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JIMD Reports

Heng Wang, Valerie Sency, Paul McJarrow, Alicia Bright, Qianyang Huang, Karen Cechner, Julia Szekely, JoAnn Brace, Andi Wang, Danting Liu, Angela Rowan, Max Wiznitzer, Aimin Zhou, Baozhong Xin
Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3D) causes an absence of GM3 and all downstream biosynthetic derivatives. The affected individuals manifest with severe irritability, intractable seizures, and profound intellectual disability. The current study is to assess the effects of an oral ganglioside supplement to patients with GM3D, particularly on their growth and development during early childhood. A total of 13 young children, 11 of them under 40 months old, received oral ganglioside supplement through a dairy product enriched in gangliosides, for an average of 34 months...
September 13, 2018: JIMD Reports
Rachel Edmiston, Stuart Wilkinson, Simon Jones, Karen Tylee, Alexander Broomfield, Iain A Bruce
BACKGROUND: Inclusion cell disease (I-cell) is a rare autosomal recessive metabolic disease involving multiple organ systems, associated with a severely restricted life expectancy. No curative therapy is currently available, with management aimed at symptom palliation. METHODS: We present a retrospective, single-centre, case series of children referred to a tertiary paediatric metabolic service. The clinical presentation, demographics, genetics and natural history of the condition are investigated...
September 13, 2018: JIMD Reports
Andreas Traschütz, Michael Thomas Heneka
Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disorder with a heterogeneous phenotype including ataxia, cognitive impairment, impairment of vertical saccades, and psychiatric symptoms, among many others. Based on clinical, genetic, and biomarker findings, recent guidelines put forward a screening for atypical and oligosymptomatic forms of NPC in clinical niches with an increased risk. Here, we report methods and results of a negative screening study in the niche of a memory clinic. We retrospectively and prospectively identified 83 patients with unclassified cognitive impairment (15 dementia, 46 mild cognitive impairment, and 22 progressive subjective cognitive decline) before 60 years of age (82 patients between 41 and 60 years)...
September 6, 2018: JIMD Reports
Naila Ismayilova, Andrew D MacKinnon, Helen Mundy, Penny Fallon
Striking MRI brain changes resembling leukoencephalopathy are rarely seen in classical homocystinuria. Our case suggests that reversible white matter changes (WMC) are linked to elevated plasma methionine levels arising during treatment.A 6-year-old boy with learning difficulties and a normal MRI brain scan was diagnosed with homocystinuria (initial total homocysteine 344 μmol/L and methionine 64 μmol/L). At the age of 6.5 years, he developed superior sagittal sinus (SSS) thrombosis. Antithrombotic and homocysteine-lowering treatments were started...
September 6, 2018: JIMD Reports
Katherine Taylor Wild, Rebecca D Ganetzky, Marc Yudkoff, Lynne Ierardi-Curto
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is an autosomal recessive disorder that is caused by a deficiency of mitochondrial ornithine transporter 1, resulting in dysfunction of the urea cycle. HHH is the rarest of the urea cycle disorders, reported in fewer than 100 patients. It is characterized by extreme phenotypic variability, including diverse ages of onset and severity of phenotype. We report the first confirmed instance of HHH syndrome in a premature infant (31 2/7 weeks) with severe hyperammonemia (1,300 μmol/L)...
September 6, 2018: JIMD Reports
Bobby G Ng, Hunter R Underhill, Lars Palm, Per Bengtson, Jean-Michel Rozet, Sylvie Gerber, Arnold Munnich, Xavier Zanlonghi, Cathy A Stevens, Martin Kircher, Deborah A Nickerson, Kati J Buckingham, Kevin D Josephson, Jay Shendure, Michael J Bamshad, Hudson H Freeze, Erik A Eklund
Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death...
August 17, 2018: JIMD Reports
Christoffer V Madsen, Erik Ilsø Christensen, Rikke Nielsen, Helle Mogensen, Åse K Rasmussen, Ulla Feldt-Rasmussen
Fabry disease (FD) is an X-linked, lysosomal storage disease. Mutations in the gene coding for alpha-galactosidase A lead to globotriaosylceramide (Gb-3) accumulation in lysosomes and in placenta and umbilical cord. Impact of FD and treatment with enzyme replacement (ERT) on foetal development is undisclosed.A 38-year-old primigravida with FD (G85N) is reported. She has 50% reduced alpha-galactosidase A activity and elevated plasma and urine-Gb-3. She was severely affected with ischaemic stroke at age 23, hypertension, albuminuria and moderately reduced renal function...
