Lowe's syndrome

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Classification according to ICD-10
E72.0 Disorders of the amino acid transport, including Lowe's syndrome
ICD-10 online (WHO version 2019)

The Lowe Syndrome , also oculo-cerebro-renal syndrome called (OCRL) is a rare, X-linked inherited multisystem disease .

frequency

Lowe's syndrome is very rare. For the general population, the prevalence is estimated at 1: 500,000. All ethnicities are affected. Due to the X-linked inheritance, boys are almost exclusively affected by the disease. Extremely rare cases of X-autosome translocations have been described in which girls also develop Lowe's syndrome.

Clinical picture

Lowe's syndrome is a systemic disease that affects several organ systems. The affected patients have an intellectual disability (mental retardation), hypotonia , a congenital cataract (cataract) and a selective proximal tubulopathy.

cataract

Even at birth, all patients have a dense cataract that develops in the uterus ( in utero ). The cataract is caused by an altered migration of the embryonic epithelium . About half of the patients also have glaucoma ( glaucoma ), some with buphthalmus (enlarged eyes). Glaucoma usually manifests itself in the first year of life.

Proximal tubulopathy

Selective proximal tubulopathy is a functional disorder in the proximal tubule that corresponds to that of De Toni Fanconi syndrome . One therefore speaks of a secondary Fanconi syndrome . Proximal tubulopathy can be very different from patient to patient, but gets worse with age. At the time of their birth, many children are still without symptoms, but these appear during the first few months of life and are characterized by loss of hydrogen carbonate , salt and water. These mineral losses lead to failure of the children to thrive . In the second decade of life, most patients develop chronic kidney failure , which can lead to terminal kidney failure. The latter requires kidney replacement therapy .

The other symptoms correspond to the De Toni Fanconi syndrome: proteinuria and renal tubular acidosis . The loss of phosphate through the kidneys leads to renal rickets , osteomalacia and spontaneous fractures . The increased excretion of calcium in the urine ( hypercalciuria ) causes nephrocalcinosis and kidney stones . Furthermore, the dysfunction in the proximal tubule leads to amino aciduria and increased potassium excretion, which triggers hypokalaemia .

Nervous system

At birth, the children have severe to very severe muscle hypotonia , which can lead to an absence of the deep tendon reflex (muscle self-reflex). Hypotension can in turn lead to severe respiratory problems in the first phase of life. Motor development is impaired and children generally only develop the ability to walk independently after they are three years old.

About 10% of the patients have a slight intellectual disability. In many cases, however, it is moderate to severe with IQ below 50. The majority of those affected (87%) show autoaggressive and heteroaggressive behavior, irritability and tantrums . Obsessive- compulsive disorder is also common. About 50% of patients over the age of 18 have epileptic seizures . Up to 9% have febrile seizures .

genetics

The structure of the phosphatidylinositol-4,5-bisphosphate

Lowe's syndrome is caused by mutations on the OCLR1 gene. This gene is located on the long arm of the X chromosome on locus q25-q26. The OCLR1 gene consists of 24 exons and codes for the enzyme phosphatidylinositol-4,5-bisphosphate-5-phosphatase (inositol-polyphosphate-5-phosphatase). This phosphatase belongs to the family of 5-phosphatases of type II and is normally located in the trans-Golgi network . There it is for the polymerization of actin needed. It de- phosphorylates in particular phosphatidylinositol-4,5-bisphosphate [PI (4,5) P2] to phosphatidylinositol-4-phosphate [PI (4) P].

Due to the lack of the enzyme, the substrate phosphatidylinositol-4,5-bisphosphate accumulates in the cells of the affected patient.

diagnosis

A preliminary diagnosis can be made based on the symptoms. Due to the extremely rare occurrence of the disease, a medical laboratory confirmation of the diagnosis is always advisable. Due to the allelic heterogeneity of the mutations in the OCRL1 gene, prenatal DNA analysis can only be performed in families in which the mutation is already known. Measuring the activity of phosphatidylinositol-4,5-bisphosphate-5-phosphatase in cultured amniocytes is a prenatal biochemical method that can be used to diagnose Lowe's syndrome.

The Dent syndrome , among other things, must be distinguished from the differential diagnosis.

therapy

Lowe's syndrome is incurable. The therapy is purely symptomatic and includes, among other things, cataract surgery, glaucoma treatment, speech and physiotherapy . Neuroleptics , stimulants , benzodiazepines and antidepressants (such as serotonin reuptake inhibitors ) can be prescribed for behavioral disorders . Good treatment results have been achieved with clomipramine , paroxetine and risperidone .

forecast

For most patients, end-stage renal disease or hypotension results in premature death; typically between the ages of 30 and 40.

