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Dyslipidemia and Sustained Transaminase Elevations from Early Childhood are Common in Lysosomal Acid Lipase Deficiency
306
Journal of Clinical Lipidology, Vol 8, No 3, June 2014
British Columbia, Canada for the measurement of LCAT activity, cholesterol esterification rates, and the amount of unesterified or free cholesterol in plasma. Further samples were sent to the Lipid Metabolism Laboratory at Tufts University. Results: Lipoprotein X was not present in either of the probands, either the index case or her affected brother. The defect was due to one common variant LCAT mutation in exon 1: c101t causing a substitution of proline (P) by leucine (L) at position 34 (P34L substitution) and c1177t causing a substitution of threonine (T) by methionine (M) at position 37 (T37M), with the former mutation being found in the father and one sibling, the latter mutation being found in the mother, and both mutations being present in the probands. The latter mutation has not previously been reported. Conclusion: It is important to understand the fundamental difference between Familial LCAT Deficiency and Fish Eye Disease. In the former disorder, there are abnormal VLDL and LDL particles including Lp-X. This disorder is associated with anemia, splenomegaly, and renal insufficiency and proteinuria. None of these findings are Table 1
Plasma Lipid and Apolipoprotein Levels (mg/dl)
Subject
HDL-C ApoA-I LDL-C sdLDL-C ApoB Triglycerides
Proband 1 Proband 2 Brother Father Mother Normal (male) Normal (female)
6.1* 3.0* 23* 32* 38* 45
36.0* 13.9* 106* 117* 127* 141
157* 156* 158* 93 156* 98
42* 70* 52* 26 21 34
142* 174* 130* 86 98 87
158* 290* 272* 140 108 121
57
166
109
25
98
116
*Starred values indicate above or below the 25th-75th percentile value) Normal levels (50th percentile values) based on 17,011 males and 17,073 females, median age 60 years). HDL-C 5 High density lipoprotein cholesterol, ApoA-1 5 Apoprotein A-1, LDL-C5 Low density lipoprotein chosterol, sdLDL-C5 small dense low density lipoprotein cholesterol, ApoB5 Apoprotein B.
Table 4 LCAT Activity, Cholesterol Esterification Rate, and Unesterified Cholesterol
Figure 2
present in Fish Eye Disease. Both Disorders share corneal opacification and marked HDL deficiency. Development of atherosclerosis has been reported in up to 30% of patients with Fish Eye Disease. In terms of therapy for FED, it appears to be prudent to lower LDL-C to decrease risk of premature CHD. In FLD patients, it is critical to control all risk for renal insufficiency including hypertension, diabetes and Lp-X. Study on recombinant LCAT infusion in this group is on going.
114 Dyslipidemia and Sustained Transaminase Elevations from Early Childhood are Common in Lysosomal Acid Lipase Deficiency Radhika Tripuraneni, Barbara Burton, Patrick Deegan, Maja Di. Rocco, Greg Enns, Ornella Guardamagna, Simon Horslen, G. K. Hovingh, Stephen Lobritto, Vera Malinova, Valerie McLin, Julian Raiman, Saikat Santra, Reena Sharma, Jolanta Sykut-Cegielska, Vassili Valayannopoulos, Stephen Eckert, Anthony G. Quinn, (Boston, MA)
Lead Author’s Financial Disclosures: R. Tripuraneni is an employee of Synageva BioPharma Corp.
Subject
LCAT Cholesterol Unesterified activity Esterification cholesterol (nmol/h/ml) Rate (nmol/h/ml) (mmol/L)
Study Funding: Yes Funding Sources: This study was funded by Synageva
Proband 1 Proband 2 Brother Father Mother *Control Pool
2.74 2.68 17.40 22.73 17.50 34.90
Background/Synopsis: LAL Deficiency (LAL D) is
68.3 60.3 54.9 83.6 86.8 152.0
*The control pool was a frozen normal plasma pool.
1.89 1.72 1.17 1.38 1.23 1.10
BioPharma Corp. an underappreciated cause of cirrhosis, dyslipidemia and premature atherosclerotic disease in children and adults. This autosomal recessive disorder results from mutations in the LIPA gene that encodes for lysosomal acid lipase. Disease manifestations resemble those seen in some common disorders and delayed diagnosis is common.
