Abderhalden-Kaufmann-Lignac syndrome: Difference between revisions
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Revision as of 11:55, 30 August 2021
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdulkerim Yassin, M.B.B.S[2]
Synonyms and keywords: Abderhalden-Lignac-Kaufmann disease; nephropathic cystinosis
Overview
Abderhalden-Kaufmann-Lignac syndrome, also called Abderhalden-Lignac-Kaufmann disease or nephropathic cystinosis, is an autosomal recessive renal disorder of childhood comprising cystinosis and renal rickets.It is caused by mutation in the CTNS gene encoding for cystinosin, transporting cystine out of the lysosomes. A defect in the cystinosin leads to accumulation of excessive cystine crystals in the lsysosomes of all body cells and organs. The most commonly affected organs are the eyes and kidneys but it can also affects the thyroid, pancreas, gonads, muscles and CNS. The symptoms are renal calculi, osteomalacia, aminoaciduria, glycosuria, polyuria, chronic acidosis, hypophosphatemia with vitamin D-resistant rickets, and often with hypokalemia, photophobia, blepharospasm, hypothyroidism, primary hypogonadism in males, hypotonia, speech delay, motor impairment, cognitive dysfunction, Diabetes, hypopigmentation, coarsened facial features and impaired sweating. The diagnosis is made with measuring cystine levels in polymorphonuclear leukocytes or cultured fibroblasts. Molecular analysis of the cystinosin gene can be done for definitive diagnosis.The mainstay of treatment is cystine-depleting therapy with cysteamine. There are no established measures for the primary or secondary prevention of Abderhalden-Kaufmann-Lignac syndrome.
Historical Perspective
Abderhalden-Kaufmann-Lignac syndrome was first described by Emil Abderhalden, Swiss biochemist in 1903 as the familial cystine accumulation disease. Abderhalden referred to a child initially encountered by Eduard Kaufmann, a German physician. George Lignac, a Dutch pathologist, was the first to give more detailed systematic description of the disease and to associate cystinosis with its major clinical manifestations such as rickets, renal disease and growth retardation. The disease is named for Emil Abderhalden, Eduard Kaufmann and George Lignac.[1]
Classification
Abderhalden-Kaufmann-Lignac syndrome may be classified according to age of onset into three types[2]:
- Infantile Nephropathic Cystinosis (95%): onset on early infancy.The most severe clinical form of cystinosis, commonly present with renal Fanconi syndrome by 6-12 months of age, and without specific treatment, almost all will develop end-stage renal disease and without specific treatment, almost all will develop end-stage renal disease (ESRD) by 10-12 years of age .
- Juvenile (5%): onset on adolescent.
- Non-nephropathic(case report): onset on adulthood. Corneal involvement with renal sparing.
Pathophysiology
It is thought that Abderhalden-Kaufmann-Lignac syndrome is the result of CTNS gene mutation which encodes for cystinosin, a transporter protein which carries cystine from lysosomes to cytosol. A defect in the CTNS gene leads to a high level of cystine accumulation in the lysosome. It is transmitted in autosomal recessive pattern, where inheritance of one defective gene from each parents who are carrrier, put at risk of their 25% of children manifest the disease. The exact pathophysiology of the disease is still not properly understood but there are suggested mechanismsm.[3][4]
- Increased cystine levels in the lysosome links to enhanced apoptosis.
- lysosomal cystine accumulation leads to cellular ATP depletion.
Causes
The cause of Abderhalden-Kaufmann-Lignac syndrome is CTNS gene mutation in the lysosomal membrane trafficking protein called cystinosin, which causes to cystine accumulation in the lysosome of all body cells and organs, leads to apoptosis and cellular ATP depletion.It is a rare autosomal recessive lysosomal storage diseases.[5]
Differentiating Abderhalden-Kaufmann-Lignac syndrome from other Diseases
Abderhalden-Kaufmann-Lignac syndrome must be differentiated from other diseases that cause renal Fanconi syndrome, photophobia, blepharospasm , and rickets or osteomalacia, such as Lowe syndrome, Dent disease; Idiopathic fanconi syndrome.[1]
Epidemiology and Demographics
- The incidence of Abderhalden-Kaufmann-Lignac syndrome is approximately 1 per 100,000 to 200,000 live births worldwide.
- Patients of all age groups may develop Abderhalden-Kaufmann-Lignac syndrome.
- Abderhalden-Kaufmann-Lignac syndrome commonly affects infants.
- End Stage Renal Disease is usually first diagnosed among 10-12 years of age with out proper treatment.[6]
- Male are more commonly affected by Abderhalden-Kaufmann-Lignac syndrome than female. The male to female ratio is approximately 1.5 to 1.
- Although a wide geographic variability has been reported, The majority of Abderhalden-Kaufmann-Lignac syndrome cases are reported in France and Canada. eg, incidence of 1:26,000 in Brittany, France and 1:62,500 in parts of Quebec, Canada.
- Abderhalden-Kaufmann-Lignac syndrome is a rare disease that tends to affect infants and adolescent.[1]
Risk Factors
There are no established risk factors for Abderhalden-Kaufmann-Lignac syndrome.
