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Familial Hypobetalipoproteinemia and Mental Retardation
250
Methods: We report a case of a 24-year old woman of Chinese descent with SLE, severe hypertriglyceridemia and recurrent pancreatitis, who was found to be heterozygous for a mutation in LMF-1. Results: The patient was diagnosed at 12 with SLE when she presented with a malar rash, positive serologies, arthritis and nephritis. She was treated with a course of Cytoxan, prednisone and Cellcept until the age of 19. One year later, she presented to an outside hospital with abdominal pain, vomiting, and CT evidence of pancreatitis, which was treated conservatively. Shortly thereafter, she presented to our hospital with recurrent abdominal pain, vomiting, and a serum triglyceride level in excess of 2,200 mg/dL. Lipids prior to this time were largely unremarkable. Her course was complicated by four episodes of pancreatitis, recurring despite dietary fat restriction and treatment with fibrates, statins, fish oil and xenical. She was additionally treated with methylprednisolone, as it was hypothesized that her pancreatitis and triglyceride elevation were related to her underlying SLE, however she did not improve. In addition, serum triglycerides did not correlate with inflammatory markers or symptomatic ‘‘flares’’ of her SLE. With her permission, the patient’s blood was sent for genotyping and found to have a novel heterozygous missense mutation of LMF-1, namely D491N. Conclusions: Severe hypertriglyceridemia with pancreatitis is a complex clinical trait caused by a range of common and rare genetic factors, including uncommon heterozygous mutations affecting LMF-1 activity. LMF-1 is an ER-bound protein involved in post-translational maturation of LPL, HL and endothelial lipase. Genetic studies in hypertriglyceridemic cohorts have recently identified nonsense mutations in LMF-1, which demonstrate variable phenotypes with shared features of severe hypertriglyceridemia and pancreatitis. This phenotype has been observed in homozygous patients, whereas our patient demonstrates heterozygosity for a mutation in LMF-1. There were no detected mutations in LPL, APOC2, APOA5 or GP1HBP1 genes. We hypothesize that a possible ‘‘double-hit’’ etiology, due to an underlying genetic predisposition along with acquired factors, led to her refractory hypertriglyceridemia. 124 Novel Revelations in Familial Hypercholesterolemia* Yajnavalka Banerjee, PhD, Khalid Al-Rasadi, MD, Ward Al-Muna Al-Zidi, MSc, Khalid Al-Waili, MD, Mohd. Al-Qafrai, PhD, (Muscat, Oman)
Lead Author’s Disclosures: None Study Funding: This study was funded by a Sultan Qaboos University college grant (IG/MED/BIOC/12/01). Synopsis: Familial hypercholesterolemia (FH) is portrayed by elevated circulating concentrations of LDL particles which in turn increases the risk of cardiovascular
Journal of Clinical Lipidology, Vol 7, No 3, June 2013 disease (CVD). Mutations in the lowdensity lipoprotein receptor (LDLR), apolipoprotein-B and proprotein convertase subtilisin/kexin 9 (PCSK9) genes are linked with FH1, FH2, and FH3, respectively. Purpose: The debilitating nature of FH has provided impetus to: (i) Identify mutations in the cognate genes in FH patients from specific population(s); (ii) Study the effect of new mutations on cognate protein structure-function (iii) Identify novel biomarkers to predict the early onset of FH. Methods: The study employed standard DNA sequencing technique for sequencing the cognate FH genes of patients diagnosed with FH according to Simon-Broome Criteria. On line web tools were used for designing the in silico strategy referred to in this study. Lastly, for studying lipidcoagulation factor interaction standard clotting assays, ELISA and surface-pleonasm resonance was used. Results: Using standard sequencing techniques a compound mutation in the LDLR and PCSK9 genes in FH patients belonging to Omani Arab family, was identified. Further an in silico strategy involving LOMET based modules to study the effect of the mutations on different structural levels of cognate proteins was designed. Lastly, we have identified two new lipids of minor physiological abundance that can be used to detect FH. These lipids christened Lead10 and Lead25 are cardio-protective as they mediate anticoagulation by inhibiting Factor Xa as evident from biochemical and biophysical studies. Additionally, Lead25 levels are higher in subjects who have elevated HDL levels. This correlation in the future can be exploited to predict the early onset of CVD in patients including FH patients. Conclusions: This is the first report of a compound mutation from the Arab population. The in silico strategy can be translated to study the effect of existing and newly discovered mutations in the FH genes on associated protein structure. Further, Lead25 provides a new paradigm in the early detection of FH. 125 Familial Hypobetalipoproteinemia and Mental Retardation A. J. Vinaya Simha, MD, (Rochester, Minnesota)
