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Abetalipoproteinemia

Bassen Kornzweig Syndrome

Abetalipoproteinemia is a rare autosomal recessive disorder characterized by the inability of the body to absorb lipoproteins from the gastroenterological system due to mutations of proteins responsible for their transport across enterocytes. Diarrhea, failure to thrive, acanthocytosis and central nervous system complications are most important features. The diagnosis requires a thorough diagnostic workup, including laboratory and genetic studies.


Presentation

The clinical presentation of abetalipoproteinemia (ABL) stems from an insufficient physiological transport of plasma B-containing lipoproteins - chylomicrons, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), due to mutations of the microsomal triglyceride transfer protein (MTP), responsible for their transfer through enterocytes [1] [2]. Malabsorption of fat and fat-soluble vitamins, principal pathological events, lead to a very early onset of failure to thrive, reduced growth and severe fatty diarrhea (steatorrhea) [1] [3]. Gradually, diarrhea can subside as patients learn to avoid foods that have shown to induce diarrhea, but the deficiency of fat-soluble vitamins can cause numerous symptoms [1] [3]. Central nervous system damage and visual deficits, due to deficiencies of vitamins E and A, respectively, are most important long-term complications. Reduced deep-tendon reflexes, dysmetria, ataxia, diminished proprioception and vibratory sense, as well as progressive neuropathy, may develop in the first two decades of life [1] [4]. Conversely, pigmentary retinopathy leads to scotomas, loss of color and night vision, and even blindness [1] [4]. Additional complications that have been documented in the literature include coagulopathies (due to vitamin K deficiency), myopathy and demyelination that can cause a spastic gait, while reduced fertility is also reported [1] [2] [4].

