitary hormone deficiencies. In recent literature there is increasing recognition of PSIS presenting in the neonatal period, mostly involving hypoglycemia. Our patient is a full-term male infant who presented in the newborn period with hypotonia and hypothermia. He also had hypoglycemia, which was initially thought to be associated to hyperinsulinism in the context of gestational diabetes. Micropenis was noted on physical exam. As part of the study for hypotonia, serial thyroid function tests were obtained revealing central hypothyroidism. A low dose ACTH stimulation test was performed which revealed adrenal insufficiency. The patient was started on cortisol and thyroid hormone replacement. Brain MRI showed an ectopic neurohypophysis located along the floor of the hypothalamus, a small anterior pituitary gland, and a partially absent infundibulum, findings consistent with pituitary stalk interruption syndrome. The patient received testosterone injections for micropenis and is being followed for development of other pituitary hormone deficiencies. PSIS is a rare congenital condition that is increasingly recognized in neonates manifesting with signs of hypopituitarism.

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General Anesthesia for a Patient With Pelizaeus-Merzbacher Disease

Anesthesia Progress ◽

10.2344/15-00022.1 ◽

2016 ◽

Vol 63 (2) ◽

pp. 91-94 ◽

Cited By ~ 2

Author(s):

Nobuhito Kamekura ◽

Yukie Nitta ◽

Shigeru Takuma ◽

Toshiaki Fujisawa

Keyword(s):

General Anesthesia ◽

Clinical Symptoms ◽

Muscle Tone ◽

Clinical Manifestations ◽

Psychomotor Retardation ◽

Cerebral White Matter ◽

Airway Complications ◽

Wisdom Teeth ◽

History Of Epilepsy ◽

Pelizaeus Merzbacher Disease

We report the successful management of general anesthesia for a patient with Pelizaeus-Merzbacher disease (PMD). PMD is one of a group of progressive, degenerative disorders of the cerebral white matter. The typical clinical manifestations of PMD include psychomotor retardation, nystagmus, abnormal muscle tone, seizures, and cognitive impairment. General anesthesia for a patient with PMD may be difficult mainly because of seizures and airway complications related to poor pharyngeal muscle control. In addition, the possibility of exacerbation of spasticity should be considered. A 20-year-old man with PMD required removal of impacted wisdom teeth under general anesthesia. General anesthesia was induced with thiamylal, fentanyl, and desflurane. Anesthesia was maintained with desflurane and continuous intravenous remifentanil under bispectral index and train-of-4 monitoring. Anesthesia lasted 1 hour 20 minutes and was completed uneventfully. Airway complications, seizures, and exacerbation of spasticity did not occur postoperatively. Preoperatively, our patient had no history of epilepsy attacks or aspiration pneumonia, and no clinical symptoms of gastroesophageal reflux disease. Therefore, exacerbation of spasticity was one of the most likely potential complications. Identification of these associated conditions and evaluation of risk factors during preoperative examination is important for performing safe anesthesia in these patients.

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Full Recovery From Cocaine-Induced Toxic Leukoencephalopathy: Emphasizing the Role of Neuroinflammation and Brain Edema

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709619868266 ◽

2019 ◽

Vol 7 ◽

pp. 232470961986826 ◽

Cited By ~ 1

Author(s):

Edward C. Mader ◽

Alexander B. Ramos ◽

Roberto A. Cruz ◽

Lionel A. Branch

Keyword(s):

