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Familial hypobetalipoproteinemia 1(FHBL1)

MedGen UID:
1639219
Concept ID:
C4551990
Disease or Syndrome
Synonyms: Acanthocytosis with hypobetalipoproteinemia; HYPOBETALIPOPROTEINEMIA, FAMILIAL; Hypobetalipoproteinemia, normotriglyceridemic
 
Gene (location): APOB (2p24.1)
 
Monarch Initiative: MONDO:0014252
OMIM®: 615558

Disease characteristics

Excerpted from the GeneReview: APOB-Related Familial Hypobetalipoproteinemia
Individuals with biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) may present from infancy through to adulthood with a range of clinical symptoms including deficiency of fat-soluble vitamins and gastrointestinal and neurologic dysfunction. Affected individuals typically have plasma total cholesterol, LDL cholesterol, and apo B levels below the fifth centile for age and sex. Acanthocytosis, elevated liver enzymes, and hyperbilirubinemia may also be found. The most common clinical findings are hepatomegaly, steatorrhea, and failure to thrive / growth deficiency. In the absence of treatment, affected individuals can develop atypical pigmentation of the retina; progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle pain or weakness; dysarthria; ataxia; tremors; and steatohepatitis, fibrosis, and rarely, cirrhosis of the liver. Individuals with a heterozygous, typically truncating pathogenic variant in APOB are usually asymptomatic with mild liver dysfunction and hepatic steatosis. However, about 5%-10% of individuals with heterozygous APOB-FHBL develop relatively more severe nonalcoholic steatohepatitis requiring medical attention and occasionally progressing to cirrhosis, albeit very rarely. [from GeneReviews]
Authors:
John R Burnett  |  Amanda J Hooper  |  Robert A Hegele   view full author information

Additional description

From OMIM
Hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL; 200100) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy, and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein B-containing particles. Obligate heterozygous parents of FHBL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance, whereas obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance (summary by Lee and Hegele, 2014). Genetic Heterogeneity of Familial Hypobetalipoproteinemia Familial hypobetalipoproteinemia-2 (FHBL2; 605019) is caused by mutation in the ANGPTL3 gene (604774) on chromosome 1p31.  http://www.omim.org/entry/615558

Clinical features

From HPO
Steatorrhea
MedGen UID:
20948
Concept ID:
C0038238
Finding
Greater than normal amounts of fat in the feces. This is a result of malabsorption of lipids in the small intestine and results in frothy foul-smelling fecal matter that floats.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Reduced tendon reflexes
MedGen UID:
356648
Concept ID:
C1866934
Finding
Diminution of tendon reflexes, which is an invariable sign of peripheral nerve disease.
Acanthocytosis
MedGen UID:
195801
Concept ID:
C0687751
Disease or Syndrome
Acanthocytosis is a type of poikilocytosis characterized by the presence of spikes on the cell surface. The cells have an irregular shape resembling many-pointed stars.
Decreased circulating vitamin E concentration
MedGen UID:
21881
Concept ID:
C0042875
Disease or Syndrome
A reduced concentration of vitamin E in the blood circulation. Vitamin E is a lipophilic vitamin that is also known as alpha-tocopherol.
Decreased HDL cholesterol concentration
MedGen UID:
57731
Concept ID:
C0151691
Finding
An decreased concentration of high-density lipoprotein cholesterol in the blood.
Hypocholesterolemia
MedGen UID:
57479
Concept ID:
C0151718
Disease or Syndrome
An decreased concentration of cholesterol in the blood.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
An abnormally high concentration in the circulation of aspartate aminotransferase (AST).
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Decreased LDL cholesterol concentration
MedGen UID:
776554
Concept ID:
C0853085
Finding
An decreased concentration of low-density lipoprotein cholesterol in the blood.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.