Difficulty Walking
  • These may include: Sensory disturbances: This includes problems with sensing temperature and touch –– especially in the hands and feet (hypesthesia) Trouble walking ( ataxia ): Approximately 33 percent of children will have difficulty walking by the time[verywellhealth.com]
  • These may include: Sensory disturbances: This includes problems with sensing temperature and touch –– especially in the hands and feet (hypesthesia) Trouble walking (ataxia): Approximately 33 percent of children will have difficulty walking by the time[verywell.com]
  • Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking, and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating[rarediseases.org]
Painter
  • Zeissig S 1 , Dougan SK , Barral DC , Junker Y , Chen Z , Kaser A , Ho M , Mandel H , McIntyre A , Kennedy SM , Painter GF , Veerapen N , Besra GS , Cerundolo V , Yue S , Beladi S , Behar SM , Chen X , Gumperz JE , Breckpot K , Raper A , Baer A , Exley[ncbi.nlm.nih.gov]
Diarrhea
  • Gradually, diarrhea can subside as patients learn to avoid foods that have shown to induce diarrhea, but the deficiency of fat-soluble vitamins can cause numerous symptoms.[symptoma.com]
  • Three months later, his fatty diarrhea becomes normal stool, his serum fat-soluble vitamins normalized, and his weight increased from 4.1 kg to 5.9 kg.[ncbi.nlm.nih.gov]
  • We investigated three unrelated Tunisian children born from consanguineous marriages, presenting hypobetalipoproteinemia associated with chronic diarrhea and retarded growth.[ncbi.nlm.nih.gov]
  • The patient complained of diarrhea, and showed a deficiency of betalipoprotein, decreased fat-soluble vitamins, acanthocytosis and a mild increase in serum creatine kinase.[ncbi.nlm.nih.gov]
  • He had a history of chronic diarrhea from the first month of life. He was cachectic and his motor development was delayed. Microscopic examination of the stool revealed fat.[ncbi.nlm.nih.gov]
Chronic Diarrhea
  • We investigated three unrelated Tunisian children born from consanguineous marriages, presenting hypobetalipoproteinemia associated with chronic diarrhea and retarded growth.[ncbi.nlm.nih.gov]
  • He had a history of chronic diarrhea from the first month of life. He was cachectic and his motor development was delayed. Microscopic examination of the stool revealed fat.[ncbi.nlm.nih.gov]
  • A five-month-old boy, born from consanguineous parents, with chronic diarrhea and severe malnutrition had extremely low plasma lipids and apoB levels suggesting the diagnosis of ABL.[ncbi.nlm.nih.gov]
  • Intestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth.[ncbi.nlm.nih.gov]
  • The diagnosis of abetalipoproteinemia was established in the case of a 17-year old man with chronic diarrhea, growth retardation, neurological derangements, visual impairment and retinitis pigmentosa, low plasma cholesterol, triglyceride and LDL cholesterol[turkjem.org]
Ataxia
  • Providing complementary sections on the anatomy of the spinocerebellar system, its normal function, and a history of ataxia research and management, the Handbook of Ataxia Disorders clarifies the impact of identifying the molecular causes of ataxia offers[books.google.ro]
  • Abetalipoproteinemia (ABL [Bassen-Kornzweig syndrome]) is characterized by marked hypolipidemia with absence of low-density lipoproteins, fat-soluble vitamin deficiency, spinocerebellar ataxia, and retinitis pigmentosa.[ncbi.nlm.nih.gov]
  • The good outcome of the early-treated patients contrasts with severe ataxia and retinopathy observed in the patient with delayed treatment.[ncbi.nlm.nih.gov]
  • Introduction The hereditary ataxias have been extensively studied clinically and pathologically, but the fundamental nature of these diseases is not known.[jamanetwork.com]
  • The broad spectrum of presentations includes malabsorption, failure to thrive and acanthocytosis in children, while later in life expected manifestations include coagulopathy, myopathy, retinitis pigmentosa, peripheral neuropathy, hyporeflexia and ataxia[ncbi.nlm.nih.gov]
Absent Deep Tendon Reflex
  • Neurological problems tend to begin with reduced or absent deep tendon reflexes (e.g. knee jerks) and loss of balance when their eyes are closed (Romberg's sign). If ABL is not treated, it progresses and a condition called ataxia develops.[forgottendiseases.org]
  • Neurological examination revealed mild dysarthria, reduced muscle bulk, bilateral proximal muscle weakness, absent deep-tendon reflexes, upgoing plantar reflexes, reduced sensitivity to light touch with loss of proprioception and vibration sense in a[ncbi.nlm.nih.gov]
  • Neurologic examination may reveal diminished or absent deep tendon reflexes and, less frequently, deficits in proprioception and ataxia. The syndrome is associated with normal longevity.[emedicine.com]
Cerebellar Ataxia
  • Clinical findings Cerebellar ataxia, peripheral neuropathy, retinitis pigmentosa, fat malabsorption, steatorrhoea, chronic diarrhoea, anaemia, failure to thrive.[medical-dictionary.thefreedictionary.com]
  • Clinical findings Cerebellar ataxia, peripheral neuropathy, retinitis pigmentosa, fat malabsorption, steatorrhea, abdominal bloating, chronic diarrhoea, anaemia, failure to thrive, progressive vision loss, retinitis pigmentosa.[medical-dictionary.thefreedictionary.com]
  • Familial hypobetalipoproteinaemia complicated by cerebellar ataxia and steatocystoma multiplex. J Intern Med . 1991 Feb. 229(2):197-9. [Medline] . Bednarska-Makaruk M, Bisko M, Pulawska MF, Hoffman-Zacharska D, Rodo M, Roszczynko M, et al.[emedicine.medscape.com]
Absent Knee Reflex
  • Motor exam showed normal tone and power in major muscle groups with absent knee reflexes. The Babinski sign was negative.[ncbi.nlm.nih.gov]
Areflexia
  • Patients develop spinocerebellar ataxia, areflexia, and weakness, accompanying a diffuse neuromuscular disease that resembles Friedreich ataxia. There are crenated or "thorny" red cells on blood smear (acanthocytosis) (Figure 1).[aao.org]

Workup

Diarrhea and failure to thrive that appears in infancy are strongly suggestive of a malabsorption syndrome. For this reason, a detailed patient history regarding the onset and course of symptoms is detrimental. In addition, a complete physical examination can detect signs of malnourishment, defects in both lower and upper motor neurons, as well as hepatomegaly and visual deficits, strengthening its equally important role in workup [1]. Laboratory studies will reveal minimal or absent low-density lipoprotein (LDL) and triglycerides, whereas increased liver enzymes (alanine and aspartate aminotransferases, or ALT and AST) due to frequent hepatic steatosis are readily observed [2]. A complete blood count (CBC) with a subsequent peripheral blood smear demarcates the presence of acanthocytes, abnormally shaped cells that comprise up to 50% of visible erythrocytes [1] [2], and their presence is considered a cardinal feature of ABL. Moreover, a profoundly reduced erythrocyte sedimentation rate (ESR), anemia and elevated prothrombin time (PT) are other notable findings, suggesting that a full coagulation panel should be included in initial workup [1]. If clinical and laboratory findings provide sufficient evidence to pursue a diagnosis of ABL, genetic testing must be conducted, even without a positive family history, which is common due to the autosomal recessive pattern of inheritance and frequent absence of symptoms in both parents. Detection of mutations in the MTP protein located on chromosome 4q22-24 will confirm the diagnosis [1]. Hepatomegaly may be seen as a result of steatosis of liver. The biopsy of liver in the diseased patients may reveal steatosis along with the raise in the level of serum transaminase.