White Matter ◽

Time Course ◽

Brain Mri ◽

White Matter Lesions ◽

Psychomotor Retardation ◽

Full Recovery ◽

White Matter Disease ◽

Mri Findings ◽

Prognostic Information ◽

Toxic Leukoencephalopathy

Toxic leukoencephalopathy (TL) is characterized by white matter disease on magnetic resonance imaging (MRI) and evidence of exposure to a neurotoxic agent. We describe a case of cocaine-induced TL in which extensive white matter disease did not preclude full recovery. A 57-year-old man with substance abuse disorder presented with a 5-day history of strange behavior. On admission, he was alert but had difficulty concentrating, psychomotor retardation, and diffuse hyperreflexia. Brain MRI revealed confluent subcortical white matter hyperintensities with restricted diffusion in some but not in other areas. Electroencephalography (EEG) showed mild diffuse slowing. Blood tests were normal except for mild hyperammonemia. Urine screen was positive for cocaine and benzodiazepine but quantitative analysis was significant only for cocaine. Prednisone 60-mg qd was initiated on day 4, tapered over a 5-day period, and discontinued on day 9. He was discharged after 3 weeks. Cognitive function returned to normal 2 weeks after discharge. Five months later, neurologic exam and EEG were normal and MRI showed near-100% resolution of white matter lesions. TL has been attributed to white matter ischemia/hypoxia resulting in demyelination/axonal injury. The clinical, EEG, and MRI findings and time course of recovery of our patient suggest that cocaine-induced inflammation/edema resulted in TL but not in ischemic/hypoxic injury. While inflammation/edema may have regressed when cocaine was discontinued, we cannot exclude a role for prednisone in protecting the patient from the ischemic/hypoxic sequelae of inflammation/edema. MRI is indispensable for diagnosing TL but EEG may provide additional useful diagnostic and prognostic information.

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ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Nature Communications ◽

10.1038/s41467-019-12428-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Marie F. Smeland ◽

Conor McClenaghan ◽

Helen I. Roessler ◽

Sanne Savelberg ◽

Geir Åsmund Myge Hansen ◽

...

Keyword(s):

Intellectual Disability ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Splice Site Mutation ◽

Cerebral White Matter ◽

Sulfonylurea Receptor ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Site Mutation ◽

Gain Of Function

Abstract Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

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Definition and Diagnosis of Acute Kidney Injury in Cirrhosis

Digestive Diseases ◽

10.1159/000375345 ◽

2015 ◽

Vol 33 (4) ◽

pp. 539-547 ◽

Cited By ~ 4

Author(s):

Florence Wong

Keyword(s):

Acute Kidney Injury ◽

Serum Creatinine ◽

Urine Output ◽

Negative Impact ◽

Kidney Injury ◽

Acute Kidney Injury Network ◽

Severe Form ◽

Loss Of Function ◽

Baseline Serum ◽

Advanced Cirrhosis

Background: Acute kidney injury (AKI) is a common complication of advanced cirrhosis. Type 1 hepatorenal syndrome is the best-known and most severe form of AKI, and it has a precise definition and a set of specific diagnostic criteria. More recently, it has become recognized that milder degrees of renal dysfunction also have a negative impact on patient outcome in various patient populations. Key Messages: Several definitions and criteria for staging the severity of AKI have been proposed, including the RIFLE (Risk, Injury, Failure, Loss of Function and End-Stage Renal Disease) group, the Acute Kidney Injury Network (AKIN), and the Kidney Disease: Improving Global Outcome (KDIGO) group. All of them incorporate some changes of serum creatinine and urine output in the definition and staging of AKI. The hepatology community has mostly embraced the AKIN diagnostic and staging criteria and has applied them in the prognostication of patients with advanced cirrhosis. However, the AKIN criteria have not been strictly applied in all studies on cirrhosis. This is partly related to the fact that changes in urine output are difficult to assess in advanced cirrhosis, and partly related to the difficulty in defining the baseline serum creatinine from which the change in serum creatinine is calculated. This has led to some confusion in the interpretation of results of the various studies on AKI in cirrhosis. More recently, some investigators have suggested incorporating the AKIN criteria with setting a lower limit of serum creatinine of 1.5 mg/dl in determining the diagnosis and prognosis of AKI in cirrhosis. Conclusions: This is an ongoing debate as to how best to define AKI in cirrhosis. In the near future there should be prospective clinical trials that will clarify which diagnostic and staging criteria of AKI will best serve the cirrhotic population.

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Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I

Clinical Genetics ◽

10.1111/cge.13084 ◽

2017 ◽

Vol 93 (2) ◽

pp. 255-265 ◽

Cited By ~ 7

Author(s):

M.C. Braunisch ◽

H. Gallwitz ◽

A. Abicht ◽

I. Diebold ◽

E. Holinski-Feder ◽

...

