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1.
Lomitapide-a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia.
Stefanutti, C
Current atherosclerosis reports. 2020;(8):38
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Abstract
PURPOSE OF REVIEW Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by high levels of Low density lipoprotein cholesterol (LDL-C); overt, early-onset atherosclerotic cardiovascular disease (ASCVD); and premature cardiovascular events and mortality. Lomitapide is a first-in-class microsomal triglyceride transfer protein inhibitor for the treatment of HoFH. This review provides an update on data emerging from real-world studies of lomitapide following on from its pivotal phase 3 clinical trial in HoFH. RECENT FINDINGS Recent registry data have confirmed that HoFH is characterized by delayed diagnosis, with many patients not receiving effective therapy until they are approaching the age when major adverse cardiovascular events may occur. Data from case series of varying sizes, and from a 163-patient registry of HoFH patients receiving lomitapide, have demonstrated that lomitapide doses are lower and adverse events less severe than in the phase 3 study. Lomitapide enables many patients to reach European Atherosclerosis Society LDL-C targets. Some patients are able to reduce frequency of lipoprotein apheresis or, in some cases, stop the procedure altogether-unless there is significant elevation of lipoprotein (a). Modelling analyses based on historical and clinical trial data indicate that lomitapide has the potential to improve cardiovascular outcomes and survival in HoFH. Real-world clinical experience with lomitapide has shown the drug to be effective with manageable, less marked adverse events than in formal clinical studies. Event modelling data suggest a survival benefit with lomitapide in HoFH.
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Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures.
Böhm, J, Malfatti, E, Oates, E, Jones, K, Brochier, G, Boland, A, Deleuze, JF, Romero, NB, Laporte, J
Journal of medical genetics. 2019;(9):617-621
Abstract
BACKGROUND The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder. OBJECTIVE We aim to contribute to a better understanding of the ASCC1-related disorder. METHODS Here, we provide a clinical, histological and genetic description of three additional ASCC1 families. RESULTS All patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations. CONCLUSION Overall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.
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Novel IFT140 variants cause spermatogenic dysfunction in humans.
Wang, X, Sha, YW, Wang, WT, Cui, YQ, Chen, J, Yan, W, Hou, XT, Mei, LB, Yu, CC, Wang, J
Molecular genetics & genomic medicine. 2019;(9):e920
Abstract
BACKGROUND The intraflagellar transport protein 140 homolog (IFT140) is involved in the process of intraflagellar transport (IFT), a process that is essential for the formation and maintenance of most eukaryotic cilia and flagella. Variants IFT140 have been reported to account for ciliopathy but association with male fertility has never been described in humans. Here we report the identification of two novel variants of IFT140 which caused spermatogenic dysfunction and male infertility. METHODS Whole-exome sequencing was performed in a 27-year-old infertile man presented with severe oligozoospermia, asthenozoospermia, and teratozoospermia (OAT) without other physical abnormality. Sanger sequencing was used to verify gene variants in the patient, his healthy brother, and their parents. Morphology and protein expression in the patient's sperm were examined by transmission electron microscopy (TEM) and immunofluorescence staining. Function of gene variants was predicted by online databases. RESULTS Compound heterozygous variants of IFT140: exon16: c.1837G > A: p.Asp613Asn and exon31: c.4247G > A: p.Ser1416Asn were identified in the patient, both of which showed autosomal recessive inheritance in his family, and had extremely low allele frequency in the population. Morphological abnormalities of the head, nucleus, and tails and the absence of IFT140 from the neck and mid-piece of the patient's spermatozoa were observed. Mutation Taster database predicted a high probability of damage-causing by both variations. CONCLUSION This study for the first time reported IFT140 variants that cause infertility in humans.
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Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature.
Sheth, J, Joseph, JJ, Shah, K, Muranjan, M, Mistri, M, Sheth, F
BMC medical genetics. 2017;(1):5
Abstract
BACKGROUND Niemann-Pick disease type C (NPC) is an inherited metabolic disorder; due to defect in cellular cholesterol trafficking. It is clinically a heterogeneous disease with variable age of onset with multiple organ systems being involved. NPC1 gene is involved in 95% cases where as remaining ~5% cases are linked with NPC2 gene. CASE PRESENTATION Case-1, a 14-months-old female presented with recurrent respiratory distress, failure to thrive and hepatosplenomegaly. Lung biopsy was suggestive of alveolar proteinosis and liver biopsy confirmed foamy macrophages. Molecular analysis revealed homozygous mutation c.141C > A in exon 2 of NPC2 gene. Case-2, a 3-year-old male presented with dyspnoea and hepatomegaly noticed at 1 year of age. HRCT-scan of thoracic region showed consolidation with mediastinal lymphadenopathy. Broncho-alveolar lavage revealed moderate amount of foamy macrophages and bone marrow examination detected foam cells. Homozygous T > C transition in intron 1 of the NPC2 gene was identified. CONCLUSION Our study demonstrates that NPC2 can present in early years of life with pulmonary complications like alveolar proteinosis and hepatosplenomegaly or hepatomegaly due to mutation in NPC2 gene. An early suspicion will help clinicians to clinch its diagnosis, management and genetic counselling.