August 17, 2018: JIMD Reports
Aya Abu-El-Haija, Bryce A Mendelsohn, Jacque L Duncan, Anthony T Moore, Orit A Glenn, Kara Weisiger, Renata C Gallagher
Cobalamin D deficiency (cblD) is one of the least common cobalamin metabolism disorders. It may result in isolated homocystinuria, isolated methylmalonic aciduria, or combined methylmalonic aciduria and homocystinuria (cblD-combined). Only seven cases of the combined cblD form have been reported to date. Due to the rarity of this disorder, the presentation and symptoms are not well described. We present an eighth case of the cblD-combined subtype, who had a positive newborn screen (NBS) on day of life 3. She was symptomatic and developed lethargy and poor oral intake at 8 days of life...
August 11, 2018: JIMD Reports
R Anderson, S Rust, J Ashworth, J Clayton-Smith, R L Taylor, P T Clayton, A A M Morris
Lathosterolosis is a rare defect of cholesterol synthesis. Only four previous cases have been reported, two of whom were siblings. We report a fifth patient, with a relatively mild phenotype. He presented at 5 years of age with bilateral posterior cataracts, which were managed with lensectomies and intraocular lens implants. He also had learning difficulties, with a full-scale IQ of 64 at 11 years of age. His head circumference is between the 0.4th and 2nd centiles, and he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes)...
August 11, 2018: JIMD Reports
Daniel A Jaramillo-Calle, Daniel C Aguirre Acevedo
BACKGROUND: There is minimal information available about acute hepatic porphyrias (AHPs) in developing countries. The aim of this study was to describe the demographics, clinical features, and mortality of AHPs in Colombia. PATIENTS AND METHODS: 121 patients with presumed diagnosis of AHPs were reported in Colombia between 1944 and 2018. A pooled analysis of 53 patients with confirmed diagnosis was performed to evaluate the demographics, clinical features, and mortality of AHPs in the country...
August 2, 2018: JIMD Reports
D Marques-da-Silva, R Francisco, V Dos Reis Ferreira, L Forbat, R Lagoa, P A Videira, P Witters, J Jaeken, D Cassiman
Congenital disorders of glycosylation (CDG) are ultra-rare diseases showing a great phenotypic diversity ranging from mono- to multi-organ/multisystem involvement. Liver involvement, mostly nonprogressive, is often reported in CDG patients. The main objectives of this work were (1) to better understand liver involvement in CDG patients through a liver electronic questionnaire targeting CDG families (LeQCDG) and (2) to compare responses from LeQCDG participants with literature review regarding the prevalence of liver disease and the occurrence of liver symptoms in CDG patients...
July 15, 2018: JIMD Reports
Melis Kose, Secil Akyildiz Demir, Gulcin Akinci, Cenk Eraslan, Unsal Yilmaz, Serdar Ceylaner, Eser Sozmen Yildirim, Volkan Seyrantepe
Krabbe disease is a lysosomal storage disease caused by galactosylceramidase deficiency, resulting in neurodegeneration with a rapid clinical downhill course within the first months of life in the classic infantile form. This process may be triggered by the accumulation of galactosylceramide (GalCer) in nervous tissues. Both the enzyme galactosylceramidase and its in vivo activator molecule, saposin A, are essential during GalCer degradation. A clinical manifestation almost identical to Krabbe disease is observed when, instead of the galactosylceramidase protein, the saposin A molecule is defective...
July 12, 2018: JIMD Reports
Gerald F Cox, Lorne A Clarke, Roberto Giugliani, Margaret M McGovern
Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease caused by the deficiency of the enzyme acid sphingomyelinase (ASM) resulting in accumulation of sphingomyelin in target tissues. Little is known regarding predictors of disease-related morbidity, healthcare use, and lifestyle impact in adults with chronic disease. A multinational retrospective study collected data on the burden of illness and healthcare resource use for 100 patients across the clinical spectrum of ASMD, including those with rapidly progressive infantile neurovisceral disease (n = 13) and those with the more slowly progressive chronic neurovisceral (n = 6) and chronic visceral (n = 81) disease...
July 12, 2018: JIMD Reports
Thirsa Conijn, Stephanie C M Nijmeijer, Hedy A van Oers, Frits A Wijburg, Lotte Haverman
BACKGROUND: Mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) is a lysosomal storage disease resulting in progressive neurocognitive decline during childhood and early demise. Its diagnosis may have a great impact on parents, potentially leading to psychosocial problems such as anxiety, depression, parental distress, and posttraumatic stress. METHODS: Twenty-six mothers and 19 fathers of 34 Dutch MPS III patients completed the "Hospital Anxiety and Depression Scale" (HADS), the "Distress Thermometer for Parents" (DT-P), and the "Self-Rating Scale for Posttraumatic Stress Disorders" (SRS-PTSD)...
