Prepared by : Eman Elkomy Supervised by : Ass.Prof. Dr./ Ragaa Abdelkadr Conditions with abnormally low levels of LIPOPROTEINS in the blood. This may involve any of the lipoprotein subclasses, including ALPHA- LIPOPROTEINS (high-density lipoproteins); BETA- LIPOPROTEINS (low-density lipoproteins); and PREBETA-LIPOPROTEINS (very-low-density lipoproteins). The unexpected finding of low cholesterol or low LDL cholesterol in a patient not taking a lipid-lowering drug should prompt a diagnostic evaluation, including measurements of AST (aspartate aminotransferase), ALT (alanine aminotransferase), and thyroid-stimulating hormone; a negative evaluation suggests a possible primary cause. Examples of primary disorders in which single or multiple genetic mutations result in underproduction or increased clearance of LDL. Abetalipoproteinemia Hypobetalipoproteinemia Chylomicron retention disease Loss of function mutations of PCSK9 (proprotein convertase subtilisin-like/kexin type 9) are another cause of low LDL levels. There are no adverse consequences and no treatment, Familial hypobetalipoproteinemia (FHBL) is a disorder that impairs the body's ability to absorb and transport fats, causing low levels of cholesterol in the blood. The severity of the condition varies widely. Mildly affected people may have no signs or symptoms. Many affected people develop an abnormal buildup of fats in the liver (called hepatic steatosis, or fatty liver). In severe cases, this may progress to cirrhosis. Some people also have digestive problems in childhood, resulting in failure to thrive. FHBL is usually caused by mutations in the APOB gene. In a few cases, it may be caused by mutations in other genes, or the cause may be unknown. It is inherited in an autosomal codominant manner. Management may include reducing fat in the diet and vitamin E supplementation. A new case of a Japanese patient with familial hypobetalipoproteinemia (FHBL) caused by a protein-truncating variant in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.1090_1091del/p.Pro364ArgfsTer62) was identified and among her family. None of them exhibited atherosclerotic cardiovascular diseases nor any other complications associated with low LDL cholesterol, including fatty liver, neurocognitive disorders, or cerebral hemorrhaging. . In racent study, genetic analysis of the APOB gene and ophthalmological diagnostics were performed for family members with FHBL. Five relatives with FHBL, including a proband who developed neurological disorders, were examined. A sequencing analysis of the whole coding region of the APOB gene, including flanking intronic regions, was performed using the next-generation sequencing (NGS) method. Electrophysiological ophthalmological examinations were also done. In the proband and his affected relatives, NGS identified the presence of the pathogenic, rare heterozygous splicing variant c.3696+1G>T. Two known heterozygous missense variants-c.2188G>A, p.(Val730Ile) and c.8353A>C, p.(Asn2785His)-in the APOB gene were also detected. In all patients, many ophthalmologic abnormalities in electrophysiological tests were also found. The identified splicing variant c.3696+1G>T can be associated with observed autosomal, dominant FHBL with coexisting neurological symptoms, and both identified missense variants could be excluded as the main cause of observed clinical signs, according to mutation databases and the literature. Electroretinography examination is a sensitive method for the detection of early neuropathy and should therefore be recommended for the care of patients with FHBL. In another racent study,Four novel variants of APOB gene identified in seven FHBL-1 heterozygotes. (c.237+1G>A, c.818+5G>A, c.3000-1G>T, and c.3842+1G>A), predicted in silico to obliterate splice site activity, were found to generate abnormal transcripts. Chylomicron retention disease is an inherited disorder that impairs the normal absorption of fats, cholesterol, and certain vitamins from food. The features of chylomicron retention disease primarily affect the gastrointestinal system and nervous system. Chylomicron retention disease begins in infancy or early childhood. Affected children have slow growth and weight gain, frequent (chronic) diarrhea, and foul-smelling stools (steatorrhea). They also have reduced blood cholesterol levels (hypocholesterolemia). Some individuals with chylomicron retention disease develop an abnormal buildup of fats in the liver called hepatic stenosis and can have an enlarged liver. other features of chylomicron retention disease develop later in childhood and often impair the function of the nervous system. affected people may develop decreased reflexes (hyporeflexia) and a decreased ability to sense vibrations. rarely, affected individuals have heart abnormalities or muscle wasting (amyotrophy). Mutations in a gene called SAR1B cause chylomicron retention disease. The SAR1B gene provides instructions for making a protein that is needed for the transport of molecules called chylomicrons. During digestion, chylomicrons are formed within cells called enterocytes that line the small intestine and absorb nutrients. Chylomicrons are needed to absorb fat-soluble vitamins and carry fats and cholesterol from the small intestine into the bloodstream. SAR1B gene mutations cause the retention of chylomicrons within enterocytes and prevent their release into the bloodstream. Impaired chylomicron transport causes severely decreased absorption (malabsorption) of dietary fats and fat-soluble vitamins, leading to nutritional and developmental problems in people with chylomicron retention disease. Affected individuals are unable to absorb sufficient fats, cholesterol, and vitamins that are necessary for normal growth and development. chylomicron retention disease is a rare condition with approximately 50 cases described worldwide. this condition is inherited in an autosomal recessive pattern Racent study reported 4 children with intestinal lipid malabsorption were found to have chylomicron retention disease due to 3 novel variants in the SAR1B gene.Case 1, a 9-month-old male, was found to be homozygous for a SAR1B variant (c.49 C>T), predicted to encode a truncated Sar1b protein devoid of function (p.Gln17*). Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant [c.409 G>C, p.(Asp137His)], which affects a highly conserved residue close to the Sar1b guanosine recognition site. Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA. The same homozygous mutation was found in an 11-month-old child (case 4) who was related to case 3. is a very rare condition that affects fat and vitamin absorption by the intestines and liver, leading to very low LDL-cholesterol and malnutrition. Early symptoms of this condition include diarrhea, vomiting, and poor growth. Without treatment, later complications may include muscle weakness, poor night and color vision, tremors, and speech difficulties. The long-term outcome can be difficult to predict. Abetalipoproteinemia is diagnosed based on clinical exam, laboratory tests showing abnormally low cholesterol, and confirmed by genetic testing. This condition is caused by genetic variants in the MTTP gene and is inherited in an autosomal recessive pattern. the signs and symptoms of abetalipoproteinemia usually appear in the first few months of life.They can include: inability to absorb fats and some vitamins poor growth in infancy digestive symptoms such as diarrhea and steatorrhea (foul- smelling stools) abnormal, star-shaped red blood cells (acanthocytosis) Because abetalipoproteinemia is extremely rare, the course of the disease is difficult to predict. This condition is usually diagnosed in infancy due to diarrhea, vomiting and poor growth. Most individuals with this condition are treated with excess vitamins and a special, fat-controlled diet and have few complications. Untreated individuals with abetalipoproteinemia can develop gradual vision loss, muscle weakness, tremors, and slow or slurred speech that gets worse over time. This condition has been treated with a low fat diet and vitamin supplements. Most people with abetalipoproteinemia who are treated do not develop complications. Abetalipoproteinemia is very rare and the exact prevalence is difficult to predict. Approximately 100 cases have been reported in the literature.[ Differential diagnoses include metabolic diseases with hepatic overload, with steatosis and/or hepatomegaly, atypical diseases of the central and peripheral nervous system, and secondary causes of hypocholesterolemia (iatrogenic or systemic). Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia, among other lipid-related traits. Racently,LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband's plasma, but with undetectable enzyme activity compared to control relatives. Familial LCAT deficiency (FLD) patients accumulate lipoprotein-X (LP-X), an abnormal nephrotoxic lipoprotein enriched