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Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: A case report and literature review.
Chen, M, Zhuang, J, Yang, J, Wang, D, Yang, Q
Medicine. 2017;(43):e8284
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Abstract
RATIONALE Methylmalonic acidemia (MMA) is a common organic acidemia, mainly due to methylmalonyl-CoA mutase (MCM) or its coenzyme cobalamin (VitB12) metabolic disorders. Cobalamin C (CblC) type is the most frequent inborn error of cobalamin metabolism; it can develop symptoms in childhood and often combine multisystem damage, which leads to methylmalonic acid, propionic acid, methyl citrate, and other metabolites abnormal accumulation, causing nerve, liver, kidney, bone marrow, and other organ damage. PATIENT CONCERNS A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury. DIAGNOSIS Based on severe normochromic anemia and acute kidney injury, renal biopsy showed membranous proliferative glomerular lesions and thrombotic microvascular disease, supporting the diagnosis of aHUS. Although the serum vitamin B12 was normal, further investigation found the concentration of urinary methylmalonic acid and serum homocysteine increased obviously, genetic analysis revealed a heterozygous MMACHC mutation (exonl: c. 80A >G, c. 609G >A). The final diagnosis was aHUS induced by inherited methylmalonic acidemia (MMACHC heterozygous mutation exonl: c. 80A >G, c. 609G >A). INTERVENTIONS The patient was treated with a 1mg vitamin B12 intramuscular injection daily for 4 days after which the dose was then adjusted to a 1mg intramuscular injection twice a week. At the same time, the girl was given levocarnitine, betaine, folic acid, along with supportive treatment. OUTCOMES After treated by vitamin B12 for 10 days, the patient condition significantly improved, Follow-up results showed complete recovery of hemoglobin and renal function. LESSONS Although the majority of MMA onset from neurological damage, our case illustrates that partial CblC-type MMA can onset with severe metabolic aHUS. On the basis of chronic thrombotic microangiopathy (TMA)-induced renal damage, it can be complicated by acute hemolytic lesions. MMA should be considered in those patients with unclear microangiopathic hemolytic anemia accompany significant megaloblastic degeneration in bone marrow. We should pay attention to the causes and adopt a reasonable treatment strategy.
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WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature.
Hoffjan, S, Ibisler, A, Tschentscher, A, Dekomien, G, Bidinost, C, Rosa, AL
Molecular and cellular probes. 2016;(1):44-9
Abstract
Mutations in the WDR45 gene have been identified as causative for the only X-linked type of neurodegeneration with brain iron accumulation (NBIA), clinically characterized by global developmental delay in childhood, followed by a secondary neurological decline with parkinsonism and/or dementia in adolescence or early adulthood. Recent reports suggest that WDR45 mutations are associated with a broader phenotypic spectrum. We identified a novel splice site mutation (c.440-2 A > G) in a 5-year-old Argentinian patient with Rett-like syndrome, exhibiting developmental delay, microcephaly, seizures and stereotypic hand movements, and discuss this finding, together with a review of the literature. Additional patients with a clinical diagnosis of Rett (-like) syndrome were also found to carry WDR45 mutations before (or without) clinical decline or signs of iron accumulation by magnetic resonance imaging (MRI). This information indicates that WDR45 mutations should be added to the growing list of genetic alterations linked to Rett-like syndrome. Further, clinical symptoms associated with WDR45 mutations ranged from early-onset epileptic encephalopathy in a male patient with a deletion of WDR45 to only mild cognitive delay in a female patient, suggesting that analysis of this gene should be considered more often in patients with developmental delay, regardless of severity. The increasing use of next generation sequencing technologies as well as longitudinal follow-up of patients with an early diagnosis will help to gain additional insight into the phenotypic spectrum associated with WDR45 mutations.
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WDR45 mutations in three male patients with West syndrome.