Lead Author’s Disclosures: None Study Funding: None Synopsis: Familial hypobetalipoproteinemia (FHBL) is an autosomal co-dominant disorder characterized by low levels (,5th percentile) of plasma LDL cholesterol and Apolipoprotein B. Most patients are asymptomatic, but some present with steatohepatitis and fat malabsorption, especially in the homozygous state. Neurological manifestations are extremely rare, and there are only 3 previous case reports linking this disorder with impaired neurological development. Purpose: We report another patient with autosomal dominant FHBL in association with mental retardation. Methods: Case Report
Abstracts
Results: The proband is an 18-year-old Caucasian female who was seen for evaluation of abnormal thyroid function tests. She was born after an uncomplicated term pregnancy to healthy, non-consanguineous parents, and was found to have torticollis, hypotonia and poor feeding at birth. These abnormalities gradually improved, but she had persistent delay in developmental milestones. She was able to sit at 9 months, walk at 2 years, and use language at 4 years. At 4.5 y chronological age, her performance on the developmental scale was consistent with an age equivalence of 2 y. She improved with physical therapy and speech therapy, but math and language skills were still at the elementary grade level. In view of mild craniofacial dysmorphy, she was initially suspected to have Cornelia de Lange syndrome, but had a negative molecular screen. A cranial MRI and other extensive tests for inborn errors of metabolism were normal. She was clinically euthyroid, but had a slight elevation in serum free thyroxine with normal thyrotropin levels, prior thyroid function tests were normal. A fasting lipid profile showed total cholesterol 63 mg/dL, triglycerides 14 mg/dL, HDL cholesterol 43 mg/dL and LDL cholesterol 17 mg/dL. Plasma Apolipoprotein B was also markedly low at 18 mg/dL. The presence of hypocholesterolemia and mental retardation was suggestive of Smith-Lemli-Opitz syndrome, but her plasma 7dehydrocholesterol was not elevated. Liver function tests and circulating levels of fat soluble vitamins and other micronutrients were normal. Her father was found to have similarly low LDL cholesterol of 22 mg/dL, thus suggesting the diagnosis of autosomal dominant FHBL. Conclusions: Hypocholesterolemia due to FHBL is generally not considered to have detrimental effects on neurological development. However, the present case, and 3 similar case reports in the past suggest a possible link between hypocholesterolemia and mental retardation. Further studies in these patients may help elucidate the role of circulating LDL particles on neurological function, which would be relevant in this age of intense LDL reduction therapies. 126 Dyslipidemia Profile in Cholesteryl Ester Storage Disorder Radhika Tripuraneni, MD, MPH, Dan Rader, MD, M. Claire Quinn, MD, Anthony G. Quinn, MD, (Philadelphia, Pennsylvania)
Lead Author’s Disclosures: Dr. Tripuraneni is employed by Synageva BioPharma Corp. Study Funding: This study was supported by Synageva BioPharma Corp. Synopsis: Cholesteryl Ester Storage Disease (CESD), also known as late onset Lysosomal Acid Lipase (LAL) Deficiency is an autosomal recessive disorder of children and adults resulting in abnormal accumulation of cholesteryl esters and triglycerides. Patients frequently present with dyslipidemia, elevated transaminases and hepatomegaly. The disorder is an underappreciated cause of cirrhosis and early