Screening
There is insufficient evidence to recommend routine screening for Abderhalden-Kaufmann-Lignac syndrome.
Natural History, Complications, and Prognosis
If left untreated, Abderhalden-Kaufmann-Lignac syndrome may progress to develop chronic renal failure and extrarenal complications such as dwarfism, rickets, hyphothyroidism, hypogonadism, hypopigmentation,Diabetes, distal vacuolar myopathy, osteoporosis, blindness, CNS comlications such as Hypotonia, speech delay, neurocognitive dysfunction, and encephalopathy.[7][8]
Prognosis of Abderhalden-Kaufmann-Lignac syndrome depends on early diagnosis, and prompt starting and good compliance with cysteamine treatment. life expectancy can extend past 50 years.[5]
Diagnosis
The diagnosis of Abderhalden-Kaufmann-Lignac syndrome is made with clinical and laboratory findings. The diagnosis is confirmed by molecular analysis of the cystinosin gene.[1]
History and Symptoms
The hallmark of Abderhalden-Kaufmann-Lignac syndrome is early corneal cystine crystal deposition. The most common symptoms of Abderhalden-Kaufmann-Lignac syndrome include renal fanconi syndrome, dwarfism, and rickets. Other presenting symptoms of Abderhalden-Kaufmann-Lignac syndrome include photophobia, blepharospasm, aminoaciduria, glycosuria, hypokalemia, vomiting, feeding difficulties, decreased appetite, nephrolithiasis, nephrocalcinosis, distal muscle wasting and weakness, hypothyroidism, hypogonadism, hypopigmentation, diabetes.[9][10]
Physical Examination
The presence of cystine crystal in the cornea, growth failure, short stature, and knock-knees (valgus deformity) on physical examination is highly suggestive of Abderhalden-Kaufmann-Lignac syndrome.[1]
Laboratory Findings
An elevated Cystine concentrations 5-10 nmol half-cystine/mg cell protein in individuals who are homozygous for Abderhalden-Kaufmann-Lignac syndrome is other diagnostic finding.Reference range levels are below 0.2 nmol half-cystine/mg cell protein. When a fetus is at risk for Abderhalden-Kaufmann-Lignac syndrome, the cystine level can be measured in chorionic villi or cultured amniotic fluid cells. Laboratory findings consistent with the diagnosis of Abderhalden-Kaufmann-Lignac syndrome include serum electrolyte abnormalities such as hypokalemia, hypophosphatemia, hypocalcemia, low bicarbonate levels, hyponatremia, ABG to detect metabolic acidosis, and urine test for glycosuria, aminoaciduria, proteinuria.[1]
Electrocardiogram
There are no ECG findings associated with Abderhalden-Kaufmann-Lignac syndrome.
X-ray
There are no specific x-ray findings associated with Abderhalden-Kaufmann-Lignac syndrome. However, an x-ray may be helpful in the diagnosis of complications of Abderhalden-Kaufmann-Lignac syndrome, which includes osteoporosis, urinary tract calcifications and rickets[9].
Echocardiography or Ultrasound
There are no specific echocardiography findings associated with Abderhalden-Kaufmann-Lignac syndrome. However, an echocardiography may be helpful in the diagnosis of Left ventricular hypertrabeculation/non-compaction (LVHT) associated with accumulation of cystine in the cardiac muscles.[11] There are no specific ultrasound findings associated with Abderhalden-Kaufmann-Lignac syndrome. However, an ultrasound may be helpful in the diagnosis of complications of Abderhalden-Kaufmann-Lignac syndrome, which include nephrolithiasis, and renal medullary nephrocalcinosis.[9]
CT scan
There are no specific CT scan findings associated with Abderhalden-Kaufmann-Lignac syndrome. However, a CT scan may be helpful in the diagnosis of complications of Abderhalden-Kaufmann-Lignac syndrome, which include isolated ventricular non-compaction Central nervous system abnormalities, nephrolithiasis, papilledema and renal medullary nephrocalcinosis.[12][13]
MRI
There are no specific MRI findings associated with Abderhalden-Kaufmann-Lignac syndrome. However, a MRI may be helpful in the diagnosis of complications of Abderhalden-Kaufmann-Lignac syndrome, which include Central nervous system abnormalities, rickets, papilledema, and osteoporosis. cognitive dysfunction could be related to abnormalities in the cerebral white matter microstructure and has been demonstrated using in magnetic resonance diffusion tensor imaging.[13]
Other Imaging Findings
other imaging findings associated with Abderhalden-Kaufmann-Lignac syndrome is decreased bone mass evaluated by Bone density scan[9].
Other Diagnostic Studies
Other diagnostic studies for Abderhalden-Kaufmann-Lignac syndrome include slit-lamp examination, which demonstrates cystine crystals deposition in the cornea[2].
Treatment
Medical Therapy
Symptomatic treatments:
- Rehydration
- High dosage of vitamin D
- Electrolyte Supplements- Sodium citrate to treat metabolic acidosis
- Electrolyte Replacement- Potassium, bicarbonate and phosphate abnormalities treated with oral or intravenous supplements.