Professional guidelines

PubMed

Long MT, Noureddin M, Lim JK
Gastroenterology 2022 Sep;163(3):764-774.e1. Epub 2022 Jul 14 doi: 10.1053/j.gastro.2022.06.023. PMID: 35842345Free PMC Article
Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, Hirayama S, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M
J Atheroscler Thromb 2021 Oct 1;28(10):1009-1019. Epub 2021 May 16 doi: 10.5551/jat.RV17056. PMID: 33994405Free PMC Article
Liu Y, Liu ZY, Wan XH, Guo Y
Chin Med Sci J 2018 Mar 30;33(1):53-59. doi: 10.24920/21802. PMID: 29620515

Recent clinical studies

Etiology

Bini S, Tramontano D, Minicocci I, Di Costanzo A, Tambaro F, D'Erasmo L, Arca M
Curr Atheroscler Rep 2023 Jan;25(1):19-29. Epub 2023 Jan 6 doi: 10.1007/s11883-022-01076-w. PMID: 36607583
Rimbert A, Yeung MW, Dalila N, Thio CHL, Yu H, Loaiza N, Oldoni F, van der Graaf A, Wang S, Said MA, Blauw LL, Girardeau A, Bray L, Caillaud A, Bloks VW, Marrec M, Moulin P, Rensen PCN, van de Sluis B, Snieder H, Di Filippo M, van der Harst P, Tybjaerg-Hansen A, Zimmerman P, Cariou B, Kuivenhoven JA
Arterioscler Thromb Vasc Biol 2022 Oct;42(10):1262-1271. Epub 2022 Sep 1 doi: 10.1161/ATVBAHA.122.317514. PMID: 36047410
Long MT, Noureddin M, Lim JK
Gastroenterology 2022 Sep;163(3):764-774.e1. Epub 2022 Jul 14 doi: 10.1053/j.gastro.2022.06.023. PMID: 35842345Free PMC Article
Rimbert A, Vanhoye X, Coulibaly D, Marrec M, Pichelin M, Charrière S, Peretti N, Valéro R, Wargny M, Carrié A, Lindenbaum P, Deleuze JF, Genin E, Redon R, Rollat-Farnier PA, Goxe D, Degraef G, Marmontel O, Divry E, Bigot-Corbel E, Moulin P, Cariou B, Di Filippo M
Arterioscler Thromb Vasc Biol 2021 Jan;41(1):e63-e71. Epub 2020 Nov 19 doi: 10.1161/ATVBAHA.120.315491. PMID: 33207932
Jung HH, Danek A, Walker RH
Orphanet J Rare Dis 2011 Oct 25;6:68. doi: 10.1186/1750-1172-6-68. PMID: 22027213Free PMC Article

Diagnosis

Long MT, Noureddin M, Lim JK
Gastroenterology 2022 Sep;163(3):764-774.e1. Epub 2022 Jul 14 doi: 10.1053/j.gastro.2022.06.023. PMID: 35842345Free PMC Article
Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, Hirayama S, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M
J Atheroscler Thromb 2021 Oct 1;28(10):1009-1019. Epub 2021 May 16 doi: 10.5551/jat.RV17056. PMID: 33994405Free PMC Article
Rimbert A, Vanhoye X, Coulibaly D, Marrec M, Pichelin M, Charrière S, Peretti N, Valéro R, Wargny M, Carrié A, Lindenbaum P, Deleuze JF, Genin E, Redon R, Rollat-Farnier PA, Goxe D, Degraef G, Marmontel O, Divry E, Bigot-Corbel E, Moulin P, Cariou B, Di Filippo M
Arterioscler Thromb Vasc Biol 2021 Jan;41(1):e63-e71. Epub 2020 Nov 19 doi: 10.1161/ATVBAHA.120.315491. PMID: 33207932
Liu Y, Liu ZY, Wan XH, Guo Y
Chin Med Sci J 2018 Mar 30;33(1):53-59. doi: 10.24920/21802. PMID: 29620515
Jung HH, Danek A, Walker RH
Orphanet J Rare Dis 2011 Oct 25;6:68. doi: 10.1186/1750-1172-6-68. PMID: 22027213Free PMC Article

Therapy

Rimbert A, Yeung MW, Dalila N, Thio CHL, Yu H, Loaiza N, Oldoni F, van der Graaf A, Wang S, Said MA, Blauw LL, Girardeau A, Bray L, Caillaud A, Bloks VW, Marrec M, Moulin P, Rensen PCN, van de Sluis B, Snieder H, Di Filippo M, van der Harst P, Tybjaerg-Hansen A, Zimmerman P, Cariou B, Kuivenhoven JA
Arterioscler Thromb Vasc Biol 2022 Oct;42(10):1262-1271. Epub 2022 Sep 1 doi: 10.1161/ATVBAHA.122.317514. PMID: 36047410
Liu Y, Liu ZY, Wan XH, Guo Y
Chin Med Sci J 2018 Mar 30;33(1):53-59. doi: 10.24920/21802. PMID: 29620515
Hooper AJ, Burnett JR, Watts GF
Circ Res 2015 Jan 2;116(1):193-205. doi: 10.1161/CIRCRESAHA.116.304637. PMID: 25552696
Clarke MW, Hooper AJ, Headlam HA, Wu JH, Croft KD, Burnett JR
Clin Chem 2006 Jul;52(7):1339-45. Epub 2006 May 25 doi: 10.1373/clinchem.2006.068692. PMID: 16728468
Jensen K, Gluud C
Hepatology 1994 Oct;20(4 Pt 1):1061-77. doi: 10.1002/hep.1840200440. PMID: 7927209