251 death and may be misdiagnosed or underdiagnosed because of low disease awareness and the potential for confusion with more common disorders. Currently, there are no approved therapies that treat the underlying pathology and lipid lowering agents have shown limited benefit. Purpose: To better understand the dyslipidemia that occurs in CESD. Methods: We conducted a systematic review of the literature to identify case reports of CESD. Key words of lysosomal acid lipase OR cholesteryl ester storage disease OR CESD OR LIPA Deficiency were applied to all available databases. For analysis of age of onset, duplicate cases and cases with no clinical data were excluded. Results: We identified 69 publications describing 111 cases; of these, 94 cases had sufficient data to analyze. 22 of these cases were either deceased, underwent liver transplant or had evidence of chronic liver disease. In more than 90% of the cases, patients had either history of hepatomegaly and/or elevated transaminases. Age was reported in 67 cases; the median age at diagnosis was 9 years. Of the cases with at least one LDL-C level reported, the median LDL-C was 243 mg/dL in females (n 5 14) and 228 mg/dL in males (n 5 16). There was marked variability in triglycerides and HDL-C but the median reported HDL-C values were 24 mg/dL in females (n 5 21) and 22 mg/dL in males (n 5 21). The median highest reported triglyceride was 222 mg/dL. Conclusions: Dyslipidemia characterized by elevated LDL-C and low HDL-C is a common finding in patients with CESD and may facilitate the suspicion and ultimate diagnosis of this disease. We conclude that the diagnosis of CESD should be considered and ruled out in patients who present with persistently elevated LDL-C together with hepatomegaly and/or elevated liver transaminases as well as in patients with only elevated LDL-C and low HDL-C. Focusing testing for CESD on non-obese patients meeting these criteria will allow enrichment in positive diagnoses by excluding many patients with similar findings due to the metabolic syndrome.
HDL Modification, Novel HDL Raising Therapies 127 Impact of Inflammatory Biomarkers on Relation of HDL-C with Incident Coronary Heart Disease and Cardiovascular Disease: Cardiovascular Health Study* David Tehrani, MS, Julius Gardin, MD, David Yanez, PhD, Calvin Hirsch, MD, Donald Lloyd-Jones, MD, Phyllis Stein, PhD, Nathan Wong, PhD, (Irvine, California)
Lead Author’s Disclosures: None Study Funding: None Synopsis: Inflammatory factors and low high density lipoprotein cholesterol (HDL-C) are associated with
Methods: We report a case of a 24-year old woman of Chinese descent with SLE, severe hypertriglyceridemia and recurrent pancreatitis, who was found to be heterozygous for a mutation in LMF-1. Results: The patient was diagnosed at 12 with SLE when she presented with a malar rash, positive serologies, arthritis and nephritis. She was treated with a course of Cytoxan, prednisone and Cellcept until the age of 19. One year later, she presented to an outside hospital with abdominal pain, vomiting, and CT evidence of pancreatitis, which was treated conservatively. Shortly thereafter, she presented to our hospital with recurrent abdominal pain, vomiting, and a serum triglyceride level in excess of 2,200 mg/dL. Lipids prior to this time were largely unremarkable. Her course was complicated by four episodes of pancreatitis, recurring despite dietary fat restriction and treatment with fibrates, statins, fish oil and xenical. She was additionally treated with methylprednisolone, as it was hypothesized that her pancreatitis and triglyceride elevation were related to her underlying SLE, however she did not improve. In addition, serum triglycerides did not correlate with inflammatory markers or symptomatic ‘‘flares’’ of her SLE. With her permission, the patient’s blood was sent for genotyping and found to have a novel heterozygous missense mutation of LMF-1, namely D491N. Conclusions: Severe hypertriglyceridemia with pancreatitis is a complex clinical trait caused by a range of common and rare genetic factors, including uncommon heterozygous mutations affecting LMF-1 activity. LMF-1 is an ER-bound protein involved in post-translational maturation of LPL, HL and endothelial lipase. Genetic studies in hypertriglyceridemic cohorts have recently identified nonsense mutations in LMF-1, which demonstrate variable phenotypes with shared features of severe hypertriglyceridemia and pancreatitis. This phenotype has been observed in homozygous patients, whereas our patient demonstrates heterozygosity for a mutation in LMF-1. There were no detected mutations in LPL, APOC2, APOA5 or GP1HBP1 genes. We hypothesize that a possible ‘‘double-hit’’ etiology, due to an underlying genetic predisposition along with acquired factors, led to her refractory hypertriglyceridemia. 124 Novel Revelations in Familial Hypercholesterolemia* Yajnavalka Banerjee, PhD, Khalid Al-Rasadi, MD, Ward Al-Muna Al-Zidi, MSc, Khalid Al-Waili, MD, Mohd. Al-Qafrai, PhD, (Muscat, Oman)
