41 research outputs found
Life with too much polyprenol: polyprenol reductase deficiency
Congenital disorders of glycosylation (CDG) are caused by a dysfunction of glycosylation, an essential step in
the manufacturing process of glycoproteins. This paper focuses on a 6-year-old patient with a new type of
CDG-I caused by a defect of the steroid 5α reductase type 3 gene (SRD5A3). The clinical features were psychomotor
retardation, pathological nystagmus, slight muscular hypotonia and microcephaly. SRD5A3 was recently
identified encoding the polyprenol reductase, an enzyme catalyzing the final step of the biosynthesis
of dolichol, which is required for the assembly of the glycans needed for N-glycosylation.
Although an early homozygous stop-codon (c.57G>A [W19X]) with no functional protein was found in the
patient, about 70% of transferrin (Tf) was correctly glycosylated. Quantification of dolichol and unreduced
polyprenol in the patient's fibroblasts demonstrated a high polyprenol/dolichol ratio with normal amounts
of dolichol, indicating that high polyprenol levels might compete with dolichol for the initiation of
N-glycan assembly but without supporting normal glycosylation and that there must be an alternative
pathway for dolichol biosynthesis
QIL1-dependent assembly of MICOS complex-lethal mutation in C19ORF70 resulting in liver disease and severe neurological retardation
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Uridine Treatment of the First Known Case of SLC25A36 Deficiency
SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by 'SLC25A36' mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the 'SLC25A36' gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment
Differences in Niemann-Pick disease Type C symptomatology observed in patients of different ages
BACKGROUND : Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive
neurovisceral symptomatology. Typically, disease progression ismore pronounced in patientswith early onset of
neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays
in diagnosis. Here we describe the prevalence of signs and symptoms observed in patientswith NP-C and analyse
the relationship between these symptoms in different age groups.
METHODS : The combined patient cohort used in the analyses comprised NP-C cases (n=164) and controls (n=
135) aged 0 to 60 years from two previously published cohorts; a cohort of all ages fromwhich patients ≤4 years
of agewere excluded and a cohortwith early-onset NP-C and age-matched controls. The analysis of relationships
between different signs and symptoms was performed for both NP-C cases and controls in two sub-groups, ≤4
and N4 years of age, using cluster analyses. The threshold of 4 years of age was selected to reflect the minimum
age cut-off for satisfactory discriminatory power of the original NP-C SI. To assess the prevalence of individual
signs and symptoms at age of diagnosis, patientswere categorised by age into 5-year sub-groups, and prevalence
values estimated for each sign and symptom of NP-C.
RESULTS : Twomain clusters of symptomswere clearly defined for NP-C cases in each age sub-group,whereas clusters
were not as clearly defined for controls. For NP-C cases ≤4 years of age, one cluster comprised exclusively
visceral symptoms; the second cluster combined all other signs and symptoms in this age group. For NP-C
cases N4 years of age, each cluster contained amixture of visceral, neurological and psychiatric items. Prevalence
estimations showed that visceral symptoms (e.g. isolated unexplained splenomegaly)were most common inNPC
cases ≤4 years of age. Neurological symptoms were generallymore common in NP-C cases N4 years of age than
in younger patients, with the exception of hypotonia and delayed developmental milestones.
CONCLUSIONS : These analyses provide a comprehensive overviewof symptomatology observed in a large combined
cohort of patients with NP-C and controls across a wide range of ages. The results largely reflect observations
from clinical practice and support the importance of multi-disciplinary approaches for identification of patients
with NP-C, taking into account age-specific manifestations and their possible correlations.Manuscript preparation for this publication was supported by
Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.EM,MP, CJH,MWand JVT have received consulting fees or honoraria from Actelion Pharmaceuticals Ltd.http://www.elsevier.com/locate/ymgmeam2017Paediatrics and Child Healt
Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report
ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction
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Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease
Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPβCD treatment. In an intravenous (IV) HPβCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPβCD treatment
Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1
Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3β,5α,6β-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3β,5α,6β-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPβCD treatment