Prognosis

Rimbert A, Yeung MW, Dalila N, Thio CHL, Yu H, Loaiza N, Oldoni F, van der Graaf A, Wang S, Said MA, Blauw LL, Girardeau A, Bray L, Caillaud A, Bloks VW, Marrec M, Moulin P, Rensen PCN, van de Sluis B, Snieder H, Di Filippo M, van der Harst P, Tybjaerg-Hansen A, Zimmerman P, Cariou B, Kuivenhoven JA
Arterioscler Thromb Vasc Biol 2022 Oct;42(10):1262-1271. Epub 2022 Sep 1 doi: 10.1161/ATVBAHA.122.317514. PMID: 36047410
Long MT, Noureddin M, Lim JK
Gastroenterology 2022 Sep;163(3):764-774.e1. Epub 2022 Jul 14 doi: 10.1053/j.gastro.2022.06.023. PMID: 35842345Free PMC Article
Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, Hirayama S, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M
J Atheroscler Thromb 2021 Oct 1;28(10):1009-1019. Epub 2021 May 16 doi: 10.5551/jat.RV17056. PMID: 33994405Free PMC Article
Jung HH, Danek A, Walker RH
Orphanet J Rare Dis 2011 Oct 25;6:68. doi: 10.1186/1750-1172-6-68. PMID: 22027213Free PMC Article
Palau F, Espinós C
Orphanet J Rare Dis 2006 Nov 17;1:47. doi: 10.1186/1750-1172-1-47. PMID: 17112370Free PMC Article

Clinical prediction guides

Rimbert A, Yeung MW, Dalila N, Thio CHL, Yu H, Loaiza N, Oldoni F, van der Graaf A, Wang S, Said MA, Blauw LL, Girardeau A, Bray L, Caillaud A, Bloks VW, Marrec M, Moulin P, Rensen PCN, van de Sluis B, Snieder H, Di Filippo M, van der Harst P, Tybjaerg-Hansen A, Zimmerman P, Cariou B, Kuivenhoven JA
Arterioscler Thromb Vasc Biol 2022 Oct;42(10):1262-1271. Epub 2022 Sep 1 doi: 10.1161/ATVBAHA.122.317514. PMID: 36047410
Long MT, Noureddin M, Lim JK
Gastroenterology 2022 Sep;163(3):764-774.e1. Epub 2022 Jul 14 doi: 10.1053/j.gastro.2022.06.023. PMID: 35842345Free PMC Article
Rimbert A, Vanhoye X, Coulibaly D, Marrec M, Pichelin M, Charrière S, Peretti N, Valéro R, Wargny M, Carrié A, Lindenbaum P, Deleuze JF, Genin E, Redon R, Rollat-Farnier PA, Goxe D, Degraef G, Marmontel O, Divry E, Bigot-Corbel E, Moulin P, Cariou B, Di Filippo M
Arterioscler Thromb Vasc Biol 2021 Jan;41(1):e63-e71. Epub 2020 Nov 19 doi: 10.1161/ATVBAHA.120.315491. PMID: 33207932
Wang LR, McIntyre AD, Hegele RA
Lipids Health Dis 2018 Mar 14;17(1):48. doi: 10.1186/s12944-018-0680-1. PMID: 29540175Free PMC Article
Jensen K, Gluud C
Hepatology 1994 Oct;20(4 Pt 1):1061-77. doi: 10.1002/hep.1840200440. PMID: 7927209

Recent systematic reviews

Lima Pessoa E, Costa Vilella Dos Reis M, Sayuri Yamamoto T, Ribeiro Neto M, Ferraro O, Alves MJ, Guedes Coelho Lopes R
Breast J 2019 Jul;25(4):763-765. Epub 2019 May 20 doi: 10.1111/tbj.13341. PMID: 31111608

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