Abstracts
Objective/Purpose: In order to better characterize the presentation and progression of LAL D, we have conducted a multinational observational study in children and adults with LAL Deficiency (n5 48). Methods: Data was compiled by performing a retrospective chart review of subjects with documented LAL Deficiency. Results: The median age (range) of first symptoms was 5.8 (0.0 to 42.0) years and the median age at diagnosis was 9.5 (1.2 to 46.1) years. The median age at which dyslipidemia or elevated transaminases was reported was 8.4 and 8.2 years, respectively. 44 of the 48 patients had an ALT above the upper limit of normal (median 80.5 U/L) at the first recorded assessment (on study), and almost all remained abnormal. (follow-up interval 3 to 24 months). The median highest reported total cholesterol, LDL and triglycerides were 316 mg/dL, 239 mg/dL, and 219 mg/dL respectively and the median lowest HDL was 26.5 mg/dL. 67% of patients had dietary interventions during the course of their disease and 65% had received lipid lowering therapy. Although improvements in serum lipids were observed in some patients, these interventions seemed to have a limited effect on controlling the liver disease. Six of the 48 patients underwent liver transplant: 4 patients were under the age of 18 at the time of transplant, while 2 were over the age of 40 and both developed end-stage liver disease rather precipitously. Conclusion: Disease appears to be progressive in some patients despite restriction of dietary fat or lipid lowering therapy. End-stage hepatic complications may develop rapidly and without apparent warning. In conclusion, this study confirms that dyslipidemia and hepatic dysfunction are common in LAL D children, although the diagnosis is often delayed because of non-specific presentation.
115 Gene Sequencing in US Patients with Severe Clinical Familial Hypercholesterolemia*
307 result from mutations in the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9). Gene sequencing for molecular diagnosis of FH is rarely performed clinically in the US. Objective/Purpose: To determine the specific mutations in patients with clinical and laboratory characteristics of severe clinical FH. Methods: DNA samples of research subjects with clinical and laboratory characteristics of FH were sent to PROGENIKA Inc for genetic sequencing. Next-generation sequencing was performed using SEQPRO LIPO v1, which is designed to detect mutations in the three known genes causing autosomal dominant hypercholesterolemia (i.e., LDLR, APOB, and PCSK9) and in the LDRAP1 gene causing autosomal recessive hypercholesterolemia. It also analyses copy number variations in the LDLR associated with FH. Results: Under an IRB-approved protocol, DNA samples from 25 patients meeting MEDPED (Make Early Diagnosis-Prevent Early Death) criteria for definite FH (mean LDL-C 406 mg/dL) were sequenced for LDLR, APOB, PCSK9, and LDLRAP1. 17 (68%) subjects were found to have a heterozygous pathogenic mutation in LDLR; 2 (8%) subjects were found to have a heterozygous variant of unknown pathogenicity in LDLR; and 6 (24%) subjects had no pathogenic mutations detected. Of the 6 without a detectable mutation, the mean LDL-C was 416 mg/dL (range 242 to 519 mg/dL) and 2 are on LDL apheresis. Conclusion: Our findings show that while pathogenic mutations or variants of unknown significance in LDLR were detected in 76% of patients selected for severe clinical FH phenotypes, no disease-causing mutations were found in 6 (24%) subjects. These findings suggest that other causes of severe FH phenotype may be present and highlight the need for further evaluation to improve diagnosis and management of these patients.
Marisa Schoen, BA, Emil deGoma, MD, Martianne Stef, PhD, Marina Cuchel, MD, PhD, Daniel Rader, MD, (Philadelphia, PA)
Lead Author’s Financial Disclosures: None Study Funding: Yes Funding Sources: Genetic sequencing was performed at no cost by Progenika Biopharma SA. Background/Synopsis: Familial hypercholesterolemia (FH) is characterized by increased plasma levels of lowdensity lipoprotein (LDL) cholesterol, tendon xanthoma, and premature atherosclerotic cardiovascular disease. FH, also called autosomal dominant hypercholesterolemia, can
Supplementary Figure Summary of results of patients sequenced* for pathogenic mutations and variants of unknown pathogenicity in LDLR, APOB, PCSK9, and LDRAP1.