Lead Author’s Disclosures: None Study Funding: This study was funded by a Sultan Qaboos University college grant (IG/MED/BIOC/12/01). Synopsis: Familial hypercholesterolemia (FH) is portrayed by elevated circulating concentrations of LDL particles which in turn increases the risk of cardiovascular
Journal of Clinical Lipidology, Vol 7, No 3, June 2013 disease (CVD). Mutations in the lowdensity lipoprotein receptor (LDLR), apolipoprotein-B and proprotein convertase subtilisin/kexin 9 (PCSK9) genes are linked with FH1, FH2, and FH3, respectively. Purpose: The debilitating nature of FH has provided impetus to: (i) Identify mutations in the cognate genes in FH patients from specific population(s); (ii) Study the effect of new mutations on cognate protein structure-function (iii) Identify novel biomarkers to predict the early onset of FH. Methods: The study employed standard DNA sequencing technique for sequencing the cognate FH genes of patients diagnosed with FH according to Simon-Broome Criteria. On line web tools were used for designing the in silico strategy referred to in this study. Lastly, for studying lipidcoagulation factor interaction standard clotting assays, ELISA and surface-pleonasm resonance was used. Results: Using standard sequencing techniques a compound mutation in the LDLR and PCSK9 genes in FH patients belonging to Omani Arab family, was identified. Further an in silico strategy involving LOMET based modules to study the effect of the mutations on different structural levels of cognate proteins was designed. Lastly, we have identified two new lipids of minor physiological abundance that can be used to detect FH. These lipids christened Lead10 and Lead25 are cardio-protective as they mediate anticoagulation by inhibiting Factor Xa as evident from biochemical and biophysical studies. Additionally, Lead25 levels are higher in subjects who have elevated HDL levels. This correlation in the future can be exploited to predict the early onset of CVD in patients including FH patients. Conclusions: This is the first report of a compound mutation from the Arab population. The in silico strategy can be translated to study the effect of existing and newly discovered mutations in the FH genes on associated protein structure. Further, Lead25 provides a new paradigm in the early detection of FH. 125 Familial Hypobetalipoproteinemia and Mental Retardation A. J. Vinaya Simha, MD, (Rochester, Minnesota)
Lead Author’s Disclosures: None Study Funding: None Synopsis: Familial hypobetalipoproteinemia (FHBL) is an autosomal co-dominant disorder characterized by low levels (,5th percentile) of plasma LDL cholesterol and Apolipoprotein B. Most patients are asymptomatic, but some present with steatohepatitis and fat malabsorption, especially in the homozygous state. Neurological manifestations are extremely rare, and there are only 3 previous case reports linking this disorder with impaired neurological development. Purpose: We report another patient with autosomal dominant FHBL in association with mental retardation. Methods: Case Report
Abstracts
Results: The proband is an 18-year-old Caucasian female who was seen for evaluation of abnormal thyroid function tests. She was born after an uncomplicated term pregnancy to healthy, non-consanguineous parents, and was found to have torticollis, hypotonia and poor feeding at birth. These abnormalities gradually improved, but she had persistent delay in developmental milestones. She was able to sit at 9 months, walk at 2 years, and use language at 4 years. At 4.5 y chronological age, her performance on the developmental scale was consistent with an age equivalence of 2 y. She improved with physical therapy and speech therapy, but math and language skills were still at the elementary grade level. In view of mild craniofacial dysmorphy, she was initially suspected to have Cornelia de Lange syndrome, but had a negative molecular screen. A cranial MRI and other extensive tests for inborn errors of metabolism were normal. She was clinically euthyroid, but had a slight elevation in serum free thyroxine with