July 7, 2018: JIMD Reports
Masashi Morita, Shun Matsumoto, Airi Sato, Kengo Inoue, Dzmitry G Kostsin, Kozue Yamazaki, Kosuke Kawaguchi, Nobuyuki Shimozawa, Stephan Kemp, Ronald J Wanders, Hirotatsu Kojima, Takayoshi Okabe, Tsuneo Imanaka
Mutations in the ABCD1 gene that encodes peroxisomal ABCD1 protein cause X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disorder. More than 70% of the patient fibroblasts with this missense mutation display either a lack or reduction of the ABCD1 protein because of posttranslational degradation. In this study, we analyzed the stability of the missense mutant ABCD1 proteins (p.A616T, p.R617H, and p.R660W) in X-ALD fibroblasts and found that the mutant ABCD1 protein p.A616T has the capacity to recover its function by incubating at low temperature...
June 21, 2018: JIMD Reports
Arcangela Iuso, Bader Alhaddad, Corina Weigel, Urania Kotzaeridou, Elisa Mastantuono, Thomas Schwarzmayr, Elisabeth Graf, Caterina Terrile, Holger Prokisch, Tim M Strom, Georg F Hoffmann, Thomas Meitinger, Tobias B Haack
SLC25A42 is an inner mitochondrial membrane protein which has been shown to transport coenzyme A through a lipid bilayer in vitro. A homozygous missense variant in this gene has been recently reported in 13 subjects of Arab descent presenting with mitochondriopathy with variable clinical manifestations. By exome sequencing, we identified two additional individuals carrying rare variants in this gene. One subject was found to carry the previously reported missense variant in homozygous state, while the second subject carried a homozygous canonical splice site variant resulting in a splice defect...
June 20, 2018: JIMD Reports
Erika F Augustine, Christopher A Beck, Heather R Adams, Sara Defendorf, Amy Vierhile, Derek Timm, Jill M Weimer, Jonathan W Mink, Frederick J Marshall
Mycophenolate, an immunosuppressant, is commonly used off-label for autoimmune neurological conditions. In CLN3 disease, a neurodegenerative disorder of childhood, preclinical and clinical data suggest secondary autoimmunity and inflammation throughout the central nervous system are key components of pathogenesis. We tested the short-term tolerability of mycophenolate in individuals with CLN3 disease, in preparation for possible long-term efficacy trials of this drug. We conducted a randomized, double-blind, placebo-controlled, crossover study of mycophenolate in 19 ambulatory individuals with CLN3 disease to determine the safety and tolerability of short-term administration (NCT01399047)...
June 20, 2018: JIMD Reports
D Quelhas, J Jaeken, A Fortuna, L Azevedo, A Bandeira, G Matthijs, E Martins
This report is on two novel patients with RFT1-CDG. Their phenotype is characterized by mild psychomotor disability, behavioral problems, ataxia, and mild dysmorphism. Neither of them shows signs of epilepsy, which was observed in all RFT1-CDG patients reported to date (n = 14). Also, deafness, which is often associated with this condition, was not observed in our patients. Molecular analysis of RFT1 showed biallelic missense variants including three novel ones: c.827G >gt; A (p.G276D), c.73C >gt; T (p...
June 20, 2018: JIMD Reports
Leanne K Winner, Neil R Marshall, Robert D Jolly, Paul J Trim, Stephen K Duplock, Marten F Snel, Kim M Hemsley
Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited neurodegenerative disease of childhood that results in early death. Post-mortem studies have been carried out on human MPS IIIA brain, but little is known about early disease development. Here, we utilised the Huntaway dog model of MPS IIIA to evaluate disease lesion development from 2 to 24 weeks of age. A significant elevation in primarily stored heparan sulphate was observed in all brain regions assessed in MPS IIIA pups ≤9.5 weeks of age. There was a significant elevation in secondarily stored ganglioside (GM3 36:1) in ≤9...
June 20, 2018: JIMD Reports
Colleen M Carlston, Sacha Ferdinandusse, Judith A Hobert, Rong Mao, Nicola Longo
Loss-of-function and hypomorphic ECHS1 variants are associated with mitochondrial short-chain enoyl-CoA hydratase deficiency, an inborn error of valine metabolism. We report an 8-year-old boy with developmental delay, ataxia, hemiplegia, and hearing loss with abnormalities in the basal ganglia. Biochemical studies were essentially normal except for a persistent mildly elevated CSF alanine. This patient demonstrates an intermediate phenotype between a Leigh-like, early-onset presentation and paroxysmal exercise-induced dyskinesia...
June 20, 2018: JIMD Reports
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