Journal of Clinical Lipidology, Vol 8, No 3, June 2014
British Columbia, Canada for the measurement of LCAT activity, cholesterol esterification rates, and the amount of unesterified or free cholesterol in plasma. Further samples were sent to the Lipid Metabolism Laboratory at Tufts University. Results: Lipoprotein X was not present in either of the probands, either the index case or her affected brother. The defect was due to one common variant LCAT mutation in exon 1: c101t causing a substitution of proline (P) by leucine (L) at position 34 (P34L substitution) and c1177t causing a substitution of threonine (T) by methionine (M) at position 37 (T37M), with the former mutation being found in the father and one sibling, the latter mutation being found in the mother, and both mutations being present in the probands. The latter mutation has not previously been reported. Conclusion: It is important to understand the fundamental difference between Familial LCAT Deficiency and Fish Eye Disease. In the former disorder, there are abnormal VLDL and LDL particles including Lp-X. This disorder is associated with anemia, splenomegaly, and renal insufficiency and proteinuria. None of these findings are Table 1
Plasma Lipid and Apolipoprotein Levels (mg/dl)
Subject
HDL-C ApoA-I LDL-C sdLDL-C ApoB Triglycerides
Proband 1 Proband 2 Brother Father Mother Normal (male) Normal (female)
6.1* 3.0* 23* 32* 38* 45
36.0* 13.9* 106* 117* 127* 141
157* 156* 158* 93 156* 98
42* 70* 52* 26 21 34
142* 174* 130* 86 98 87
158* 290* 272* 140 108 121
57
166
109
25
98
116
*Starred values indicate above or below the 25th-75th percentile value) Normal levels (50th percentile values) based on 17,011 males and 17,073 females, median age 60 years). HDL-C 5 High density lipoprotein cholesterol, ApoA-1 5 Apoprotein A-1, LDL-C5 Low density lipoprotein chosterol, sdLDL-C5 small dense low density lipoprotein cholesterol, ApoB5 Apoprotein B.
Table 4 LCAT Activity, Cholesterol Esterification Rate, and Unesterified Cholesterol
Figure 2
present in Fish Eye Disease. Both Disorders share corneal opacification and marked HDL deficiency. Development of atherosclerosis has been reported in up to 30% of patients with Fish Eye Disease. In terms of therapy for FED, it appears to be prudent to lower LDL-C to decrease risk of premature CHD. In FLD patients, it is critical to control all risk for renal insufficiency including hypertension, diabetes and Lp-X. Study on recombinant LCAT infusion in this group is on going.
114 Dyslipidemia and Sustained Transaminase Elevations from Early Childhood are Common in Lysosomal Acid Lipase Deficiency Radhika Tripuraneni, Barbara Burton, Patrick Deegan, Maja Di. Rocco, Greg Enns, Ornella Guardamagna, Simon Horslen, G. K. Hovingh, Stephen Lobritto, Vera Malinova, Valerie McLin, Julian Raiman, Saikat Santra, Reena Sharma, Jolanta Sykut-Cegielska, Vassili Valayannopoulos, Stephen Eckert, Anthony G. Quinn, (Boston, MA)
Lead Author’s Financial Disclosures: R. Tripuraneni is an employee of Synageva BioPharma Corp.
Subject
LCAT Cholesterol Unesterified activity Esterification cholesterol (nmol/h/ml) Rate (nmol/h/ml) (mmol/L)
Study Funding: Yes Funding Sources: This study was funded by Synageva
Proband 1 Proband 2 Brother Father Mother *Control Pool
2.74 2.68 17.40 22.73 17.50 34.90
Background/Synopsis: LAL Deficiency (LAL D) is
68.3 60.3 54.9 83.6 86.8 152.0
*The control pool was a frozen normal plasma pool.
1.89 1.72 1.17 1.38 1.23 1.10
BioPharma Corp. an underappreciated cause of cirrhosis, dyslipidemia and premature atherosclerotic disease in children and adults. This autosomal recessive disorder results from mutations in the LIPA gene that encodes for lysosomal acid lipase. Disease manifestations resemble those seen in some common disorders and delayed diagnosis is common.