Treatment

  • Follow-up includes monitoring for ophthalmologic, neurologic, hematologic, and hepatic complications, as well as compliance with treatment.[ncbi.nlm.nih.gov]
  • Testosterone treatment and administration of hydrocortisone, fludrocortisone and dehydroepiandrosterone resulted in a significant improvement in a patient's condition.[ncbi.nlm.nih.gov]
  • He was not responsive to treatment with low-fat diet and fat-soluble vitamins and died at 13 months of age with severe malnutrition.[ncbi.nlm.nih.gov]
  • Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients.[ncbi.nlm.nih.gov]
  • Despite appropriate treatment with high doses of fat-soluble vitamins in all subjects, there was a wide variation in the progression and severity of the clinical phenotypes.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis The prognosis is severe, with a significantly reduced life expectancy. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • The long-term outlook (prognosis) is reasonably good for most people who are diagnosed and treated early. However, how well each person does depends on the amount of brain and nervous system problems. Therefore, the prognosis can vary.[checkorphan.org]
  • Prognosis is variable, but early diagnosis and strict adherence to treatment can recover normal neurological function and halt disease progression.[ncbi.nlm.nih.gov]

Etiology

  • Forty-two years after its initial description, a molecular etiology of ABL has been reported to be a deficiency of a microsomal transfer protein, thus suggesting that this protein plays a key role in lipoprotein particle assembly and secretion both in[ncbi.nlm.nih.gov]
  • Etiology Abetalipoproteinemia is a result of mutations of two alleles of the MTTP gene ( MTP ; 4q24).[orpha.net]
  • In 183 short chapters, the book provides the essentials clinicians need on symptoms/signs, diagnostic tests, and neurologic disorders of all etiologies. For this edition, Timothy A.[books.google.ro]

Epidemiology

  • Summary Epidemiology It is very rare, with an estimated prevalence of less than 1/1,000,000. Clinical description ABL/HoFHBL manifests during the first year of life or in young childhood.[orpha.net]
  • This timely reference presents, for the first time, new findings in molecular genetics that are applicable to the epidemiology, pathogenesis, neuropathology, clinical features, and management of ataxia-bridging the gap between scientific and clinical[books.google.ro]
  • Summary Epidemiology It is very rare, with an estimated prevalence of less than 1/1,000,000. Clinical description Abetalipoproteinemia manifests during the first year of life or in young childhood.[orpha.net]
  • 2015 A Compendium of Inherited Disorders and the Eye, Oxford University Press Genetics Also called Bassen-Kornzweig syndrome OMIM Numbers 200100 Inheritance Autosomal recessive Gene/Gene Map Microsomal triglyceride transfer protein deficiency 4q22-q24 Epidemiology[aao.org]
Sex distribution
Age distribution

Pathophysiology

  • The clinical and pathophysiological features of a case of abetalipoproteinemia in a 34-year-old patient are described. This patient is the first case reported in Japan.[ncbi.nlm.nih.gov]
  • Abstract The clinical and pathophysiological features of a case of abetalipoproteinemia in a 34-year-old patient are described. This patient is the first case reported in Japan.[jstage.jst.go.jp]
  • Molecular and Systemic Pathophysiology The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apoB containing lipoproteins in the liver and intestine [ 3 ].[link.springer.com]
  • The 32 cases, carefully selected to cover common diseases and important principles, are supplemented by clinical descriptions of each disease and a comprehensive discussion of the underlying pathophysiological mechanisms and associated enzymatic and chemical[books.google.com]
  • The primary pathophysiology is demyelination due to deficiency of lipid-soluble vitamins. The central and peripheral nervous systems are both affected.[statpearls.com]

Prevention

  • A supplementation to prevent or at least slow the progression of neuromuscular and retinal degenerative disease.[ncbi.nlm.nih.gov]
  • In conclusion, early diagnosis and early management are essential to prevent the manifestations following the fat-soluble vitamin deficiencies.[ncbi.nlm.nih.gov]
  • This prevents assembly of lipoproteins that can be secreted through the normal intracellular communicating tubular network and, consequently, fat accumulates in the cytoplasm of the hepatocytes.[ncbi.nlm.nih.gov]
  • 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[ncbi.nlm.nih.gov]

References

Article

  1. Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet Journal of Rare Diseases. 2008;3:19.
  2. Ferreira F, Patel V, Matts S. A successful spontaneous pregnancy in abetalipoproteinemia: Amsterdam or the art of vitamin replacement? BMJ Case Rep. 2014;2014:bcr2014206754.
  3. Burnett JR, Hooper AJ. Vitamin E and oxidative stress in abetalipoproteinemia and familial hypobetalipoproteinemia. Free Radic Biol Med. 2015;88(Pt A):59-62.
  4. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.

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Last updated: 2019-07-11 21:11