normal thyrotropin levels, prior thyroid function tests were normal. A fasting lipid profile showed total cholesterol 63 mg/dL, triglycerides 14 mg/dL, HDL cholesterol 43 mg/dL and LDL cholesterol 17 mg/dL. Plasma Apolipoprotein B was also markedly low at 18 mg/dL. The presence of hypocholesterolemia and mental retardation was suggestive of Smith-Lemli-Opitz syndrome, but her plasma 7dehydrocholesterol was not elevated. Liver function tests and circulating levels of fat soluble vitamins and other micronutrients were normal. Her father was found to have similarly low LDL cholesterol of 22 mg/dL, thus suggesting the diagnosis of autosomal dominant FHBL. Conclusions: Hypocholesterolemia due to FHBL is generally not considered to have detrimental effects on neurological development. However, the present case, and 3 similar case reports in the past suggest a possible link between hypocholesterolemia and mental retardation. Further studies in these patients may help elucidate the role of circulating LDL particles on neurological function, which would be relevant in this age of intense LDL reduction therapies. 126 Dyslipidemia Profile in Cholesteryl Ester Storage Disorder Radhika Tripuraneni, MD, MPH, Dan Rader, MD, M. Claire Quinn, MD, Anthony G. Quinn, MD, (Philadelphia, Pennsylvania)
Lead Author’s Disclosures: Dr. Tripuraneni is employed by Synageva BioPharma Corp. Study Funding: This study was supported by Synageva BioPharma Corp. Synopsis: Cholesteryl Ester Storage Disease (CESD), also known as late onset Lysosomal Acid Lipase (LAL) Deficiency is an autosomal recessive disorder of children and adults resulting in abnormal accumulation of cholesteryl esters and triglycerides. Patients frequently present with dyslipidemia, elevated transaminases and hepatomegaly. The disorder is an underappreciated cause of cirrhosis and early
251 death and may be misdiagnosed or underdiagnosed because of low disease awareness and the potential for confusion with more common disorders. Currently, there are no approved therapies that treat the underlying pathology and lipid lowering agents have shown limited benefit. Purpose: To better understand the dyslipidemia that occurs in CESD. Methods: We conducted a systematic review of the literature to identify case reports of CESD. Key words of lysosomal acid lipase OR cholesteryl ester storage disease OR CESD OR LIPA Deficiency were applied to all available databases. For analysis of age of onset, duplicate cases and cases with no clinical data were excluded. Results: We identified 69 publications describing 111 cases; of these, 94 cases had sufficient data to analyze. 22 of these cases were either deceased, underwent liver transplant or had evidence of chronic liver disease. In more than 90% of the cases, patients had either history of hepatomegaly and/or elevated transaminases. Age was reported in 67 cases; the median age at diagnosis was 9 years. Of the cases with at least one LDL-C level reported, the median LDL-C was 243 mg/dL in females (n 5 14) and 228 mg/dL in males (n 5 16). There was marked variability in triglycerides and HDL-C but the median reported HDL-C values were 24 mg/dL in females (n 5 21) and 22 mg/dL in males (n 5 21). The median highest reported triglyceride was 222 mg/dL. Conclusions: Dyslipidemia characterized by elevated LDL-C and low HDL-C is a common finding in patients with CESD and may facilitate the suspicion and ultimate diagnosis of this disease. We conclude that the diagnosis of CESD should be considered and ruled out in patients who present with persistently elevated LDL-C together with hepatomegaly and/or elevated liver transaminases as well as in patients with only elevated LDL-C and low HDL-C. Focusing testing for CESD on non-obese patients meeting these criteria will allow enrichment in positive diagnoses by excluding many patients with similar findings due to the metabolic syndrome.
HDL Modification, Novel HDL Raising Therapies 127 Impact of Inflammatory Biomarkers on Relation of HDL-C with Incident Coronary Heart Disease and Cardiovascular Disease: Cardiovascular Health Study* David Tehrani, MS, Julius Gardin, MD, David Yanez, PhD, Calvin Hirsch, MD, Donald Lloyd-Jones, MD, Phyllis Stein, PhD, Nathan Wong, PhD, (Irvine, California)
Lead Author’s Disclosures: None Study Funding: None Synopsis: Inflammatory factors and low high density lipoprotein cholesterol (HDL-C) are associated with