Initial description

The oculo-cerebro-renal syndrome was first described in 1952 by the American pediatrician Charles Upton Lowe and colleagues as a syndrome with aciduria, decreased urea production, hydrophthalmos and mental retardation .

further reading

  • JK Brooks, R. Ahmad: Oral anomalies associated with the oculocerebrorenal syndrome of Lowe: case report with multiple unerupted teeth and pericoronal radiolucencies. In: Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. Volume 107, Number 3, March 2009, pp. E32-e35, ISSN  1528-395X . doi : 10.1016 / j.tripleo.2008.11.023 . PMID 19217010 . (Review).
  • AC Ruellas, MM Pithon et al. a .: Lowe syndrome: literature review and case report. In: Journal of orthodontics. Volume 35, Number 3, September 2008, pp. 156-160, ISSN  1465-3125 . doi : 10.1179 / 146531207225022599 . PMID 18809779 . (Review).
  • MT Rodrigues Santos, MM Watanabe et al. a .: Oculocerebrorenal Lowe syndrome: a literature review and two case reports. In: Special care in dentistry: official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. Volume 27, Number 3, 2007 May-Jun, pp. 108-111, ISSN  0275-1879 . PMID 17658186 . (Review).
  • M. Lowe: Structure and function of the Lowe syndrome protein OCRL1. In: Traffic. Volume 6, Number 9, September 2005, pp. 711-719, ISSN  1398-9219 . doi : 10.1111 / j.1600-0854.2005.00311.x . PMID 16101675 . (Review).
  • M. Harrison, EW Odell, EC Sheehy: Dental findings in Lowe's syndrome. In: Pediatric dentistry. Volume 21, Number 7, 1999 Nov-Dec, pp. 425-428, ISSN  0164-1263 . PMID 10633515 . (Review).
  • M. Addis, M. Loi et al. a .: OCRL mutation analysis in Italian patients with Lowe syndrome. In: Human mutation. Volume 23, Number 5, May 2004, pp. 524-525, ISSN  1098-1004 . doi : 10.1002 / humu.9239 . PMID 15108291 .
  • G. Amirhakimi, MH Fallahzadeh, H. Saneifard: Lowe Syndrome: Report of a Case and Brief Literature Review. In: Iran J Pediatr. Volume 19, Number 4, 2009, pp. 417-420.
  • T. Menke, SM Gu et al. a .: Lowe's syndrome - clinical findings and evidence of a gene mutation in a 4-year-old boy. In: Pediatrics. Volume 146, Number 2, pp. 125-128, doi : 10.1007 / s001120050257
  • Lowe Syndrome (PDF; 414 kB) Kinderetzwerk eV

Individual evidence

  1. ↑ a b c d e f g h i M. Loi: Lowe syndrome. In: Orphanet Journal of Rare Diseases. Volume 1, 2006, p. 16, ISSN  1750-1172 . doi : 10.1186 / 1750-1172-1-16 . PMID 16722554 . PMC 1526415 (free full text). (Review).
  2. ^ OT Mueller, JK Hartsfield et al. a .: Lowe oculocerebrorenal syndrome in a female with a balanced X; 20 translocation: mapping of the X chromosome breakpoint. In: American Journal of Human Genetics . Volume 49, Number 4, October 1991, pp. 804-810, ISSN  0002-9297 . PMID 1897526 . PMC 1683175 (free full text).
  3. ^ RC Tripathi, GW Cibis, BJ Tripathi: Pathogenesis of cataracts in patients with Lowe's syndrome. In: Ophthalmology. Volume 93, Number 8, August 1986, pp. 1046-1051, ISSN  0161-6420 . PMID 3763153 .
  4. ^ LR Charnas, I. Bernardini et al. a .: Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. In: The New England journal of medicine . Volume 324, Number 19, May 1991, pp. 1318-1325, ISSN  0028-4793 . doi: 10.1056 / NEJM199105093241904 . PMID 2017228 .
  5. ↑ L. Kenworthy, T. Park, LR Charnas: Cognitive and behavioral profile of the oculocerebrorenal syndrome of Lowe. In: American journal of medical genetics. Volume 46, Number 3, May 1993, pp. 297-303, ISSN  0148-7299 . doi: 10.1002 / ajmg.1320460312 . PMID 8488875 .
  6. ↑ L. Charnas, J. Bernar et al. a .: MRI findings and peripheral neuropathy in Lowe's syndrome. In: Neuropediatrics. Volume 19, Number 1, February 1988, pp. 7-9, ISSN  0174-304X . doi: 10.1055 / s-2008-1052393 . PMID 2834662 .
  7. ↑ K. McSpadden, Z. Dolinsky, E. Schroerlucke: Report on the Lowe's syndrome comprehensive survey. West Lafayette: Lowe Syndrome Association; 1991.
  8. ↑ VA van Rahden: Effects of a depletion of the human inositol polyphosphate 5-phosphatase OCRL on transport routes of the mannose 6-phosphate receptor. (PDF; 5.6 MB) Dissertation, University of Hamburg, 2011, p. 1.
  9. ^ Lowe's syndrome.  In: Online Mendelian Inheritance in Man . (English)
  10. ^ CU Lowe, M. Terrey, EA MacLachlan: Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity. In: American Journal of Diseases of Children . Volume 83, Number 2, February 1952, pp. 164-184, ISSN  0096-8994 . PMID 14884753 .

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