Abstracts
Objective/Purpose: In order to better characterize the presentation and progression of LAL D, we have conducted a multinational observational study in children and adults with LAL Deficiency (n5 48). Methods: Data was compiled by performing a retrospective chart review of subjects with documented LAL Deficiency. Results: The median age (range) of first symptoms was 5.8 (0.0 to 42.0) years and the median age at diagnosis was 9.5 (1.2 to 46.1) years. The median age at which dyslipidemia or elevated transaminases was reported was 8.4 and 8.2 years, respectively. 44 of the 48 patients had an ALT above the upper limit of normal (median 80.5 U/L) at the first recorded assessment (on study), and almost all remained abnormal. (follow-up interval 3 to 24 months). The median highest reported total cholesterol, LDL and triglycerides were 316 mg/dL, 239 mg/dL, and 219 mg/dL respectively and the median lowest HDL was 26.5 mg/dL. 67% of patients had dietary interventions during the course of their disease and 65% had received lipid lowering therapy. Although improvements in serum lipids were observed in some patients, these interventions seemed to have a limited effect on controlling the liver disease. Six of the 48 patients underwent liver transplant: 4 patients were under the age of 18 at the time of transplant, while 2 were over the age of 40 and both developed end-stage liver disease rather precipitously. Conclusion: Disease appears to be progressive in some patients despite restriction of dietary fat or lipid lowering therapy. End-stage hepatic complications may develop rapidly and without apparent warning. In conclusion, this study confirms that dyslipidemia and hepatic dysfunction are common in LAL D children, although the diagnosis is often delayed because of non-specific presentation.
115 Gene Sequencing in US Patients with Severe Clinical Familial Hypercholesterolemia*
307 result from mutations in the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9). Gene sequencing for molecular diagnosis of FH is rarely performed clinically in the US. Objective/Purpose: To determine the specific mutations in patients with clinical and laboratory characteristics of severe clinical FH. Methods: DNA samples of research subjects with clinical and laboratory characteristics of FH were sent to PROGENIKA Inc for genetic sequencing. Next-generation sequencing was performed using SEQPRO LIPO v1, which is designed to detect mutations in the three known genes causing autosomal dominant hypercholesterolemia (i.e., LDLR, APOB, and PCSK9) and in the LDRAP1 gene causing autosomal recessive hypercholesterolemia. It also analyses copy number variations in the LDLR associated with FH. Results: Under an IRB-approved protocol, DNA samples from 25 patients meeting MEDPED (Make Early Diagnosis-Prevent Early Death) criteria for definite FH (mean LDL-C 406 mg/dL) were sequenced for LDLR, APOB, PCSK9, and LDLRAP1. 17 (68%) subjects were found to have a heterozygous pathogenic mutation in LDLR; 2 (8%) subjects were found to have a heterozygous variant of unknown pathogenicity in LDLR; and 6 (24%) subjects had no pathogenic mutations detected. Of the 6 without a detectable mutation, the mean LDL-C was 416 mg/dL (range 242 to 519 mg/dL) and 2 are on LDL apheresis. Conclusion: Our findings show that while pathogenic mutations or variants of unknown significance in LDLR were detected in 76% of patients selected for severe clinical FH phenotypes, no disease-causing mutations were found in 6 (24%) subjects. These findings suggest that other causes of severe FH phenotype may be present and highlight the need for further evaluation to improve diagnosis and management of these patients.
Marisa Schoen, BA, Emil deGoma, MD, Martianne Stef, PhD, Marina Cuchel, MD, PhD, Daniel Rader, MD, (Philadelphia, PA)
Lead Author’s Financial Disclosures: None Study Funding: Yes Funding Sources: Genetic sequencing was performed at no cost by Progenika Biopharma SA. Background/Synopsis: Familial hypercholesterolemia (FH) is characterized by increased plasma levels of lowdensity lipoprotein (LDL) cholesterol, tendon xanthoma, and premature atherosclerotic cardiovascular disease. FH, also called autosomal dominant hypercholesterolemia, can
Supplementary Figure Summary of results of patients sequenced* for pathogenic mutations and variants of unknown pathogenicity in LDLR, APOB, PCSK9, and LDRAP1.