The mainstay of treatment for Abderhalden-Kaufmann-Lignac syndrome is cysteamine. It is available in two formulations; tablet and eyedrops. cysteamine, facilitates lysosomal cystine clearance and delays progression to ESRD, significantly improves growth, decreases the frequency and severity of extrarenal complications, and is associated with extended life expectancy; however, no curative treatment is yet available.[1]
Surgery
The mainstay of treatment for Abderhalden-Kaufmann-Lignac syndrome is medical therapy. Surgery is may be needed for patients with complications of Abderhalden-Kaufmann-Lignac syndrome such as End Stage Renal Disease or nephrolithiasis.[14][10]
Primary Prevention
There are no established measures for the primary prevention of Abderhalden-Kaufmann-Lignac syndrome[1].
Secondary Prevention
There are no established measures for the secondary prevention of Abderhalden-Kaufmann-Lignac syndrome[1].
Related Chapters
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Gahl WA, Thoene JG, Schneider JA (2002). "Cystinosis". N Engl J Med. 347 (2): 111–21. doi:10.1056/NEJMra020552. PMID 12110740.
- ↑ 2.0 2.1 Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P; et al. (2014). "Nephropathic cystinosis: an international consensus document". Nephrol Dial Transplant. 29 Suppl 4: iv87–94. doi:10.1093/ndt/gfu090. PMC 4158338. PMID 25165189.
- ↑ Park M, Helip-Wooley A, Thoene J (2002). "Lysosomal cystine [[storage]] augments [[apoptosis]] in [[cultured]] human [[fibroblasts]] and [[renal]] [[tubular]] [[epithelial]] cells". J Am Soc Nephrol. 13 (12): 2878–87. doi:10.1097/01.asn.0000036867.49866.59. PMID 12444206. URL–wikilink conflict (help)
- ↑ Sansanwal P, Yen B, Gahl WA, Ma Y, Ying L, Wong LJ; et al. (2010). "Mitochondrial autophagy promotes cellular injury in nephropathic cystinosis". J Am Soc Nephrol. 21 (2): 272–83. doi:10.1681/ASN.2009040383. PMC 2834547. PMID 19959713.
- ↑ 5.0 5.1 Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E (2016). "Cystinosis: a review". Orphanet J Rare Dis. 11: 47. doi:10.1186/s13023-016-0426-y. PMC 4841061. PMID 27102039.
- ↑ Greco M, Brugnara M, Zaffanello M, Taranta A, Pastore A, Emma F (2010). "Long-term outcome of nephropathic cystinosis: a 20-year single-center experience". Pediatr Nephrol. 25 (12): 2459–67. doi:10.1007/s00467-010-1641-8. PMID 20803298.
- ↑ Fivush B, Green OC, Porter CC, Balfe JW, O'Regan S, Gahl WA (1987). "Pancreatic endocrine insufficiency in posttransplant cystinosis". Am J Dis Child. 141 (10): 1087–9. doi:10.1001/archpedi.1987.04460100065027. PMID 3307383.
- ↑ Fink JK, Brouwers P, Barton N, Malekzadeh MH, Sato S, Hill S; et al. (1989). "Neurologic complications in long-standing nephropathic cystinosis". Arch Neurol. 46 (5): 543–8. doi:10.1001/archneur.1989.00520410077027. PMID 2712751.
- ↑ 9.0 9.1 9.2 9.3 Florenzano P, Ferreira C, Nesterova G, Roberts MS, Tella SH, de Castro LF; et al. (2018). "Skeletal Consequences of Nephropathic Cystinosis". J Bone Miner Res. 33 (10): 1870–1880. doi:10.1002/jbmr.3522. PMID 29905968.
- ↑ 10.0 10.1 Ariceta G, Giordano V, Santos F (2019). "Effects of [[long-term]] [[cysteamine]] [[treatment]] in patients with [[cystinosis]]". Pediatr Nephrol. 34 (4): 571–578. doi:10.1007/s00467-017-3856-4. PMC 6394685. PMID 29260317. URL–wikilink conflict (help)
- ↑ Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA (2001). "Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy". Heart. 86 (6): 666–71. doi:10.1136/heart.86.6.666. PMC 1730012. PMID 11711464.
- ↑ Stöllberger C, Finsterer J (2006). "Pitfalls in the diagnosis of left ventricular [[hypertrabeculation/non-compaction]]". Postgrad Med J. 82 (972): 679–83. doi:10.1136/pgmj.2006.046169. PMC 2653912. PMID 17068279. URL–wikilink conflict (help)
- ↑ 13.0 13.1 Bava S, Theilmann RJ, Sach M, May SJ, Frank LR, Hesselink JR; et al. (2010). "Developmental changes in cerebral white matter [[microstructure]] in a disorder of lysosomal storage". Cortex. 46 (2): 206–16. doi:10.1016/j.cortex.2009.03.008. PMC 3351112. PMID 19427638. URL–wikilink conflict (help)
- ↑ Nesterova G, Gahl WA (2013). "Cystinosis: the evolution of a treatable disease". Pediatr Nephrol. 28 (1): 51–9. doi:10.1007/s00467-012-2242-5. PMC 3505515. PMID 22903658.