Keyword(s):

Severe Form ◽

Type I ◽

Loss Of Function ◽

Pontocerebellar Hypoplasia

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An Atypical Presentation of a Male with Oral-Facial-Digital Syndrome Type 1 Related Ciliopathy

Case Reports in Nephrology ◽

10.1155/2016/3181676 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Sheena Sharma ◽

Jennifer M. Kalish ◽

Ethan M. Goldberg ◽

Francis Jeshira Reynoso ◽

Madhura Pradhan

Keyword(s):

Primary Cilia ◽

Brain Mri ◽

Rare Condition ◽

Chronic Hemodialysis ◽

Syndrome Type ◽

Cystic Changes ◽

Stage Renal Disease ◽

End Stage ◽

Case Diagnosis

Background. Oral-facial-digital syndrome type 1 (OFD1) is a rare condition with X-linked dominant inheritance caused by mutations in theCxorf5(OFD1) gene. This gene encodes the OFD1 protein located within centrosomes and basal bodies of primary cilia. Approximately 15–50% of patients with OFD1 progress to end-stage kidney disease following development of polycystic changes within the kidneys. This condition almost always causes intrauterine lethality in males.Description of Case Diagnosis and Treatment. A Caucasian male aged 9 years and 9 months presented with increased urinary frequency, increased thirst, and decreased appetite. Physical examination demonstrated short stature, hearing loss, photophobia, murmur, and hypogonadism. He had no other dysmorphic features. Laboratory results revealed anemia, renal insufficiency, and dilute urine with microscopic hematuria but no proteinuria. Ultrasound showed small kidneys with increased echogenicity but no evidence of cystic changes. A Ciliopathy Panel showed a novel and likely pathogenic deletion, approximately 7.9 kb, in theOFD1gene encompassing exons 16, 17, and 19 (c.1654+833_2599+423del). Brain MRI did not demonstrate typical OFD1 findings. He is currently on chronic hemodialysis awaiting transplant from a living donor.Conclusions. We present a male patient withOFD1mutation who lacks the classic OFD1 phenotype who presented with end-stage renal disease without evidence of polycystic changes within the kidneys.

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Cyclopia: A Rare Condition with Unusual Presentation - A Case Report

Clinical Medicine Insights Pediatrics ◽

10.4137/cmped.s21107 ◽

2015 ◽

Vol 9 ◽

pp. CMPed.S21107

Author(s):

Ghassan S.A. Salama ◽

Mahmoud A.F. Kaabneh ◽

Mohamed K. Al-Raqad ◽

Ibrahim M.H. Al-Abdallah ◽

Ayoub Ga Shakkoury ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Pregnancy Termination ◽

Brain Mri ◽

External Genitalia ◽

Rare Condition ◽

Renal Dysplasia ◽

Military Hospital ◽

Single Orbit ◽

History Of ◽

Term Baby

Introduction Cyclopia (alobar holoprosencephaly) (OMIM% 236100) is a rare and lethal complex human malformation, resulting from incomplete cleavage of prosencephalon into right and left hemispheres occurring between the 18th and the 28th day of gestation. Holoprosencephaly occurs in 1/16,000 live births, and 1/250 during embryogenesis. Approximately 1.05 in 100,000 births are identified as infants with cyclopia, including stillbirths. Cyclopia typically presents with a median single eye or a partially divided eye in a single orbit, absent nose, and a proboscis above the eye. Extracranial malformations described in stillbirths with cyclopia include polydactyl, renal dysplasia, and an omphalocele. The etiology of this rare syndrome, which is incompatible with life, is still largely unknown. Most cases are sporadic. Heterogeneous risk factors have been implicated as possible causes. Case Presentation A live full-term baby with birth weight of 2900 g, product of cesarean section because of severe fetal bradycardia, was born at Prince Hashem Military Hospital – Zarqa city/Jordan. This newborn was the first baby to a non-consanguineous family, and a healthy 18-year-old mother, with no history of drug ingestion or febrile illnesses during pregnancy. Antenatal history revealed severe hydrocephalus diagnosed early by intrauterine ultrasound but the pregnancy was not terminated because of the lack of medical legitimization in the country. On examination, the newborn was found to have a dysmorphic face, with a median single eye, absence of nose, micrognathia, and a proboscis above the eye, all of which made cyclopia the possible initial diagnosis. Multiple unusual abdominal defects were present that include a huge omphalocele containing whole liver and spleen, urinary bladder extrophy, and undefined abnormal external genitalia, which called for urgent confirmation. Brain MRI was done and revealed findings consistent with alobar holoprosencephaly (cyclopia). Conclusion Presentation of cyclopia is not fully exposed and new cyclopian syndromes still can appear. The prenatal diagnosis of cyclopia can be made early by ultrasound, and the awareness of the spectrum of sonographic findings of cyclopia can improve the accuracy of prenatal diagnosis. The legitimization of pregnancy termination for indexed cases in many countries around the world should be revised.

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