Nakashima, M, Takano, K, Tsuyusaki, Y, Yoshitomi, S, Shimono, M, Aoki, Y, Kato, M, Aida, N, Mizuguchi, T, Miyatake, S, et al
Journal of human genetics. 2016;(7):653-61
Abstract
West syndrome is an early-onset epileptic encephalopathy characterized by clustered spasms with hypsarrhythmia seen on electroencephalogram (EEG). West syndrome is genetically heterogeneous, and its genetic causes have not been fully elucidated. WD Repeat Domain 45 (WDR45) resides on Xp11.23, and encodes a member of the WD repeat protein interacting with phosphoinositides (WIPI) family, which is crucial in the macroautophagy pathway. De novo mutations in WDR45 cause beta-propeller protein-associated neurodegeneration characterized by iron accumulation in the basal ganglia. In this study, we performed whole exome sequencing of individuals with West syndrome and identified three WDR45 mutations in three independent males (patients 1, 2 and 3). Two novel mutations occurred de novo (patients 1 and 2) and the remaining mutation detected in a male patient (patient 3) and his affected sister was inherited from the mother, harboring the somatic mutation. The three male patients showed early-onset intractable seizures, profound intellectual disability and developmental delay. Their brain magnetic resonance imaging scans showed cerebral atrophy. We found no evidence of somatic mosaicism in the three male patients. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
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Hereditary pancreatitis of 3 Chinese children: Case report and literature review.
Dai, LN, Chen, YW, Yan, WH, Lu, LN, Tao, YJ, Cai, W
Medicine. 2016;(36):e4604
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BACKGROUND Hereditary pancreatitis (HP) is quite rare and is distinguished by incomplete penetrance presentation as early-onset relapsing pancreatitis, usually beginning in childhood. HP is now known to be commonly relevant to mutations in the PRSS1 (gene-encoding cationic trypsinogen), SPINK1 (serine protease inhibitor, Kazal type 1), CFTR (cystic fibrosis), carboxypeptidase A1 (CPA1), and chymotrypsin C (CTRC) genes as reported in some Caucasian studies. HP has a variable spectrum of severity and may develop complications. METHODS & RESULTS We describe the clinical course of 3 preschool children, hospitalized with postprandial abdominal pain, whose laboratory tests showed high serum amylase. Similar episodes of abdominal pain led to readmission, and the patients recovered quickly after using symptomatic therapy. The condition of the first boy, who developed a pancreatic tail pseudocyst and splenic infarction, was especially complicated. The boy underwent 2 endoscopic retrograde cholangiopancreatographies and stenting, along with a surgical procedure that completely relieved his symptoms for 3 months. The 3 patients and their parents were given genetic testing. All of the patients carried 1 or more gene mutations inherited from their mothers, fathers, or both parents; however, none of the parents were affected. CONCLUSION For children with repeated pancreatitis, clinicians should consider HP in the differential diagnosis. It is reliable to perform gene sequencing on suspicious patients and their parents. Multidisciplinary and comprehensive treatment should be recommended to manage HP and its complications. Cholangiopancreatography and stenting is a relatively minimally invasive approach when compared with surgery and can be tried as an early intervention. Surgical procedures should be reserved for patients with complications.
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Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review.
Gurgel-Giannetti, J, Oliveira, G, Brasileiro Filho, G, Martins, P, Vainzof, M, Hirano, M
JAMA neurology. 2013;(2):258-61
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Abstract
OBJECTIVES To review all patients with SCO2 mutations and to describe a Brazilian patient with cardioencephalomyopathy carrying compound heterozygous mutations in SCO2, one being the known pathogenic p.E140K mutation and the other a novel 12-base pair (bp) deletion at nucleotides 1519 through 1530 (c.1519_1530del). DESIGN Case report and literature review. SETTING University hospital. PATIENT Infant girl presenting with an encephalomyopathy, inspiratory stridor, ventilator failure, progressive hypotonia, and weakness, leading to death. MAIN OUTCOME MEASURES Clinical features, neuroimaging findings, muscle biopsy with histochemical analysis, and genetic studies. RESULTS This infant girl was the first child of healthy, nonconsanguineous parents. She developed progressive muscular hypotonia and ventilatory failure. At the end of the first month of life, she developed cardiomegaly and signs of cardiac failure. Routine blood tests showed lactic acidosis and mild elevation of the creatine kinase level. Brain magnetic resonance imaging showed increased T2 and fluid-attenuated inversion recovery signals in the putamen bilaterally. Nerve conduction studies showed severe axonal sensorimotor neuropathy. Muscle biopsy revealed a neurogenic pattern with mitochondrial proliferation and total absence of cytochrome- c oxidase histochemical stain. Sequencing of SCO2 showed that the patient had compound heterozygote SCO2 mutations: the previously described c.1541G>A (p.E140K) mutation and a novel 12-bp deletion at nucleotides 1519 through 1530 (c.1519_1530del). The patient died at age 45 days. CONCLUSIONS Our findings and the literature review indicate that it is important to consider the diagnosis of mitochondrial disease in newborns with hypotonia and cardiomyopathy. In our case, the accurate diagnosis of SCO2 mutations is particularly important for genetic counseling.
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Abetalipoproteinemia: two case reports and literature review.
Zamel, R, Khan, R, Pollex, RL, Hegele, RA
Orphanet journal of rare diseases. 2008;:19
Abstract
Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL.